The ZDSD Rat as a Translational Model for the Development of Drugs for Obesity, Metabolic Syndrome and Diabetes. This presentation describes the ZDSD rat. This rat is a model of obesity, metabolic syndrome and diabetes. In the pre-diabetic state it demonstrates all of the characteristics of human metabolic syndrome including obesity, glucose intolerance, insulin resistance, increased cardiovascular biomarkers and hypertension. In the diabetic state it expresses diabetic complications such as diabetic nephropathy, osteoporosis and delayed wound healing.
ZDSD Overview a model of obesity, metabolic syndrome and diabetes, 28 June 2013PreClinOmics
This presentation describes the ZDSD rat. This rat is a model of obesity, metabolic syndrome and diabetes. In the pre-diabetic state it demonstrates all of the characteristics of human metabolic syndrome including obesity, glucose intolerance, insulin resistance, increased cardiovascular biomarkers and hypertension. In the diabetic state it expresses diabetic complications such as diabetic nephropathy, osteoporosis and delayed wound healing.
The document describes research using the ZDSD rat model to study diabetic nephropathy. Key findings include:
1) ZDSD rats exhibit nephropathy that closely mimics that observed in obese, insulin resistant patients as shown by elevated biomarkers, albuminuria, oxidative stress, and histological analysis.
2) Terminal kidney weights are highest in ZDSD rats, indicating significant diabetic nephropathy, along with increased urine volume and microalbumin levels.
3) Histological analysis shows glomerular sclerosis, nodular sclerosis, thickened glomerular basement membranes, and podocyte effacement in ZDSD rats, consistent with diabetic nephropathy
This document describes studies examining the FATZO mouse as a model for obesity, metabolic syndrome, and diabetes. The studies found that male FATZO mice spontaneously developed obesity, dyslipidemia, and insulin resistance from 6-14 weeks of age. Treatment with rosiglitazone for 4 weeks improved these parameters in FATZO mice. Male C57BL6 mice fed a high fat diet also developed obesity, dyslipidemia and insulin resistance, which rosiglitazone also improved. The FATZO mouse was found to be a useful model for evaluating potential drug treatments for these conditions.
This document outlines the philosophy and interests of Steve Lawatsch, a teacher at Holt High School. He believes in constructivism where students can excel given high expectations. He does not use textbooks to allow flexibility in teaching. His passions include helping students learn effectively through technology and developing math intervention strategies for struggling students.
John Lennon was a founding member of The Beatles, one of the most influential rock bands in history. The Beatles evolved from Lennon's first band The Quarrymen and achieved worldwide success in the early 1960s. Some of their most popular albums included Sgt. Pepper's Lonely Hearts Club Band and Abbey Road. After The Beatles split up in 1970, Lennon had a successful solo career but was tragically assassinated outside his New York apartment in 1980 by Mark David Chapman.
The document appears to be about a team called the KWIATKOWSKI Team. However, no other details are provided about the team, its purpose, members, or activities. The single word "KWIATKOWSKI Team" is the only information given in the original document.
This document contains a syllabus for an Industrial Statistics course. The course introduces students to basic probability concepts and descriptive and inferential statistics. It includes collecting, analyzing, and graphically presenting data, as well as applying statistical methods using SPSS. The course assessments include quizzes, tests, and other tasks like tutorials, projects, and reflective journals. The syllabus outlines 5 chapters that will be covered: introduction to statistics, sampling and collection methods, data presentation, numerical descriptive measures, and probability.
ZDSD Overview a model of obesity, metabolic syndrome and diabetes, 28 June 2013PreClinOmics
This presentation describes the ZDSD rat. This rat is a model of obesity, metabolic syndrome and diabetes. In the pre-diabetic state it demonstrates all of the characteristics of human metabolic syndrome including obesity, glucose intolerance, insulin resistance, increased cardiovascular biomarkers and hypertension. In the diabetic state it expresses diabetic complications such as diabetic nephropathy, osteoporosis and delayed wound healing.
The document describes research using the ZDSD rat model to study diabetic nephropathy. Key findings include:
1) ZDSD rats exhibit nephropathy that closely mimics that observed in obese, insulin resistant patients as shown by elevated biomarkers, albuminuria, oxidative stress, and histological analysis.
2) Terminal kidney weights are highest in ZDSD rats, indicating significant diabetic nephropathy, along with increased urine volume and microalbumin levels.
3) Histological analysis shows glomerular sclerosis, nodular sclerosis, thickened glomerular basement membranes, and podocyte effacement in ZDSD rats, consistent with diabetic nephropathy
This document describes studies examining the FATZO mouse as a model for obesity, metabolic syndrome, and diabetes. The studies found that male FATZO mice spontaneously developed obesity, dyslipidemia, and insulin resistance from 6-14 weeks of age. Treatment with rosiglitazone for 4 weeks improved these parameters in FATZO mice. Male C57BL6 mice fed a high fat diet also developed obesity, dyslipidemia and insulin resistance, which rosiglitazone also improved. The FATZO mouse was found to be a useful model for evaluating potential drug treatments for these conditions.
This document outlines the philosophy and interests of Steve Lawatsch, a teacher at Holt High School. He believes in constructivism where students can excel given high expectations. He does not use textbooks to allow flexibility in teaching. His passions include helping students learn effectively through technology and developing math intervention strategies for struggling students.
John Lennon was a founding member of The Beatles, one of the most influential rock bands in history. The Beatles evolved from Lennon's first band The Quarrymen and achieved worldwide success in the early 1960s. Some of their most popular albums included Sgt. Pepper's Lonely Hearts Club Band and Abbey Road. After The Beatles split up in 1970, Lennon had a successful solo career but was tragically assassinated outside his New York apartment in 1980 by Mark David Chapman.
The document appears to be about a team called the KWIATKOWSKI Team. However, no other details are provided about the team, its purpose, members, or activities. The single word "KWIATKOWSKI Team" is the only information given in the original document.
This document contains a syllabus for an Industrial Statistics course. The course introduces students to basic probability concepts and descriptive and inferential statistics. It includes collecting, analyzing, and graphically presenting data, as well as applying statistical methods using SPSS. The course assessments include quizzes, tests, and other tasks like tutorials, projects, and reflective journals. The syllabus outlines 5 chapters that will be covered: introduction to statistics, sampling and collection methods, data presentation, numerical descriptive measures, and probability.
The document provides an evaluation of a student film project about a thriller involving a boy named Xavier and his imaginary friend, a teddy bear. Key points:
1) The film aimed to subvert expectations by making the antagonist a little girl but had to change it to a boy due to casting issues, and then made the teddy bear the real antagonist.
2) It drew inspiration from other films like Halloween that featured a disturbed child killer.
3) The house setting was chosen to be unsettling by disrupting the sense of comfort and relaxation usually associated with homes.
4) Planning and learning the necessary technologies like Final Cut and camera use were important lessons from creating the project.
This document contains the introductory slides for a U.S. History class. It includes bell ringer questions to start class discussions on goals for the course and class rules. Students are also prompted to write in their journals about themselves, their definition of history, where historical knowledge comes from, and the purpose of studying history. The slides then discuss what history is, how it is studied, and themes of the course around knowledge, change, governance, national identity, and life. Students are assigned homework to analyze the epistemology of another school subject.
Este documento presenta una estrategia metodológica de situación problema para enseñar historia a estudiantes de sexto grado. La estrategia explora por qué Europa se convirtió en un continente importante durante el Renacimiento a través de preguntas generadoras, conceptos centrales y una secuencia didáctica que incluye lluvias de ideas, lecturas, discusión en grupo y la creación de trípticos. El objetivo es que los estudiantes analicen las causas del crecimiento de las ciudades europeas y comprendan la importancia
This one sentence document repeats the phrase "School Girl Friends". It suggests a topic about friends in a school setting but provides no other details, context, or information to summarize in additional sentences.
