This document summarizes insights and perspectives on the role of vitamins in preventing type 2 diabetes mellitus (T2DM) and its complications from a public health perspective. It discusses how T2DM is caused by impaired glucose tolerance and insulin resistance leading to inflammation. Certain vitamins like C, D and E are highlighted as having anti-inflammatory properties that could help reduce the risk of T2DM and its complications by attenuating inflammation. The document focuses on vitamin C in more detail, outlining its role in immune function and reducing oxidative stress and inflammation, suggesting it may help prevent T2DM. It reviews several epidemiological studies that have found inverse associations between vitamin C levels or intake and biomarkers of inflammation and T2DM risk.
The document discusses evidence from studies on the effect of lifestyle modifications such as caloric restriction, physical activity, and weight loss on health outcomes. It summarizes key findings from several studies:
1) The Diabetes Prevention Program clinical trial found that intensive lifestyle intervention reduced the risk of developing type 2 diabetes by 58% compared to 31% for treatment with metformin.
2) Studies on caloric restriction in primates showed decreased fasting glucose and insulin levels as well as reduced risk of age-related diseases like diabetes and cardiovascular disease.
3) Physical activity has been shown to increase lifespan in animal models, and a study of over 1300 male rats found a 10% reduction in body weight led to a 13.5
Nutrease powder- A natural plant based nutritional shake helps to supports in...SriramNagarajan16
Supplementation of Nutrease powder is essential for proactive prevention and also for the best outcome therapy in Diabetes.
Supplementing essential and conditionally essential nutrients like Nutrease powder to support essential metabolic pathways
is required for immune defense and repair, neuro-hormone balance as well as digestive and detox competencies.
Impaired antioxidant status has been shown to have a definite role in the development of insulin resistance and type 2
diabetes. Overproduction of oxidants (reactive oxygen species and reactive nitrogen species) in the human body is
responsible for the pathogenesis of some diseases. The scavenging of these oxidants is thought to be an effective measure to
depress the level of oxidative stress of organisms. It has been reported that intake of Nutrease powder is inversely associated
with the risk of many chronic diseases, and antioxidant phytochemicals in Nutrease powder are considered to be responsible
for these health benefits. Antioxidant phytochemicals found in Nutrease powder plays an important role in the prevention
and treatment of chronic diseases caused by oxidative stress. They often possess strong antioxidant and free radical
scavenging abilities, which are also the basis of other bioactivities and health benefits, such as diabetes mellitus.
Phytonutrients in Nutrease powder play a positive role by maintaining and modulating immune function to prevent specific
diseases. Being natural products, they hold a great promise in clinical therapy. Phytonutrients are the plant nutrients with
specific biological activities that support human health. Some of the important bioactive phytonutrients include polyphenols,
terpenoids, resveratrol, flavonoids, isoflavonoids, carotenoids, limonoids, glucosinolates, phytoestrogens, phytosterols,
anthocyanins, and probiotics. They play specific pharmacological effects in human health. This article reviews the current
available scientific literature regarding the effect of Nutrease powder as an effective supplementation for a daily energy
need in life style disorders like diabetes.
Diabetes is a condition where the body cannot properly process glucose due to a lack of insulin production (Type 1) or insulin resistance (Type 2). It has been known since ancient Greece and gets its name from frequent urination, a symptom. Long term complications include damage to blood vessels and organs. Treatment involves monitoring blood sugar levels and administering insulin or oral medications, with lifestyle changes also important for managing the disease.
Crimson Publishers-Highlighting Significance of Weight Loss and Malnutrition ...CrimsonPublishersGGS
This document discusses anorexia and weight loss in older adults. It notes that appetite and dietary intake can decline with age, leading to weight loss and malnutrition in 15-30% of older adults. Significant unintentional weight loss of over 5-10% within a year is associated with increased health issues and mortality. The causes of weight loss and malnutrition in older adults can include physiological changes, underlying diseases, medications, psychological and social factors. Proper diagnosis and treatment involving dietary changes, supplements, appetite stimulants and treating any underlying conditions aim to reverse weight loss and malnutrition.
A document that I received which is interesting for those looking to maintain healthy eating and fitness during Ramadan (i.e don't dehydrate and don't put on weight :) )
The effect of diet-induced weight loss on bone turn over in patients with typ...Aasritha William
1) Diabetes is a chronic metabolic disorder resulting from inadequate insulin production or secretion that causes hyperglycemia. The main types are type 1 (insulin dependent), type 2 (non-insulin dependent), gestational diabetes, and those associated with other conditions.
2) Bone turnover refers to the rate of bone resorption and formation, which can be estimated by biomarkers like urinary NTX and CTX.
3) India has a high prevalence of diabetes and is the diabetes capital of the world, with over 62 million diabetic individuals in 2015 and a projected number of 101 million by 2030. Obesity is a major risk factor for type 2 diabetes.
Personalized nutrition takes into account many individual factors like genetics, metabolism, microbiome, lifestyle and more to determine the optimal diet for health and well-being. It aims to manage and prevent chronic diseases through personalized sciences, guidance, and education. A personalized nutrition care model assesses individual data through tests and screens, interprets the results, designs targeted interventions like dietary changes, and monitors outcomes. Nutritional genomics and epigenetics research how genes and environment interact to influence health and disease, helping personalized nutrition better address individual needs.
Antihyperlipidemic Activity of Torbangun Extract (Coleus amboinicus Lour) on ...iosrphr_editor
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
The document discusses evidence from studies on the effect of lifestyle modifications such as caloric restriction, physical activity, and weight loss on health outcomes. It summarizes key findings from several studies:
1) The Diabetes Prevention Program clinical trial found that intensive lifestyle intervention reduced the risk of developing type 2 diabetes by 58% compared to 31% for treatment with metformin.
2) Studies on caloric restriction in primates showed decreased fasting glucose and insulin levels as well as reduced risk of age-related diseases like diabetes and cardiovascular disease.
3) Physical activity has been shown to increase lifespan in animal models, and a study of over 1300 male rats found a 10% reduction in body weight led to a 13.5
Nutrease powder- A natural plant based nutritional shake helps to supports in...SriramNagarajan16
Supplementation of Nutrease powder is essential for proactive prevention and also for the best outcome therapy in Diabetes.
Supplementing essential and conditionally essential nutrients like Nutrease powder to support essential metabolic pathways
is required for immune defense and repair, neuro-hormone balance as well as digestive and detox competencies.
Impaired antioxidant status has been shown to have a definite role in the development of insulin resistance and type 2
diabetes. Overproduction of oxidants (reactive oxygen species and reactive nitrogen species) in the human body is
responsible for the pathogenesis of some diseases. The scavenging of these oxidants is thought to be an effective measure to
depress the level of oxidative stress of organisms. It has been reported that intake of Nutrease powder is inversely associated
with the risk of many chronic diseases, and antioxidant phytochemicals in Nutrease powder are considered to be responsible
for these health benefits. Antioxidant phytochemicals found in Nutrease powder plays an important role in the prevention
and treatment of chronic diseases caused by oxidative stress. They often possess strong antioxidant and free radical
scavenging abilities, which are also the basis of other bioactivities and health benefits, such as diabetes mellitus.
Phytonutrients in Nutrease powder play a positive role by maintaining and modulating immune function to prevent specific
diseases. Being natural products, they hold a great promise in clinical therapy. Phytonutrients are the plant nutrients with
specific biological activities that support human health. Some of the important bioactive phytonutrients include polyphenols,
terpenoids, resveratrol, flavonoids, isoflavonoids, carotenoids, limonoids, glucosinolates, phytoestrogens, phytosterols,
anthocyanins, and probiotics. They play specific pharmacological effects in human health. This article reviews the current
available scientific literature regarding the effect of Nutrease powder as an effective supplementation for a daily energy
need in life style disorders like diabetes.
Diabetes is a condition where the body cannot properly process glucose due to a lack of insulin production (Type 1) or insulin resistance (Type 2). It has been known since ancient Greece and gets its name from frequent urination, a symptom. Long term complications include damage to blood vessels and organs. Treatment involves monitoring blood sugar levels and administering insulin or oral medications, with lifestyle changes also important for managing the disease.
Crimson Publishers-Highlighting Significance of Weight Loss and Malnutrition ...CrimsonPublishersGGS
This document discusses anorexia and weight loss in older adults. It notes that appetite and dietary intake can decline with age, leading to weight loss and malnutrition in 15-30% of older adults. Significant unintentional weight loss of over 5-10% within a year is associated with increased health issues and mortality. The causes of weight loss and malnutrition in older adults can include physiological changes, underlying diseases, medications, psychological and social factors. Proper diagnosis and treatment involving dietary changes, supplements, appetite stimulants and treating any underlying conditions aim to reverse weight loss and malnutrition.
A document that I received which is interesting for those looking to maintain healthy eating and fitness during Ramadan (i.e don't dehydrate and don't put on weight :) )
The effect of diet-induced weight loss on bone turn over in patients with typ...Aasritha William
1) Diabetes is a chronic metabolic disorder resulting from inadequate insulin production or secretion that causes hyperglycemia. The main types are type 1 (insulin dependent), type 2 (non-insulin dependent), gestational diabetes, and those associated with other conditions.
2) Bone turnover refers to the rate of bone resorption and formation, which can be estimated by biomarkers like urinary NTX and CTX.
3) India has a high prevalence of diabetes and is the diabetes capital of the world, with over 62 million diabetic individuals in 2015 and a projected number of 101 million by 2030. Obesity is a major risk factor for type 2 diabetes.
Personalized nutrition takes into account many individual factors like genetics, metabolism, microbiome, lifestyle and more to determine the optimal diet for health and well-being. It aims to manage and prevent chronic diseases through personalized sciences, guidance, and education. A personalized nutrition care model assesses individual data through tests and screens, interprets the results, designs targeted interventions like dietary changes, and monitors outcomes. Nutritional genomics and epigenetics research how genes and environment interact to influence health and disease, helping personalized nutrition better address individual needs.
Antihyperlipidemic Activity of Torbangun Extract (Coleus amboinicus Lour) on ...iosrphr_editor
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
The document discusses diabetic mellitus (diabetes). It aims to help participants understand what diabetes is, normal and abnormal blood sugar levels, the causes and types of diabetes, symptoms, complications if untreated, and ways to manage blood sugar levels through diet, exercise, medication and lifestyle changes. The two main types of diabetes - type 1 caused by lack of insulin production and type 2 caused by insulin resistance - are explained in further detail.
This document discusses different types of diabetes mellitus. It describes the three main types: type 1 diabetes which results from failure to produce insulin; type 2 diabetes which results from insulin resistance; and gestational diabetes which occurs during pregnancy. It provides details on symptoms, causes, treatment and prevalence of each type. Other less common forms are also mentioned. The document emphasizes the importance of proper treatment and control of diabetes to prevent complications.
This document provides information about diabetes, including:
- There are several types of diabetes defined by etiology and treatment needs. Type 1 is insulin dependent while Type 2 is typically non-insulin dependent.
- Diabetes is associated with increased risk of cardiovascular, eye, kidney, and neurological complications if not properly managed and controlled. Tight glycemic control is important to reduce risks.
- Risk factors include family history, obesity, age, and ethnicity. Management involves lifestyle changes like diet, exercise, and medication to control blood sugar, lipids, and blood pressure.
Living Well with Cancer Presentation (Webinar)KellyGCDET
This document discusses the importance of nutrition for cancer patients. It notes that malnutrition is common in 50% of cancer patients and is associated with weight loss, fatigue, weakness and impaired treatment tolerance. Early nutrition intervention can help preserve muscle mass and strength, improving quality of life and ability to complete cancer treatment. Screening tools like the Malnutrition Screening Tool and Patient Generated Subjective Global Assessment are recommended to assess nutritional status and guide appropriate nutrition support and interventions.
Presentation at the Ancestral Health Symposium. Government can provide education and oversight of scientific publications and the press which accounts for the current nutrition mess.
Type 1 diabetes is an autoimmune disease where the body's immune system destroys the beta cells in the pancreas that produce insulin. It requires lifelong treatment with insulin injections and careful management of diet and blood sugar levels. The document provides details on the history, causes, symptoms, diagnosis, treatment, and lifelong prognosis of Type 1 diabetes. Treatment involves regulating blood sugar through insulin injections, diet, exercise, and personal hygiene. The costs of managing the disease are significant. While it currently has no cure, advances in treatment have improved life expectancy and quality of life for those living with Type 1 diabetes.
This document provides information on diabetes, exercise, and weight loss. It discusses the two main types of diabetes - Type 1 caused by lack of insulin production and Type 2 caused by insulin resistance. Good management of both types involves monitoring food intake, counting carbohydrates, incorporating protein and fiber into meals, checking blood sugar levels before and after exercise, and treating low blood sugar during workouts. The document provides guidelines for developing healthy habits including recommended pre and post-workout snacks.
This document discusses strategies for managing blood sugar levels for those with diabetes or pre-diabetes. It recommends reducing after-meal spikes in blood sugar by slowing the absorption of glucose from foods. It emphasizes choosing complex carbohydrates and fiber-rich foods over refined sugars and processed carbs. It also stresses the importance of optimal nutrient intake to support insulin function and sensitivity. Maintaining a healthy weight and lifestyle can help prevent nutritional and oxidative stress on the body.
Weight loss: A key for prevention of type 2 DMNilly Shams
This document discusses lifestyle interventions for the prevention and treatment of type 2 diabetes. It notes that type 2 diabetes and obesity are twin epidemics linked by excess weight gain leading to insulin resistance. Lifestyle interventions focused on modest weight loss through diet and exercise have been shown to significantly reduce the risk of developing type 2 diabetes by as much as 58% according to studies like the Diabetes Prevention Program. Reversing type 2 diabetes may be possible for some through sustained lifestyle changes that improve insulin sensitivity.
This document provides information about diabetes mellitus. It begins with an acknowledgement section thanking various individuals who helped with a school project. It then lists the contents to be covered, including the aim, introduction, causes, signs and symptoms, diagnosis, and prevention and treatment of diabetes. The introduction provides definitions and descriptions of the three main types of diabetes: type 1, type 2, and gestational diabetes. Causes, signs and symptoms, and methods of diagnosis are then discussed in further detail over multiple paragraphs.
The document discusses the importance of healthy eating habits for students. It defines health as the functional efficiency of living beings and nutrition as providing necessary materials through food to support life. Simple ways to be healthy include eating fruits and vegetables, reducing fat, salt and sugary drinks, avoiding junk food and eating in front of the TV, drinking water, and walking daily. Junk food is defined as having little nutritional value and potentially being dangerous to health, as it can lead to diseases like heart disease, obesity, and reduced cooking skills.
India has a high burden of diabetes, with over 61 million diabetic patients. Type 1 diabetes incidence is increasing, with around 78,000 children developing it annually. Genetic and environmental factors contribute to type 1 diabetes risk. Vaccination for type 1 diabetes aims to induce regulatory T-cells to prevent immune destruction of insulin-producing beta cells. While antigens and clinical trials show promise, challenges remain in identifying biomarkers, developing animal models, and determining optimal combinations or adjunct therapies.
Type 2 diabetes is characterized by hyperglycemia due to insulin resistance and relative insulin deficiency. It is a chronic disease with a high and growing global prevalence, particularly in urban and high-income areas. Key risk factors include lack of exercise and obesity. Common symptoms include increased urination, thirst, and weight loss. Diagnosis involves tests such as HbA1c, fasting blood glucose, and oral glucose tolerance test. Treatment focuses on medications like metformin and lifestyle changes involving diet and exercise to manage blood sugar levels and prevent complications like renal failure.
Diabetes is a chronic disease that has become a global pandemic. It occurs when the pancreas does not produce enough insulin or the body cannot effectively use the insulin it produces, resulting in high blood sugar. The document discusses the history and types of diabetes and provides statistics on the rising global prevalence of the disease, particularly in the Middle East and Gulf countries, where some of the highest rates in the world exist. It is predicted that diabetes will become one of the leading causes of death by 2030 if preventative measures are not taken.
An introduction to the paleo diet and its health benefits. A short summary of research is presented as well as a description of blood sugar managment.
