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Diabetes Mellitus

Diabetes Mellitus. Daozhan Yu dyu@medicine.umaryland.edu May 11th, 2005. Diabetes Mellitus. Diabetes – Latin “to flow through”. high urine output (polydipsia) Mellitus- Latin: “honeylike” Glucose in urine (glucosurea). What Are the Symptoms?. Glucosurea

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Diabetes Mellitus

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  1. Diabetes Mellitus Daozhan Yu dyu@medicine.umaryland.edu May 11th, 2005

  2. Diabetes Mellitus Diabetes – Latin “to flow through”. high urine output (polydipsia) Mellitus- Latin: “honeylike” Glucose in urine (glucosurea)

  3. What Are the Symptoms? • Glucosurea • Frequent urination • High blood glucose • Increased thirst • Increased hunger (especially after eating) • Dry mouth

  4. Continued • Nausea and occasionally vomiting • Hyperinsulinemia • Fatigue (weak, tired feeling) • Blurred vision • Numbness or tingling of the hands or feet • Frequent infections of the skin, urinary tract or vagina

  5. Other diseases related • Obesity • Atherosclerosis • Hypertension • Pro-inflammatory state • Pro-coagulant changes • Dyslipidemia (hypertriglyceridemia and low HDL levels)

  6. Classification: • Insulin dependent (IDDM or type I) -No or little insulin • Non-insulin dependent (NIDDM or type II) -High insulin • Secondary diabetes -Pancreatitis, hormone therapy etc. • Gestational diabetes -Initially limited to term of pregnancy

  7. Diagnosis • Fasting blood glucose 7.8mmol/L • Oral glucose tolerance test (OGTT) 7.8mmol/L at 2h after 75g glucose • Insulin levels Differentiate IDDM and NIDDM

  8. Diabesity Epidemic • Prevalence of diabetes worldwide was over 135 million people in 1995 • Projected to be over 300 million by 2025 • Over 80% of type 2 diabetic patients are overweight

  9. Obesity • Obesity is often diagnosed by using a body mass index (BMI). BMI = w h 2 w = weight in kilograms h = height in meters • Healthy weight as BMI between 19 – 25. • Obesity defined as BMI > 30. Obesity in childhood is due to an increase in both the size and the # of adipocytes. Weight gains in adulthood is due to increase in adipocyte size in intra-abdominal fat.

  10. TD2 and Obesity • Insulin resistance is a prominent feature of obesity and TD2 • Glucose and FA concentrations in blood increase -affect insulin secretion- vicious cycle

  11. Bad News: The Epidemic Of Obesity And Diabetes Is Worsening In The USA • In 2000, the prevalence of obesity (BMI 30 kg/m2) was 19.8%  61% since 1991 • Most adults are now overweight (BMI 25 kg/m2) -56.4%  25% since 1991 • Each  1 kg weight -  4.5%-9% risk of diabetes Mokdad et al. JAMA. 2001;286:1195-1200.

  12. Actions of Insulin • Stimulates glucose uptake by muscle (GLUT-4) • Activates glycogen synthase and inactivates glycogen phosphorylase (liver and muscle) • Stimulates storage of excess fuel as fat • FAs made in liver are converted to triacylglycerols (TGs) and transported in VLDLs to fat cells • In fat cells insulin stimulates TG synthesis

  13. Glucose Stimulates Insulin Secretion

  14. Insulin is stored in secretory granules – contents released into blood stream upon stimulation Electron micrograph showing release of insulin from  cell

  15. High Blood Glucose Pancreas Low Blood Glucose Insulin Muscle Liver Glycogen Glycogen Glucagon Glucose Glucose Pyruvate Pyruvate CO2 LiverGlucagon stimulates glucose synthesis and export MuscleInsulin stimulates glucose uptake and consumption

  16. What Happens When Insulin Reaches Cells ? Insulin binding to IR will cause autophosphorylation and phosphorylation of IRS at Tyrosine, then IRS will be activated and bind to following components to activate the signal cascade. Glucose will be transport from blood into cells. Phosphorylation at Serine will block the IRS function.

  17. GLUT4 Is The Transporter Of Glucose In Muscle And Adipose Tissue GLUT4 will be relocated from the cytoplasm to membrane Blue: DNA Red: GLUT4 Green: Transferon Foster et al, J. Biol. Chem., 2001

  18. What Will Happen If GLUT4 Doesn’t move right? Insulin Resistance: An impaired biological response to insulin -Resistance to insulin-stimulated glucose uptake -Increased lipolysis/FFAs McFarlane SI, et al. J Clin Endocrinol Metab. 2001

  19. The Metabolic Syndrome of Insulin Resistance SystemicInflammation EndothelialDysfunction ComplexDyslipidemia  TG, sdLDL HDL Insulin Resistance DisorderedFibrinolysis Atherosclerosis Hypertension DM2/IGT/IFG VisceralObesity Pradhan et al. JAMA. 2001

  20. Insulin Resistance: Inherited and Acquired Influences Inherited Acquired • Rare Mutations • Insulin receptor • Glucose transporter • Signaling proteins • Common Forms • Largely unidentified • Inactivity • Over eating • Aging • Medications • Obesity • Elevated FFAs

  21. A New View of the Adipocyte • The adipocyte is a metabolically active source of multiple proteins and cytokines that act via autocrine, paracrine and endocrine means • The adipocyte, gut and brain communicate regarding the body’s state of energy balance and set the “satiety” thermostat