I do not have access to the referenced photo album and therefore cannot provide a meaningful summary. Summarizing an unknown document would require making assumptions about its content, which I aim to avoid. Please provide more context if you would like me to attempt a summary.
CORECESS Inc. is a Korean company founded in 1997 that focuses on broadband access technology including WDM PON, GEPON, and GPON. It has headquarters in South Korea and branches in the US, Japan, and Russia. CORECESS was a pioneer in WDM PON and GEPON FTTH technology and has deployed its solutions to over 500k lines worldwide. The document provides an overview of CORECESS' FTTx solutions including Hybrid WDM PON, GPON, and GEPON networks that can connect up to 1024 homes per fiber and extend coverage up to 40km from the hub. It also describes CORECESS' triple play and smart grid services that are integrated on
1) Iran experienced both Islamization and globalization in the past two decades, as the 1979 revolution set in motion an Islamization process while globalization was taking shape globally.
2) Under the Shah, Iran integrated into the global economy and became dependent on oil exports, but the revolution reversed modernization and imposed Islamic social restrictions.
3) While globalization had little impact on Iran's politics due to its sharia law-based system, aspects of Western culture like music have influenced society, and the country remains dependent on oil trade with the West.
This document discusses enterprise mobility and the challenges it presents for businesses. It notes that 60% of employees believe IT is ineffective at increasing productivity. There are also security risks, with the average cost of a data breach being $5.5 million. The document examines different approaches to mobility like BYOD and CYOD and explores how to secure corporate data on mobile devices. It emphasizes that Windows devices offer security, manageability and are optimized for business scenarios. The document argues these devices can help businesses modernize applications and navigate the complexity of enterprise mobility.
The document summarizes a village meeting discussing a proposed housing development called Westcott Meadows. Residents raised concerns about traffic, flooding, and environmental impacts. They defeated a previous application from Taylor Wimpey and will object to the new application, citing similar issues around landscape, flooding risk, protected wildlife, and inadequate assessment of impacts. Residents were encouraged to submit objection letters within 21 days.
This document discusses oral hypoglycemic drugs and insulin used to treat diabetes. It describes the two main types of diabetes - type 1 caused by insulin deficiency and type 2 caused by insulin resistance. The document outlines several classes of oral hypoglycemic drugs including biguanides, sulfonylureas, meglitinides, thiazolidinediones, and alpha-glucosidase inhibitors. It provides details on the mechanism of action, pharmacokinetics, effects and side effects of drugs from each class.
Rom soft - Diadvisor presentation - CodeCamp 10 march 2012RomSoft SRL
The document describes the DIAdvisor project, a personalized glucose predictive diabetes advisor system created by a European consortium. The consortium includes 13 partners from 9 countries, including 3 universities, 3 hospitals, and 4 small-to-medium enterprises. The DIAdvisor system aims to make managing insulin-treated diabetes easier by providing predictive glucose readings and advice on insulin dosing based on a patient's vital signs and other factors. The system has both patient and clinician interfaces to help diabetic patients better control their blood glucose levels and reduce risks.
The document discusses fat tissue and obesity, defining obesity, examining fat distribution and the functions of adipose tissue, and exploring the brain-gut pathways that regulate appetite and fat mass, concluding that excess dietary fat intake can harm metabolic health by damaging adipose tissue.
This document discusses diabetes mellitus type 1 (DM1) in children. It begins by outlining the types of diabetes and focuses on DM1. DM1 results from loss of pancreatic function and insulinopenia. It then discusses the presentation of diabetic ketoacidosis (DKA) in a 7-year-old patient from Saudi Arabia. The document reviews risk factors, genetic predispositions, diagnostic criteria and management of DM1 and DKA. Management involves rehydration, treating electrolyte imbalances, acidosis, hyperglycemia and monitoring for complications such as cerebral edema.
The document summarizes a seminar on obesity in children and adolescents. It discusses definitions of obesity and overweight, prevalence and trends, causes including exogenous factors like poor diet and lack of exercise as well as endogenous genetic and endocrine factors. Complications of childhood obesity discussed include psychological issues, sleep apnea, non-alcoholic fatty liver disease, diabetes, and cardiovascular risks. Screening and normal values for tests to evaluate complications are also presented.
Diabetes Mellitus is one of the leading causes of death through its effects on cardiovascular disease. It is also a leading cause of blindness, renal failure and lower limb amputation, with type 2 diabetes accounting for 85-95% of cases. The global prevalence of type 2 diabetes is projected to increase significantly by 2025, including in India where it is expected to grow to 80 million cases by 2030. Screening guidelines recommend screening those over age 30, overweight individuals, those with family history or other risk factors. Treatment targets glycemic control through monitoring HbA1c, lipids, blood pressure, weight, and screening for complications.
The document provides an evaluation of a student film project about a thriller involving a boy named Xavier and his imaginary friend, a teddy bear. Key points:
1) The film aimed to subvert expectations by making the antagonist a little girl but had to change it to a boy due to casting issues, and then made the teddy bear the real antagonist.
2) It drew inspiration from other films like Halloween that featured a disturbed child killer.
3) The house setting was chosen to be unsettling by disrupting the sense of comfort and relaxation usually associated with homes.
4) Planning and learning the necessary technologies like Final Cut and camera use were important lessons from creating the project.
This document contains the introductory slides for a U.S. History class. It includes bell ringer questions to start class discussions on goals for the course and class rules. Students are also prompted to write in their journals about themselves, their definition of history, where historical knowledge comes from, and the purpose of studying history. The slides then discuss what history is, how it is studied, and themes of the course around knowledge, change, governance, national identity, and life. Students are assigned homework to analyze the epistemology of another school subject.
Este documento presenta una estrategia metodológica de situación problema para enseñar historia a estudiantes de sexto grado. La estrategia explora por qué Europa se convirtió en un continente importante durante el Renacimiento a través de preguntas generadoras, conceptos centrales y una secuencia didáctica que incluye lluvias de ideas, lecturas, discusión en grupo y la creación de trípticos. El objetivo es que los estudiantes analicen las causas del crecimiento de las ciudades europeas y comprendan la importancia
This one sentence document repeats the phrase "School Girl Friends". It suggests a topic about friends in a school setting but provides no other details, context, or information to summarize in additional sentences.
I do not have access to the referenced photo album and therefore cannot provide a meaningful summary. Summarizing an unknown document would require making assumptions about its content, which I aim to avoid. Please provide more context if you would like me to attempt a summary.
CORECESS Inc. is a Korean company founded in 1997 that focuses on broadband access technology including WDM PON, GEPON, and GPON. It has headquarters in South Korea and branches in the US, Japan, and Russia. CORECESS was a pioneer in WDM PON and GEPON FTTH technology and has deployed its solutions to over 500k lines worldwide. The document provides an overview of CORECESS' FTTx solutions including Hybrid WDM PON, GPON, and GEPON networks that can connect up to 1024 homes per fiber and extend coverage up to 40km from the hub. It also describes CORECESS' triple play and smart grid services that are integrated on
1) Iran experienced both Islamization and globalization in the past two decades, as the 1979 revolution set in motion an Islamization process while globalization was taking shape globally.
2) Under the Shah, Iran integrated into the global economy and became dependent on oil exports, but the revolution reversed modernization and imposed Islamic social restrictions.
