This document summarizes research on the effects of intranasal administration of insulin to the brain. It discusses how intranasal insulin impacts both cognitive function and peripheral metabolism in the following ways:
1) Intranasal insulin improves memory function in studies with healthy subjects and memory-impaired patients by enhancing synaptic plasticity in the hippocampus and possibly increasing cerebral glucose metabolism.
2) It enhances neurobehavioral measures of brain activity and reduces activity in brain regions involved in food reward processing.
3) It reduces food intake and body fat content while increasing thermogenesis and fat oxidation, indicating effects on energy homeostasis.
4) It may regulate hepatic glucose production and insulin secretion from the pancreas through brain
This research article investigates how circulating glucose levels modulate neural control of the desire for high-calorie foods in humans. The study found that:
1) Mild hypoglycemia preferentially activated brain regions involved in reward and motivation (e.g. striatum, insula) and increased reported desire for high-calorie foods, compared to a state of euglycemia.
2) Euglycemia preferentially activated brain regions involved in inhibitory control (e.g. prefrontal cortex, anterior cingulate cortex) and resulted in less interest in food stimuli.
3) Higher circulating glucose levels predicted greater activation of the medial prefrontal cortex, and this response was absent in obese
This document discusses the role of 14-3-3 proteins in mediating the actions of insulin. It begins by explaining that insulin has wider physiological effects beyond regulating blood glucose levels, and that 14-3-3 proteins help integrate insulin signaling pathways. Specifically, 14-3-3 proteins bind to phosphorylated proteins regulated by the PI3K-PKB-mTORC1 and ERK-p90RSK pathways. They interact with AS160 and TBC1D1 to regulate glucose uptake in response to insulin and energy stress. Studying the dynamic 14-3-3 phosphoproteome is providing new insights into how insulin triggers shifts in metabolism.
Frederick Banting had the idea that led to the discovery of insulin. He performed surgeries on dogs with Charles Best assisting. Before insulin, physicians endorsed fasting and low-calorie diets for diabetes, which provided some relief but death often followed. The first human given insulin was Leonard Thompson in 1922. Later, Frederick Sanger determined insulin's structure, winning a Nobel Prize in 1958. Rosalyn Yalow developed radioimmunoassay, allowing accurate insulin measurement, earning her a 1977 Nobel Prize. Today, recombinant DNA technology produces human insulin.
Insulin degludec is an ultralong-acting basal insulin analogue administered via once daily subcutaneous injection to help control blood sugar levels in diabetes. It has a duration of action of up to 40 hours, making it suitable as a once-daily treatment. Clinical trials found it to be as effective as insulin glargine at reducing HbA1c levels while having a lower risk of hypoglycemia, especially nocturnal hypoglycemia. Insulin peglispro is an experimental basal insulin consisting of insulin lispro covalently attached to polyethylene glycol. Phase II clinical trials found it reduced blood glucose variability compared to insulin glargine while maintaining similar HbA1c lowering and hypoglycemia rates,
Before the discovery of insulin in 1921, people with type 1 diabetes died within weeks to years of disease onset. In the early 1900s, attempts were made to treat diabetes with pancreatic extracts with temporary success. In 1921-1922, Banting, Best, Macleod, and Collip discovered insulin by extracting it from pancreatic islets, and tested it successfully on the first patient Leonard Thompson. Insulin production began commercially in 1922 and significantly increased life expectancy for people with diabetes from average ages of 11-34 years before insulin to 45-65 years by the 1940s.
Insulin is a hormone produced by beta cells in the pancreas that regulates glucose levels. It is composed of two chains of amino acids that are linked together. Glucose triggers the release of insulin which binds to receptors on cells to stimulate glucose and amino acid uptake and inhibit gluconeogenesis. Diabetes occurs when there is insufficient insulin production or the body does not respond properly to insulin, leading to high blood glucose levels and damage to organs over time. The two main types are type 1 diabetes caused by autoimmune destruction of beta cells, and type 2 diabetes related to insulin resistance.
This research article investigates how circulating glucose levels modulate neural control of the desire for high-calorie foods in humans. The study found that:
1) Mild hypoglycemia preferentially activated brain regions involved in reward and motivation (e.g. striatum, insula) and increased reported desire for high-calorie foods, compared to a state of euglycemia.
2) Euglycemia preferentially activated brain regions involved in inhibitory control (e.g. prefrontal cortex, anterior cingulate cortex) and resulted in less interest in food stimuli.
3) Higher circulating glucose levels predicted greater activation of the medial prefrontal cortex, and this response was absent in obese
This document discusses the role of 14-3-3 proteins in mediating the actions of insulin. It begins by explaining that insulin has wider physiological effects beyond regulating blood glucose levels, and that 14-3-3 proteins help integrate insulin signaling pathways. Specifically, 14-3-3 proteins bind to phosphorylated proteins regulated by the PI3K-PKB-mTORC1 and ERK-p90RSK pathways. They interact with AS160 and TBC1D1 to regulate glucose uptake in response to insulin and energy stress. Studying the dynamic 14-3-3 phosphoproteome is providing new insights into how insulin triggers shifts in metabolism.
Frederick Banting had the idea that led to the discovery of insulin. He performed surgeries on dogs with Charles Best assisting. Before insulin, physicians endorsed fasting and low-calorie diets for diabetes, which provided some relief but death often followed. The first human given insulin was Leonard Thompson in 1922. Later, Frederick Sanger determined insulin's structure, winning a Nobel Prize in 1958. Rosalyn Yalow developed radioimmunoassay, allowing accurate insulin measurement, earning her a 1977 Nobel Prize. Today, recombinant DNA technology produces human insulin.
Insulin degludec is an ultralong-acting basal insulin analogue administered via once daily subcutaneous injection to help control blood sugar levels in diabetes. It has a duration of action of up to 40 hours, making it suitable as a once-daily treatment. Clinical trials found it to be as effective as insulin glargine at reducing HbA1c levels while having a lower risk of hypoglycemia, especially nocturnal hypoglycemia. Insulin peglispro is an experimental basal insulin consisting of insulin lispro covalently attached to polyethylene glycol. Phase II clinical trials found it reduced blood glucose variability compared to insulin glargine while maintaining similar HbA1c lowering and hypoglycemia rates,
Before the discovery of insulin in 1921, people with type 1 diabetes died within weeks to years of disease onset. In the early 1900s, attempts were made to treat diabetes with pancreatic extracts with temporary success. In 1921-1922, Banting, Best, Macleod, and Collip discovered insulin by extracting it from pancreatic islets, and tested it successfully on the first patient Leonard Thompson. Insulin production began commercially in 1922 and significantly increased life expectancy for people with diabetes from average ages of 11-34 years before insulin to 45-65 years by the 1940s.
Insulin is a hormone produced by beta cells in the pancreas that regulates glucose levels. It is composed of two chains of amino acids that are linked together. Glucose triggers the release of insulin which binds to receptors on cells to stimulate glucose and amino acid uptake and inhibit gluconeogenesis. Diabetes occurs when there is insufficient insulin production or the body does not respond properly to insulin, leading to high blood glucose levels and damage to organs over time. The two main types are type 1 diabetes caused by autoimmune destruction of beta cells, and type 2 diabetes related to insulin resistance.