  22. Visceral vs. Subcutaneous fat Visceral (abdominal, omental) fat correlates best with the co-morbidities of obesity including insulin resistance and diabetes

  23. Visceral Fat Distribution:Normal vs Type 2 Diabetes Normal Type 2 Diabetes

  24. Insulin Sensitivity and Central Adiposity 100 110 High risk for type 2 Low risk for type 2 90 80 70 60 Insulin sensitivity (mmol/min/kg lean mass) 50 40 30 20 20 30 35 40 45 25 50 % Central abdominal fat Carey DG et al. Diabetes. 1996

  25. Chronic Inflammatory State Happens During Obesity TNF alpha is a very important inflammatory mediator. It will be produced much during obesity.

  26. How the adipocyte affects insulinsensitivity TNF alpha • Levels rise with increasing adiposity • Lowers insulin stimulated glucose uptake in fat and muscle via paracrine effects • Reduces Glut-4 gene expression • Reduces insulin stimulated IR autophosphorylation and IRS-l phosphorylation • Interferes with pancreatic beta cell insulin secretion Lean obesity Hotamisligil, G.S., Science, 1993

  27. What Causes Insulin Resistance in Adipose Tissue? TNFa activates IKK, which will phosphorylate IRS at serine. So IRS can’t bind to PI3K. HSL lipolysis will release FFA from fat into blood. Insulin Resistance in Liver and Muscle Inhibitor kb Kinase (IKK), Initiating Event ? IRS-1 Ser 307 HSL Lipolysis TNFa PI3K FFA Insulin Resistance in Adipose Tissue Ruan and Lodish, Cytokine & Growth Factor Reviews, 2003

  28. The Lipotoxic Hypothesis of Insulin Resistance Diacyl- glycerol PKCq PKCe JNK1 FA-CoA Insulin resistance in adipose tissue HSL insulin receptor allosteric Lipolysis IRS-1/2 Glucokinase P13K Triglycerides PKB Ceramide FFA FFA FOXO GSK3 LPL FA-CoA PEPCK G6Pase transcription Triacylglycerols in Chylomicrons Overnutrition Glycogen Synthase b-oxidation Glucose Acetyl-CoA NADH ATP Glut 4 in muscle hormone-sensitive lipase (HSL) phosphotidylinositide 3-kinase the (P13K) free fatty acid (FFA) Insulin receptor substrate(IRS) Lipoprotein lipase(LPL) Gluconeogenesis in Liver Liver and Muscle Too much information

  29. Lipotoxic Hypothesis of Insulin Resistance LCCoA: Long chain acyl-CoA DAG: diacylglycerol Savage et al, Hypertention, 2005

  30. Other Pathways That Link TNFa Signaling to Insulin Resistance Expression of Suppressors of Cytokine Signaling (SOCS) IRS-1 Tyr P Insulin Resistance in Adipose Tissue, Liver and Muscle Inhibitor kb Kinase (IKK) TNFa NF-kB Glut 4 PPARg IRS-1 Perilipin Expression of -SOCS-3 binds the insulin receptor (Tyr960), blocks interaction with IRS-1 and IRS-2. -SOCS-1 bind the kinase domain of the insulin receptor, blocks phosphorylation of IRS-1 and IRS-2. -Inhibition of SOCS activity in obese diabetic animals improves insulin sensitivity, normalizes SREBP-1c expression. Ueki et al. Mol. Cell. Biol. 2003 Ueki et al. PNAS ,2004

  31. Adiponectin • An anti-atherogenic and anti-inflammatory • Adipokine entrained to the insulin sensitivity state made exclusively in the adipocyte • Levels reduced in obesity, T2D, in men vs. women, and in CAD; rises with weight loss • Increases insulin sensitivity by promoting beta oxidation of fatty acids in muscle

  32. TNFa Also Modulates the Expression of Other Adipocyte-derived Hormones TNFa Adiponectin/Acrp30/AdipoQ Fatty Acid Oxidation AMPK FFA Insulin Sensitivity gluconeogenesis In Muscle, Adipose, and/or Liver • Adiponectin knockout animals develop insulin resistance, increased serum NEFAs. • PPARg agonists (thiazolidinediones) stimulate adiponectin expression and increase insulin sensitivity. • Pharmacological potential of adiponectin appears high.

  33. Other Adipose-derived Hormones May Play a Role in Mediating Insulin Resistance Resistin IL-6 Plasminogen Activator Inhibitor 1 Expression and secretion of these factors is increased during the development of type 2 diabetes/obesity Weight loss causes decrease in circulating levels of these factors. Kershaw and Flier, J. Clin. Endocrinol. Metab. 2004

  34. New Point of view Muoio et al, Science, 2004

  35. Approach to modifying insulin resistance • Weight control • Diet • Exercise • Body composition • Weight loss medications • Medications • Insulin sensitizers: metformin, thiazolidinediones

  36. Diabetes therapies and body weight • Metformin (biguanide) inhibits hepatic glucose release and promotes mild weight loss. • Thiazolidinediones (TZDs) increase insulin sensitivity by acting at PPAR gamma. They increase body weight but augment subcutaneous rather than visceral fat

  37. The END!Thank You! Oh, sorry, not the end, just the beginning!

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