3) While globalization had little impact on Iran's politics due to its sharia law-based system, aspects of Western culture like music have influenced society, and the country remains dependent on oil trade with the West.
This document discusses enterprise mobility and the challenges it presents for businesses. It notes that 60% of employees believe IT is ineffective at increasing productivity. There are also security risks, with the average cost of a data breach being $5.5 million. The document examines different approaches to mobility like BYOD and CYOD and explores how to secure corporate data on mobile devices. It emphasizes that Windows devices offer security, manageability and are optimized for business scenarios. The document argues these devices can help businesses modernize applications and navigate the complexity of enterprise mobility.
The document summarizes a village meeting discussing a proposed housing development called Westcott Meadows. Residents raised concerns about traffic, flooding, and environmental impacts. They defeated a previous application from Taylor Wimpey and will object to the new application, citing similar issues around landscape, flooding risk, protected wildlife, and inadequate assessment of impacts. Residents were encouraged to submit objection letters within 21 days.
This document discusses oral hypoglycemic drugs and insulin used to treat diabetes. It describes the two main types of diabetes - type 1 caused by insulin deficiency and type 2 caused by insulin resistance. The document outlines several classes of oral hypoglycemic drugs including biguanides, sulfonylureas, meglitinides, thiazolidinediones, and alpha-glucosidase inhibitors. It provides details on the mechanism of action, pharmacokinetics, effects and side effects of drugs from each class.
Rom soft - Diadvisor presentation - CodeCamp 10 march 2012RomSoft SRL
The document describes the DIAdvisor project, a personalized glucose predictive diabetes advisor system created by a European consortium. The consortium includes 13 partners from 9 countries, including 3 universities, 3 hospitals, and 4 small-to-medium enterprises. The DIAdvisor system aims to make managing insulin-treated diabetes easier by providing predictive glucose readings and advice on insulin dosing based on a patient's vital signs and other factors. The system has both patient and clinician interfaces to help diabetic patients better control their blood glucose levels and reduce risks.
The document discusses fat tissue and obesity, defining obesity, examining fat distribution and the functions of adipose tissue, and exploring the brain-gut pathways that regulate appetite and fat mass, concluding that excess dietary fat intake can harm metabolic health by damaging adipose tissue.
This document discusses diabetes mellitus type 1 (DM1) in children. It begins by outlining the types of diabetes and focuses on DM1. DM1 results from loss of pancreatic function and insulinopenia. It then discusses the presentation of diabetic ketoacidosis (DKA) in a 7-year-old patient from Saudi Arabia. The document reviews risk factors, genetic predispositions, diagnostic criteria and management of DM1 and DKA. Management involves rehydration, treating electrolyte imbalances, acidosis, hyperglycemia and monitoring for complications such as cerebral edema.
The document summarizes a seminar on obesity in children and adolescents. It discusses definitions of obesity and overweight, prevalence and trends, causes including exogenous factors like poor diet and lack of exercise as well as endogenous genetic and endocrine factors. Complications of childhood obesity discussed include psychological issues, sleep apnea, non-alcoholic fatty liver disease, diabetes, and cardiovascular risks. Screening and normal values for tests to evaluate complications are also presented.
Diabetes Mellitus is one of the leading causes of death through its effects on cardiovascular disease. It is also a leading cause of blindness, renal failure and lower limb amputation, with type 2 diabetes accounting for 85-95% of cases. The global prevalence of type 2 diabetes is projected to increase significantly by 2025, including in India where it is expected to grow to 80 million cases by 2030. Screening guidelines recommend screening those over age 30, overweight individuals, those with family history or other risk factors. Treatment targets glycemic control through monitoring HbA1c, lipids, blood pressure, weight, and screening for complications.
Diabetes self-management involves understanding the different types of diabetes, treatment options, and applying the chronic care model. It is important for healthcare providers to empower patients by making them knowledgeable experts in managing their own condition through education, goal setting, and addressing concerns about treatments like insulin. Proper self-management can help delay or prevent diabetes complications through techniques like regular blood sugar testing and lifestyle changes.
The passage discusses the pathogenesis of diabetes complications. It states that glucose is highly reactive and damages tissues when insulin is deficient. The complications are divided into short term metabolic issues like diabetic ketoacidosis and long term angiopathy issues involving the microvasculature and macrovasculature. The pathogenesis involves excess glucose damaging insulin independent tissues through mechanisms like increased sorbitol, activation of protein kinase C, and formation of advanced glycation end products.
All what you have to know about Diabetes MellitusYapa
All what you have to know about Diabetes Mellitus is here.Introduction of Diabetes,Regulation of blood glucose,Predisposing factors of DM,Clinical presentation,DM and pregnancy ,Diabetes ketoacidosis ,Complications of DM ,Diagnosis ,Dietary management of DM & Prevention of DM.
Student seminar on Diabetes Mellitus presented by 2007/2008 Batch students of Faculty of Medicine,University of Peradeniya,Sri Lanka.
The document presents guidelines from the ADA and EASD on managing hyperglycemia in type 2 diabetes, recommending a patient-centered approach focusing on individualized glycemic targets and treatment options including lifestyle changes, oral medications, and insulin to reduce risks of complications while avoiding hypoglycemia. The pathogenesis of type 2 diabetes involves insulin resistance and defects in insulin secretion, incretin effect, and glucagon secretion leading to hyperglycemia.
ADA EASD Management of hyperglycemia in type 2Mgfamiliar Net
Management of Hyperglycemia in Type 2 Diabetes:
A Patient-Centered Approach: Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
Inzucchi SE, Bergenstal RM, Buse JB, et al.
Diabetes Care. 2012 Apr 19.
This document discusses the natural history of type 2 diabetes, including:
1) Type 2 diabetes progresses from normal glucose tolerance to prediabetes and eventually overt diabetes, driven by deteriorating beta cell function and insulin resistance over time.
2) Several pathophysiological defects contribute to type 2 diabetes, including insulin resistance, relative insulin deficiency, and impaired incretin effect.
3) Obesity is a major risk factor for developing insulin resistance and type 2 diabetes by promoting increased secretion of fatty acids and inflammatory cytokines from abdominal fat cells.
1. The document classifies and describes the main types of diabetes mellitus including Type 1, Type 2, LADA, gestational diabetes, and genetic subtypes like MODY.
2. It provides details on the pathogenesis, clinical features, diagnostic criteria and management of each type of diabetes.
3. The document also presents 5 clinical cases of patients with diabetes and asks the reader to determine the type of diabetes based on the history and investigations provided.
Diabetic retinopathy is a complication of diabetes that affects the small blood vessels in the retina. It is a leading cause of blindness in developed countries. As diabetes rates rise globally, diabetic retinopathy cases are projected to increase substantially. Early stages may be asymptomatic, but later stages can cause vision loss or blindness if not treated. Annual dilated eye exams are important for early detection and treatment to prevent vision loss from this progressive disease.
Diabetic retinopathy is a complication of diabetes that affects the small blood vessels in the retina. It is a leading cause of blindness in developed countries. Strict control of blood sugar and blood pressure as well as annual eye exams are important for preventing vision loss from diabetic retinopathy. The disease progresses through stages from mild nonproliferative retinopathy to more severe proliferative retinopathy. Laser treatment and anti-VEGF drugs can help treat more advanced stages to prevent blindness.
Getting drugs to the market becoms harder and harder (the diabetes exemple)MelanieTilte
Getting drugs to reach the market becomes harder and harder as regulatory requirements for approval have increased over time. Antidiabetic drugs in particular now face rigorous clinical trial requirements to demonstrate not only efficacy in lowering blood glucose but also safety, especially regarding cardiovascular risks. This heightened level of scrutiny from regulators has caused some drugs to be withdrawn or face restrictions after approval when safety issues emerge from further study.