This document discusses newer insulin preparations that have been developed through genetic engineering to better mimic the body's natural insulin secretion patterns. It introduces several newer rapid-acting and long-acting insulin analogs such as insulin lispro, insulin aspart, insulin glargine, and insulin detemir. These analogs were designed to have faster onset of action, shorter duration, or longer duration compared to older insulin preparations. The document also briefly discusses inhaled insulin and newer advances in insulin delivery technologies.
The document discusses various types of insulin and insulin delivery methods for managing diabetes. It describes a 37-year-old man with type 1 diabetes of 18 years whose HbA1c is consistently high at 9.0-10.5% despite different insulin regimens. It then discusses options like Glargine insulin and education programs that can help improve blood sugar control and reduce hypoglycemia for patients.
Insulin is a hormone produced by the pancreas that regulates blood sugar levels. It allows the body to use and store carbohydrates from food. Without enough insulin, blood sugar levels rise and a person develops diabetes. There are different types of insulin that work in various timeframes to mimic the body's natural insulin release and keep blood sugar stable. Insulin is essential for diabetes treatment but requires careful dosing to avoid hypoglycemia from too much insulin or hyperglycemia from too little insulin. New delivery methods like insulin pens and pumps aim to more closely match a person's changing insulin needs.
Manish Kumar presented a seminar on novel approaches to insulin delivery. The document discussed various traditional and novel insulin delivery systems including insulin syringes, pens, pumps, and jet injectors. It also described newer insulin formulations like insulin glargine and degludec that have longer durations of action. The seminar examined barriers to traditional needle-based injections and strategies to overcome these barriers through novel delivery routes like oral, pulmonary, transdermal and nasal administration.
The document discusses the need for new insulin analogs to better control blood glucose levels. It notes that current insulin regimens often fail to adequately control fasting plasma glucose, which is important for reducing complications. Newer long-acting basal insulin analogs like insulin glargine are presented as an improvement over NPH insulin because they more closely mimic the body's natural basal insulin secretion pattern, providing steady insulin levels throughout the day and night with no peaks. This allows for better control of fasting glucose and fewer instances of hypoglycemia compared to NPH. The document advocates for insulin analogs like glargine that provide a true basal insulin effect to be used earlier in treatment to improve glycemic control and reduce the risk
The document discusses insulin, its synthesis and secretion, mechanisms of action, and effects on metabolism. It also covers oral hypoglycemic agents and their mechanisms. Insulin is synthesized in the pancreas as proinsulin and processed into insulin and C-peptide. Insulin regulates glucose and lipid metabolism through effects on liver, muscle and adipose tissue. Insulin resistance and deficiency lead to hyperglycemia and other metabolic abnormalities.
The document discusses insulin, its biosynthesis and secretion, types of insulin preparations, and management of diabetes. It covers:
1) How insulin is synthesized and secreted in the pancreas and the three products - proinsulin, C-peptide, and insulin.
2) Factors that stimulate and inhibit insulin secretion.
3) Different types of insulin preparations including short-acting, intermediate-acting, long-acting, and premixed insulins.
4) Treatment of diabetes including insulin therapy, oral hypoglycemic agents, monitoring of blood glucose and HbA1c levels.
The document discusses sleep in elite athletes and potential nutritional interventions to enhance sleep. It summarizes that sleep is important for physiological recovery but many athletes experience reduced quality and quantity of sleep, which can negatively impact performance. Certain nutrients like carbohydrates, tryptophan, and melatonin have been investigated as possible sleep aids. While some research has studied the effects of nutrition on sleep, more research is still needed to determine the best nutritional interventions to enhance sleep for athletes.
Insulin is a hormone produced in the pancreas that allows cells to take up glucose from the bloodstream. It was discovered in the 1920s and has since been used to treat diabetes. There are various types of insulin that differ in their onset, peak, and duration of action. Insulin therapy is indicated when fasting blood glucose is above 250 mg/dL or HbA1c is over 9.0%. Common types of insulin regimens and delivery methods are also discussed.
This document presents information about diabetes and the production of insulin. It discusses the history of extracting insulin from animals, the limitations of this process, and the development of recombinant DNA technology to produce human insulin in bacteria. This allowed large-scale production of insulin without relying on animal sources. The document also describes efforts to develop improved second generation recombinant insulins through protein engineering to provide faster acting versions for treatment of diabetes.
Insulin is a hormone produced by the pancreas that regulates blood sugar levels. It allows glucose in the bloodstream to enter cells and be used for energy. Without insulin, blood sugar builds up and cells are deprived of energy, leading to serious health issues. Diabetes occurs when the body does not produce enough insulin or the cells do not respond properly to insulin. Historically, insulin was purified from animals but is now commonly produced through recombinant DNA technology using modified bacteria. This process involves isolating the human insulin gene, inserting it into bacterial DNA, and causing the bacteria to express and mass produce human insulin.
This document discusses various peptides and hormones involved in insulin production and diabetes, including proinsulin, C-peptide, glucagon, GLP-1, TNFa, and adiponectin. It notes that proinsulin to insulin ratio above 20% predicts future type 2 diabetes. C-peptide measures endogenous insulin secretion and its presence reduces diabetes complications. TNFa causes insulin resistance while adiponectin increases insulin sensitivity, and their levels are useful markers. The conclusion emphasizes measuring proinsulin, C-peptide, adiponectin and TNFa to monitor insulin resistance and drug responses.
1) Insulin is a polypeptide hormone composed of two chains that is secreted by the pancreas and regulates blood glucose levels.
2) Insulin secretion is regulated through chemical, hormonal, and neural mechanisms in response to glucose levels and other factors. It acts to promote glucose and lipid uptake and utilization and inhibits gluconeogenesis.
3) There are various insulin preparations including regular human insulin, lente/NPH insulin, and analogues like lispro, glargine, and detemir with different onset/duration profiles. Insulin is used to treat diabetes mellitus and diabetic ketoacidosis.
- Insulin is a hormone produced by beta cells in the pancreas that regulates carbohydrate and fat metabolism. It promotes the absorption of glucose from the blood into liver, muscle, and fatty tissue.
- Insulin was first isolated in 1922 which revolutionized treatment for diabetes. It binds to insulin receptors on cells and triggers effects like increasing glucose uptake and glycogen/lipid synthesis while inhibiting gluconeogenesis and lipolysis.
- Insulin secretion is stimulated by high blood glucose levels after eating to promote storage of excess glucose. Multiple factors affect its secretion including hormones like glucagon, growth hormone, cortisol, and epinephrine.
1. Insulin is stored in the body as a hexamer but is active as a monomer. Cow and pig are the best sources for animal insulin due to easy availability and high similarity to human insulin.
2. Porcine insulin differs from human insulin by one amino acid while bovine insulin differs at two amino acid positions. Minor differences do not impact receptor binding or activity.
3. Insulin and proinsulin have different molecular structures - insulin is a double-stranded polypeptide while proinsulin is single-stranded. This results in insulin having a faster formation of correct disulfide bonds when purified compared to proinsulin.
This document discusses the entero-insular axis, which refers to the gut factors that contribute to enhanced insulin secretion after eating a meal. It has neural, endocrine, and metabolic components. Neural factors like cholinergic innervation account for 20% of the insulin response, while hormonal factors like GLP-1 and GIP account for 30%. These hormones are secreted from the gut in response to food ingestion and stimulate insulin secretion from pancreatic beta cells in a glucose-dependent manner. They also inhibit glucagon secretion and slow gastric emptying. The document further discusses the roles of various nutrients like carbohydrates, proteins, and fatty acids in stimulating insulin secretion and their implications for diabetes treatment and management.