Best Nutritionist in Sarastoa, Cynthia Clark, http://www.cranehealth.net
Fasting and Caloric Restriction Show Promise for Reducing Type 2 Diabetes Bio...Premier Publishers
The global epidemic of type 2 diabetes (T2D) and its co-morbidities threatens to overwhelm public health services and urgent patient intervention is necessary. A review of mainly randomised controlled trials investigating the reduction of biochemical T2D risk markers through fasting or caloric restriction (CR) found that in T2D or where baseline fasting glucose or HbA1c were elevated, there were significant improvements in fasting glucose and HbA1c, while fasting insulin and insulin resistance may show improvement regardless of condition or baseline levels. There may, however, be ethnic differences, with a clear positive correlation found only in Caucasians. Intermittent CR (i.e. non-continuous periods of fasting) is at least as effective as isocaloric continuous CR, while CR of 400-800 kcal/day is possibly more effective than higher levels for reducing fasting glucose and HbA1c. Time restricted feeding also shows promise but there are few human studies. The findings suggest that the optimum regimen to reduce biochemical risk markers for T2D is an intermittent fasting programme employing a very low-calorie diet with the longest possible number of consecutive days of fasting. The addition of liquid meal replacements, low carbohydrate CR and supplementation of vitamin D, ω-3 PUFAs and L-carnitine may also be of benefit.
This document discusses the relationship between various autoimmune diseases and nutrition/food. It begins by introducing common autoimmune diseases that affect different organ systems. It then discusses evidence that vitamin D deficiency is associated with increased risk of inflammatory bowel disease and rheumatoid arthritis. Food restriction is also found to lower risk of systemic lupus erythematosus. The document focuses on links between vitamin D and multiple sclerosis, finding that low vitamin D levels correlate with higher MS risk and severity. Vitamin D is thought to have immunomodulatory effects that may help prevent and treat MS. Cow's milk consumption is also discussed in relation to increased type 1 diabetes risk through potential molecular mimicry.
"Empowered Living with Diabetes: Navigating the Path to Wellness" is an indispensable guide for individuals seeking comprehensive knowledge and practical strategies for effectively managing diabetes. Written by Dr. Olivia Mitchell, a renowned expert in the field of diabetes management, this book offers a holistic approach to understanding and navigating the complexities of diabetes.
From the introductory chapters that provide a thorough overview of diabetes and its various types, to the detailed discussions on prevention, management, and coexisting conditions, this book covers it all. With clarity and expertise, Dr. Mitchell delves into topics such as blood glucose monitoring, medication management, healthy eating, physical activity, stress management, and the emotional well-being of individuals with diabetes.
Through insightful chapters that address common comorbidities associated with diabetes, readers will gain valuable knowledge on how to effectively manage cardiovascular health, hypertension, kidney disease, eye complications, nerve damage, and mental health concerns. Practical tips, evidence-based recommendations, and real-life examples provide readers with the tools needed to take control of their health and embrace a life of empowerment.
Furthermore, this book offers guidance for navigating special occasions, traveling with diabetes, and staying motivated while overcoming challenges. Dr. Mitchell emphasizes the importance of a supportive environment, self-advocacy, and the power of a positive mindset in achieving long-term success in diabetes management.
"Empowered Living with Diabetes" is not just a guidebook, but a source of inspiration and empowerment for individuals living with diabetes. Dr. Olivia Mitchell's expertise and compassionate approach create a valuable resource that will help readers develop the skills, knowledge, and confidence to thrive while managing their condition.
Whether you are newly diagnosed, have been living with diabetes for years, or are a caregiver or healthcare professional seeking comprehensive insights, this book is an invaluable companion on your journey towards wellness and empowerment. With its practical advice, empowering strategies, and the belief that a fulfilling life with diabetes is possible, "Empowered Living with Diabetes" will guide you towards a healthier, happier, and more empowered future.
This document discusses diabetes, including the different types and causes. Some key points:
- Diabetes is a group of metabolic diseases where a person has high blood glucose due to inadequate insulin production or cells not responding properly to insulin.
- There are an estimated 347 million people worldwide with diabetes, and it is predicted to become the 7th leading cause of death by 2030.
- The main types of diabetes are type 1, where the body does not produce insulin, and type 2, where the body does not produce enough insulin or cells do not respond properly to insulin.
- Risk factors for type 2 diabetes include family history, age, weight, and physical inactivity. Prevention focuses on maintaining a healthy weight and
The document discusses diabetic mellitus (diabetes). It aims to help participants understand what diabetes is, normal and abnormal blood sugar levels, the causes and types of diabetes, symptoms, complications if untreated, and ways to manage blood sugar levels through diet, exercise, medication and lifestyle changes. The two main types of diabetes - type 1 caused by lack of insulin production and type 2 caused by insulin resistance - are explained in further detail.
This document discusses different types of diabetes mellitus. It describes the three main types: type 1 diabetes which results from failure to produce insulin; type 2 diabetes which results from insulin resistance; and gestational diabetes which occurs during pregnancy. It provides details on symptoms, causes, treatment and prevalence of each type. Other less common forms are also mentioned. The document emphasizes the importance of proper treatment and control of diabetes to prevent complications.
This document provides information about diabetes, including:
- There are several types of diabetes defined by etiology and treatment needs. Type 1 is insulin dependent while Type 2 is typically non-insulin dependent.
- Diabetes is associated with increased risk of cardiovascular, eye, kidney, and neurological complications if not properly managed and controlled. Tight glycemic control is important to reduce risks.
- Risk factors include family history, obesity, age, and ethnicity. Management involves lifestyle changes like diet, exercise, and medication to control blood sugar, lipids, and blood pressure.
Living Well with Cancer Presentation (Webinar)KellyGCDET
This document discusses the importance of nutrition for cancer patients. It notes that malnutrition is common in 50% of cancer patients and is associated with weight loss, fatigue, weakness and impaired treatment tolerance. Early nutrition intervention can help preserve muscle mass and strength, improving quality of life and ability to complete cancer treatment. Screening tools like the Malnutrition Screening Tool and Patient Generated Subjective Global Assessment are recommended to assess nutritional status and guide appropriate nutrition support and interventions.
Presentation at the Ancestral Health Symposium. Government can provide education and oversight of scientific publications and the press which accounts for the current nutrition mess.
Type 1 diabetes is an autoimmune disease where the body's immune system destroys the beta cells in the pancreas that produce insulin. It requires lifelong treatment with insulin injections and careful management of diet and blood sugar levels. The document provides details on the history, causes, symptoms, diagnosis, treatment, and lifelong prognosis of Type 1 diabetes. Treatment involves regulating blood sugar through insulin injections, diet, exercise, and personal hygiene. The costs of managing the disease are significant. While it currently has no cure, advances in treatment have improved life expectancy and quality of life for those living with Type 1 diabetes.
This document provides information on diabetes, exercise, and weight loss. It discusses the two main types of diabetes - Type 1 caused by lack of insulin production and Type 2 caused by insulin resistance. Good management of both types involves monitoring food intake, counting carbohydrates, incorporating protein and fiber into meals, checking blood sugar levels before and after exercise, and treating low blood sugar during workouts. The document provides guidelines for developing healthy habits including recommended pre and post-workout snacks.
This document discusses strategies for managing blood sugar levels for those with diabetes or pre-diabetes. It recommends reducing after-meal spikes in blood sugar by slowing the absorption of glucose from foods. It emphasizes choosing complex carbohydrates and fiber-rich foods over refined sugars and processed carbs. It also stresses the importance of optimal nutrient intake to support insulin function and sensitivity. Maintaining a healthy weight and lifestyle can help prevent nutritional and oxidative stress on the body.
Weight loss: A key for prevention of type 2 DMNilly Shams
This document discusses lifestyle interventions for the prevention and treatment of type 2 diabetes. It notes that type 2 diabetes and obesity are twin epidemics linked by excess weight gain leading to insulin resistance. Lifestyle interventions focused on modest weight loss through diet and exercise have been shown to significantly reduce the risk of developing type 2 diabetes by as much as 58% according to studies like the Diabetes Prevention Program. Reversing type 2 diabetes may be possible for some through sustained lifestyle changes that improve insulin sensitivity.
This document provides information about diabetes mellitus. It begins with an acknowledgement section thanking various individuals who helped with a school project. It then lists the contents to be covered, including the aim, introduction, causes, signs and symptoms, diagnosis, and prevention and treatment of diabetes. The introduction provides definitions and descriptions of the three main types of diabetes: type 1, type 2, and gestational diabetes. Causes, signs and symptoms, and methods of diagnosis are then discussed in further detail over multiple paragraphs.
The document discusses the importance of healthy eating habits for students. It defines health as the functional efficiency of living beings and nutrition as providing necessary materials through food to support life. Simple ways to be healthy include eating fruits and vegetables, reducing fat, salt and sugary drinks, avoiding junk food and eating in front of the TV, drinking water, and walking daily. Junk food is defined as having little nutritional value and potentially being dangerous to health, as it can lead to diseases like heart disease, obesity, and reduced cooking skills.
India has a high burden of diabetes, with over 61 million diabetic patients. Type 1 diabetes incidence is increasing, with around 78,000 children developing it annually. Genetic and environmental factors contribute to type 1 diabetes risk. Vaccination for type 1 diabetes aims to induce regulatory T-cells to prevent immune destruction of insulin-producing beta cells. While antigens and clinical trials show promise, challenges remain in identifying biomarkers, developing animal models, and determining optimal combinations or adjunct therapies.
Type 2 diabetes is characterized by hyperglycemia due to insulin resistance and relative insulin deficiency. It is a chronic disease with a high and growing global prevalence, particularly in urban and high-income areas. Key risk factors include lack of exercise and obesity. Common symptoms include increased urination, thirst, and weight loss. Diagnosis involves tests such as HbA1c, fasting blood glucose, and oral glucose tolerance test. Treatment focuses on medications like metformin and lifestyle changes involving diet and exercise to manage blood sugar levels and prevent complications like renal failure.
Diabetes is a chronic disease that has become a global pandemic. It occurs when the pancreas does not produce enough insulin or the body cannot effectively use the insulin it produces, resulting in high blood sugar. The document discusses the history and types of diabetes and provides statistics on the rising global prevalence of the disease, particularly in the Middle East and Gulf countries, where some of the highest rates in the world exist. It is predicted that diabetes will become one of the leading causes of death by 2030 if preventative measures are not taken.
An introduction to the paleo diet and its health benefits. A short summary of research is presented as well as a description of blood sugar managment.
Best Nutritionist in Sarastoa, Cynthia Clark, http://www.cranehealth.net
Fasting and Caloric Restriction Show Promise for Reducing Type 2 Diabetes Bio...Premier Publishers
The global epidemic of type 2 diabetes (T2D) and its co-morbidities threatens to overwhelm public health services and urgent patient intervention is necessary. A review of mainly randomised controlled trials investigating the reduction of biochemical T2D risk markers through fasting or caloric restriction (CR) found that in T2D or where baseline fasting glucose or HbA1c were elevated, there were significant improvements in fasting glucose and HbA1c, while fasting insulin and insulin resistance may show improvement regardless of condition or baseline levels. There may, however, be ethnic differences, with a clear positive correlation found only in Caucasians. Intermittent CR (i.e. non-continuous periods of fasting) is at least as effective as isocaloric continuous CR, while CR of 400-800 kcal/day is possibly more effective than higher levels for reducing fasting glucose and HbA1c. Time restricted feeding also shows promise but there are few human studies. The findings suggest that the optimum regimen to reduce biochemical risk markers for T2D is an intermittent fasting programme employing a very low-calorie diet with the longest possible number of consecutive days of fasting. The addition of liquid meal replacements, low carbohydrate CR and supplementation of vitamin D, ω-3 PUFAs and L-carnitine may also be of benefit.
This document discusses the relationship between various autoimmune diseases and nutrition/food. It begins by introducing common autoimmune diseases that affect different organ systems. It then discusses evidence that vitamin D deficiency is associated with increased risk of inflammatory bowel disease and rheumatoid arthritis. Food restriction is also found to lower risk of systemic lupus erythematosus. The document focuses on links between vitamin D and multiple sclerosis, finding that low vitamin D levels correlate with higher MS risk and severity. Vitamin D is thought to have immunomodulatory effects that may help prevent and treat MS. Cow's milk consumption is also discussed in relation to increased type 1 diabetes risk through potential molecular mimicry.
"Empowered Living with Diabetes: Navigating the Path to Wellness" is an indispensable guide for individuals seeking comprehensive knowledge and practical strategies for effectively managing diabetes. Written by Dr. Olivia Mitchell, a renowned expert in the field of diabetes management, this book offers a holistic approach to understanding and navigating the complexities of diabetes.
From the introductory chapters that provide a thorough overview of diabetes and its various types, to the detailed discussions on prevention, management, and coexisting conditions, this book covers it all. With clarity and expertise, Dr. Mitchell delves into topics such as blood glucose monitoring, medication management, healthy eating, physical activity, stress management, and the emotional well-being of individuals with diabetes.
Through insightful chapters that address common comorbidities associated with diabetes, readers will gain valuable knowledge on how to effectively manage cardiovascular health, hypertension, kidney disease, eye complications, nerve damage, and mental health concerns. Practical tips, evidence-based recommendations, and real-life examples provide readers with the tools needed to take control of their health and embrace a life of empowerment.
Furthermore, this book offers guidance for navigating special occasions, traveling with diabetes, and staying motivated while overcoming challenges. Dr. Mitchell emphasizes the importance of a supportive environment, self-advocacy, and the power of a positive mindset in achieving long-term success in diabetes management.
"Empowered Living with Diabetes" is not just a guidebook, but a source of inspiration and empowerment for individuals living with diabetes. Dr. Olivia Mitchell's expertise and compassionate approach create a valuable resource that will help readers develop the skills, knowledge, and confidence to thrive while managing their condition.
Whether you are newly diagnosed, have been living with diabetes for years, or are a caregiver or healthcare professional seeking comprehensive insights, this book is an invaluable companion on your journey towards wellness and empowerment. With its practical advice, empowering strategies, and the belief that a fulfilling life with diabetes is possible, "Empowered Living with Diabetes" will guide you towards a healthier, happier, and more empowered future.
This document discusses diabetes, including the different types and causes. Some key points:
- Diabetes is a group of metabolic diseases where a person has high blood glucose due to inadequate insulin production or cells not responding properly to insulin.
- There are an estimated 347 million people worldwide with diabetes, and it is predicted to become the 7th leading cause of death by 2030.
- The main types of diabetes are type 1, where the body does not produce insulin, and type 2, where the body does not produce enough insulin or cells do not respond properly to insulin.
- Risk factors for type 2 diabetes include family history, age, weight, and physical inactivity. Prevention focuses on maintaining a healthy weight and
Diabetes is a multifactorial disease leading to several complications, and therefore demands a multiple therapeutic approach. Patients of diabetes either do not make enough insulin or their cells do not respond to insulin. In case of total lack of insulin, patients are given insulin injections. Whereas in case of those where cells do not respond to insulin many different drugs are developed taking into consideration possible disturbances in carbohydrate-metabolism. For example, to manage post-prandial hyper-glycaemia at digestive level, glucosidase inhibitors such as acarbose, miglitol and voglibose are used. These inhibit degradation of carbohydrates there by reducing the glucose absorption by the cells. To enhance glucose uptake by peripheral cells biguanide such as metformin is used. Sulphonylureas, like glibenclamide, is insulinotropic and work as secretogogue for pancreatic cells. Although several therapies are in use for treatment, there are certain limitations due to high cost and side effects such as development of hypoglycemia, weight gain, gastrointestinal disturbances, liver toxicity etc. Based on recent advances and involvement of oxidative stress in complicating diabetes mellitus, efforts are on to find suitable antidiabetic and antioxidant therapy.
Medicinal plants are being looked upon once again for the treatment of diabetes. Many conventional drugs have been derived from prototypic molecules in medicinal plants. Metformin exemplifies an efficacious oral glucose-lowering agent. To date, over 400 traditional plant treatments for diabetes have been reported, although only a small number of these have received scientific and medical evaluation to assess their efficacy. The hypoglycemic effect of some herbal extracts has been confirmed in human and animal models of type 2 diabetes. The World Health Organization Expert Committee on diabetes has recommended that traditional medicinal herbs be further investigated. The present paper Reviews the Role of Insulike tablets developed by R&D cell of Lactonova Nutripharm Pvt Ltd. Hyderabad in the role of herbal nutraceutical drug INSULIKE, A nutriphenotypic approach for the treatment of diabetes.