Getting Drugs To Reach The Market Becomes Harder And Harder (Antidiabetics)Pauline Flipo
The document discusses the history of antidiabetic drugs from the early 2000s, including the approval and eventual restrictions of the thiazolidinedione rosiglitazone (Avandia) due to safety concerns about increased cardiovascular risk. It also notes pioglitazone (Actos) was found to potentially increase bladder cancer risk with long-term use greater than 12 months based on epidemiological studies from 2002 and 2007.
Diabetes and Its Cardiovascular Complications.pptxMuzammal Wattoo
This document discusses diabetes and its cardiovascular complications. It begins by defining diabetes and classifying its four main types. It then discusses how angiogenesis, lymphangiogenesis and dysfunctional endothelial cells contribute to vascular complications in diabetes. Specifically, it explores how this impacts wound healing, development of collateral blood vessels, pregnancy outcomes, transplant rejection, and endothelial repair capacity. It also notes that cardiovascular disease causes the majority of deaths in diabetic patients. The document further examines links between diabetes and retinopathy, cardiomyopathy, cancer risk and peripheral artery disease. It outlines several pathological factors and molecular mechanisms involved in diabetic complications.
This patient is a 28-year-old female presenting with irregular menses for 6 months, weight gain, worsening acne, and excess hair growth. Her labs show an elevated testosterone level and glucose intolerance. She is diagnosed with polycystic ovarian syndrome (PCOS), a common endocrine disorder characterized by ovulatory dysfunction and hyperandrogenism. PCOS is associated with insulin resistance and increased risk of metabolic complications like diabetes as well as infertility challenges. Lifestyle changes like weight loss and medication are treatment options.
1) The presentation reviewed the rising rates of chronic lifestyle-related diseases like diabetes, heart disease, and obesity in America and their associated healthcare costs.
2) It discussed how Americans are eating more processed foods, sugar, salt, fat and meat/dairy while exercising less. This has led to increasing rates of metabolic syndrome, diabetes, and cardiovascular disease.
3) The aging of the population combined with these disease trends means that healthcare spending, much of which goes towards treating chronic diseases, has risen to 17.7% of GDP. Interventions targeting lifestyle factors like diet and exercise could help curb costs.
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Challenges: The hurdles in monetizing open-source projects and measuring user engagement.
Development Practices: Best practices for creating, maintaining, and scaling open-source libraries, including code hygiene, CI/CD, and fast iteration.
Community Building: Strategies for making adoption easy, iterating quickly, and fostering a vibrant, engaged community.
Marketing: Both online and offline marketing tactics, focusing on real, impactful interactions and collaborations.
Mental Health: Maintaining balance and not feeling pressured by user demands.
Key insights include the importance of automation, making the adoption process seamless, and leveraging offline interactions for marketing. The presentation also emphasizes the need for continuous small improvements and building a friendly, inclusive community that contributes to the project's growth.
Vladimir Iglovikov brings his extensive experience as a Kaggle Grandmaster, ex-Staff ML Engineer at Lyft, sharing valuable lessons and practical advice for anyone looking to enhance the adoption of their open-source projects.
Explore more about Albumentations and join the community at:
GitHub: https://github.com/albumentations-team/albumentations
Website: https://albumentations.ai/
LinkedIn: https://www.linkedin.com/company/100504475
Twitter: https://x.com/albumentations
Enchancing adoption of Open Source Libraries. A case study on Albumentations.AI
ZDSD Overview a model of obesity, metabolic syndrome and diabetes, 24 May-2011
1. INDEX
1. Introduction Page 2-
2. Spontaneous or Synchronous Diabetes Page 7-
3. Metabolic Syndrome Elements Page 10-
A. Visceral Obesity Page 13-
B. Insulin Resistance Page 19-
C. Clamp Study Page 28-
D. Dyslipidemia Page 32-
E. Hypertension Page 35-
4. Eating Behavior Page 37- →
5. Beta cell Failure Page 38-
6. Renal Injury Page 41-
A. Urinary biomarkers, Exp. 1, 2 Page 44-
B. RBM Biomarkers – Renal, Exp 3 Page 55-
C. Glomerular Pathology, EM, Exp 4 Page 64-
D. Synchronized Nephropathy, Exp 5 Page 76-
7. Osteoporosis Page 86-
8. Wound Healing Page 92-
9. RBM Biomarkers – Pro-Thrombotic Page 96-
10. RBM Biomarkers - Inflammation Page 102-
11. Therapeutic Efficacy
A. Common Anti-diabetic Compounds Page 110-
B. Rimonabant Page 115-
C. Niacin Page 123-
12. Summary Page 125-
1
2. ← →
The ZDSD Rat as a Translational Model for the
Development of Drugs for Obesity, Metabolic
Syndrome and Diabetes that Demonstrates
Many of the Serious Complications of Diabetes.
PreClinOmics, Inc.
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2
3. • Most rodent models of type 2 diabetes
Background have a monogenetic mutation that is
responsible for the initiation of obesity
and subsequent insulin resistance.
• The two most common obesity-
causing mutations are
← – the leptin receptor →
• Zucker Fatty; ZF rat
• Zucker Diabetic Fatty; ZDF rat
• db/db mouse
– the leptin molecule
• ob/ob mouse
• Both leptin and leptin receptor
mutations are rare in humans.
• The ZDSD rat does not have these
mutations but still has obesity PDF Return to Index, For
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metabolic syndrome and diabetes. 3
4. Development Scheme
Zucker Diabetic-Sprague Dawley Rat (ZDSD)
• Produced by crossing diet induced obese (DIO) rat derived
from the Crl:CD(SD) strain (exhibiting polygenetic obesity and
← insulin resistance) with homozygous lean ZDF/Crl rat (which →
will express beta cell failure with the Leprfa/Leprfa genotype).
• Selectively bred for obesity and diabetes.
• Selected for genetically matched breeders to develop
phenotypic homogeneity.
• Studied male rats at different ages.
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4
5. Characteristics of The ZDSD Rat
• Unique translational model for obesity, metabolic
syndrome/type II diabetes - 35 generations inbred
• Polygenic obesity and phenotype can be modulated by diet.
• Phenotype is expressed in the presence of a functional leptin
← pathway. →
• Insulin resistance development starts at an early age.
• Early onset of hyperglycemia and slower progression to frank
diabetes when compared to the ZDF rat.
– Slower deterioration of beta cell function.
• Manifests diabetic complications:
Diabetic nephropathy Hypertension
Cardiovascular markers Inflammation
Osteoporosis Delayed Wound Healing
• In production PDF Return to Index, For
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5
6. The ZDSD Rat:
One rodent – Many Models ZDSD
Obesity
Metabolic Syndrome
Diabetes
Obesity Model
before
Metabolic Syndrome Diabetes Model
diabetes develops,
← →
5-16 weeks of age
Natural/Spontaneous Diet Synchronized
Insulin Development (LabDiet 5008) (RD D12468 or Purina Test
Resistance Slower & more random Diet 5SCA)
Diabetic Diabetic
Hyperlipidemia Nephropathy Nephropathy
Obesity Osteoporosis Osteoporosis
Cardiovascular/ Cardiovascular/
Inflammatory Inflammatory
Hypertension Biomarkers Biomarkers
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Delayed Wound Delayed Wound
Delayed Wound Healing Healing
Web Use Refresh Above
Healing
6
7. Spontaneous 700
development of 600
diabetes 500
Body weight (g)
400
The ZDSD Rat when 300
maintained on Lab Diet 5008
200
chow will spontaneously
← develop diabetes as it ages 100
→
4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
beyond 16 wks. As fed serum Age (weeks)
glucose levels begin to 450
increase above ~350 mg/dl, 400
body weight begins to Serum glucose (mg/dL)
350
decrease. 300
250
200
150
100
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
Age (weeks) PDF Return to Index, For
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7
8. Synchronization 600
of diabetic onset
Glucose (mg/dl)
400 SD Male Rats
The ZDSD Rat can be placed ZDSD Males
on either D12468 (Research 200
ZDSD Females
Diets) or 5SCA (LabDiet) to
synchronize the onset of 0
diabetes.