Contents
1. Insulin Molecule
2. Effect of Insulin in Body
3. History of Insulin
4. Recent Trends in Insulin Productions and Types
4.1 Animal Insulins
4.2 Long-Acting Insulins
4.3 Human Insulins
4.4 Insulin Analogues
4.5 Biosimilar Insulins
5. Insulin Production (Chain A and Chain B Method)
5.1 Upstream Processing
5.2 Downstream Processing
6. The Proinsulin Process
7. Insulin Available in Market with Different Brand Names
8. References
Manish Kumar presented a seminar on novel approaches to insulin delivery. The document discussed various traditional and newer methods for insulin delivery including insulin syringes, pens, pumps, and jet injectors. It also described advances in insulin therapy including newer insulin analogs with altered pharmacokinetic properties. Barriers to traditional insulin injection like needle phobia and lipodystrophy were mentioned. The seminar aimed to explore novel delivery routes for insulin through the eye, rectum, lungs, buccal mucosa, skin and nose to overcome the challenges with subcutaneous injections.
Insulin
Dose
6.4
10.1
55
6.1
55
6.4
8.1
55
6.9
9.1
55
55
Thursday
5.8
7.6
Friday
5.2
11.5
Saturday
6.4
5.9
Sunday
7.1
55
55
1) Patrick has type 2 diabetes and has been on multiple oral agents and long-acting insulin glargine.
2) His fasting blood sugars are now controlled but post-pr
The document discusses two studies related to the role of insulin signaling in the brain and its effects on hepatic glucose metabolism. The first study found that arterial infusion of insulin into dog brains modestly reduced hepatic glucose output without changing endogenous production. The second study reports the successful generation of a human pancreatic beta cell line called EndoC-βH1 that secretes insulin in response to glucose, achieving a long sought goal.
Current Paradigms to Explore the Gut Microbiota Linkage to Neurological Disor...Dr Varruchi Sharma
It has been suggested that an intricate communication link exists between the gut microbiota and the brain and its ability to modulate behaviour of an individual governing homeostasis. Metabolic activity of the microbiota is considered to be relatively constant in healthy individuals, despite diff erences in the composition of microbiota. The metabolites produced by gut microbiota and their homeostatic balance is often perturbed as a result of neurological complications. Therefore, it is of paramount importance to explore the link between gut microbiota and brain function and behaviour through neural, endocrine, and immune pathways. This current review focusses on the impact of altered gut microbiota on brain functions and how microbiome modulation by use of probiotics, prebiotics, and synbiotics might prove benefi cial in the prevention and/or treatment of neurological disorders. It is important to carefully understand the complex mechanisms underlying the gut–brain axis so as to use the gut microbiota as a therapeutic intervention strategy for neurological disorders.
This document discusses newer insulin preparations that have been developed through genetic engineering to better mimic the body's natural insulin secretion patterns. It introduces several newer rapid-acting and long-acting insulin analogs such as insulin lispro, insulin aspart, insulin glargine, and insulin detemir. These analogs were designed to have faster onset of action, shorter duration, or longer duration compared to older insulin preparations. The document also briefly discusses inhaled insulin and newer advances in insulin delivery technologies.
The document discusses various types of insulin and insulin delivery methods for managing diabetes. It describes a 37-year-old man with type 1 diabetes of 18 years whose HbA1c is consistently high at 9.0-10.5% despite different insulin regimens. It then discusses options like Glargine insulin and education programs that can help improve blood sugar control and reduce hypoglycemia for patients.
Insulin is a hormone produced by the pancreas that regulates blood sugar levels. It allows the body to use and store carbohydrates from food. Without enough insulin, blood sugar levels rise and a person develops diabetes. There are different types of insulin that work in various timeframes to mimic the body's natural insulin release and keep blood sugar stable. Insulin is essential for diabetes treatment but requires careful dosing to avoid hypoglycemia from too much insulin or hyperglycemia from too little insulin. New delivery methods like insulin pens and pumps aim to more closely match a person's changing insulin needs.
Manish Kumar presented a seminar on novel approaches to insulin delivery. The document discussed various traditional and novel insulin delivery systems including insulin syringes, pens, pumps, and jet injectors. It also described newer insulin formulations like insulin glargine and degludec that have longer durations of action. The seminar examined barriers to traditional needle-based injections and strategies to overcome these barriers through novel delivery routes like oral, pulmonary, transdermal and nasal administration.
The document discusses the need for new insulin analogs to better control blood glucose levels. It notes that current insulin regimens often fail to adequately control fasting plasma glucose, which is important for reducing complications. Newer long-acting basal insulin analogs like insulin glargine are presented as an improvement over NPH insulin because they more closely mimic the body's natural basal insulin secretion pattern, providing steady insulin levels throughout the day and night with no peaks. This allows for better control of fasting glucose and fewer instances of hypoglycemia compared to NPH. The document advocates for insulin analogs like glargine that provide a true basal insulin effect to be used earlier in treatment to improve glycemic control and reduce the risk
The document discusses insulin, its synthesis and secretion, mechanisms of action, and effects on metabolism. It also covers oral hypoglycemic agents and their mechanisms. Insulin is synthesized in the pancreas as proinsulin and processed into insulin and C-peptide. Insulin regulates glucose and lipid metabolism through effects on liver, muscle and adipose tissue. Insulin resistance and deficiency lead to hyperglycemia and other metabolic abnormalities.
The document discusses insulin, its biosynthesis and secretion, types of insulin preparations, and management of diabetes. It covers:
1) How insulin is synthesized and secreted in the pancreas and the three products - proinsulin, C-peptide, and insulin.
2) Factors that stimulate and inhibit insulin secretion.
3) Different types of insulin preparations including short-acting, intermediate-acting, long-acting, and premixed insulins.
4) Treatment of diabetes including insulin therapy, oral hypoglycemic agents, monitoring of blood glucose and HbA1c levels.
The document discusses sleep in elite athletes and potential nutritional interventions to enhance sleep. It summarizes that sleep is important for physiological recovery but many athletes experience reduced quality and quantity of sleep, which can negatively impact performance. Certain nutrients like carbohydrates, tryptophan, and melatonin have been investigated as possible sleep aids. While some research has studied the effects of nutrition on sleep, more research is still needed to determine the best nutritional interventions to enhance sleep for athletes.
Insulin is a hormone produced in the pancreas that allows cells to take up glucose from the bloodstream. It was discovered in the 1920s and has since been used to treat diabetes. There are various types of insulin that differ in their onset, peak, and duration of action. Insulin therapy is indicated when fasting blood glucose is above 250 mg/dL or HbA1c is over 9.0%. Common types of insulin regimens and delivery methods are also discussed.
This document presents information about diabetes and the production of insulin. It discusses the history of extracting insulin from animals, the limitations of this process, and the development of recombinant DNA technology to produce human insulin in bacteria. This allowed large-scale production of insulin without relying on animal sources. The document also describes efforts to develop improved second generation recombinant insulins through protein engineering to provide faster acting versions for treatment of diabetes.
Insulin is a hormone produced by the pancreas that regulates blood sugar levels. It allows glucose in the bloodstream to enter cells and be used for energy. Without insulin, blood sugar builds up and cells are deprived of energy, leading to serious health issues. Diabetes occurs when the body does not produce enough insulin or the cells do not respond properly to insulin. Historically, insulin was purified from animals but is now commonly produced through recombinant DNA technology using modified bacteria. This process involves isolating the human insulin gene, inserting it into bacterial DNA, and causing the bacteria to express and mass produce human insulin.