The document is a major project report on diabetes and its management submitted by Dhawal Pal to Rajiv Gandhi Proudyogik Vishwavidyalaya, Bhopal for his Bachelor of Pharmacy degree. It includes certificates of completion signed by the principal and project guide, as well as acknowledgements recognizing those who provided support and guidance. The project aims to discuss diabetes, its types, symptoms, causes, diagnosis, prevention, management, and treatment.
This document discusses diabetes, including the different types, causes, risk factors, management, treatment, and prevention. It provides statistics on the growing prevalence of diabetes in the United States and the economic and public health burden associated with the disease. The document also outlines innovative strategies and emerging technologies for managing diabetes.
This document provides a comprehensive review of in vitro and in vivo models used to study antidiabetic activity. It discusses insulin and the types of diabetes (type 1 and type 2). Common in vivo models include alloxan-induced, streptozotocin-induced, and diathizone-induced diabetes in animals. In vitro models assess alpha-amylase and alpha-glucosidase inhibition to study mechanisms of antidiabetic compounds. The review covers the mechanisms, advantages, and limitations of these important preclinical models for antidiabetic drug development and evaluation.
Type 1 diabetes mellitus is an autoimmune disease that results in insulin dependence due to the failure of insulin secretion by pancreatic beta cells. It typically manifests in childhood under 20 years of age. Proper management involves early detection, patient education, and compliance with treatment, which usually involves insulin injections. Regular exercise and healthy lifestyle choices are also important for management. The disease is managed by measuring blood glucose levels and administering both long-acting and rapid-acting types of insulin.
This document discusses diabetes mellitus (DM), a metabolic disorder caused by factors that result in chronic hyperglycemia. It begins with background on DM and how it is an increasing health problem. DM is classified into type 1, caused by autoimmune destruction of insulin-producing beta cells, and type 2, caused by insulin resistance. Signs and symptoms of DM include frequent urination, excessive thirst, hunger, and weight loss. DM is diagnosed through blood tests measuring glucose levels when fasting and after consuming glucose. Treatment depends on the type, with type 1 requiring insulin injection and type 2 often controlled through diet, exercise and oral medication.
With the rapidly rising rates of diabetes has come refreshed research efforts to understand the biological process impacting glucose tolerance. Glucose tolerance depends on a complex interaction among insulin secretion from the β-cells, clearance of the hormone, and the actions of insulin to accelerate glucose disappearance and inhibit endogenous glucose production. The research approaches the topic from several directions including insights into mechanisms of action, development of screening methods and novel therapeutic targets and the effectiveness of lifestyle and pharmacologic interventions in improving glucose tolerance. This book summarises the recent advances in research relating to glucose tolerance.
The book is divided into four sections and each section subdivided into individual chapters contributed by experts in that particular field. The progression from normal glucose tolerance to impaired glucose tolerance known as a prediabetic state, and then to overt diabetes is reviewed in the first section of this book. Usefulness of the oral glucose tolerance test in basic and clinical investigations and the effectiveness of interventions to prevent or delay the progression from a prediabetic to a diabetic state as demonstrated by findings of clinical trials are included in this section.
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Diabetes_ A chronic metabolic disorder characterized by high blood sugar leve...Shankar794304
This document discusses diabetes, a chronic metabolic disorder characterized by high blood sugar levels. It begins with an introduction that defines diabetes as a condition caused by the body's inability to produce or effectively use insulin. It then covers the types of diabetes, including type 1 which results from the immune system attacking insulin-producing cells, and type 2 which occurs when the body becomes resistant to insulin. The document also discusses risk factors for diabetes such as genetics, obesity, physical inactivity, and lifestyle choices. It emphasizes that diabetes is a lifelong condition but can be managed through treatment including lifestyle changes and medication.
Diabetes mellitus (DM) is a group of metabolic diseases characterized by high blood glucose levels resulting from defects in insulin secretion, insulin action, or both. Type 2 DM accounts for 90-95% of cases and results from the body's ineffective use of insulin and inability to produce enough insulin. Key risk factors include obesity, family history, age over 30, and physical inactivity. Long-term complications of poorly controlled DM include damage to blood vessels, nerves, eyes, kidneys and heart. Management involves lifestyle changes like diet, exercise and medication or insulin to control blood glucose levels. Nurses play an important role in educating patients on self-care, monitoring for complications, and supporting lifestyle modifications to prevent or delay
This document discusses Diabetic Ketoacidosis (DKA), a life-threatening complication of diabetes that occurs when there is a severe lack of insulin. It presents when blood sugar levels rise, fat is broken down instead of glucose, and acid builds up in the blood. Symptoms include nausea, vomiting, and fruity breath. DKA is most common in type 1 diabetes but can occur in other types during illness or medication changes. Treatment involves fluids, electrolytes, and insulin to stabilize the condition. Cerebral edema is a risk, especially in children, where the swelling can be fatal if not addressed.
Makalah bahasa inggris diabetes melitusWarnet Raha
1. The document discusses diabetes mellitus, including its definition, pathophysiology, classification, signs and symptoms, and diagnosis. It is a metabolic disorder caused by many factors that results in chronic hyperglycemia and impaired processing of carbohydrates, fats, and proteins.
2. There are two main types of diabetes - type 1 is characterized by an inability to produce insulin, while type 2 involves decreased sensitivity to insulin. Diagnosis involves measuring fasting blood glucose levels and levels after consuming glucose.
3. Common symptoms include frequent urination, excessive thirst, unexplained weight loss, and tingling or numbness in the extremities. Diagnosis is based on blood tests measuring glucose levels according to WHO criteria.
This document provides an introduction to diabetes mellitus, including:
1. A definition of diabetes mellitus and discussion of its pathophysiology and classification into types 1 and 2.
2. Details on the signs and symptoms, diagnosis, and factors that can contribute to diabetes.
3. An overview of treatment approaches including physical exercise, medications like sulfonylureas, and management of blood sugar levels.
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Learning objectives:
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3. Describe the functions of the dorsal and respiratory groups of neurons
4. Describe the influences of the Pneumotaxic and Apneustic centers
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- Video recording of this lecture in English language: https://youtu.be/Pt1nA32sdHQ
- Video recording of this lecture in Arabic language: https://youtu.be/uFdc9F0rlP0
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5. To Stop Diabetes In Few Days Click Here!!
Contents
Preface IX
Chapter 1 The Utility of Vitamins in the Prevention of
Type 2 Diabetes Mellitus and Its Complications:
A Public Health Perspective 1
Alaa Badawi, Bibiana Garcia-Bailo, Paul Arora,
Mohammed H. Al Thani, Eman Sadoun,
Mamdouh Farid and Ahmed El-Sohemy
Chapter 2 Aldose Reductase Inhibitors as Potential
Therapeutic Drugs of Diabetic Complications 17
Changjin Zhu
Chapter 3 Behavioral Problems and Depressive Symptoms
in Adolescents with Type 1 Diabetes Mellitus:
Self and Parent Reports 47
Nienke M. Maas- van Schaaijk, Angelique B.C.
Roeleveld-Versteegh, Roelof R.J. Odink and Anneloes L. van Baar
Chapter 4 GPR119 Agonists:
A Novel Strategy for Type 2 Diabetes Treatment 59
Xiaoyun Zhu, Wenglong Huang and Hai Qian
Chapter 5 The Role of Nutrition in
the Management of Diabetes Mellitus 83
Olabiyi Folorunso and Oluwafemi Oguntibeju
Chapter 6 Can Lifestyle Factors of Diabetes Mellitus
Patients Affect Their Fertility? 95
Guillaume Aboua, Oluwafemi O. Oguntibeju
and Stefan S. du Plessis
Chapter 7 The Role of Fruit and Vegetable Consumption
in Human Health and Disease Prevention 117
O. O. Oguntibeju, E. J. Truter and A. J. Esterhuyse
6. VI Contents
Chapter 8 Diabetes Mellitus in Developing
Countries and Case Series 131
Omiepirisa Yvonne Buowari
Chapter 9 Principles of Exercise and Its Role
in the Management of Diabetes Mellitus 149
Yıldırım Çınar, Hakan Demirci and Ilhan Satman
Chapter 10 Hyperglycemia and Diabetes in Myocardial Infarction 169
Marco A. López Hernández
Chapter 11 Physical Activity in the Management
of Diabetes Mellitus 193
N.A. Odunaiya and O.O. Oguntibeju
Chapter 12 Copper, Zinc and Magnesium
in Non-Insulin-Dependent Diabetes
Mellitus Treated with Metformin 209
Monica Daniela Dosa, Cecilia Ruxandra Adumitresi,
Laurentiu Tony Hangan and Mihai Nechifor
Chapter 13 Animal Models for Study of Diabetes Mellitus 229
A. Lukačínová, B. Hubková, O. Rácz and F. Ništiar
Chapter 14 Essentials of Diabetes Care in Family Practice 255
Hakan Demirci, Ilhan Satman, Yıldırım Çınar and Nazan Bilgel
Chapter 15 Spontaneous Diabetes Mellitus in Animals 271
Emilia Ciobotaru
Chapter 16 A New Behavioral Model (Health Belief Model Combined
with Two Fear Models): Design, Evaluation and Path Analysis
of the Role of Variables in Maintaining Behavior 297
Alireza Shahab Jahanlou, Masoud Lotfizade
and Nader Alishan Karami
Chapter 17 Development of Improved Animal Models
for the Study of Diabetes 313
Emilia Ciobotaru
7.
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Here!!
Preface
The book "Diabetes Mellitus - Insights and Perspectives" is organized into 17 chapters
and focused primarily on the management of diabetes mellitus from different
perspectives. It also examines animal models in the study and potential management
of diabetes mellitus. Each chapter is unique in content, style of writing and scientific and
professional background and all these add flavour to the taste of the book. The book
provides expert insights and perspectives in terms of scientific and professional
knowledge on this important health issue-diabetes mellitus. I strongly believe that
scientists, academics and different health professionals would find this book very useful.
Students would equally find the scientific and professional insights and perspectives
contained in the different chapters very helpful. It is my strong view that this book
would add value to the pool of knowledge on the management of diabetes mellitus. The
references cited in each chapter definitely acts as additional and important source
of information for readers.
Oluwafem. O. Oguntibeju
Department of Biomedical Sciences,
Faculty of Health & Wellness Sciences, Cape Peninsula
University of Technology, Bellville,
South Africa
9.
10. Chapter 1
To Kill Diabetes Forever!! Click Here
The Utility of Vitamins in the Prevention of
Type 2 Diabetes Mellitus and Its Complications:
A Public Health Perspective
Alaa Badawi, Bibiana Garcia-Bailo, Paul Arora, Mohammed H. Al Thani,
Eman Sadoun, Mamdouh Farid and Ahmed El-Sohemy
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/47834
1. Introduction
Type 2 diabetes mellitus (T2DM) is currently considered as a global health problem where
about six people die every minute from the disease worldwide. This rate will make T2DM one
of the world’s most prevalent causes of preventable mortality [1]. T2DM is caused by impaired
glucose tolerance (IGT) as a result of insulin resistance and consequential islet β- cell
exhaustion, with ensuing insulin deficiency [2]. In individuals with IGT, numerous genetic,
host-related, and environmental factors contribute to the progression of insulin resistance to
T2DM [3-7]. Obesity, however, is a major cause of insulin resistance [5] and can be
complicated by metabolic dysregulation including hypertension and dyslipidemia [known
collectively as the metabolic syndrome] which is a precursor of T2DM. The dyslipidemia
involves high levels of triacylglycerides and circulating fatty acids originating from the diet
or accelerated lipolysis in adipocytes. Direct exposure of muscle cells to these fatty acids
impairs insulin-mediated glucose uptake and, therefore, may contribute to insulin
resistance [8,9]. Within the last decade, a hypothesis was proposed to explain the pathogenesis
of T2DM that connects the disease to a state of subclinical chronic inflammation
[10,11]. Inflammation is a short-term adaptive response of the body elicited as a principle
component of tissue repair to deal with injuries and microbial infections (e.g., cold, flu, etc.).
It can be also elevated in chronic conditions such as peripheral neuropathy, chronic kidney
disease and fatty liver. While the influence of fats is well known (see below), current thinking
suggests that abnormal levels of chemokines released by the expanding adipose tissue in
obesity activate monocytes and increase the secretion of pro-inflammatory adipokines. Such
cytokines in turn enhance insulin resistance in adipose and other tissues, thereby increasing
the risk for T2DM [12,13]. Together, lipid toxicity and low-grade
11. 2 Diabetes Mellitus – Insights and Perspectives
The Utility of Vitamins in the Prevention of
Type 2 Diabetes Mellitus and Its Complications: A Public Health Perspective 2
inflammation appear to be major assaults on insulin sensitivity in insulin-responding tissues
[9,14,15].
Activation of innate immunity promotes various inflammatory reactions that provide the
first line of defense the body invokes against microbial, chemical, and physical injury,
leading to repair of damage, isolation of microbial infectious threats and restoration of tissue
homeostasis [16,17]. Inherited variations in the degree of innate immune response may
determine the lifetime risk of diseases upon exposure to adverse environmental stimuli [18].
Therefore, innate immune responses can be viewed as the outcome of interaction between
genetic endowment and the environment [19].
This article was undertaken in an attempt to evaluate the current knowledge linking vitamin
intake to attenuating inflammation, and thereby reducing the risk of T2DM and its
complications.
2. Micronutrients, T2DM and inflammation
Factors that attenuate inflammation could provide an important public health tool to reduce
the burden of diseases related to this pathway, such as obesity, T2DM and cardiovascular
diseases, in the general population. The feasibility of modulating innate immunity-related
inflammation as an approach for the prevention of T2DM is based on reports that evaluated
the efficacy of anti-inflammatory pharmaceutical agents on disease manifestation and
outcome [12,20].
A therapeutic strategy for T2DM that would act primary on the inflammatory system has been
proposed in the form of salicylates, an anti-inflammatory agent long known to have a
hypoglycemic effect [21,22]. Nonsteroidal anti-inflammatory drugs (NSAIDs) and
cyclooxygenase inhibitors are able to enhance glucose-induced insulin release, improve
glucose tolerance, and increase the effect of insulin in patients with T2DM [15,23,24]. In
humans, treatment with NSAIDs improved various biochemical indices associated with
T2DM [25]. Although these observations support the notion that inflammation plays a
pivotal role in T2DM, attenuating inflammation as a strategy for disease prevention in a public
health setting will necessitate a substantially different perspective. In this case, a strategy that
can be introduced into the general population with the least (if any) side effects and the
maximal preventive outcome should be adopted. In this context, a nutritional intervention
approach would be a desirable option.
Numerous nutritional factors can modify innate immune-related responses and,
subsequently, modify the risk of a range of chronic conditions. With respect to T2DM, the
consensus of available information suggests that micronutrient intake modulates the innate
immune system [26] and can subsequently influence the predisposition to [and prevention
of] disease [26-28]. By virtue of this observation, the hope is that the outcome of nutritional
supplementation can be simply monitored via its modifying action on the levels of
inflammatory biomarkers. Many micronutrients exhibit well-characterized anti-
inflammatory or immunomodulatory functions [25]. Vitamins (e.g., D, E, and C), certain
fatty acids (e.g., omega-3 fatty acid) and trace elements (e.g., selenium, zinc, copper and
12. 3 Diabetes Mellitus – Insights and Perspectives
The Utility of Vitamins in the Prevention of
Type 2 Diabetes Mellitus and Its Complications: A Public Health Perspective 3
iron) are known to improve the overall function of the immune system, prevent excessive
expression and synthesis of inflammatory cytokines, and increase the ‘oxidative burst’
potential of macrophages [25]. Vitamin C is the major water-soluble dietary antioxidant anti-
inflammatory factor, exerting its actions in the aqueous phase. In contrast, vitamins E and D
are lipid-soluble and protect against inflammation in the lipid phase, e.g., adipocytes.