← 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Age (wks) →
When the ZDSD rat was 600
placed on either diet at 17
wks of age, the plasma 400
Weight (g)
glucose levels of the animals
averaged over 450 mg/dl 200
SD Male Rats
ZDSD Males
within 1 week. Following a
ZDSD Females
return to LabDiet 5008 at 19 0
wks of age, the animals 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Age (wks)
maintained the diabetic state.
PCO now recommends a 3 Area shaded in grey indicates
week synchronization time frame of diabetogenic diet PDF Return to Index, For
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protocol
8
9. Synchronization
of diabetic onset
% Body Fat by QNMR
Body composition 30
changes in response 25
← to diabetogenic diet 20 SD Male Rats
→
% Body Fat
ZDSD Males
(5SCA or D12468). 15
ZDSD Females
10
5
0
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Age (wks)
Area shaded in grey indicates
time frame of diabetogenic diet
PDF Return to Index, For
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9
10. ZDSD as a preclinical model of Metabolic Syndrome
Metabolic syndrome affects a large proportion of the population and is becoming
increasingly important in adolescents. The syndrome has many components
including central obesity, insulin resistance, dyslipidemia and hypertension. In
addition, the syndrome features a chronic low grade inflammatory state, vascular
endothelial dysfunction, and a prothrombotic environment. Long standing
← →
metabolic syndrome can thus pre-dispose to atherosclerosis, microvasculature
disease (retina), stroke, renal injury and diabetes. Due to the complicated
mechanisms involved in the syndrome and its sequelae, current standard of care
reflects poly-pharmacy and is aimed at controlling atherogenic dyslipidemia,
hyperglycemia and hypertension as well as intervening in secondary diseases such
as renal dysfunction, stroke, and micro-vascular disease related to retinopathy.
Development of new chemical entities with the potential to control more than one
risk factor is hampered by currently available animal models. To that end, the ZDSD
rat was designed to spontaneously develop a phenotype that mimics many aspects
of the human metabolic syndrome, including hypertension and the progression to
frank diabetes with long-standing disease.
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10
11. Metabolic Syndrome
• Metabolic syndrome is most frequently
defined by a presence of certain traits,
← →
including:
– abdominal obesity
– insulin resistance
– Dyslipidemia
– elevated blood pressure and
– pro-thrombotic and pro-inflammatory states
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11
12. Characteristics of Metabolic
Syndrome Seen in the ZDSD Rat
• Increased body weight with increased
abdominal fat
← →
• Insulin resistance / Glucose intolerance
• Hyper-lipidemia
• Increased blood pressure / Hypertension
• Increased Serum BioMarkers of Coagulation
inflamation and Vascular Disease
• Increased fed and fasting glucose and
PDF Return to Index, For
HbA1c levels Web Use Refresh Above
12
13. Visceral Obesity
A prominent component of metabolic syndrome is insulin resistance which is
thought to be mediated by an increase in metabolically active visceral fat. Visceral
fat accumulation occurs in human patients in the presence of a functional leptin
← pathway as leptin deficiencies and receptor defects are rarely reported. According →
to published growth charts for male leptin resistant ZDF rats, the new ZDSD rats are
heavier when fed a normal diet (PMI 5008) and exhibit a body composition
(increased % fat) comparable to age matched DIO-LE model which is a mainstay for
anti-obesity research. In addition, the ZDSD responds to a common reference anti-
obesity agent (rimonabant) with significant loss of body fat. Interestingly, ZDSD rats
are not typically nocturnal in that they exhibit significant feed intake during the
daylight hours. Exogenously administered leptin results in an acute anorexic effect
quite similar to normal SD rats and indicates the presence of a functioning leptin
pathway
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13
14. Comparative Growth Curves
in SD and ZDSD Rat Fed 5008 chow
ZDSD rats were significantly
← (15%) heavier than their SD →
counterparts at 8 weeks of
age. In addition, the rate of
body weight gain was
increased in ZDSD animals as
evidenced by an 82% vs 62%
weight gain in SD animals
during the 24 weeks.
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All time points statistically different
14
Study # 09-550-170
15. Spontaneous Development of Obesity in ZDSD
Rats Fed 5008 Chow
Body composition was
assessed using QNMR . The
percentage of body weight
← identified as fat was 50 %
→
higher in ZDSD compared to
SD controls as early as 8 weeks
of age. Body fat percentage
continued to increase
throughout the study and
remained significantly higher
than control rats at each time-
point.
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All time points statistically different
15
Study # 09-550-170
16. Visceral Obesity in the ZDSD Rat
CT Scan
Sub-cutaneous fat
← →
Retroperitoneal fat
Visceral fat
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16
17. Terminal Body Weight Comparison
ZDF
CRL-SD, CD
700
+/fa
ZDSD, Diabetic 7-11 weeks
ZDSD, Diabetic 12-21 weeks
600
← →
500
Weight (g)
400
300
200
100
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Terminal animal weights in diabetic and control animals. Web Use Refresh Above
17
18. Terminal Comparison
Liver Weight Food & Water Consumption
30 ZDF
350
CRL-SD, CD
+/fa
ZDSD, Diabetic 7-11 weeks ZDF
25 300
ZDSD, Diabetic 12-21 weeks CRL-SD, CD
+/fa
← 250
ZDSD, Diabetic 7-11 weeks
→
Amount/rat (gram)
ZDSD, Diabetic 12-21 weeks
20
Weight (gram)
200
15
150
10
100
5 50
0 0
Terminal liver weights, water intake and food consumption are highest in the diabetic groups.
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18
19. Development of Insulin Resistance in the
ZDSD Rat on 5008 Purina chow
• Rats tested started at 8 weeks of age (SD & ZDSD)
• Weight, glucose and insulin measured weekly
← • Animals fasted every two weeks for OGTT →
• Data analyzed
– Weight
– Body composition
– Glucose levels
– OGTT glucose and insulin
– Glucose disposal
– HOMA-IR
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19
20. Comparative Growth Curves
in SD and ZDSD Rat Fed 5008 chow
ZDSD rats were significantly
← (15%) heavier than their SD →
counterparts at 8 weeks of
age. In addition, the rate of
body weight gain was
increased in ZDSD animals as
evidenced by an 82% vs 62%
weight gain in SD animals
during the 24 weeks.
PDF Return to Index, For
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All time points statistically different
20
Study # 09-550-170
21. Spontaneous Development of Obesity in ZDSD
Rats Fed 5008 Chow
Body composition was
assessed using QNMR . The
percentage of body weight
← identified as fat was 50 %
→
higher in ZDSD compared to
SD controls as early as 8 weeks
of age. Body fat percentage
continued to increase
throughout the study and
remained significantly higher
than control rats at each time-
point.