This document discusses various peptides and hormones involved in insulin production and diabetes, including proinsulin, C-peptide, glucagon, GLP-1, TNFa, and adiponectin. It notes that proinsulin to insulin ratio above 20% predicts future type 2 diabetes. C-peptide measures endogenous insulin secretion and its presence reduces diabetes complications. TNFa causes insulin resistance while adiponectin increases insulin sensitivity, and their levels are useful markers. The conclusion emphasizes measuring proinsulin, C-peptide, adiponectin and TNFa to monitor insulin resistance and drug responses.
1) Insulin is a polypeptide hormone composed of two chains that is secreted by the pancreas and regulates blood glucose levels.
2) Insulin secretion is regulated through chemical, hormonal, and neural mechanisms in response to glucose levels and other factors. It acts to promote glucose and lipid uptake and utilization and inhibits gluconeogenesis.
3) There are various insulin preparations including regular human insulin, lente/NPH insulin, and analogues like lispro, glargine, and detemir with different onset/duration profiles. Insulin is used to treat diabetes mellitus and diabetic ketoacidosis.
- Insulin is a hormone produced by beta cells in the pancreas that regulates carbohydrate and fat metabolism. It promotes the absorption of glucose from the blood into liver, muscle, and fatty tissue.
- Insulin was first isolated in 1922 which revolutionized treatment for diabetes. It binds to insulin receptors on cells and triggers effects like increasing glucose uptake and glycogen/lipid synthesis while inhibiting gluconeogenesis and lipolysis.
- Insulin secretion is stimulated by high blood glucose levels after eating to promote storage of excess glucose. Multiple factors affect its secretion including hormones like glucagon, growth hormone, cortisol, and epinephrine.
1. Insulin is stored in the body as a hexamer but is active as a monomer. Cow and pig are the best sources for animal insulin due to easy availability and high similarity to human insulin.
2. Porcine insulin differs from human insulin by one amino acid while bovine insulin differs at two amino acid positions. Minor differences do not impact receptor binding or activity.
3. Insulin and proinsulin have different molecular structures - insulin is a double-stranded polypeptide while proinsulin is single-stranded. This results in insulin having a faster formation of correct disulfide bonds when purified compared to proinsulin.
This document discusses the entero-insular axis, which refers to the gut factors that contribute to enhanced insulin secretion after eating a meal. It has neural, endocrine, and metabolic components. Neural factors like cholinergic innervation account for 20% of the insulin response, while hormonal factors like GLP-1 and GIP account for 30%. These hormones are secreted from the gut in response to food ingestion and stimulate insulin secretion from pancreatic beta cells in a glucose-dependent manner. They also inhibit glucagon secretion and slow gastric emptying. The document further discusses the roles of various nutrients like carbohydrates, proteins, and fatty acids in stimulating insulin secretion and their implications for diabetes treatment and management.
Contents
1. Insulin Molecule
2. Effect of Insulin in Body
3. History of Insulin
4. Recent Trends in Insulin Productions and Types
4.1 Animal Insulins
4.2 Long-Acting Insulins
4.3 Human Insulins
4.4 Insulin Analogues
4.5 Biosimilar Insulins
5. Insulin Production (Chain A and Chain B Method)
5.1 Upstream Processing
5.2 Downstream Processing
6. The Proinsulin Process
7. Insulin Available in Market with Different Brand Names
8. References
Manish Kumar presented a seminar on novel approaches to insulin delivery. The document discussed various traditional and newer methods for insulin delivery including insulin syringes, pens, pumps, and jet injectors. It also described advances in insulin therapy including newer insulin analogs with altered pharmacokinetic properties. Barriers to traditional insulin injection like needle phobia and lipodystrophy were mentioned. The seminar aimed to explore novel delivery routes for insulin through the eye, rectum, lungs, buccal mucosa, skin and nose to overcome the challenges with subcutaneous injections.
Insulin
Dose
6.4
10.1
55
6.1
55
6.4
8.1
55
6.9
9.1
55
55
Thursday
5.8
7.6
Friday
5.2
11.5
Saturday
6.4
5.9
Sunday
7.1
55
55
1) Patrick has type 2 diabetes and has been on multiple oral agents and long-acting insulin glargine.
2) His fasting blood sugars are now controlled but post-pr
The document discusses two studies related to the role of insulin signaling in the brain and its effects on hepatic glucose metabolism. The first study found that arterial infusion of insulin into dog brains modestly reduced hepatic glucose output without changing endogenous production. The second study reports the successful generation of a human pancreatic beta cell line called EndoC-βH1 that secretes insulin in response to glucose, achieving a long sought goal.
Current Paradigms to Explore the Gut Microbiota Linkage to Neurological Disor...Dr Varruchi Sharma
It has been suggested that an intricate communication link exists between the gut microbiota and the brain and its ability to modulate behaviour of an individual governing homeostasis. Metabolic activity of the microbiota is considered to be relatively constant in healthy individuals, despite diff erences in the composition of microbiota. The metabolites produced by gut microbiota and their homeostatic balance is often perturbed as a result of neurological complications. Therefore, it is of paramount importance to explore the link between gut microbiota and brain function and behaviour through neural, endocrine, and immune pathways. This current review focusses on the impact of altered gut microbiota on brain functions and how microbiome modulation by use of probiotics, prebiotics, and synbiotics might prove benefi cial in the prevention and/or treatment of neurological disorders. It is important to carefully understand the complex mechanisms underlying the gut–brain axis so as to use the gut microbiota as a therapeutic intervention strategy for neurological disorders.
This study investigated the activation of Raphe nuclei neurons, the main source of serotonin in the brain, through immunodetection of c-Fos protein in trained and sedentary rats. Sixteen male rats were divided into trained (5 weeks, 15-60 minutes swimming) and sedentary groups. After c-Fos immunocytochemistry and neuron counting, evaluation showed no significant differences in most Raphe nuclei except the most caudal part of the Dorsal Raphe nuclei and Raphe Palidus nuclei, where trained rats had more c-Fos immunoreactive neurons. These regions may be related to excitatory respiratory modulation. The study aimed to better understand central fatigue mechanisms by examining serotonin
This study investigated the activation of Raphe nuclei neurons, the main source of serotonin in the brain, through immunodetection of c-Fos protein in trained and sedentary rats. Sixteen male rats were divided into trained (5 weeks, 15-60 minutes swimming) and sedentary groups. After c-Fos immunocytochemistry and neuron counting, evaluation showed no significant differences in most Raphe nuclei except the most caudal part of the Dorsal Raphe nuclei and Raphe Palidus nuclei, where trained rats had more c-Fos immunoreactive neurons. These regions may be related to excitatory respiratory modulation. The study examined central nervous system adaptation to prolonged exercise through analysis
Neuro inflammation plays a pivotal role in the regulation of aging, Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), multiple sclerosis (MS), stroke, depression, dementia, and metabolic anomalies such as hypertension and diabetes. Neuro inflammation is also the pathogenic hallmark of the aging-related neurodegenerative conditions. Therefore, anti-inflammatory strategies and analysis could be efficient prophylactic and therapeutic management strategies for the number of central nervous system (CNS) disorders. CNS disorders may develop owing to the chronic microglial activation. Glial cells, specifically microglia, are immune cells in the CNS that are responsible for the maintenance of normal homeostasis as well as the repair after injury in the brain.