Although acting primarily in different phases, these micronutrients can function together by
regenerating each other in the reduced form [29]. Indeed, exploring the possibility that
supplementation with selected micronutrients can attenuate obesity-related inflammation in
order to delay the development of T2DM should be considered alongside existing public
health practices to reduce the disease rising rates.
3. Vitamin C
Vitamin C (ascorbic acid or ascorbate), an essential nutrient, is a 6-carbon lactone and the
primary hydrophilic antioxidant found in human plasma [30]. Circulating concentrations of
ascorbate in blood are considered adequate if at least 28 μM, but they are considerably
higher in most cells due to active transport. The daily recommended dietary allowance for
vitamin C is 75 mg for women and 90 mg for men, with an additional 35 mg for smokers
due to the higher metabolic turnover of the vitamin in this group as compared to non- smokers
[31]. Ascorbate appears in the urine at intakes of roughly 60 mg/day. However, the results of
a depletion/repletion study in healthy young women showed that ascorbate plasma and
white blood cell concentrations only saturate at intakes of 200 mg/day or higher [32]. These
results suggest that the current dietary recommendations may not provide tissue-
saturating ascorbate concentrations [33]. Indeed, epidemiologic findings suggest that serum
ascorbic acid deficiency may be relatively common. For example, a recent cross- sectional
survey of healthy young adults of the Toronto Nutrigenomics and Health (TNH) Study
reported that 1 out 7 individuals is deficient in serum ascorbic acid [34].
Vitamin C has an important role in immune function and various oxidative and inflammatory
processes, such as scavenging reactive oxygen species (ROS), preventing the initiation of chain
reactions that lead to protein glycation [31;35] and protecting against lipid peroxidation [31,
36]. The oxidized products of vitamin C, ascorbyl radical and dehydroascorbic acid, are easily
regenerated to ascorbic acid by glutathione, NADH or NADPH [31]. In addition, ascorbate
can recycle vitamin E and glutathione back from their oxidized forms [31, 33]. For this reason,
there has been interest in determining whether vitamin C might be used as a therapeutic agent
against the oxidative stress and subsequent inflammation associated with T2DM.
A variety of epidemiologic studies have assessed the effect of vitamin C on biomarkers of
oxidation, inflammation and/or T2DM risk [30, 37-42]. A large cross-sectional evaluation of
healthy elderly men from the British Regional Heart Study reported that plasma vitamin C,
dietary vitamin C and fruit intake were inversely correlated with serum CRP and tissue
plasminogen activator [tPA], a biomarker of endothelial disfunction [134]. However, only
plasma vitamin C was inversely associated with fibrinogen levels [30]. Another cross-
sectional study of adolescents aged 13-17 found inverse associations between intakes of
13. 4 Diabetes Mellitus – Insights and Perspectives
The Utility of Vitamins in the Prevention of
Type 2 Diabetes Mellitus and Its Complications: A Public Health Perspective 4
fruit, vegetables, legumes and vitamin C and urinary F2-isoprostane, CRP, and IL-6 [43]. A
recent cross-sectional evaluation of healthy young adults from the TNH Study
demonstrated that serum ascorbic acid deficiency is associated with elevated CRP and other
factors related to the metabolic syndrome such as waist circumference, BMI and high blood
pressure [34]. Finally, the European Prospective Investigation of Cancer (EPIC)-Norfolk
Prospective Study examined the link between fruit and vegetable intake and plasma levels
of vitamin C and risk of T2DM. During 12-year follow-up, 735 incident cases of diabetes
were identified among nearly 21,000 participants [44]. A significant inverse association was
found between plasma levels of vitamin C and risk of diabetes (OR=0.38, 95% CI=0.28-0.52).
In the same study, a similar association was observed between fruit and vegetable intake
and T2DM risk (OR=0.78, 95% CI=0.60-1.00) [44].
Despite epidemiologic findings generally pointing towards an association between increased
vitamin C and reduced oxidation and inflammation, intervention trials assessing the effect of
vitamin C supplementation on various markers of T2DM have yielded inconsistent results. One
randomized, cross-over, double-blind intervention trial reported no improvement in fasting
plasma glucose and no significant differences in levels of CRP, IL-6, IL-1 receptor agonist or
oxidized LDL after supplementation with 3000 mg/day of vitamin C for 2 weeks in a group of
20 T2DM patients, compared to baseline levels [45]. Chen and colleagues performed a
randomized, controlled, double-blind intervention on a group of 32 diabetic subjects with
inadequate levels of vitamin C and found no significant changes in either fasting glucose or
fasting insulin after intake of 800 mg/day of vitamin C for 4 weeks [46].
On the other hand, Wang and colleagues showed that the red blood cell sorbitol/plasma
glucose ratio was reduced after supplementation with 1000 mg/day vitamin C for 2 weeks in
a group of eight diabetics, although no differences were found in fasting plasma glucose
[47]. Since sorbitol is a product of the pro-oxidative polyol pathway, this observation may
suggest an inhibition of the polyol pathway by vitamin C among subjects with diabetes.
Another study has shown that daily intake of ascorbic acid at 2000 mg/day improved fasting
plasma glucose, HbA1c, cholesterol levels and triglycerides in 56 diabetics [48]. In
agreement, Paolisso et. al. found that 1000 mg/day of vitamin C for 4 months improved LDL
and total cholesterol, fasting plasma insulin and free radicals, although it did not affect
triglycerides or HDL levels in a group of 40 diabetics [49].
Overall, it remains unclear whether vitamin C intake has an effect on factors related to
T2DM. Although the epidemiologic evidence suggests that vitamin C, whether as a
supplement or as part of a diet rich in fruits and vegetables, beneficially affects
inflammatory markers and disease risk, the results of intervention trials in T2DM are
conflicting. Small sample sizes, genetic variation, short intervention duration, insufficient
dosage and disease status of the assessed cohorts may account for the lack of effect and the
inconsistent outcomes observed in intervention studies. However, it is possible also that the
status of vitamin C deficiency is a result of the oxidative and pro-inflammatory challenges
associated with T2DM rather than a determinant of disease pathogenesis. Therefore, further
research and long-term prospective studies are needed to elucidate the role of vitamin C as a
modulator of inflammation and T2DM risk, and to evaluate its potential role as a preventive
agent at a population level.
14. 5 Diabetes Mellitus – Insights and Perspectives
The Utility of Vitamins in the Prevention of
Type 2 Diabetes Mellitus and Its Complications: A Public Health Perspective 5
4. Vitamin E
Vitamin E encompasses a group of 8 compounds, including α, β, γ, and δ tocopherols and α,
β, γ, and δ tocotrienols, with differing biological activities. Each compound contains a
hydroxyl-containing chromanol ring with a varying number and position of methyl groups
between the α, β, γ, and δ forms [29]. It is known to have a significant impact on improving
a variety of immune functions [50]. Supplementation with vitamin E increases the rate of
lymphocyte proliferation by enhancing the ability of T cells to undergo cell division cycles
[51]. The effective anti-inflammatory action of vitamin E was substantiated from
observations such as the increased expression of the IL-2 gene and IL-1 receptor antagonist
and the decreased expression of IL-4 following vitamin E supplementation in animal models
[50]. Furthermore, vitamin E reduced the serum levels of inflammatory factors such as IL-1β,
IL-6, TNF-α , PAI-1, and CRP in T2DM patients [52, 53]. Furthermore, vitamin E
downregulates NFκB [52], the principal mediator of inflammatory signaling cascade and its
potent lipophilic antioxidant effect on internal and external cell membranes as well as
plasma lipoproteins, notably LDL. Based on this latter characteristic, studies in both animal
models and humans have demonstrated that vitamin E intake blocks LDL lipid
peroxidation, prevents the oxidative stress linked to T2DM-associated abnormal metabolic
patterns [hyperglycemia, dyslipidemia, and elevated levels of FFAs], and, subsequently,
attenuates cytokine gene expression [50, 52, 56, 57]. Despite these findings, a recent study
evaluated the effects of a combination of vitamin C (1000 mg/day) and vitamin E (400
IU/day) for four weeks on insulin sensitivity in untrained and trained healthy young men and
concluded that such supplementation may preclude the exercise-induced amelioration of
insulin resistance in humans [58]. This may relate to the source of vitamin E used, i.e., α-, β-,
γ-, or δ-tocopherol [59].
Overall, the immunomodulatory, anti-inflammatory and anti-oxidative functions of vitamin
E strongly support its possible application in designing effective prevention and/or
treatment protocols for T2DM [25, 56]. Current practices for diabetes prevention in the general
population include lifestyle change, dietary intervention and exercise. Vitamin E
supplementation may further aid in T2DM prevention and control through its anti-oxidant,
anti-inflammatory and immunomodulatory properties. It seems reasonable, therefore, to
suggest supplementation with vitamin E together with lifestyle change may be combined into
a single program to enhance the success and effectiveness of intervention. This strategy could
be more efficient in reducing the low-grade inflammation associated with pre-clinical T2DM
and, subsequently the disease burden, than when a single approach is considered. Moreover,
such a combined strategy can be introduced in general practice settings and in a population-
based fashion with low expenditure and minimal side effects.
5. Vitamin D
The role of vitamin D in calcium and phosphorus homeostasis and bone metabolism is well
understood. However, more recently vitamin D and calcium homeostasis have also been
linked to a number of conditions, such as neuromuscular function, cancer, and a wide range
of chronic diseases, including autoimmune diseases, atherosclerosis, obesity, cardiovascular
15. 6 Diabetes Mellitus – Insights and Perspectives
The Utility of Vitamins in the Prevention of
Type 2 Diabetes Mellitus and Its Complications: A Public Health Perspective 6
diseases, diabetes and associated conditions such as the metabolic syndrome and insulin
resistance [25, 60-63]. In T2DM, the role of vitamin D was suggested from the presence of
vitamin D receptors (VDR) in the pancreatic β-islet cells [63]. In these cells, the biologically
active metabolite of vitamin D (i.e., 1,25-dihydroxy-vitamin D; 1,25[OH]D) [64] enhances
insulin production and secretion via its action on the VDR [63]. Indeed, the presence of vitamin
D binding protein (DBP), a major predictor of serum levels of 25(OH)D and response
to vitamin D supplementation [65, 66], and VDR initiated several studies demonstrating a
relationship between single nucleotide polymorphisms (SNPs) in the genes regulating VDR
and DBP and glucose intolerance and insulin secretion [67-69]. This further supports a role for
vitamin D in T2DM and may explain the reduced overall risk of the disease in subjects who
ingest >800 IU/d of vitamin D [61,70]. However, an alternative, and perhaps related, explanation
was recently proposed for the role of vitamin D in T2DM prevention based on its potent
immunomodulatory functions [71-73]. 1,25(OH)D modulates the production of the
immunostimulatory IL-12 and the immunosuppressive IL-10 [74] and VDRs are present in most
types of immune cells [75]. In this respect, supplementation with vitamin D [76] or its bioactive
form, 1,25(OH)D [64], improved insulin sensitivity by preventing the excessive synthesis of
inflammatory cytokines. This effect of vitamin D on cytokine synthesis is due to its interaction
with vitamin D response elements (VDRE) present in the promoter region of cytokine-
encoding genes. This interaction downregulates the transcriptional activities of cytokine
genes and attenuates the synthesis of the corresponding proteins [76]. Vitamin D also
deactivates NFκB, which transcriptionally upregulates the pro-inflammatory cytokine-encoding
genes [77]. Downregulating the expression of NFκB and downstream cytokine genes inhibits β-
cell apoptosis and promotes their survival [76].
As reviewed by Pittas et al [78], a number of cross-sectional studies in both healthy and
diabetic cohorts have shown an inverse association between serum 25(OH)D and glycemic
status measures such as fasting plasma glucose, oral glucose tolerance tests, hemoglobin A1c
(HbA1c), and insulin resistance as measured by the homeostatic model assessment (HOMA-
R), as well as the metabolic syndrome [79-84]. For example, data from the National Health and
Nutrition Examination Survey (NHANES) showed an inverse, dose-dependent association
between serum 25(OH)D and diabetes prevalence in non-Hispanic whites and Mexican
Americans, but not in non-Hispanic blacks [81,84]. The same inverse trend was observed
between serum 25(OH)D and insulin resistance as measured by HOMA-R, but there was no
correlation between serum levels of vitamin D and β-cell function, as measured by HOMA-β
[81,84]. Data from the same cohort also showed an inverse association between
25(OH)D and prevalence of the metabolic syndrome [81].
In prospective studies, dietary vitamin D intake has been associated with incidence of
T2DM. For example, data from the Women’s Health Study showed that, among middle-
aged and older women, taking >511 IU/day of vitamin D reduced the risk of developing
T2DM, as compared to ingesting 159 IU/day [85]. Furthermore, data from the Nurses Health
Study also found a significant inverse correlation between total vitamin D intake and T2DM
risk, even after adjusting for BMI, age, and non-dietary covariates [70]. Intervention studies
have shown conflicting results about the effect of vitamin D on T2DM incidence. One study
reported that supplementation with 1,25[OH]2D3 for 1 week did not affect fasting glucose or
16. 7 Diabetes Mellitus – Insights and Perspectives
The Utility of Vitamins in the Prevention of
Type 2 Diabetes Mellitus and Its Complications: A Public Health Perspective 7
insulin sensitivity in 18 young healthy men [86]. Another study found that, among 14 T2DM
patients, supplementing with 80 IU/day of 1 α-OHD3 ameliorated insulin secretion but did not
improve glucose tolerance after a 75 g oral load [87]. Yet another study showed that, among
65 middle-aged men who had IGT or mild T2DM and adequate serum vitamin D levels at
baseline, supplementation with 30 IU/day of 1-α-OHD3 for 3 months affected neither fasting nor
stimulated glucose tolerance [88]. However, in a cross-over design, 20 diabetics with inadequate
vitamin D serum levels who were given 40 IU/day of 1,25-OHD for 4 days had improved insulin
secretion, but showed no changes in fasting or stimulated glucose or insulin concentrations [89].
Although the short duration of this cross-over trial may account for the lack of a significant
overall effect, the results suggest that improving vitamin D status can modulate factors
associated with the development and progression of T2DM.
The data from a 2-year-long trial designed to assess the effects of vitamin D3 or 1-α-OHD3
supplementation on bone health in non-diabetic postmenopausal women were analyzed a
posteriori and found no significant effect on fasting glucose levels [90]. A post-hoc analysis of
data from a 3-year trial for bone health showed that daily supplementation with 700 IU of
vitamin D3 and 500 mg of calcium citrate malate did not change blood glucose levels or
insulin resistance in elderly adults with normal glucose tolerance. These measures, however,
were significantly improved in subjects with IGT at baseline [91]. In this trial the effect of
fasting glucose levels in the high-risk group (i.e., IGT) was similar to that observed in the
Diabetes Prevention Program after an intensive lifestyle intervention or metformin
treatment [92]. Taken together, the available information warrants exploring the possibility
that vitamin D (alone or in combination with calcium) can be employed in developing
population-based strategies for T2DM prevention and control.
6. β-carotene and lycopene
As previously stated, oxidative stress is involved in the development and complications of
T2DM [60]. Patients with T2DM exhibit a reduced antioxidative defence, which negatively
correlates with glucose levels and duration of the disease [93]. In diabetic subjects, the lack
of metabolic homeostasis, the increased plasma ROS generation and the decreased efficiency
of inhibitory and scavenger systems [60], all can that result in a status of oxidative stress that
can have an etiological role in T2DM complications, e.g., retinopathy, chronic kidney
disease, and cardiovascular diseases [94]. The synthesis of ROS was proposed to be
primarily due to hyperglycaemia [95] resulting in stimulation of the polyol pathway,
formation of advanced glycosylation endproducts, and subsequent formation of ROS.
Hyperinsulinaemia, insulin resistance and inflammation, may all play a role in the synthesis
of ROS in pre-diabetic and diabetic patients [60].