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All time points statistically different
21
Study # 09-550-170
22. Spontaneous Development of Hyperglycemia in
ZDSD Rats Fed 5008 Chow
← →
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All time points statistically different
22
Study # 09-550-170
23. Spontaneous Development of Glucose Intolerance
Shown by OGTT in ZDSD Rats Fed 5008 Chow
← →
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23
24. Spontaneous Development of Insulin Resistance
Shown by OGTT in ZDSD Rats Fed 5008 Chow
← →
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24
25. Spontaneous Development of Impairment in Glucose
Disposal in ZDSD Rats as Demonstrated by OGTT, AUC
Impairment in glucose
disposal as represented
by the area under the
← glucose curve during an
→
oral glucose tolerance
test developed
spontaneously in ZDSD
rats and was evident as
early as 8 weeks of age
(fed Purina 5008 chow).
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All time points statistically different
25
Study # 09-550-170
26. Progressive Development of Insulin Resistance
(HOMA-IR) in ZDSD Rats
ZDSD rats become
increasingly more insulin
← resistant with age as →
evidenced by the calculated
HOMA-IR. The insulin
resistance is evident
compared to SD rats as early
as 8 weeks of age (fed Purina
5008 chow).
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All time points statistically different
26
27. Glucose and Glycated Hemoglobin Levels in CD
and Prediabetic ZDSD Rats
Glucose in CD vs ZDSD Glycated Hb in CD vs ZDSD
16 weeks of age 16 weeks of age
150 4.0
CD CD
Blood Glucose mg/dL
← 140 ZDSD 3.8 ZDSD
→
Glycated Hb
130 3.6
120 3.4
110 3.2
100 3.0
D
SD
D
SD
C
C
ZD
ZD
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27
28. Pre-diabetic Insulin Design
Sensitivity, – Rosiglitazone treatment: 3 mg/kg
hyperinsulinemic- PO, QD for 2 weeks
euglycemic glucose – Comparison of insulin sensitivity
clamp at 9 wks of age in
• The ZDSD Rat,
← →
• Zucker Fatty (ZF), and
• Sprague Dawley (SD) rats
– Assessed by exogenous glucose
infusion rate (GIR) during
hyperinsulinemic (25
mU/kg/min)-euglycemic glucose
clamp
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28
29. Body Weight and Basal Glucose of Rats Before
Undergoing Glucose Clamp
Basal Blood Glucose (mg/dl)
500 200
Vehicle (n=6-8)
Rosiglitazone (3 mg/kg PO, n=6-8)
400 # 160
Body Weight (g)
300 120
← →
200 80
100 40
0 0
SD (age) SD (wt) ZDSD ZF SD (age) SD (wt) ZDSD ZF
Rat Strain (SD rats are age or weight matched) Rat Strain (SD rats are age or weight matched)
* P<0.05 compared to SD rat (age matched) group
# P<0.05 compared to vehicle treated group
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29
30. ZDSD and ZF Rats are Insulin Resistant which
Improved with Rosiglitazone Treatment
60 Vehicle (n=6-8)
Rosiglitazone (3 mg/kg PO, n=6-8)
Glucose Infusion Rate
50
(mg/kg/min)
#
← 40 # →
30
20
10
0
SD (age) SD (wt) ZDSD ZF
Rat Strain (SD rats are age or weight matched)
* P<0.05 compared to SD rat (age matched) group PDF Return to Index, For
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# P<0.05 compared to vehicle treated group
30
31. ZDSD Rats Have Modest Visceral and
Whole Body Obesity Unlike ZF Rats
12 # 40 #
Vehicle (n=6-8)
Epididymal Fat Pad (g)
Rosiglitazone (3 mg/kg PO, n=6-8) Vehicle (n=6-8)
10
30
Body Fat (%)
8
← 6 20 →
4
10
2
0 0
SD (age) SD (wt) ZDSD ZF SD (age) SD (wt) ZDSD ZF
Rat Strain (SD rats are age or weight matched) Rat Strain (SD rats are age or weight matched)
* P<0.05 compared to SD rat (age matched) group
# P<0.05 compared to vehicle treated group
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31
32. Dyslipidemia
Patients with Type II diabetes and metabolic syndrome often present with
dyslipidemia including elevated cholesterol and triglycerides and decreased HDL-
← C. These lipids have been shown to impact cardiovascular and renal co- →
morbidities. Hypertriglyceridemia expresses as early as 12 weeks of age in ZDSD
rats when maintained on a normal diet and levels progress up to 500 mg/dL by 15
weeks. Similar to the fructose fed rat, a model commonly used for the study of
dyslipidemia, the spontaneous nature of the ZDSD lipid abnormality may provide a
relevant model for the examination of compounds affecting the up-regulated
lipogenic pathway seen in metabolic syndrome. The dyslipidemia in this model
responds to classic reference agents including rosiglitazone. Increases in
cholesterol are not as dramatic and may be induced by feeding a high fat diet
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32
33. Terminal Comparison of Models
1300
1200
1100
1000 ZDF
CRL-SD, CD
700 +/fa
900 ZDSD, Diabetic 7-11 weeks
(mg/dL) ZDSD, Diabetic 12-21 weeks
800
600
← 700 →
Analytes
500
600
Weight (g)
500
400
400
300
300
200
100
200
0
100
TG
e
L
s
O
co
H
C
lu
G
Glucose, triglyceride and cholesterol levels. Glucose, triglyceride and cholesterol
PDF Return to Index, For
levels are elevated in all of the diabetic groups (ZDF and ZDSD). The model and Web Use Refresh Above
duration of diabetes did not have a significant effect on these measurements.
33
34. Dyslipidemia in ZDSD
Treatment ofEffect of 7 Days of Niacin Treatment with Niacin
Weight Glucose
Vehicle 250 Vehicle
600
Niacin Niacin
200
Glucose (mg/dL)
Weight (grams)
400 150
100 *
200
50
← 0 0
→
Fed Fasted Fed Fasted Fed Fasted Fed Fasted
Before Treatment After Treatment Before Treatment After Treatment
Triglyceride Free Fatty Acids
600 Vehicle 1.5 Vehicle
Niacin Niacin
Triglyceride (mg/dL)
FFA (mEq/L)
400 1.0
*
200 0.5
* * *
0 0.0
Fed Fasted Fed Fasted Fed Fasted Fed Fasted
Before Treatment After Treatment Before Treatment After Treatment PDF Return to Index, For
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7 days of treatment 34
35. Hypertension
← →
High blood pressure is a key symptom of metabolic syndrome and is a major
contributor to the increased risk of cardiovascular disease, kidney disease and
ischemic stroke seen in these patients. Examination of the interactions of all the
components of the syndrome in rats is complicated by the absence of high blood
pressure in current models (i.e., Zucker fatty rat). Indirect evidence of probable
elevated pressure in the form of elevated biomarkers for an activated RAAS
,endothelial dysfunction and aberrant vasoconstriction is noted in ZDSD rats.
Direct evidence of Hypertension has been confirmed in the pre-diabetic state via
the tail-cuff method.