The document discusses the brain's role in glucose homeostasis. It begins with a historical perspective on the discovery of the brain's endocrine functions in glucose regulation in the 19th century. It then outlines the brain's control of glucose homeostasis through various hypothalamic centers that regulate peripheral organs like the liver. Specifically, it describes the brain-centered glucoregulatory system (BCGS) that maintains glucose levels through direct and indirect control of hepatic glucose production. The document also discusses the concept of glucose effectiveness and potential dysfunctions in the BCGS that can lead to diabetes.
The document discusses the brain's role in glucose homeostasis. It begins with a historical perspective on the discovery of the brain's endocrine functions in glucose regulation in the 19th century. It then outlines the brain centers involved in glucose regulation, including glucose excited and inhibited neurons. The brain centered glucoregulatory system controls glucose homeostasis through direct and indirect regulation of hepatic glucose production. Dysfunctions in this system can lead to impaired glucose handling and diabetes. The document concludes by framing diabetes as a failure of both the brain centered and pancreatic centered glucoregulatory systems.
This document describes a modern neuroscience approach for treating chronic spinal pain that combines pain neuroscience education with cognition-targeted motor control training. It discusses evidence that chronic spinal pain patients have abnormalities in brain structure and function, including decreased grey matter density, impaired motor control-related brain areas, and a sensitized brain due to central sensitization. The proposed approach has three phases: 1) Therapeutic pain neuroscience education to reconceptualize pain and explain central sensitization, 2) Cognition-targeted motor control training to address motor dysfunction, 3) Both 1) and 2) together to target peripheral and central mechanisms of chronic spinal pain.
Regeneration of Brain with new understanding gives us good ground to be optimistic in matters of research and also day to day clinics. This presentation at the most introduces you to the potential stride of the field.
By binding to a new nuclear-associated receptor, opioid
growth factor (OGF), also known by its chemical name
[Met5]-enkephalin, promotes cellular homeostasis.
Serum OGF levels are high in diabetic individuals.
In the animal model, opioid receptor antagonists like
naltrexone (NTX) alleviate many of the consequences of
diabetes
This document summarizes the neurobiology of obsessive-compulsive disorder (OCD). It discusses the neuroanatomical basis involving regions like the anterior cingulate cortex and orbitofrontal cortex. It outlines the relevant neural pathways like the cortico-striatal-thalamic-cortical loop and their involvement in OCD. The neurochemicals implicated are serotonin, glutamate, and dopamine. Brain imaging studies have shown changes in brain volumes and activity in OCD patients in areas within these circuits.
Patrik Brundin - Are Synucleinopathies Prion Diseases?Alzforum
Presentation made April 8, 2016 at the live webinar hosted by Alzforum - http://www.alzforum.org/webinars/webinar-pathogenic-protein-spread-lets-think-again
This document provides an overview of Parkinson's syndrome, a degenerative nervous disorder. It discusses the anatomy of the brain and division of the brain. Parkinson's disease is defined as a slow progressing movement disorder characterized by slowness in movement initiation and execution. It results from the depletion of dopamine in the substantia nigra, which leads to the development of Lewy bodies. Common clinical manifestations include tremor, rigidity, bradykinesia, and postural instability. Treatment involves the use of dopamine agonists, anticholinergics, MAO inhibitors, and COMT inhibitors. Nursing management is based on assessing mobility, self-care, nutrition, elimination, and communication to establish goals and interventions.
This study investigated how insulin deficiency affects mitochondrial oxidative phosphorylation in the hearts of diabetic mice. The key findings were:
1) Activity of oxidative phosphorylation complex V (ATP synthase) was significantly reduced in the hearts of streptozotocin-induced diabetic mice.
2) Normalizing blood glucose with phlorizin treatment did not improve complex V activity, but insulin treatment did normalize it, indicating the reduction was caused by insulin deficiency rather than hyperglycemia.
3) Acute insulin stimulation induced phosphorylation and translocation of Akt to mitochondria in heart muscle. This translocation was enhanced in diabetic mice and blocked inhibition of Akt, blunting the activation of complex V by insulin.
Efficacy of Souvenaid in Mild Alzheimer’s Disease: Results from a Randomized,...Nutricia
1) This randomized controlled trial found that consumption of Souvenaid, a medical food containing nutrients to support synaptic function, led to improved memory performance over 24 weeks in patients with mild Alzheimer's disease compared to a control group.
2) The primary outcome measure, the memory domain z-score of the Neuropsychological Test Battery, was significantly higher in the Souvenaid group than the control group after 24 weeks.
3) Secondary EEG measures showed significantly different functional brain connectivity in the delta band between the groups over 24 weeks, supporting the hypothesis that Souvenaid affects synaptic activity.
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1. Intranasal administration of insulin to the brain impacts cognitive function
and peripheral metabolism
Volker Ott1*, Christian Benedict2, Bernd Schultes3,
Jan Born4, Manfred Hallschmid1
1
Department of Neuroendocrinology, University of Luebeck, Germany; 2Department of Neuroscience,
Functional Pharmacology, Uppsala University, Uppsala, Sweden; 3Interdisciplinary Obesity Center,
Cantonal Hospital St. Gallen, Switzerland; 4Department of Medical Psychology and Behavioral
Neurobiology, University of Tübingen, Tübingen, Germany
Key Terms: Insulin, intranasal, central nervous system, glucose homeostasis, energy homeostasis,
thermogenesis, cognitive function, insulin resistance, hepatic glucose production
Word Count: 3487
* To whom correspondence and reprint requests should be addressed:
Department of Neuroendocrinology, Hs. 50.1
University of Luebeck
Ratzeburger Allee 160
23538 Luebeck, Germany
Phone: ++49-451-500-5375
Fax: ++49-451-500-3640
E-mail: ott@kfg.uni-luebeck.de
This is an Accepted Article that has been peer-reviewed and approved for publication in the Diabetes,
Obesity and Metabolism, but has yet to undergo copy-editing and proof correction. Please cite this
article as an "Accepted Article"; doi: 10.1111/j.1463-1326.2011.01490.x
1
2. Abstract
In recent years, the central nervous system (CNS) has emerged as a principle site of insulin action.
This notion is supported by studies in animals relying on intracerebroventricular insulin infusion and
by experiments in humans that make use of the intranasal pathway of insulin administration to the
brain. Employing neurobehavioral and metabolic measurements as well as functional imaging
techniques, these studies have provided insight into a broad range of central and peripheral effects of
brain insulin. The present review focuses on CNS effects of insulin administered via the intranasal
route on cognition, in particular memory function, and whole-body energy homeostasis including
glucose metabolism. Furthermore, evidence is reviewed that suggests a pathophysiological role of
impaired brain insulin signaling in obesity and type 2 diabetes, which are hallmarked by peripheral
and possibly central nervous insulin resistance, as well as in conditions such as Alzheimer´s disease
where CNS insulin resistance might contribute to cognitive dysfunction.
2
3. Introduction
In the mid-eighteen-hundreds, Claude Bernard demonstrated that puncture of the fourth cerebral
ventricle induces glucosuria in mice [1], giving rise to the assumption that the central nervous system
(CNS) is involved in glucose homeostasis. However, interest in the role the brain might play in the
regulation of glucose metabolism abated and was only sparked again more than a century later.