As we reviewed recently, the risk of T2DM can be mitigated by increased antioxidants
intake [60]. Intake of α- and β-carotene and lycopene has been shown to improve glucose
metabolism in subjects at high risk of T2DM [96], and glucose metabolism has been associated
with oxidative stress [95]. Indeed, diabetic patients have shown a predominantly elevated
levels of lipid peroxidation (F2-isoprostanes) [97]. In vivo lipid peroxidation, measured as F2-
isoprostanes, apprears to be influenced by the consumption of dietary
17. 8 Diabetes Mellitus – Insights and Perspectives
The Utility of Vitamins in the Prevention of
Type 2 Diabetes Mellitus and Its Complications: A Public Health Perspective 8
components such as antioxidants. It is therefore critical to examine the dietary effects of α- and
β-carotene and lycopeneon lipid peroxidation in patients with T2DM. The relationship
between plasma levels of antioxidants and markers of oxidative stress and inflammation
have been described in healthy population [58,98] and is yet to be identified in diabetic
subjects. This will allow us to better define the role of α- and β-carotene and lycopene in
attenuating inflammation and modulating the oxidative stress during the course of T2DM
development and progression.
7. T2DM complications: Cardiometabolic disease
It is well-established that T2DM is a risk factor for cardiometabolic diseases. Studies from
our group demonstrated a relationship between T2DM and its risk factors and
cardiometabolic disease markers [98,99]. We observed an apparent profile of metabolic
phenotypes and inflammatory biomarkers, known to be related to the cardiometabolic disease
risk, that emerges with the susceptibility to T2DM. These findings allowed us to establish a
composite metabolic trait that lead to the development of improved strategies for early risk
prediction and intervention.
In the same study population, we further demonstrated an association between plasma vitamin
D level and T2DM risk, e.g., insulin resistance [100]. We found that the likelihood that T2DM
develops and results in related complications is further increased as plasma vitamin D levels
decrease. These studies highlights the possibility that micronutrient supplementation can be
employed in the prevention of various T2Dm complications including cardimetabolic diseases.
Moreover, there is a need to develop adequately powered randomized controlled clinical trials
to evaluate the value of replenishment of vitamin D on T2DM and the related conditions, e.g.,
obesity, insulin resistance and cardiovascular diseases, as an approach for an effective
population based strategy for disease prevention.
8. Public health prespectives
Introducing novel and effective prevention strategies in a public health setting necessitates
considering approaches with the least [if any] side effects and the maximal preventive
efficacy and outcome. Furthermore, the heterogeneity of the general Western population in
terms of culture, location and resources renders creating a unified intervention program a
formidable endeavour. In this context, applying nutritional intervention as an approach to
attenuate inflammation and oxidative stress would be a feasible public health strategy for
the T2DM. A conceptual model need to be implemented to improve the availability and
accessibility of nutritious food as a factor that can be integrated into a comprehensive public
health intervention strategy aimed at T2DM prevention.
Combining micronutrients supplementation or encouraging the consumption of nutritious
diet should be explored in pre-diabetic subjects and the outcome should be compared to the
effect(s) of changing current practices, such as lifestyle change, dietary intervention and
exercise. The effectiveness of lifestyle-change intervention programmes for pre-diabetes also
shows a promising effect on the reduction of overall incidence of T2DM or its complications,
18. 9 Diabetes Mellitus – Insights and Perspectives
The Utility of Vitamins in the Prevention of
Type 2 Diabetes Mellitus and Its Complications: A Public Health Perspective 9
and it can be implemented in general clinical practice [95]. A lifestyle-change programme
including increased exercise and diet change (either by reduction in glycemic load or reduced-
fat diet) demonstrated a significant difference between control and intervention groups in
markers for risk of progression to T2DM including weight, BMI, and waist circumference
[101]. In general, current approaches for the prevention of T2DM have been shown to be
effective in delaying or preventing the progression from pre-diabetes to diabetes [102].
In patients with insulin resistance, these practices are known to improve insulin sensitivity
and the overall predisposition to T2DM [103]. On the other hand, increasing intake of vitamin
D to greater than 800 IU daily along with 1200 mg of calcium was reported to reduce the risk
of developing T2DM by 33% [78]. In agreement, healthy older adults with impaired fasting
glucose showed significant improvement in attenuating the glycemic response and insulin
resistance when they increased the vitamin D to 700 IU/d and calcium to 500 mg/d for 3 yrs
[70]. It seems reasonable, therefore, to suggest that the two preventive approaches for T2DM,
i.e., micronutrient supplementation and lifestyle change, may be combined into a single
successful intervention programme. This strategy may be more efficient in reducing the
burden of the disease in the general population and in vulnerable subpopulations than when
a single approach is proposed. Moreover, such a combined approach may be introduced into
the general practice setting and to the general population with low expenditure and minimal
side effects [25,60].
Overall, the current state of knowledge warrants further study into the extent to which
micronutrients can modify the association between markers of inflammation and oxidative
stress and early stages of T2DM. There is evidence supporting the idea that vitamin
supplementation can modify the genotype-phenotype association within the innate immune
response (i.e., the pro-inflammatory and inflammatory markers), and that it has an
ameliorating effect on oxidative stress and the subsequent inflammatory signalling. This
proposition may provide the mechanism by which nutritional factors prevent or delay disease
development and can be introduced into the general population, as well as susceptible
subpopulations. In relation to the current preventive approaches for T2DM, e.g., lifestyle
changes, exercise, and dietary intervention, exploring the efficacy of micronutrient
supplementation on attenuating oxidative stress, the innate immune response and the ensuing
inflammation and evaluating the outcome of this strategy on T2DM incidence may be assessed
through a series of prospective population-based studies, first, to determine the feasibility and
effectiveness of this protocol; second, to validate and evaluate this strategy and ensure
replication of results; and, third, to monitor the outcome to quantify the overall preventive
response in comparison with the current approaches.
Author details
Alaa Badawi*
Office for Biotechnology, Genomics and Population Health, Public Health Agency of Canada,
Toronto, ON, Canada
*
Corresponding Author
19. 10 Diabetes Mellitus – Insights and Perspectives
The Utility of Vitamins in the Prevention of
Type 2 Diabetes Mellitus and Its Complications: A Public Health Perspective 10
Bibiana Garcia-Bailo
Office for Biotechnology, Genomics and Population Health, Public Health Agency of Canada,
Toronto, ON, Canada
Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, ON, Canada
Paul Arora
Office for Biotechnology, Genomics and Population Health, Public Health Agency of Canada,
Toronto, ON, Canada
Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
Mohammed H. Al Thani and Eman Sadoun
Supreme Council of Health, Doha, Qatar
Mamdouh Farid
Queen Medical research Office, Doha, Qatar
Ahmed El-Sohemy
Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, ON, Canada
Acknowledgement
This work is supported by the Public Health Agency of Canada.
9. References
[1] Wild S, Rolic C, Green A. Global prevalence of diabetes: Estimates for the year 2000 and
projection for 2030. Diabetes Care. 2004;37:1047–1053.
[2] Stumvoll M, Goldstein B, van Haeften T. Type 2 diabetes: principles of pathogenesis
and therapy. Lancet. 2005;365:1333–1346.
[3] Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes
epidemic. Nature. 2001;414:782–787.
[4] Alberti KG. Treating type 2 diabetes–today’s targets, tomorrow’s goals. Diabetes
Obesity Metabolism. 2001;3(Suppl 1):S3–S10.
[5] Dandona P, Aljada A, Bandyopadhyay A. Inflammation: the link between insulin
resistance, obesity and diabetes. Trends Immunology. 2004;25:4–7.
[6] Dandona P, Aljada A. A rational approach to pathogenesis and treatment of type 2
diabetes mellitus, insulin resistance, inflammation, and atherosclerosis. American
Journal Cardiology. 2002;90:27G–33G.
[7] Dandona P, Aljada A, Chaudhuri A, Bandyopadhyay A. The potential influence of
inflammation and insulin resistance on the pathogenesis and treatment of
atherosclerosis-related complications in type 2 diabetes. Journal Clinical Endocrinology
Metabolism. 2003;88:2422–2429.
[8] Dimopoulos N, Watson M, Sakamoto K, Hundal HS. Differential effects of palmitate
and palmitoleate on insulin action and glucose utilization in raty L6 skeletal muscle
cells. Biochemistry Journal. 2006;399:473–481.
20. 11 Diabetes Mellitus – Insights and Perspectives
The Utility of Vitamins in the Prevention of
Type 2 Diabetes Mellitus and Its Complications: A Public Health Perspective 11
[9] Bilan PJ, Samokhvalov V, Koshkina A, Schertzer JD, Samaan MC, Klip A. Direct and
macrophage-mediated actions of fatty acids causing insulin resistance in muscle cells.
Archive Physiology Biochemistry. 2009;115:176–190.
[10] Pickup JC, Crook MA. Is type II diabetes mellitus a disease of the innate immune
system? Diabetologia. 1998;41:1241–1248.
[11] Pickup JC, Matttock MB, Chusney GD, Burt D. NIDDM as a disease of the innate
immune system: association of acute phase reactants and interleukin-6 with metabolic
syndrome X. Diabetologia. 1997;40:1286–1292.
[12] King GL. The role of inflammatory cytokines in diabetes and its complications. Journal
Periodontology. 2008;79:1527–1534.
[13] Larsen GL, Henson PM. Mediators of inflammation. Annals Review Immunology.
1983;1:335–359.
[14] Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis
factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993;259:87–91.
[15] Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444:860–867.
[16] Beutler B. Innate immunity: an overview. Molecular Immunology. 2004;40:845–859.
[17] Takeda K, Akira S. TLR signaling pathways. Seminars Immunology. 2004;16:3–9.
[18] Le Souëf PN. Gene-environmental interaction in the development of atopic asthma:
new developments. Current Opinion Allergy Clinical Immunology. 2009;9:123–127.
[19] Fernandez-Real JM, Pickup JC. Innate immunity, insulin resistance and type 2 diabetes.
Trends Endocrinology Metabolism. 2007; 19:10–16.
[20] Liu G, Rondinone CM. JNK: bridging the insulin signaling and inflammatory pathway.
Curr Opin Investig Drugs. 2005; 6:979–987.
[21] Robertson RP. Prostaglandins as modulators of pancreatic islet function. Diabetes.
1979;28:942–948.
[22] Robertson RP. Arachidonic acid metabolism, the endocrine pancreas, and diabetes
mellitus. Pharmacology Therapy. 1984;24:91–106.
[23] Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. Journal Clinical
Investigation. 2005;115:1111–1119.
[24] Hundal RS, Peterson KF, Mayerson AB, et al. Mechanism by which high-dose aspirin
improves glucose metabolism in type 2 diabetes. Journal Clinical Investigation.
2002;109:1321–1326.
[25] Badawi, A., Klip, A., Haddad, P., Cole, D.E.C., Bailo, B.G., El-Sohemy, A., and Karmali,
M. Type 2 diabetes mellitus and inflammation: Prospects for biomarkers of risk and
nutritional intervention. Diabetes Metabolic Syndrome Obesity. 2010;3:173-186.
[26] Maggini S, Wintergerst ES, Beveridge S, Hornig DH. Selected vitamins and trace
elements support immune function by strengthening epithelial barriers and cellular and
humoral immune responses. British Journal Nutrition 2007;98(Suppl 1):S29–S35.
[27] Pittas AG, Lau J, Hu FB, Dawson-Hughes B. Review: The role of vitamin D and calcium
in type 2 diabetes. A systematic review and meta-analysis. Journal Clinical Endocrinology
Metabolism. 2007;92:2017–2029.
[28] Pittas AG, Dawson-Hughes B, Li T, et al. Vitamin D and calcium intake in relation to type
2 diabetes in women. Diabetes Care. 2006;29:650–656.
21. 12 Diabetes Mellitus – Insights and Perspectives
The Utility of Vitamins in the Prevention of
Type 2 Diabetes Mellitus and Its Complications: A Public Health Perspective 12
[29] Da Costa, L.A., García-Bailo, B., Badawi, A., and El-Sohemy, A. Genetic determinants of
dietary antioxidant status. In: Bouchard, C. and Ordovas, J.M. [eds.]. Recent Advances
in Nutrigenetics and Nutrigenomics. Elsevier, New York, NY. 2012, in press.
[30] Wannamethee SG, Lowe GD, Rumley A, Bruckdorfer KR, Whincup PH. Associations of
vitamin C status, fruit and vegetable intakes, and markers of inflammation and
hemostasis. American Journal Clinical Nutrition 2006;83:567-574.
[31] Calder PC, Albers R, Antoine JM, Blum S, Bourdet-Sicard R, Ferns GA, Folkerts G,
Friedmann PS, Frost GS, Guarner F, Lovik M, Macfarlane S, Meyer PD, M'Rabet L,
Serafini M, et al. Inflammatory disease processes and interactions with nutrition. British
Journal Nutrition 2009;101 (Suppl 1):S1-S45.
[32] Levine M, Wang Y, Padayatty SJ, Morrow J. A new recommended dietary allowance of
vitamin C for healthy young women. Proceedings National Acadamy Science USA.
2001; 98:9842-9846.
[33] Aguirre R, May JM. Inflammation in the vascular bed: importance of vitamin C.
Pharmacolocial Therapy. 2008;119:96-103.
[34] Cahill L, Corey PN, El-Sohemy A. Vitamin C deficiency in a population of young
Canadian adults. American Journal Epidemiology. 2009;170:464-471.
[35] Bartlett HE, Eperjesi F. Nutritional supplementation for type 2 diabetes: a systematic
review. Ophthalmic Physiology Opt. 2008; 28:503-523.
[36] Young IS, Tate S, Lightbody JH, McMaster D, Trimble ER. The effects of
desferrioxamine and ascorbate on oxidative stress in the streptozotocin diabetic rat.
Free Radical Biology Medicine 1995;18:833-840.
[37] Ford ES, Liu S, Mannino DM, Giles WH, Smith SJ. C-reactive protein concentration and
concentrations of blood vitamins, carotenoids, and selenium among United States
adults. European Journal Clinical Nutrition 2003; 57:1157-1163.
[38] Hamer M, Chida Y. Intake of fruit, vegetables, and antioxidants and risk of type 2
diabetes: systematic review and meta-analysis. Journal Hypertension 2007;25:2361-2369.
[39] Woodward M, Lowe GD, Rumley A, Tunstall-Pedoe H, Philippou H, Lane DA,
Morrison CE. Epidemiology of coagulation factors, inhibitors and activation markers: The
Third Glasgow MONICA Survey. II. Relationships to cardiovascular risk factors and
prevalent cardiovascular disease. British Journal Haematology. 1997;97:785-797.
[40] Woodward M, Rumley A, Tunstall-Pedoe H, Lowe GD. Associations of blood rheology
and interleukin-6 with cardiovascular risk factors and prevalent cardiovascular disease.
British Journal Haematology. 1999; 104:246-257.
[41] Woodward M, Rumley A, Lowe GD, Tunstall-Pedoe H. C-reactive protein: associations
with haematological variables, cardiovascular risk factors and prevalent cardiovascular
disease. British Journal Haematology 2003;122:135-141.
[42] Gao X, Bermudez OI, Tucker KL. Plasma C-reactive protein and homocysteine
concentrations are related to frequent fruit and vegetable intake in Hispanic and non-
Hispanic white elders. Journal Nutrition. 2004;134:913-918.
[43] Holt EM, Steffen LM, Moran A, Basu S, Steinberger J, Ross JA, Hong CP, Sinaiko AR.
Fruit and vegetable consumption and its relation to markers of inflammation and
22. 13 Diabetes Mellitus – Insights and Perspectives
The Utility of Vitamins in the Prevention of
Type 2 Diabetes Mellitus and Its Complications: A Public Health Perspective 13
oxidative stress in adolescents. Journal American Dietetics Association 2009;109:414-
421.
[44] Harding AH, Wareham NJ, Bingham SA, Khaw K, Luben R, Welch A, Forouhi NG.
Plasma vitamin C level, fruit and vegetable consumption, and the risk of new-onset
type 2 diabetes mellitus: the European prospective investigation of cancer--Norfolk
prospective study. Archives Internal Medicine. 2008; 168:1493-1499.
[45] Lu, Q, Bjorkhem,I, Wretlind,B, Diczfalusy,U, Henriksson,P, Freyschuss,A: Effect of
ascorbic acid on microcirculation in patients with Type II diabetes: a randomized placebo-
controlled cross-over study. Clinical Science. 2005;108:507-513.