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35
36. Blood pressure in ZDSD vs CD Rats
8-16 weeks of age
160
ZDSD
CD
140
Systolic BP
← →
120
100
80
60 70 80 90 100
Age in Days
Blood pressure data produced in collaboration with
Dr. Subah Packer’s Laboratory, IU School of Medicine PDF Return to Index, For
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36
37. 30
ANOVA/pooled t
Leptin Physiology
dark cycle (p<0.05) compared
light cycle to SD animals
25 daily total
Food intake (g/period)
Food intake of ZDSD Rats is 20
more evenly divided between 15
day and night
10
← 5
→
0
SD ZDSD
10
ANOVA/pooled t (p<0.05) compared
Food Intake of ZDSD Rats is
9 to corresponding saline control
Food intake 4 hrs after treatment
8
Reduced in Response to 7
Leptin Indicating a 6
Functioning Leptin Pathway. 5
Leptin was given just before 4
3
the start of the dark cycle and 2
food intake was measured for 1
the first 4 dark hours. 0
SD-saline SD-leptin ZDSD-saline ZDSD-leptin
PDF Return to Index, For
Assessment of leptin pathway function as determined by Web Use Refresh Above
feeding response to leptin injection (1 mg/kg, IP)
37
38. Insulin Levels Decline as Diabetes Progresses
Glucose Insulin
8
600 7
11-13 WEEKS
← 500 6
15 WEEKS
17 WEEKS →
Insulin (ng/ml)
5
Glucose (mg/dl)
400
4
300
11-17 WEEKS
3
200
2
100 1
0 0
5 7 9 11 13 15 17 19 21 23 25 27 29 5 7 9 11 13 15 17 19 21 23 25 27 29
Age (wks) Age (wks)
Insulin levels of the group that become diabetic between 11-17 weeks of age. The animals that
become diabetic earlier have higher insulin levels than those who become diabetic later.
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38
39. Average Glucose
Pancreatic Insulin Content % Diabetic
500
The glucose levels for ZDSD rats 400
Glucose (mg/dL)
were followed from 16 to 28 300
weeks of age (upper figure). At 200
28 weeks of age approximately 100 3.6% 13.1% 18.0% 32.8% 52.5% 62.3% 70.5% 75.8%
75% of the animals were overtly
← diabetic. The average glucose
0
15 20 25 30 →
levels for each animal (16 to 28 Age (weeks)
weeks) were correlated with
Correlation Between
insulin content of the pancreas Pancreatic Insulin and
when the animals were Blood Glucose Level
terminated at about 28 weeks of 600
age (lower figure). Higher
Glucose (mg/dL)
400
average glucose levels were
associated with lower insulin
200
content in the pancreas.
0 PDF Return to Index, For
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0 200 400 600 800
Insulin ng/g 39
40. Representative Islets from ZDSD Rats
Pre-diabetic Diabetic
← →
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40
41. Renal Injury
Obesity and metabolic syndrome are clear predictors
← of chronic kidney disease largely due to the →
potentiation of chronic inflammation by insulin
resistance. In addition, the lipoprotein abnormalities,
increased hemodynamics, hypercoagulability and
vascular dysfunction associated with metabolic
syndrome have all been implicated as causative for
renal disease. Biomarkers for renal dysfunction (i.e.,
IL6, TNF-α,NGAL,KIM-1, VEGF etc.) as well as significant
albuminuria , elevated free fatty acids with oxidative
stress, and histological analysis have shown the ZDSD
rat to exhibit nephropathy that closely mimics that
observed in obese insulin resistant patients.
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41
42. Diabetic Nephropathy
in the ZDSD Rat
• Increased kidney weight
• Increased urinary markers for kidney disease
← →
• Increased serum markers for kidney disease
• Glomerular sclerosis
• Nodular sclerosis, KW nodules
• Thickening basement membrane of
glomerular capillaries
• Podocyte effacement on capillaries PDF Return to Index, For
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42
43. Terminal Comparison
Kidney Weight Urine Analysis
300
7
ZDF
CRL-SD, CD
+/fa 250
6 ZDSD, Diabetic 7-11 weeks
ZDF
ZDSD, Diabetic 12-21 weeks
CRL-SD, CD
+/fa
5 200 ZDSD, Diabetic 7-11 weeks
ZDSD, Diabetic 12-21 weeks
← →
Weight (gram)
4 150
3 100
2
50
1
0
0
Terminal kidney weights are highest in the ZDSD Rat groups. These increased kidney weights and high
urinary volume along with increased micro-albumin concentration and the total amount of micro-
albumin indicate that there may be significant diabetic nephropathy in the ZDSD Rat model.
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43
44. Experiment 1
← ZDSD Diabetic Nephropathy →
Spontaneous Diabetes
ELISA Analysis of Markers
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44
45. WEIGHT GLUCOSE
600 600
SD SD
ZDSD ZDSD
Weight (grams)
Glucose (mg/dL)
500 400
400 200
← 300
10 12 14 16 18 20 22 24 26 28 30
0
10 12 14 16 18 20 22 24 26 28 30
→
Age (weeks) Age (weeks)
Urine volume
200
Urinary volume (mls/24hr)
SD
ZDSD
150
100
50
0
10 20 22 24 26 30
Age (weeks)
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45
46. Urinary albumin beta-2 microglobulin
Urinary -2 microglobulin (g/day)
150 2000
Urinary albumin (mg/day)
SD SD
125 ZDSD ZDSD
1500
100
75 1000
50
500
25
← 0
10 20 22 24 26 30
0
10 20 22 24 26 30 →
Age (weeks) Age (weeks)
Cystatin C KIM-1
30 15.0
Urinary cystatin C ( g/day)
SD SD
Urinary KIM-1 (ng/day)
ZDSD 12.5 ZDSD
20 10.0
7.5
10 5.0
2.5
0 0.0
10 20 22 24 26 30 10 20 22 24 26 30
Age (weeks) Age (weeks)
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46
47. Experiment 2
Urine BioMarkers of Renal Disease
Study Details
← • Male ZDSD Rats were allowed to become diabetic →
spontaineously on Purina 5008 and aged to 33 weeks.
Two groups of animals were selected for further study: animals that
were diabetic for longer than 16 weeks and animals that were
diabetic for less than 8 weeks.
• Mesoscale (MSD) urine panels were run on urine (Argutus
AKI test, Kidney Injury Panel 1 and Rat Clusterin)
• Pathological evaluation of the kidneys was done.
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47
48. Data From Urinary Excretion Study
← →
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48
49. Urinary Excretion of Kidney Markers
← →
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49
50. Urinary Excretion of Kidney Markers
← →
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50
51. Pathological Evaluation of Kidney
• Glomerulopathy: Changes in the renal glomeruli consisted of one or more of the following: increased
cellularity in the mesangium; increased in mesangial connective tissue; thickening of Bowman’s capsule;
hypertrophy of capsular epithelium; dilation of the capsular space. Individual glomeruli appeared
moderately enlarged. The lesions were highly variable within individual glomeruli and between glomeruli
within a kidney. The changes were most usually segmental, although a rare glomeruli was fibrotic
(condensed). Expanded mesangial material stained positively with the PAS stain and to a lesser extent
with the Trichrome stain.
←
• Tubular dilation/degeneration: This change was mainly in the cortex and consisted of irregularly dilated, →
empty tubules, that sometimes were lined by cuboidal epithelium that stained basophilic compared to the
expected normal eosinophilic tubular epithelium. In some individual tubules the epithelium were
flattened. These dilated/degenerate tubules were randomly scattered throughout the cortex, and
sometimes were associated with protein casts and/or non-suppurative inflammation (see below). Focal
mild increases in fibrous connective tissue within the interstitial space was present, frequently in
association with the interstitial inflammatory response, but not restrictively so.
• Protein casts: Individual tubules contained acellular, uniformly staining eosinophilic material consistent
with protein. These protein casts were present in the cortex and in the medulla, as well as at the cortico-
medullary junction in various sections. Often, several such dilated tubules containing protein casts were
clustered together, usually in the cortex.
• Inflammation: The inflammatory process consisted of focal collections of lymphocytes and
macrophages, which were seen in the cortical interstitial space, adjacent to individual glomeruli PDF Return to Index, For
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and individual blood vessels, and in association with the renal pelvic epithelium.