Havrankova and coworkers demonstrated in 1978 that insulin receptors are present throughout the rat
CNS [2], followed closely by the demonstration that insulin receptors are also expressed in the human
brain [3,4]. The insulin receptor, a tyrosine kinase receptor, is found in particularly high densities in
brain regions like the olfactory bulb, the cerebellum, the dentate gyrus, the pyriform cortex, the
hippocampus, the choroid plexus and the arcuate nucleus of the hypothalamus [5]. Some animal
studies suggest that insulin gene expression takes place within the CNS [6,7]. However, although
indicators of insulin transcription in human brain tissue have been presented [8], solid evidence for
local insulin production in the human CNS is still lacking [9]. It is rather assumed that peripheral
insulin crosses the blood-brain barrier (BBB) by a saturable, receptor-mediated transport mechanism
[9-11] and by binding to brain insulin receptors affects functions as diverse as energy and glucose
homeostasis [12-14], reproduction [13], growth [15] and neuronal plasticity [16]. Woods and co-
workers were the first to perform seminal studies indicating that insulin, circulating within the blood
stream in proportion to body fat stores, acts as an adiposity signal within in the CNS. In conjunction
with the adipokine leptin it provides the brain with negative feedback on the amount of peripheral
energy (i.e., fat) depots [17; for review see reference 18]. In line with this notion, CNS administration
of insulin reduces body adiposity by down-regulating food intake [12,19,20]. This catabolic effect has
been observed mainly in males, indicating that the role of insulin in central nervous body weight
regulation may have sex-specific properties [21-23]. Moreover, as will be outlined in this review,
insulin’s impact on the brain exceeds its involvement in energy homeostasis and pertains to cognitive
functions (Figure 1). Brain insulin signaling might even constitute a neuroendocrine link between both
domains and is therefore emerging as a potential target in the treatment of metabolic and cognitive
disorders [24].
3
4. Enhancing central nervous insulin signaling by intranasal insulin administration in humans
Whereas in animals effective modes of insulin administration to the CNS, e.g., direct
intracerebroventricular (ICV) [25] or hypothalamic infusion [26] are routinely employed, insulin
administration to the human brain is more complicated. The conventional way of increasing CNS
concentrations of insulin to investigate effects of brain insulin relies on the intravenous (IV) infusion
of the hormone which has been shown to result in an increase in cerebrospinal fluid (CSF) insulin
concentrations [27]. This parenteral route, however, faces several serious drawbacks. The fall in blood
glucose levels resulting from systemic insulin infusion triggers the graded activation of endocrine axes
that can affect brain function [28], and below certain threshold levels inevitably impairs cognition
[29]. Insulin-induced hypoglycemia and its potentially harmful effects can be prevented by
simultaneous continuous glucose infusion that per se may exert a biasing impact on (cognitive) brain
functioning. Moreover, the euglycemic-hyperinsulinemic clamp procedure implies considerable time
and labor investments and, generally, systemic insulin administration does not permit the dissection of
insulin’s effects on the CNS from its direct peripheral actions e.g. in liver [30] and adipose tissue [31].
These methodological limitations are avoided by the intranasal (IN) route of administration that has
been shown in humans to bypass the BBB and effectively deliver insulin as well as other peptide
hormones to the CNS within one hour after administration in the absence of relevant systemic
absorption [32]. Accordingly, findings in animals demonstrate that intranasally administered
neuropeptides reach brain structures involved in the regulation of metabolism and cognition [33,34].
Intra-neuronal transport of neuropeptides from the nasal cavity to the olfactory bulb takes several
hours [35]. Thus, extra-neuronal passage through intercellular clefts of the olfactory epithelium,
situated on the superior turbinate and opposite the nasal septum [36], is assumed to be the preferential
path of peptide transport into the CNS compartment [32,37], with additional transport along trigeminal
nerve branches to brainstem regions [38].
IN administration of insulin preparations for the purpose of systemic insulin substitution, i.e.,
as an alternative approach to subcutaneous insulin injection, is not within the scope of this review.
4
5. Information on this aspect of nasal insulin administration can be found elsewhere [e.g. references
39,40].
Insulin modulates neurobehavioral measures of brain activity and cognition in humans
Insulin effects on human brain activity have been revealed in a number of studies relying on different
methodological approaches. CNS responses to IN insulin were observed in the form of distinct
alterations in auditory evoked electroencephalographic brain potential responses during an oddball-
paradigm in healthy men while peripheral blood glucose levels remained unchanged [41] . In a related
study, the IN administration of 60 international units of insulin induced a negative shift in direct
current brain potentials that was also found after IV bolus injection of the hormone [42]. Both the IN
and the intravenous effects emerged within 20 min after insulin administration, indicating that
increases in systemic insulin concentrations are rapidly reported to the brain and that IN delivery of
the compound bypassing the body periphery can have a comparable impact on brain activity. The
impact of systemic insulin on cerebrocortical activity was likewise measured in euglycemic-
hyperinsulinemic clamp studies that utilized magnetoencephalographic (MEG) recordings and
demonstrated that obesity [43,44] and the fat-mass and obesity associated (FTO) allele variant
rs8050136 [45] modify insulin’s effects on cerebrocortical beta- and theta-wave activity .
Experiments employing functional magnetic resonance imaging (fMRI) have shown a positive
relationship between plasma insulin levels and activation of the right hippocampus in response to
viewing photographs of high-caloric food items [46]. In some contrast to these results, in another
fMRI study, food picture-related activity of this and other brain regions was found to be reduced after
IN insulin in comparison to placebo administration [47], raising the question if insulin acting on the
hippocampus is relevant for the regulation of ingestive behavior. On the other hand, the hippocampus
is highly relevant for the formation and maintenance of declarative memory, i.e. memory for facts and
episodes that is accessible to conscious recollection [for review see reference 48]. The ability to
acquire and retain memories depends on synaptic plasticity. Thus, long-term potentiation (LTP) and
long-term depression (LTD) of synaptic transmission, i.e. the augmentation or reduction of synaptic
efficacy are assumed to be important modulators of the strength of a memory representation [49,50].
5
6. Several studies indicate that insulin contributes to changes in hippocampal synaptic plasticity by
potentiating LTD and LTP, respectively, at different synapses [for review see reference 51]. Moreover,
insulin receptors have been found to increase synapse density and dendritic plasticity in structures that
process visual input [52]. In addition to these mechanims, insulin may promote glucose utilization of
neuronal networks [53]. Although globally glucose transport to the CNS is assumed to be insulin-
independent [54-56], hyperinsulinemia has been shown in rodents to exert effects on glucose
metabolism in regions like the anterior hypothalamus and the basolateral amygdale [57].