[46] Chen H, Karne RJ, Hall G, Campia U, Panza JA, Cannon RO, III, Wang Y, Katz A,
Levine M, Quon MJ. High-dose oral vitamin C partially replenishes vitamin C levels in
patients with Type 2 diabetes and low vitamin C levels but does not improve
endothelial dysfunction or insulin resistance. American Journal Physiology Heart
Circulation Physiology. 2006; 290:H137-H145.
[47] Wang H, Zhang ZB, Wen RR, Chen JW. Experimental and clinical studies on the
reduction of erythrocyte sorbitol-glucose ratios by ascorbic acid in diabetes mellitus.
Diabetes Research Clinical Practice 1995; 28:1-8.
[48] Eriksson J, Kohvakka A. Magnesium and ascorbic acid supplementation in diabetes
mellitus. Annals Nutrition Metabolism. 1995;39:217-223.
[49] Paolisso G, Balbi V, Volpe C, Varricchio G, Gambardella A, Saccomanno F, Ammendola
S, Varricchio M, D'Onofrio F. Metabolic benefits deriving from chronic vitamin C
supplementation in aged non-insulin dependent diabetics. Journal American College
Nutrition. 1995;14:387-392.
[50] Han SN, Adolfsson O, Lee CK, Prolla TA, Ordovas J, Meydani SN. Vitamin E and gene
expression in immune cells. Annals NY Academy Science. 2004;1031:96–101.
[51] Adolfsson O, Huber BT, Meydani SN. Vitamin E-enhanced IL-2 production in old mice:
naive but not memory T cells show increased cell division cycling and IL-2 -producing
capacity. Journal Immunology. 2001;167:3809–3817.
[52] Singh U, Jialal I. Anti-inflammatory effects of α-tocopherol. Annals NY Academy
Science. 2004;1031:195–203.
[53] Devaraj JS, Jialal I. Alpha-tocopherol decreases interleukin-1 beta release from activated
human monocytes by inhibition of 5-lipoxygenase. Arteriosclerosis Thrombosis
Vascular Biology. 1999;19:1125–1133.
[54] Scott JA, King GL. Oxidative stress and antioxidant treatment in diabetes. Annals NY
Academy Science. 2004;1031:204–213.
[55] Thomas SR, Stocker R. Molecular action of vitamin E in lipoprotein oxidation:
Implications for athrosclerosis. Free Radical Biology Medicine. 2000;28:1795–1805.
[56] Ristow M, Zarse K, Oberbach A, et al. Antioxidants prevent healthpromoting effects of
physical exercise in humans. Proceeding National Academy Science USA.
2009;106:8665–8670.
[57] Buijsee B, Feskens EJM, Kwape L, Kok FJ, Kormhout D. Both alphaand beta-carotene,
but not tocopherols and vitamin C, are inversely related to 15-year cardiovascular
mortality in Dutch elderly men. Journal Nutrition. 2008;138:344–350.
23. 14 Diabetes Mellitus – Insights and Perspectives
The Utility of Vitamins in the Prevention of
Type 2 Diabetes Mellitus and Its Complications: A Public Health Perspective 14
[58] Garcia-Bailo, B., El-Sohemy, A., Haddad, P., Arora, P., BenZaied, F., Karmali, M. and
Badawi, A. Vitamins D, C and E in the prevention of type II diabetes mellitus: modulation
of inflammation and oxidative stress. Biologics, 2011;5:7-19.
[59] Pittas AG, Lau J, Hu FB, Dawson-Hughes B. Review: The role of vitamin D and calcium
in type 2 diabetes. A systematic review and meta-analysis. Journal Clinical
Endocriology Metabolism 2007; 92:2017-2029.
[60] Botella-Carretero JI, Alvarez-Blasco F, Villafruela JJ, Balsa JA, Vazquez C, Escobar-
Morreale HF. Vitamin D deficiency is associated with the metabolic syndrome in
morbid obesity. Clinical Nutrition. 2004;26:573-580.
[61] Teegarden D, Donkin SS. Vitamin D: emerging new roles in insulin sensitivity.
Nutrition Research Reviews, 2009; 22:82-92.
[62] Holick MF. Diabetes and the vitamin D connection. Current Diabetes Reports 2008;
8:393-398.
[63] Maggini S, Wintergerst ES, Beveridge S, Hornig DH. Selected vitamins and trace
elements support immune function by strengthening epithelial barriers and cellular and
humoral immune responses. British Journal Nutrition. 2007;98(Suppl 1):S29-S35.
[64] Anan F, Takahashi N, Nakagawa M, Ooie T, Saikawa T, Yoshimatsu H. High-sensitivity
C-reactive protein is associated with insulin resistance and cardiovascular autonomic
dysfunction in type 2 diabetic patients. Metabolism 2005;54:552-558.
[65] Fu L, Yun F, Oczak M, Wong BY, Vieth R, Cole DE. Common genetic variants of the
vitamin D binding protein (DBP) predict differences in response of serum 25-
hydroxyvitamin D (25(OH)D) to vitamin D supplementation. Clinical Biochemistry.
2009;42:1174-1177.
[66] Szathmary EJ. The effect of Gc genotype on fasting insulin level in Dogrib Indians.
Human Genetics. 1987;75:368-372.
[67] Hirai M, Suzuki S, Hinokio Y, Hirai A, Chiba M, Akai H, Suzuki C, Toyota T. Variations
in vitamin D-binding protein (group-specific component protein) are associated with
fasting plasma insulin levels in Japanese with normal glucose tolerance. Journal Clinical
Endocrinology Metabolism. 2000;85:1951-1953.
[68] Baier LJ, Dobberfuhl AM, Pratley RE, Hanson RL, Bogardus C. Variations in the
vitamin D-binding protein (Gc locus) are associated with oral glucose tolerance in
nondiabetic Pima Indians. Journal Clinical Endocrinology Metabolism. 1998;83:2993-
2996.
[69] Pittas AG, Dawson-Hughes B, Li T, Van Dam RM, Willett WC, Manson JE, Hu FB.
Vitamin D and calcium intake in relation to type 2 diabetes in women. Diabetes Care.
2006;29:650-656.
[70] Hayes CE, Nashold FE, Spach KM, Pedersen LB. The immunological functions of the
vitamin D endocrine system. Cellular Molecular Biology. 2003; 49:277-300.
[71] Griffin MD, Xing N, Kumar R. Vitamin D and its analogs as regulators of immune
activities and antigen presentation. Annual Reviews Nutrition. 2003;23:117-145.
[72] Cantorna MT, Zhu Y, Froicu M, Wittke A. Vitamin D status, 1,25-dihydroxy- vitamin
D3, and the immune system. American Journal Clinical Nutrition. 2004;80:1717S-1720S.
24. 15 Diabetes Mellitus – Insights and Perspectives
The Utility of Vitamins in the Prevention of
Type 2 Diabetes Mellitus and Its Complications: A Public Health Perspective 15
[73] DeLuca HF, Cantorna MT. Vitamin D: its role and uses in immunology. FASEB Journal.
2001;15:2579-2585.
[74] Veldman CM, Cantorna MT, DeLuca HF. Expression of 1,25-dihydroxyvitamin D3
receptor in the immune system. Archive Biochemistry Biophysics. 2000;374:338.
[75] Riachy R, Vandewalle B, Kerr CJ, Moerman E, Sacchetti P, Lukowiak B, Gmyr V,
Bouckenooghe T, Dubois M, Pattou F. 1,25-dihydroxyvitamin D3 protects RINm5F and
human islet cells against cytokine-induced apoptosis: implication of the antiapoptotic
protein A20. Endocrinology. 2002;143:4809-4819.
[76] van Etten E, Mathieu C. Immunoregulation by 1,25-dihydroxyvitamin D3: basic
concepts. Journal Steroides Biochemistry Molecular Biology. 2005;97:93-101.
[77] Pittas AG, Lau J, Hu FB, Dawson-Hughes B. Review: The role of vitamin D and calcium
in type 2 diabetes. A systematic review and meta-analysis. Journal Clinical
Endocriology Metabolism. 2007;92:2017-2029.
[78] Mokdad AH, Bowman BA, Ford ES, Vinicoor F, Marks JS, Koplan JP. The continuing
epidemics of obesity and diabetes in the United States. Journal American Medical
Association. 2001;286:1195-1200.
[79] Chiu KC, Chu A, Go VL, Saad MF. Hypovitaminosis D is associated with insulin
resistance and beta cell dysfunction. American Journal Clinical Nutrition. 2004;79:820-
825.
[80] Ford ES, Ajani UA, McGuire LC, Liu S. Concentrations of serum vitamin D and the
metabolic syndrome among U.S. adults. Diabetes Care. 2005;28:1228-1230.
[81] Hypponen E, Power C. Vitamin D status and glucose homeostasis in the 1958 British
birth cohort: the role of obesity. Diabetes Care. 2006;29:2244-2246.
[82] Need AG, O'Loughlin PD, Horowitz M, Nordin BE. Relationship between fasting serum
glucose, age, body mass index and serum 25 hydroxyvitamin D in postmenopausal
women. Clinical Endocrinology. 2005;62:738-741.
[83] Scragg R, Sowers M, Bell C. Serum 25-hydroxyvitamin D, diabetes, and ethnicity in the
Third National Health and Nutrition Examination Survey. Diabetes Care. 2004;27:2813-2818.
[84] Liu S, Song Y, Ford ES, Manson JE, Buring JE, Ridker PM. Dietary calcium, vitamin D,
and the prevalence of metabolic syndrome in middle-aged and older U.S. women.
Diabetes Care, 2005;28:2926-2932.
[85] Fliser D, Stefanski A, Franek E, Fode P, Gudarzi A, Ritz E. No effect of calcitriol on
insulin-mediated glucose uptake in healthy subjects. European Journal Clinical
Investigation. 1997;27:629-633.
[86] Inomata S, Kadowaki S, Yamatani T, Fukase M, Fujita T. Effect of 1 alpha (OH)-vitamin
D3 on insulin secretion in diabetes mellitus. Bone Mineral 1986;1:187-192.
[87] Ljunghall S, Lind L, Lithell H, Skarfors E, Selinus I, Sorensen OH, Wide L. Treatment
with one-alpha-hydroxycholecalciferol in middle-aged men with impaired glucose
tolerance--a prospective randomized double-blind study. Acta Medica Scandnavia.
1987;222:361-367.
[88] Orwoll E, Riddle M, Prince M. Effects of vitamin D on insulin and glucagon secretion in
non-insulin-dependent diabetes mellitus. American Journal Clinical Nutrition.
1994;59:1083-1087.
25. 16 Diabetes Mellitus – Insights and Perspectives
The Utility of Vitamins in the Prevention of
Type 2 Diabetes Mellitus and Its Complications: A Public Health Perspective 16
[89] Nilas L, Christiansen C. Treatment with vitamin D or its analogues does not change
body weight or blood glucose level in postmenopausal women. Intnational Journal
Obesity. 1984;8:407-411.
[90] Pittas AG, Harris SS, Stark PC, Dawson-Hughes B. The effects of calcium and vitamin D
supplementation on blood glucose and markers of inflammation in nondiabetic adults.
Diabetes Care 2007; 30:980-986.
[91] Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA,
Nathan DM. Reduction in the incidence of type 2 diabetes with lifestyle intervention or
metformin. New England Journal Medicine. 2002;346:393-403.
[92] Colak E, Majkic-Singh N, Stankovic S, Sreckovic-Dimitrijevic V, Djordjevic PB, Lalic K,
Lalic N. Parameters of antioxidative defense in type 2 diabetic patients with
cardiovascular complications. Annals Medicine. 2005;37:613–620.
[93] Baynes JW. Role of oxidative stress in development of complications in diabetes.
Diabetes. 1991;40:405–412.
[94] Ceriello A. Acute hyperglycaemia and oxidative stress generation. Diabet Med.
1997;14:45–49.
[95] Ylönen K, Alfthan G, Groop L, Saloranta C, Aro A, Virtanen SM. Dietary intakes and
plasma concentrations of carotenoids and tocopherols in relation to glucose metabolism
in subjects at high risk of type 2 diabetes: the Botnia Dietary Study. American Journal
Clinical Nutrition. 2003;77:1434–1441.
[96] Helmersson J, Vessby B, Larsson A, Basu S. Association of type 2 diabetes with
cyclooxygenase-mediated inflammation and oxidative stress in an elderly population.
Circulation. 2004;109:1729–1734.
[97] Block G, Dietrich M, Norkus E, Jensen C, Benowitz NL, Packer L, et al. Intraindividual
variability of plasma antioxidants, markers of oxidative stress, C-reactive protein,
cotinine, and other biomarkers. Epidemiology. 2006;17:404–412.
[98] Brenner DR, Arora P, Garcia-Bailo B, El-Sohemy A, Karmali M and Badawi A. The
relationship between metabolic syndrome components and inflammatory markers
among non-diabetic Canadian adults. Journal Diabetes Metabolism. 2012;
doi:10.4172/2155-6156.S2-003.
[99] Brenner DR, Arora P, Garcia-Bailo B, Wolever TMS, Morrison H, El-Sohemy A, Karmali
M, and Badawi A. Plasma vitamin D and risk of the metabolic syndrome in Canadians.
Clinical Investigative Medicine. 2011;34: E377-E384.
[100] Barclay C, Procter KL, Glendenning R, Marsh P, Freeman J, Mathers N. Can type 2
diabetes be prevented in UK general practice? A lifestyle-change feasibility study
[ISAIAH]. British Journal General Practice. 2008;58:541-547.
[101] Norris SL, Zhang X, Avenell A, Gregg E, Bowman B, Schmid CH, Lau J. Long-term
effectiveness of weight-loss interventions in adults with pre-diabetes: a review.
American Journal Preventive Medicine. 2005;28:126-139.
[102] Frost G, Leeds A, Trew G, Margara R, Dornhorst A. Insulin sensitivity in women at
risk of coronary heart disease and the effect of a low glycemic diet. Metabolism
1998;47:1245-1251.
26. Chapter 2
Click Here!! For Best Diabetes Treatment
Aldose Reductase Inhibitors as Potential
Therapeutic Drugs of Diabetic Complications
Changjin Zhu
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/54642
1. Introduction
Diabetes mellitus has become a major health threat as a global rise in it has been seen. The
chronic disease has afflicted over 171 million people worldwide in 2000 and the incidence is
expected to grow steadily to 366 million by 2030. As of May 2008, an estimated 92 million
adults in China of the most populous country were living with diabetes and 148 million adults
with prediabetes [1]. Diabetes mellitus is one of the leading causes of death across the globe
particularly in the developing world. Most diabetic patients suffer from so-called long-
term complications such as neuropathy, nephropathy, retinopathy, cataracts and even stroke.
These complications arise from chronic hyperglycemia, which causes damage to blood
vessels and peripheral nerves, greatly increasing the risk of heart attack. A number of
mechanistic explanations for the complications have been proposed (for the reviews, see
Refs. [2-5]). First, they include hyperactivity of polyol metabolic pathway that produces
elevated accumulation of cellular sorbitol leading to osmotic stresses on cells, and is then
implicated mainly in microvascular damage to retina, kidney, and nerve systems. As the
second mechanism, increased formation of advanced glycation end products (AGEs) activates
nonenzymatic glycosylation of proteins and lipids, and in turn leads to dysfunctional
behaviors of related enzymes and receptors. The third of them is hyperglycemia-induced
activation of protein kinase C (PKC) isoforms which evokes pathological changes in growth
factor expression. The fourth is diverting of excess intracellular glucose into the hexosamine
pathway and consequent overmodification of enzymatic proteins by N-acetylglucosamine
along with abnormal enzyme behaviors. Finally, the fifth mechanism is recently proposed
in which an hyperglycemia-induced impairment of antioxidant defense such as the
overproduction of reactive oxygen species (ROS) readily initiates inflammation responses.