51
52. ← →
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52
53. ← →
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53
54. Kidney Histopathology of the ZDSD Rat
4.0
A Novel Animal Model of Diabetes
non-diabetic
compared to Non-diabetic animals (t-test)
diabetic
3.5
Histopathology Score (0-5)
3.0
← 2.5 →
2.0
1.5
1.0
0.5
0.0
Glomerulopathy Tubular dilation Protein casts Inflammation PDF Return to Index, For
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/degeneration
54
55. Experiment 3
← →
Serum BioMarkers of Renal Disease
RBM Collaboration
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55
Rules Based Medicine
56. Renal Injury
Obesity and metabolic syndrome are clear predictors of
chronic kidney disease largely due to the potentiation of
chronic inflammation by insulin resistance. In addition, the
← →
lipoprotein abnormalities, increased hemodynamics,
hypercoagulability and vascular dysfunction associated with
metabolic syndrome have all been implicated as causative
for renal disease. Biomarkers for renal dysfunction (i.e., IL6,
TNF-α, NGAL, KIM-1, VEGF etc.) as well as significant
albuminuria , elevated free fatty acids with oxidative stress,
and histological analysis have shown the ZDSD rat to exhibit
nephropathy that closely mimics that observed in obese
insulin resistant patients. PDF Return to Index, For
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56
57. Experimental details
• Male ZDSD rats were placed on a high-fat diet
(RD12468) between 17 and 19 weeks of age. 15 out
← of 21 animals in this experiment developed diabetes →
during this period (this is usually 90%+).
• Rules Based Medicine panels (Rat Metabolic MAP,
Rat Kidney MAP and RodentMAP™) were run on
serum samples that were collected:
– before diabetes developed (14 weeks)
– while diabetic on the high fat diet (18 weeks) and
– one week after they were taken off the high fat diet PDF Return to Index, For
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57
58. Serum BioMarkers of Renal Disease
Neutrophil Gelatinous Associated Protein
•also called lipocalin2
compared to SD
•levels up-regulated during 1400 Sprague-Dawley (5)
inflammation ZDSD (6)
Diabetic ZDSD (15)
•protective protein can trigger 1200
nephrogenesis
Serum NGAL (ng/ml)
← •associated with obesity, insulin 1000 →
resistance and hyperglycemia
800
600
400
200
14 18 20
Age (weeks)
14 weeks = non-diabetic
18 weeks = on diabetogenic diet one week
20 weeks = off diabetogenic diet one week
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58
59. Serum BioMarkers of Renal Disease
Beta-2-microglobulin
80
•a protein present in all nucleated cells
Sprague-Dawley (5)
which is normally reabsorbed in renal ZDSD (6)
Serum beta-2-microglobulin (ug/ml)
tubules 75 Diabetic ZDSD (15)
•increased circulating levels indicate
glomerular membrane disease and 70
← inflammation
→
65
#
60
55
compared to SD
# Diabetic vs. non-diabetic
50
14 18 20
Age (weeks)
14 weeks = non-diabetic
18 weeks = on diabetogenic diet one week
20 weeks = off diabetogenic diet one week
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59
60. Serum BioMarkers of Renal Disease
Kidney-injury molecule-1
0.30
•a membrane protein, not normally compared to SD
Sprague-Dawley (5)
# diabetic vs. non-diabetic
present but appears in urine in ZDSD (6)
0.25 Diabetic ZDSD (15)
response to acute kidney tubular
injury
Serum Kim-1 (ng/ml)
0.20
•highly sensitive predictor of renal #
← injury when elevated in urine
0.15
→
0.10
0.05
0.00
14 18 20
Age (weeks)
14 weeks = non-diabetic
18 weeks = on diabetogenic diet one week
20 weeks = off diabetogenic diet one week
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60
61. Serum BioMarkers of Renal Disease
Glutathione-S-transferase-alpha 60
compared to SD
•enzyme that reduces toxin levels by Sprague-Dawley (5)
ZDSD (6)
# Diabetic vs. non-diabetic
50
conjugation with glutathione Diabetic ZDSD (15)
Serum GST-alpha (ng/ml)
•localized in proximal convoluted 40
tubules, medullary tubules and loop of
Henle 30
← •in diabetes, hyperglycemia triggers →
oxidative stress which increases the 20 #
renal excretion of this enzyme and
therefore removes this protective 10
function and increases blood levels.
0
•Biomarker for tubular kidney disease
14 18 20
Age (weeks)
14 weeks = non-diabetic
18 weeks = on diabetogenic diet one week
20 weeks = off diabetogenic diet one week
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61
62. Serum BioMarkers of Renal Disease
Clusterin
500
•(apolipoprotein J) is a protein highly Sprague-Dawley (5) comapred to SD
correlated with apoptosis and the ZDSD (6) # Diabetic vs. non-diabetic
clearance of cellular debri Diabetic ZDSD (15)
400
•It is elevated in glomeruli and tubules
Serum Clusterin (g/ml)
of diabetic kidneys
← 300
→
200
#
100
14 18 20
Age (weeks)
14 weeks = non-diabetic
18 weeks = on diabetogenic diet one week
20 weeks = off diabetogenic diet one week
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62
63. Serum BioMarkers of Renal Disease
von Willebrand factor 300
compared to SD
•required for platelet adhesion, makes
Serum von Willebrand Factor (ng/ml)
# Diabetic vs. non-diabetic
platelets "sticky“ 250 #
•vWF binds inactive Factor VIII,
#
protecting it from degradation 200
•defiency leads to bleeding disorders
•increased levels predispose to stroke
← •increases precede microalbuminuria
150 →
in diabetic nephropathy
100
Sprague-Dawley (5)
50 ZDSD (6)
Diabetic ZDSD (15)
0
14 18 20
Age (weeks)
14 weeks = non-diabetic
18 weeks = on diabetogenic diet one week
20 weeks = off diabetogenic diet one week
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63
64. Experiment 4
← →
Diabetic Nephropathy,
EM of Glomerular Pathology
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64
65. Experimental details
• Male ZDSD rats allowed to become spontaneously
diabetic.
← • Animals were terminated by perfusion at about 35 →
weeks of age. We evaluated the following groups:
– Control CD rats
– ZDSD rats that had been diabetic from 12-13 weeks
– ZDSD rats that had been diabetic from 16-17 weeks
• Took pictures of glomerular capillaries and BM
– Measured GBM thickness
– Evaluated podocyte morphology PDF Return to Index, For
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65
66. Glomerular Capillary
Control, Age Matched Diabetic, 12 Weeks
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66
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66
67. Glomerular Capillary, Basement Membrane
Control, Age Matched Diabetic, 12 Weeks
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67
68. Glomerular Capillary, Basement Membrane
Control, Age Matched Diabetic, 12 Weeks
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68
69. Glomerular Capillary
Control, Age Matched Diabetic, 16.5 Weeks
← →
69
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69
70. Glomerular Capillary, Basement Membrane
Control, Age Matched Diabetic, 16.5 Weeks
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70
71. Glomerular Basement
Membrane Thickness
500
Thickness in nm 400
← →
300
200
100
0
ks
ks
ol
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ee
ee
on
W
W
C
12
.5
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16
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Time of diabetes in the ZDSD Rat 09-550-187
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71
72. Scanning Microscopy
Glomerular Capillaries
Control Diabetic
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72
73. Scanning Microscopy
Control Glomerular Capillary with Normal Podocyte Foot Processes
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73
74. Scanning Microscopy
Diabetic Glomerular Capillaries Demonstrating Effacement
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74