In accordance with insulin’s effects on synaptic plasticity [52] and regional glucose uptake
[52], central nervous administration of the hormone via the IN route has been shown to improve
memory functions in studies in healthy humans [23,58,59]. In experiments performed in our lab, a
declarative memory test was conducted at the beginning and end of eight weeks of IN insulin
treatment (160 international units/d). In brief, lists of 30 words were presented and in addition to an
immediate recall 3 min after presentation, in a delayed recall one week later subjects wrote down all
words they still remembered. The delayed recall of words was significantly improved after eight
weeks of IN insulin administration whereas immediate word recall and non-declarative memory
functions were not affected [58]. In line with the strong accumulation of insulin receptors in
hippocampal and cortical brain structures [60], this finding indicates that insulin signaling contributes
to the formation of declarative, hippocampus-dependent memory contents. Noteworthy, beneficial
effects of IN insulin on declarative memory are not restricted to healthy subjects but have also been
shown in memory-impaired subjects [e.g. references 61,62]. Suzanne Craft and co-workers performed
a study in adults with mild cognitive impairments including amnestic symptoms (e.g., due to
Alzheimer´s disease) who were treated with IN insulin over a period of three weeks (2x20
international units/d) [61]. The primary outcome measure was the recall of a story containing 44
informational bits to which subjects listened and that they were asked to recall immediately and after a
20-minute delay. Patients treated with insulin showed significantly increased memory savings over the
21-day period compared to placebo. Considering reports of impaired brain glucose metabolism in
Alzheimer’s disease [63-65], it might be speculated that these effects and, in particular, acute insulin-
induced enhancements of cognitive function in memory-impaired patients occurring within minutes
6
7. [66] at least in part derive from increases in cerebral glucose metabolism. In related animal studies, IN
administration of the peptide slowed the development of diabetes-induced brain changes in a murine
model of type 1 diabetes [67].
CNS insulin signaling has been linked not only to cognitive but also to emotional functions of
the brain. Most recently, lentivirus-mediated downregulation of hypothalamic insulin receptor
expression in rats has been shown to elicit depressive and anxiety-like behaviors [68]. Vice versa, the
8-week IN insulin treatment described above induced an improvement in rated mood in our human
subjects [58]. In mice, IN insulin enhanced object-memory and induced anxiolytic behavioral effects
[69]. However, in mice with impaired glucose tolerance due to diet-induced obesity receiving the same
dose of IN insulin both effects were abrogated [69]. These findings suggest that disturbed CNS insulin
signaling/CNS insulin resistance might link metabolic disorders like obesity with cognitive
impairments and also depressive symptoms. Further evidence for this assumption is discussed below.
CNS insulin signaling and peripheral metabolism
In animal experiments, brain insulin signaling has emerged as an important regulator of energy
balance [70-72]. Insulin’s net effect on energy homeostasis depends on several factors. Whereas
intravenously administered insulin exerts direct peripheral and, after BBB transport, central nervous
effects, intransally administered insulin selectively targets the CNS. In this context it is interesting to
note that the central nervous action of insulin on energy homeostasis partly opposes its peripheral
effects. Whereas after peripheral (IV or subcutaneous) administration insulin acts as an anabolic
hormone by promoting weight gain in form of muscle and fat mass [73,74], IN and ICV insulin
administration in humans and animals, respectively, induces catabolic effects by reducing food intake
[19,23] and as a consequence body fat content [20,21] particularly in the male organism [21-23]. In
parallel, central insulin exerts an anabolic impact on adipose tissue: in addition to the inhibition of
lipolysis by peripheral insulin [75,76], CNS insulin has been found to likewise inhibit lipolysis and
also to enhance lipogenesis [75,77,78]. Recent murine data also suggest that hypothalamic insulin
signaling potentiates brown adipose tissue thermogenesis through inhibition of warm sensitive neurons
[79]. Our group corroborated these findings in humans by demonstrating that IN insulin enhances
7
8. postprandial thermogenesis [80]. Thus, the catabolic effect of IN insulin appears to stem from reduced
energy intake [21,23] and increased energy expenditure [79,80] alike.
Within the last decade, evidence has amounted that the impact of brain insulin signaling on
energy balance extends to glucose homeostasis. Hepatic glucose metabolism is an important
determinant of euglycemia [81]. By glycogenesis on the one hand and glycogenolysis and
gluconeogenesis on the other hand the liver stabilizes plasma glucose concentrations during
(postprandial) glucose abundance and (fasting) glucose depletion, respectively [82]. These processes
have long been known to be mediated by direct insulin action on hepatic insulin receptors and indirect
insulin effects on liver functions, including the downregulation of glucagon secretion and circulating
plasma nonesterified fatty acid concentrations [for review see reference 83]. However, hepatic
glucose metabolism also seems to be under the control of a brain-liver axis. Obici and co-workers
have shown in rodents that genetic downregulation of hypothalamic insulin receptor expression
disinhibits hepatic glucose production [84]. This finding clearly hints at a reduction in hepatic insulin
sensitivity as a consequence of impaired hypothalamic insulin signaling. Fittingly, insulin has been
found to open ATP-sensitive potassium channels on glucose-responsive hypothalamic neurons and
the resulting neuronal hyperpolarization seems to be responsible for the vagal transmission of a signal
that downregulates hepatic glucose production [14,84]. However, in an experiment in dogs,
quadrupling the concentration of circulating insulin selectively in brain afferent arteries did not
enhance the inhibition of hepatic glucose production [85] which leaves open the question whether the
contribution of hypothalamic insulin signaling to insulin’s hepatic effects has a species-dependent
component.
In humans it has recently been shown that IV pretreatment with insulin potentiates glucose-
induced pancreatic insulin secretion by 40%, suggesting that circulating insulin exerts a direct positive
feedback on its own secretion [86]. Interestingly, a similar effect was found for brain insulin over 30
years ago in dogs, where ICV insulin administration increased pancreatic insulin secretion via a feed-
forward mechanism [87,88]. This brain-pancreatic crosstalk involving the vagal nerve has been
hypothesized to be another regulator of blood glucose. While effects of CNS insulin on peripheral
insulin sensitivity and pancreatic insulin secretion in humans are largely unexplored, two recent
8
9. studies have gathered evidence that insulin delivery to the brain does affect peripheral glucose
metabolism. IN insulin administration before intake of a liquid meal reduced postprandial circulating
insulin levels in healthy subjects while plasma glucose levels were unchanged in comparison to
placebo [80]. This finding suggests that brain insulin administration can enhance postprandial
peripheral insulin sensitivity, adding to the feed-forward effect of brain insulin on pancreatic insulin
secretion observed in animals. Another recent set of experiments performed by Stockhorst and
colleagues indicates that such brain-pancreatic cross-talk is accessible to classical conditioning [89].
On day 1, the investigators administered IN insulin vs. placebo that both have the same specific odor
due to the formulation with meta-cresol (a stabilizing agent in insulin solutions). They found an
increase in serum insulin concentrations and a reduction in blood glucose levels (within the
euglycemic range) after insulin compared with placebo, suggesting that activation of the brain-liver
axis enhanced pancreatic insulin secretion. On day 2, the procedure was repeated but placebo was
administered in both groups with the smell of meta-cresol functioning as a conditioned stimulus. Here,
the presentation of the conditioned stimulus alone after pretreatment with IN insulin on day 1 was
sufficient to cause an even enhanced increasing effect on serum insulin concentrations, which points to
a significant contribution of neurocognitive learning mechanisms to the regulation of peripheral
glucose homeostasis by brain insulin.