Among these mechanisms, the polyol pathway was first discovered and in fact is generally
accepted to be the mechanism of prime importance in the pathogenesis of diabetic
27. 18 Diabetes Mellitus – Insights and PerspectivesAldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications 18
complications. Aldose reductase (AR, EC 1.1.1.21) that is the first and rate-controlling
enzyme in the polyol pathway is of importance for the pathway and in turn has been a
potential target for drug design, therefore, the inhibition of aldose reductase has been an
attractive approach to the prevention and treatment of diabetic complications. In line with
the focus of this chapter, ARIs and their therapeutic functions will be discussed in the
following sections.
2. Aldose reductase and the polyol metabolic pathway of glucose
2.1. The polyol pathway
Aldose reductase together with sorbitol dehydrogenase (SDH) forms the polyol pathway as
shown in Figure 1. In the polyol pathway, AR initially catalyzes the NADPH-dependent
reduction of the aldehyde form of glucose to form sorbitol. Sorbitol dehydrogenase then
utilizing NAD oxidizes the intermediate sorbitol to fructose. The conversion of glucose to
sorbitol catalyzed by AR was first identified in 1956 by Hers in the seminal vesicles where
glucose is converted into fructose to provide an energy source for sperm [6]. Soon after, the
polyol pathway sorbitol was found in diabetic rat lens by Van Heyningen [7]. In 1965,
pathogenic effects of AR and its associated polyol pathway were first identified in the lens
by Kinoshita, and these works formed the basis for the osmotic stress hypothesis of sugar
cataract formation [8]. It proposes that intracellular excess sorbitol produced by AR
accumulates in cells and is difficult to diffuse across the cell membranes, and consequently
the osmotic damage to cells occurs which eventually leads to diabetic cataract complication
[9]. These discoveries taken together led to the opening for studies on the pathogenic role of
AR and the polyol pathway in the development of diabetic complications, and also made
the beginning of research for the mechanism of diabetic complications. AR is now known to
be present in most of the mammalian cells. Normally, the cellular glucose is oxidatively
metabolized through the glycolysis pathway and then the Krebs cycle to produce the building
blocks and energy for cells. Under hyperglycemic conditions, however, the increased amount
of glucose activates AR and is metabolized by the activated polyol pathway.
Figure 1. Polyol metabolic pathway of glucose
After finding the AR-mediated glucose metabolism, several mechanisms other than the AR-
initiated polyol pathway for diabetic complications were successively proposed. Nevertheless,
the polyol pathway appears still to be a compelling mechanism of diabetic
28. 19 Diabetes Mellitus – Insights and PerspectivesAldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications 19
complications because growing evidences have been shown for an involvement of the
abnormally activated polyol pathway in the pathogenesis of diabetic complications.
Biomolecular evidences for the role of the polyol pathway are recently provided by cellular
experiments and regulations of AR gene expression in the presence of high glucose induction.
The protein expression of AR, and the intracellular sorbitol and fructose contents appeared to
be up-regulated in mouse Schwann cells under high glucose conditions [10, 11]. In transgenic
mice with AR overexpression, an elevated accumulation of sorbitol and fructose along
with a simulteneous decrease in tibial motor nerve conduction velocity were found [12]. In
peripheral blood mononuclear cells from nephropathy, high glucose increased NF-kB binding
activities, which in turn induced an expression of AR protein [13]. Observations in high
glucose-induced rat mesangial cells suggested that altered protein kinase C activity mediated
through activation of the polyol-pathway contributes to a loss of mesangial cell contractile
responsiveness [14]. A particular convincing finding is that these detrimental alterations could
be prevented or reversed by the treatment with AR inhibitors (ARIs).
Consistent findings can be also traced in the animals with a deficient AR gene expression. In
db/db mice with an AR null mutation, diabetes-induced reduction of platelet/endothelial
cell adhesion molecule-1 expression and increased expression of vascular endothelial
growth factor were prevented which may have contributed to blood-retinal barrier
breakdown. As a result, long-term diabetes-induced neuro-retinal stress and apoptosis and
proliferation of blood vessels were less present [15]. This suggests that AR is responsible for
the early events in the pathogenesis of diabetic retinopathy, leading to a cascade of retinal
lesions. Also, AR-deficient mice were protected from delayed motor nerve conduction
velocity, increased c-Jun NH2-terminal kinase activation, depletion of reduced glutathione,
increased superoxide accumulation, and DNA damage [16]. AR-deficient or ARI-treated
mice were protected from severe ischaemic limb injury and renal failure, showing only modest
muscle necrosis and significant suppression of serum markers of renal failure and
inflammation [17]. In addition, AR inhibition counteracted diabetes-induced oxidative-
nitrosative stress and poly(ADP-ribose) polymerase activation in sciatic nerve and retina
[18]. Very recently in human mesangial cells in culture, exposure to high glucose and
overexpression AR increased the expression of fibronectin. This increase was prevented by
the AR inhibitors sorbinil and zopolrestat. Treatment with high glucose and transfected
with plasmid PcDNA3.0-AR, resulted in phosphorylation and activation of ERK, JNK and
AKT signaling pathway, and an increase in the expression of fibronectin. Treatment with
inhibitor of JNK and AKT signaling pathway decreased the expression of fibronectin.
Obviously, AR may be linked to extracellular matrix deposition in diabetic nephropathy,
which is regulated by JNK and AKT [19].
On the other hand, in streptozotocin-diabetic rats, significantly delayed motor nerve
conduction velocity, decreased R-R interval variation, reduced sciatic nerve blood flow and
decreased erythrocyte 2,3-diphosphoglycerate concentrations were all ameliorated by
treatment with ARI [5-(3-thienyl) tetrazol-1-yl]acetic acid. The inhibitor also reduced platelet
hyperaggregation activity, decreased sorbitol accumulation and prevented not only myo-
29. 20 Diabetes Mellitus – Insights and PerspectivesAldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications 20
inositol depletion but also free-carnitine deficiency in diabetic nerves. Therefore, there is a
close relationship between increased polyol pathway activity and carnitine deficiency in the
development of diabetic neuropathy [20].
Similar to the results from cellular experiments and gene expression regulations, the role of
the polyol pathway has been confirmed by animal models. Marked muscle necrosis and
renal failure with accumulation of sorbitol and fructose were identified in ischaemic muscles
of mice [17], and the disturbance in the renal medulla including oxygen tension, oxygen
consumption, lactate/pyruvate ratio and pH were observed in diabetic rats [21]. Notably, these
alterations were preventable by either ARI treatment or AR-deficient suggesting the
involvement of the polyol pathway in the acute kidney injury.
Besides, the pathways of AGEs, PKC, hexosamine, and ROS can be causally linked to
downstream events of the increased polyol pathway flux including alterations in cellular
redox balance and fructose concentration [2, 5, 22, 23]. As described above, for example, the
loss of mesangial cell contractile responsiveness in high glucose-induced rat mesangial cells
resulted from the activation of the polyol-pathway could be mediated by altered PKC
activity [14]. In vitro studies on cultured human mesangial cells and in vivo studies in the
diabetic renal cortex of streptozotocin-diabetic rats have indicated the presence of both
increased AR activity and oxidative/nitrosative stress in the pathogenesis of diabetic
nephropathy, and the nitrosative stress and polymerase activation could be counteracted by
AR inhibition [24]. Moreover, the increased kinase activation, depletion of reduced
glutathione, increased superoxide accumulation, and DNA damage could be prevented by
AR-deficiency in the amelioration of motor nerve conduction velocity [16]. Recently, osmotic
stress resulting from the accumulation of sugar alcohols in lens epithelial cells which contain
mitochondria, has been shown to induce endoplasmic reticulum stress that leads to the
generation of reactive ROS and apoptotic signaling [25].
The polyol pathway is in fact supported by successfully therapeutic applications of ARI drugs
epalrestat and tolrestat in diabetic complications such as neuropathy. Epalrestat is now on
the markets in Japan, China, and India while tolrestat was marketed in several countries
although it was withdrawn. Also, a few of other ARIs involving fidalrestat and ranirestat have
been advanced to late stage of clinical trials.
2.2. Properties of AR
AR belongs to the aldo-keto reductase enzyme superfamily. Crystallized complexes of AR
with ligands and site directed mutagenesis allowed the enzyme structure to be identified.
The enzyme is a single polypeptide domain composed of 315 amino acid residues [26]. The
peptide chain blocked at the amino terminus folds into a β/α-barrel structural motif containing
eight parallel β strands which are connected to each other by eight peripheral α- helical
segments running anti-parallel to the β sheet. The active site is located in a large and deep
crevice in the C-terminal end of the β barrel, and the NADPH cofactor binds in an extended
conformation to the bottom of the active site [27, 28]. However, it is likely that the active site
often changes its conformational shape because a variety of binding
30. 21 Diabetes Mellitus – Insights and PerspectivesAldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications 21
conformations bound by ARIs, represented by the complexes with ligands sorbinil (PDB
entry code 1AH051), tolrestat (PDB entry code 2FDZ52), and IDD594 (PDB entry code
1US053), have been reported [29-32]. These ligand-dependent conformations indicate a
remarkable induced fit or flexibility of the active site. Nevertheless, at least three distinct
binding pockets in the active site can be proposed as shown in Figure 2 according to a number
of studies on crystal structures of AR by X-ray crystallography and mutagenesis [30,
33-38]. The first is usually occupied by the anion head of ligand and thus named “anion
binding pocket”. It is made up of Tyr48, His110, Trp20, and Trp111 side chains and the
positively charged nicotinamide moiety of the cofactor NADP+. The second is a
hydrophobic pocket, known as specificity pocket, and lined by the residues Leu300, Cys298,
Cys303, Trp111, Cys303, and Phe122 [30]. The specificity pocket displays a high degree of
flexibility and the residues lining this pocket are not conserved in other aldo-keto reductases
such as aldehyde reductase, The third is another hydrophobic pocket formed by the
residues Trp20, Trp111, Phe122, and Trp219 [34].
Figure 2. Proposed binding pockets in the active site of AR
Aldehyde reductase (EC 1.1.1.2) , another member of the aldo-keto reductase superfamily, is
mentioned here because of its close similarities to AR which may be associated with the
specificity of ARIs. The two closely related enzymes share a high degree of sequence (∼65%)
and three dimensional structure homology with the majority of the differences present at
the C-terminal end of the enzyme proteins, where is the region containing the least
31. 22 Diabetes Mellitus – Insights and PerspectivesAldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications 22
conserved residues and lining the hydrophobic pocket of the active site called the specificity
pocket [30, 39-42]. The specificity pocket is responsible for substrate and inhibitor specificity
in the aldo-keto reductases.
Aldehyde reductase plays a detoxification role, as it specifically metabolizes toxic aldehydes
such as hydroxynonenal (HNE), 3-deoxyglucosone, and methylglyoxal, which arise in large
quantities from pathological conditions connected with oxidative stress, as in
hyperglycemia, and are intermediates for the formation of AGEs [43-45]. Thus, aldehyde
reductase inhibition may account for some of the undesirable toxicities associated with the
present ARIs. It is believable that the development of more structurally diverse ARIs and in
turn the identification of molecularly targeted candidates that specifically block AR are
important approaches in the search of new drugs.
3. AR inhibitors
In spite of a range of structurally varied ARIs developed up to date [46, 47], carboxylic acids
have been the most important and largest class of ARIs. This class readily shows activity in
the AR inhibition because of the structural feature of carboxylate anion head group which
may fit well in the so-called anion binding pocket of AR as described above (Figure. 2). At
the beginning of research on AR properties, it was found that the enzyme is sensitive to
organic anions, particularly to long-chain fatty acids [48], leading to the identification of
tetramethyleneglutaric acid (TMG) as the first decent ARI in the 1960s. Since then, the more
potent and early inhibitor alrestatin (AY-22,284) was developed [46]. Now the number of
carboxylic acid ARIs is still growing. Among them is epalrestat, the only ARI given
marketing approval as a therapeutic drug applied in the clinical treatment of diabetic
neuropathy. Epalrestat was developed in 1983 [49] and has been marketed in Japan, and
recently in China and India. Tolrestat, a strong ARI and potential drug for the treatment of
diabetic complications [50], was approved to several markets, but withdrawn for the reason
of risk of severe liver toxicity and death.The typical carboxylic acid ARIs also include
zenarestat [51], zopolrestat [52], and ponalrestat [53]. Zenarestat is a potential drug for the
treatment of diabetic neuropathy, retinopathy and cataracts. Both zenarestat and zopolrestat
proceeded into late phase research of clinical trials. However, research results from Phase III
trials showed zenarestat therapy in the dose level of 1200 mg/day to be linked with renal
toxicity in a small number of patients [54]. Ponalrestat was withdrawn from clinical trials
32. 23 Diabetes Mellitus – Insights and PerspectivesAldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications 23
due to lack of efficacy. Besides, a number of potent ARIs were recently designed and
synthesized based on various chemical core structures including (benzothiazol-2-yl)methyl-
indole (lidorestat) [36], naphtho[1,2-d]isothiazole [55], oxadiazole [56], aromatic thiadiazine-
1,1-dioxide [57, 58], and quinoxalinone [59]. All of them bear a chemical group of acetic acid
on the core. However, poor tissue penetration has been observed as the major shortcoming for
some individual inhibitors of the carboxylic acid ARI class [60, 61].
The second chemical class of ARIs includes spirohydantoin derivatives and their analogs. In
this class, sorbinil was the first ARI capable of preventing the entire cataractogenic process
in diabetic rats [62, 63]. The exquisite spiro system is well formed based on the combination
of structures chroman and hydantoin. The hydantoin and the spiro in sorbinil may be key
structures responsible for the strong inhibition against AR. In the binding interaction in the
active site of AR, the hydantoin ring occupies the anion pocket as does the anion head group
of carboxylate ARIs. Carbonyl oxygens and amino nitrogens in the hydantoin could make a
33. 24 Diabetes Mellitus – Insights and PerspectivesAldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications 24
tight hydrogen-bonding network with residues Tyr48, His110 and Trp111 of AR [30]. The
conformationally constrained spiro system made the ring planes of the hydantoin and
chroman perpendicular to each other which may be the conformational shape of the
inhibitor favored for the binding to AR. Sorbinil has proved an excellent ARI both in vitro and
in vivo. However, in the research of clinical trials it was found that as many as 10% of patients
receiving sorbinil may be at increased risk for developing hypersensitivity reactions
characterized by fever, skin rash, and myalgia due to a potentially toxic intermediate
oxidatively metabolized from sorbinil [64, 65]. The adverse reaction may also be attributed
to the poor selectivity of sorbinil for AR versus aldehyde reductase [42].
While development of this important drug was hampered by potentially severe reactions,
sorbinil has been a distinguish leading inhibitor or a reference widely used in the development
of new ARIs and in the research of AR and the polyol pathway.
Based on the structure of sorbinil, several other spirohydantoins and related cyclic amides
were developed. Addition of a methyl or a carbamoyl substituent at the 2-position of
sorbinil resulted in the formation of M79175 and fidarestat, respectively. Replacement of the
chroman ring system with a planar fluorene ring produced imirestat. Then, the
spirohydantoin-like spiroimide minalrestat was formed by the replacements of both the
chroman and hydantoin with isoquinoline-1,3(2H,4H)-dione ring and succinimide ring,
respectively, and the addition of benzyl side chain at the 2-position. Further replacement of
the isoquinoline-1,3(2H,4H)-dione ring of minalrestat with pyrrolo[1,2-a]pyrazine-
1,3(2H,4H)-dione led to ranirestat (AS-3201) [66]. Imirestat was withdrawn from clinical
trials due to toxicity. However, fidarestat and ranirestat have been identified as powerful ARIs
with beneficial efficacy in diabetic complications [67-69]. There are no adverse effects
reported to the two agents.
34. 25 Diabetes Mellitus – Insights and PerspectivesAldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications 25
In another design, the orthogonal spirohydantoin moiety of the above ARIs was changed
into a more flexible structure, which is bridged by sulfonyl group leading to Tri-CI-PSH and
Di-CI-PSH with IC50 values of 0.28 μM and 0.36 μM, respectively [70, 71]. They were found
to inhibit sorbitol accumulation in the sciatic nerve completely and in the lens by up to 92%.
Modification of aryl moieties of the arylsulfonylhydantoins has generated a group of
benzofuransulfonylhydantoins. Of these, two compounds M16209 and M16287 indicated
potent AR inhibition [72]. Recently, more modifications of the arylsulfonylhydantoins resulted
in a new series of ARIs that are designed based on SO2 linker-bearing sulfonylpyridazinone.
Among them, the most potent and selective compound was profiled to be 6-(5-chloro-3-
methylbenzofuran-2-sulfonyl)-2H-pyridazin-3-one (ARI-809) with IC50 value of 1 nM in vitro
and ED50 of 0.8 mg/kg in vivo. ARI-809 is a highly selective (1:930) inhibitor of AR relative to
aldehyde reductase, and such selectivity distinguishes it from sorbinil, which inhibits AR and
aldehyde reductase to a comparable extent [73, 74]. In addition, introduction of phenol moiety
into the sulfonyl-bridged system has provided benzenesulfonamide ARIs, which could not
only inhibit AR but also exhibit potent antioxidant activity [75]. Moreover,
phenylpyridopyrimidinone (PPP) was developed as a flavinoid bioisoster, and exhibited AR
inhibition activity level in the submicromolar range and significant antioxidant properties [76].
35. 26 Diabetes Mellitus – Insights and PerspectivesAldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications 26
4. Therapeutic properties of ARIs in the diabetic complications
The diabetic complications include typically neuropathy, nephropathy, and retinopathy and
cataract although a substantial increase of atherosclerotic disease of large vessels, including
cardiac and cerebral diseases, has been seen in the complications. ARIs appear to be a
specific option for the improvement of the diabetic abnormalities according to the study
results from experiments in vitro, in animal models, and clinical trials.
4.1. Retinopathy and cataract
Diabetic eye damages including retinopathy and cataract are characteristic of diabetes. ARIs
sorbinil, ARI-809, ranirestat, fidarestat, zenarestat, M79175, and KinostatTM have shown an
activity for the treatment of the diabetic retinopathy and cataract. KinostatTM is a new ARI
developed by Kador [77].
It was found early that potent ARI sorbinil was effective in preventing cataractous changes
in diabetic rats. Diabetic rats treated with sorbinil showed no lens changes during the 5- month
period of the experiment. In contrast, untreated diabetic rats developed early lens changes by
3 weeks and dense nuclear opacities by 6 to 9 weeks [62]. It was evident by later independent
studies in which sorbinil prevented the galactose-induced retinal microangiopathies and was
also effective in preventing cataractous changes in diabetic rats [63]. In recent studies,
treatment of diabetic Sprague Dawley rats with oral ARI imirestat prevented cataract by
inhibiting sorbitol formation in the lens [78]. In insulinized streptozotocin-induced diabetic
rats, ARI-809 improved survival, inhibited cataract development, normalized retinal sorbitol
and fructose, and protected the retina from abnormalities that also occur in human diabetes:
neuronal apoptosis, glial reactivity, and complement deposition [74]. Streptozotocin-diabetic
rats could developed early lens opacities 8 weeks after streptozotocin injection and could
have cataract. These alterations were prevented by the ranirestat treatment [69].
From several investigations performed recently with rat models, it appears that ARI fidarestat
is active in the treatment of diabetic retinopathy. In streptozotocin-diabetic rats, fidarestat
treatment reduced diabetes-associated cataract formation, and retinal oxidative- nitrosative
stress, glial activation, and apoptosis [79]. Similar results were obtained in the rat model with
retinal ischemia-reperfusion injury. The retinal injury-associated dramatic increase in cell
death, elevated AR expression, and sorbitol pathway intermediate accumulation were
prevented or alleviated by fidarestat treatment [80]. Also in the streptozotocin-diabetic rats,
fidarestat treatment significantly decreased concentrations of sorbitol and fructose in the rat
retinas. The expression of ICAM-1 mRNA and eukocyte accumulation in the retinas were
significantly reduced. Immunohistochemical study also revealed the suppressive effect of
fidarestat on the expression of ICAM-1 [81].
In addition, the study using Zucker diabetic fatty rats, an animal model of type 2 diabetes,
showed that the administration of a combination of four plant extracts inhibited the
development of diabetic cataract through the inhibition of AR activity and protein
expression in diabetic lenses [82].
36. 27 Diabetes Mellitus – Insights and PerspectivesAldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications 27
In galactose-fed dogs, cataract formation was delayed or prevented either by oral
administration of the ARI M79175 [83, 84], or topical administration of the formulation
KinostatTM [77]. This has been further confirmed by the more recent experiment in a similar
dog model. In a randomized, prospective, double-masked placebo control pilot study
conducted with 40 dogs diagnosed with diabetes mellitus by topical administration of the ARI
Kinostat™ for 12 months, the cataract score was significantly less with seven developing
anterior equatorial vacuoles, two developing incipient anterior cortical cataracts, and four
developing mature cataracts. It was noted that the cataract scores of the Kinostat™ group at
12 months did not in fact significantly increase from the score at the time of enrollment [85].
According to the results from phase III trial research in Japan, zenarestat developed as an
eyedrop formulation was specifically effective for the treatment of diabetic retinopathy [54].
The beneficial effects of these different types of ARIs on the diabetic cataract and
retinopathy support the notion that AR is the key relay that converts hyperglycemia into
glucose toxicity in neural and glial cell types in the retina [74]. This provides a rationale for
the development of ARIs, and in particular for the prevention and treatment of diabetic ocular
complications [79].
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Diabetes
4.2. Neuropathy
Nerve injuries of the respective organs are thought to be the root cause of diabetes
complications. Pharmaceutical options in the treatment of diabetic neuropathy include
antidepressants, anticonvulsants, tramadol, serotonin–norepinephrine reuptake inhibitors,
and capsaicin [86]. These agents are modestly effective for symptomatic relief, but they do not
affect the underlying pathology nor do they slow progression of the disease. In addition, they
carry a risk of side effects. Therefore, the application of ARIs are expected to address this
issue. Epalrestat, fidarestat, ranirestat (AS-3201), zenalrestat, sorbinil, and tolrestat will be
described in this section.
4.2.1. Epalrestat
Epalrestat is undoubtedly the first agent for the treatment of diabetic neuropathy because of
its effectiveness and safety. It is approved in Japan, China and India for the improvement of
subjective neuropathy symptoms, abnormality of vibration sense and abnormal changes in
heart beat associated with diabetic peripheral neuropathy. Long-term treatment with
epalrestat in a clinic trial was well tolerated and could effectively delay the progression of
diabetic neuropathy and ameliorate the associated symptoms of the disease, particularly in
subjects with good glycemic control and limited microangiopathy [87]. Epalrestat is easily
absorbed into neural tissue and potently inhibits AR with minimum adverse effects. Unlike
the current pharmaceutical options for diabetic neuropathy, epalrestat may affect or delay
progression of the underlying disease process. Data from experimental studies indicate that
epalrestat reduces sorbitol accumulation in the sciatic nerve, erythrocytes, and ocular tissues
in animals, and in erythrocytes in humans. On the bases of several clinical trials, treatment
37. 28 Diabetes Mellitus – Insights and PerspectivesAldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications 28
with epalrestat in a dose of 50 mg 3 times/day may improve motor and sensory nerve
conduction velocity and subjective neuropathy symptoms. The most frequently reported
adverse effects for epalrestat include elevations in liver enzyme levels and gastrointestinal-
related events such as nausea and vomiting [88].
The diabetic patients treated with epalrestat for 2 years showed a significant suppression of
deterioration of motor nerve conduction velocity and minimum F-wave latency in the tibial
nerve, and sensory nerve conduction velocity in the sural nerve. In fact, there was a significant
difference in change in the level of serum N(ɛ)-carboxymethyl lysine after 1 year treatment.
Therefore, it is suggested that epalrestat suppressed the deterioration of diabetic peripheral
neuropathy, especially in the lower extremity, and the effects might be mediated by
improvement of the polyol pathway and suppression of production of AGEs [89]. In a clinical
trial in India, more than 2000 patients with diabetic neuropathy were treated with epalrestat
for 3-12 months, the results showed that the improvement rate of the subjective symptoms
was 75% and that of the nerve function tests 36%. Adverse drug reactions were encountered
in 52 (2.5%) of the 2190 patients, none of which was severe [90]. Although data are limited, it
is strongly suggested that epalrestat is a highly effective and safe agent for the treatment of
diabetic neuropathy.
Clinical efficacy of epalrestat for diabetic peripheral neuropathy has been well documented
by Hotta and coworkers [87, 91]. When patients with diabetic peripheral neuropathy were
treated with epalrestat for period of 3 years, significantly better efficacy was found in
patients with good glycaemic control and less severe diabetic complications. Nerve function
deteriorated less or improved in patients whose symptoms improved. The odds ratio of the
efficacy of epalrestat versus control subjects was approximately 2:1 [91].
In diabetic nerves, activation of the polyol pathway via AR and the resulting impairment of
the Na(+)-K(+) pump would lead to a decreased transaxonal Na+ gradient, and thereby
reduced nodal Na+ currents. In a 6-month, open clinical trial with epalrestat in 30 patients
with mild-to-moderate diabetic neuropathy, results from excitability testing and extensive
nerve conduction studies including F-wave analyses displayed that within a month of the start
of treatment, there was a significant improvement in nerve conduction, particularly in
conduction times across the carpal tunnel and F-wave latencies. It suggested an increased
nodal persistent Na+ currents. At 6 months, nerve conduction continued to improve.
Therefore, AR pathway inhibition could rapidly increase nodal Na+ currents and thereby
improve the slowing of nerve conduction, presumably because of a restoration of the
membranous Na+ gradient [92].
Earlier investigation on streptozotocin-induced diabetic neuropathy in rats showed that the
treatment with epalrestat resulted in a significant improvement of nerve growth factor content
and faster H-wave-related sensory nerve conduction velocity. At the same time, epalrestat
treatment showed the stimulating effect on nerve growth factor synthesis/secretion in rat
Schwann cell culture in vitro. Consequently, these results suggest that decreased levels of
nerve growth factor in diabetic sciatic nerves may be involved in the pathogenesis of diabetic
neuropathy in these rats and indicated that epalrestat can be useful
38. 29 Diabetes Mellitus – Insights and PerspectivesAldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications 29
for the treatment of diabetic neuropathy through nerve growth factor-induction and
inhibition of the polyol pathway [93].
Therefore, epalrestat may serve as a new therapeutic option to prevent or slow the progression
of diabetic neuropathy. However, long-term, comparative studies in diverse patient
populations are needed for clinical application.
4.2.2. Fidarestat
In a 52-week multicenter placebo-controlled double-blind parallel group study in 279
patients with diabetes and associated peripheral neuropathy, the group of fidarestat-treated
at a daily dose of 1 mg was significantly improved compared with the placebo group in two
electro physiological measures (i.e., median nerve F-wave conduction velocity and minimal
latency). Subjective symptoms (including numbness, spontaneous pain, sensation of
rigidity, paresthesia in the sole upon walking, heaviness in the foot, and hypesthesia)
benefited from fidarestat treatment, and all were significantly improved in the treated
versus placebo group. At the dose used, fidarestat was well tolerated, with an adverse event
profile that did not significantly differ from that seen in the placebo group [94].
In experimental rats with diabetic neuropathy, oral administration of fidarestat at a dose of 1
or 4 mg/kg for 10 weeks significantly improved nerve blood flow, compound muscle action
potential, and amplitude of C-potential. Fidarestat suppressed the increase in sorbitol and
fructose, normalised reduced glutathione in sciatic nerve, and reduced the number of 8-
hydroxy-2'-deoxyguanosine-positive cells in dorsal root ganglion neurons. This indicates
that the fidarestat-improved neuropathy may be via an improvement in oxidative stress and
supports a role for fidarestat in the treatment of diabetic neuropathy [95].
4.2.3. Ranirestat (AS-3201)
Ranirestat is an orally available ARI under development for the potential treatment of diabetic
complications, such as neuropathy, cataracts, retinopathy and nephropathy [96]. It appears to
be in late phase of clinical trials.
In the sciatic nerve and lens of streptozotocin-diabetic rats, ranirestat treatment reduced
sorbitol accumulation in the sciatic nerve and improved the decrease in motor nerve
conduction velocity. Morphological and morphometric examination of changes in sural
nerve revealed that the treatment with ranirestat prevented both the deformity of
myelinated fibers and the decrease in their axonal and myelin areas (atrophy). Ranirestat
also averted the changes in the size frequency histogram of myelinated fibers. The studies
showed that ranirestat is an agent for the management of diabetic sensorimotor
polyneuropathy [69, 97].
Ranirestat has been well studied by Bril and coworkers [98, 99]. In a double-blind, placebo-
controlled nerve biopsy trial study, 12-week-treatment with ranirestat at a dose of 5 or 20
mg/day improved nerve function in patients with diabetic sensorimotor polyneuropathy,
and the improvement could be maintained. When patients completing this biopsy study
39. 30 Diabetes Mellitus – Insights and PerspectivesAldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications 30
were offered a 48-week extension at the same ranirestat dose or at 5 mg/day ranirestat if
they were originally treated with placebo, it was found that nerve conduction velocity of
peroneal motor improved in the 20 mg/day group following 60 weeks of treatment while those
of sural and median sensory improved after both 12 and 60 weeks of treatment with
20 mg/day. Vibration perception threshold improved after 60 weeks of treatment with 20
mg/day. The improved sensory nerve function observed after 12 weeks of therapy was
maintained at 60 weeks, and improved motor nerve function was observed at 60 weeks.
Ranirestat was found to be well tolerated with no difference in adverse events between the
5- and 20-mg/day groups [98]. In a further multicenter, double-blind study, patients with
diabetic sensorimotor polyneuropathy were treated with 10, 20, or 40 mg/day ranirestat for
52 weeks. At week 52, the summed sensory (bilateral sural plus proximal median sensory)
nerve conduction velocity did not show significant changes from baseline. However,
significant improvement in the summed motor (peroneal, tibial, and median) nerve
conduction velocity was observed with 20 and 40 mg/day ranirestat treatment at week 12
and at weeks 24 and 36. The peroneal motor nerve conduction velocity was improved at weeks
36 and 52 for the 20 mg/day ranirestat group. Therefore, the treatment with ranirestat might
have an effect on motor nerve function in mild to moderate diabetic sensorimotor
polyneuropathy. However, it failed to show a statistically significant difference in sensory
nerve function relative to placebo. Ranirestat was well tolerated with no pertinent
differences in drug-related adverse events or in effects on clinical laboratory parameters,
vital signs, or electrocardiograms among the four groups [99].
4.2.4. Zenarestat
Zenarestat has proved to affect peripheral neuropathy in Zucker diabetic fatty rats, an
animal model of type 2 diabetes. In the control group of Zucker diabetic fatty rats, a
remarkable accumulation of sorbitol, a delay in F-wave minimal latency, and a slowing of
motor nerve conduction velocity were observed compared with lean rat counterparts.
Zenarestat, orally administrated at a dose of 3.2 mg/kg/day for 8 weeks, had no significant
effect on the delay in F-wave minimal latency and the slowing of motor nerve conduction
velocity, although the sorbitol accumulation in the sciatic nerve was partially inhibited. On
the other hand, 32 mg/kg zenarestat treatment improved these nerve dysfunctions, along with
a reduction of nerve sorbitol accumulation almost to the normal level [100]. Obviously,
zenarestat could improve diabetic peripheral neuropathy in Zucker diabetic fatty rats. Also,
the effects of zenarestat on nerves were confirmed in streptozotocin-induced diabetic rat
model. When the diabetic model rats were maintained on a diet of containing 0.09% zenarestat
for 8 weeks, endoneurial blood flow was significantly reduced by the application of nitric
oxide synthase inhibitor, NG-nitro-L-arginine, whereas that in diabetic control rats was not
affected by the inhibitor. Considerable levels of zenarestat were confirmed in the sciatic nerve
in the drug treated rats. These thereby suggested that ARI zenarestat might restore or prevent
the alteration of endoneurial blood flow resulting from an impairment of nitric oxide function
[101]. The dorsal root ganglia has been identified as the target tissue in diabetic somatosensory
neuropathy. Recent study in streptozotocin-induced diabetic rats