Central nervous system insulin resistance
Peripheral insulin resistance is a well-known feature of type 2 diabetes and obesity. Insulin resistance
in central nervous structures might likewise contribute to the development not only of these metabolic
disorders but also of cognitive impairments. Raising systemic insulin levels by IV infusion results in
increased CSF insulin concentrations in healthy, normal-weight subjects [27]. Obese subjects and
Alzheimer patients seem to display relatively decreased CSF insulin concentrations suggesting
reduced insulin transport across the BBB [90,91]. Likewise, in comparison to normal-weight subjects,
overweight humans show a decrease in MEG-recorded cortical activity during hyperinsulinemic-
euglycemic clamp experiments that is directly related to the amount of body fat and the degree of
peripheral insulin resistance [43]. These findings support the notion that in obesity both BBB insulin
transport and the central nervous sensitivity to insulin are reduced. Related studies relying on acute
9
10. and prolonged IN administration of the hormone have refined this picture. In further MEG-based
experiments, IN insulin acutely increased cerebrocortical activity in response to food vs. non-food
pictures in lean but not in obese subjects [92]. Long-term (8 weeks) administration of IN insulin in
obese subjects failed to affect body weight and fat mass [93] but still enhanced declarative memory
and dampened HPA-axis activity to a degree comparable with that observed in normal-weight subjects
[58,94]. This differential insulin response implies that brain regions involved in energy and glucose
homeostasis might be particularly prone to develop insulin resistance in obesity. In accordance with
these findings, in rats diet-induced obesity abolishes the catabolic actions of ICV insulin
administration, and a reduction in insulin receptor density in the hypothalamic arcuate nucleus causes
hyperphagia (and, as mentioned above, also disinhibits hepatic glucose production) [84]. On a
molecular level, activation of the PI-3 signaling cascade subsequent to the binding of insulin to its
receptor mediates the majority of central nervous insulin effects on energy homeostasis [for review see
reference 95], while disturbances of this pathway are regarded as a likely cause of neuronal insulin
resistance [for review see 96].
Reduced central nervous sensitivity might represent a pathophysiological link between
obesity, peripheral insulin resistance and cognitive disorders that have been found to be significantly
related in epidemiological studies [97,98]. Central insulin resistance seems to impair neuronal
plasticity via detrimental effects on glutamatergic and cholinergic pathways [99,100]. Such processes
are assumed to be influenced by genetic predisposition. One indicator for this assumption is that IN
insulin administration to patients with memory impairments improved memory functions
predominantly in non-carriers of the APOE*E4 allele, a risk factor for the development of Alzheimer’s
disease [62,66; for review see reference 101]. In this context, several further genetic polymorphisms
associated with reduced central nervous responsiveness to insulin have been characterized. Subjects
with the FTO gene polymorphism rs8050136 as well as carriers of the Gly972Arg polymorphism of
the Insulin Receptor Substrate 1 (IRS1) exhibit a decreased cerebrocortical response to IV insulin
[43,45]. Interestingly, these data support the suggested connection between the FTO variant and a
hyperphagic phenotype [102] characterised by a predilection for energy-dense foods [103], which
might involve decreased insulin sensitivity of food reward-related brain pathways [104].
10
11. Potential therapies aimed at overcoming CNS insulin resistance might include the IN
administration of insulin but could also rely on the insulin-sensitizing properties of the peroxisome
proliferator-activated receptor-ƴ (PPAR-ƴ) agonist rosiglitazone [105-108] and of metformin [109].
Regarding glucose homeostasis, enhancing central nervous/hypothalamic insulin signaling by insulin
administration to the brain might reinforce a vagally transmitted inhibitory signal on hepatic
gluconeogenesis [110], whose disinhibition represents a hallmark of type 2 diabetes and peripheral
insulin resistance [84]. The latter, moreover, appears to be highly associated with central nervous
insulin resistance [111]. IN insulin has been found to reduce HPA axis activity [58,93,94], thus
potentially opposing visceral adiposity and cognitive impairments due to stress-induced chronic HPA-
axis overactivation [112-114]. Moreover, in light of IN insulin’s acute memory-improving effects in
patients with mild cognitive impairments [61,62], the compound might ameliorate the harmful effects
on cognition that obesity and diabetes are suspected to engender [97].
Notwithstanding these encouraging results, some caveats need to be addressed. In light of the
hyperinsulinemia that accompanies peripheral insulin resistance, it might be argued that the reduction
of CSF insulin levels observed in obese subjects [91] could represent a protective mechanism that
limits central nervous hyperinsulinemia and the potentially detrimental sequelae of cellular insulin
resistance inside the brain. Although speculative, this assumption is in line with findings that hint at a
dose-dependent directionality of central insulin’s impact on memory function. For example, acute IN
insulin administration to Alzheimer patients improved verbal memory recall only at lower doses (20
international units), whereas higher doses (up to 60 international units) were not effective and, in
carriers of the APOE*E4 allele, even induced a decline in memory performance [62]. In healthy
subjects, the induction of acute moderate euglycemic hyperinsulinemia has been found to trigger
central nervous system inflammation and beta-amyloid formation [115], both of which are known risk
factors for the development of cognitive impairments. The notion that brain hyperinsulinemia might
promote central nervous insulin resistance is supported by a recent in vitro-study showing that
prolonged (4-24 h) exposure of hypothalamic cells to high concentrations of insulin led to inactivation
and degradation of the insulin receptor and IRS-1 [116]. Against this background and considering that
long-term data on therapeutic and side effects of IN insulin in humans are so far lacking, obviously
11
12. much work is still necessary to sound the potential of brain insulin administration in the treatment of
cognitive and metabolic disorders.
Conclusion
Insulin binding to its receptors in the brain impacts a number of pivotal physiological functions,
including energy uptake and expenditure, glucose metabolism, adipocyte function and cognition. The
experimental data briefly summarized here clearly implicate CNS insulin resistance as a potentially
important factor in the pathophysiology of obesity and systemic insulin resistance as well as of
cognitive impairments like Alzheimer’s disease. Moreover, the association between these disorders
found in epidemiological investigations may at least partly rely on dysregulated central nervous
insulin signaling. Although further studies are needed to substantiate the promising results of proof-of-
concept experiments on central nervous insulin administration, overcoming insulin resistance in the
brain may prove a viable therapeutic option in the treatment of these increasingly prevalent afflictions.
Acknowledgments
This work was supported by Deutsche Forschungsgemeinschaft (KFO126/B5), Germany. The funding
source had no input in the preparation, review, or approval of the manuscript.
12
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20
21. Figure 1. Insulin-mediated crosstalk between brain and body periphery
Intranasal/CNS and systemic insulin affect hepatic glucose production, pancreatic insulin secretion,
adipocyte function, energy homeostasis, and cognitive function. Respective citations in text boxes
refer to the reference list of the main text.
21
22. 2-4-1-9-5-8-3
Moon-Night
Intranasal/CNS insulin enhances
Intranasal insulin declarative (e.g. word pairs) and
bypasses the BBB and working memory (e.g. number
achieves maximal CSF sequences) learning [23;58;59].
concentrations within 40
minutes [32].
Intranasal Insulin reaches the brain via
receptor-mediated saturable
insulin transport across the blood- Intranasal/CNS insulin decreases
brain-barrier [9;10]. CNS insulin, like food intake and enhances
CNS insulin inhibits systemic insulin, postprandial thermogenesis
hepatic gluconeogenesis inhibits lipolysis and [21;23;80].
CNS insulin increases
via vagal efferences pancreatic insulin secretion stimulates lipogenesis
[14;110]. (feed-forward loop [87;88].) [77;78].
Liver Pancreas
Systemic insulin
Adipocytes
inhibits gluco- Systemic insulin
neogenesis via inhibits lipolysis and
hepatic insulin stimulates
receptors [82;83]. lipogenesis [75;76].
22