Pathogenesis of Diabetes Mellitus

Transcription

1 Pathogenesis of Diabetes Mellitus Young-Bum Kim, Ph.D. Associate Professor of Medicine Harvard Medical School

2 Definition of Diabetes Mellitus a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both. Chronic hyperglycemia of diabetes is associated with long term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels.

3 Diabetes Mellitus in the U.S. Prevalence: Affects >22 million Americans One in every people One-fourth don t know they have it Incidence: ~650,000 new cases annually Impact: Leading cause in adults of: Renal failure Blindness Amputation ~17% of total health care costs used by diabetic patients

4 Diagnosis of Diabetes Mellitus (American Diabetes Association) Fasting serum or plasma glucose >126 mg/dl (7.0 mm)* or 2-hour glucose level >200 mg/dl (11.0 mm)* during 75g oral glucose tolerance test * Glucose levels high enough to cause long-term complications

5 Type 1 Diabetes Insulin-Dependent Diabetes Mellitus (IDDM) juvenile-onset diabetes Immune-mediated selective destruction of b-cells Consequence: loss of insulin (absolute insulin deficiency) Severe hyperglycemia, dehydration, ketoacidosis, death Second most common type (~10%) Appear in childhood or in the early teenage years Requires insulin injections.

6 Type 2 Diabetes Non-Insulin-Dependent Diabetes Mellitus (NIDDM) adult-onset (or maturity-onset) diabetes b-cells are present and often hyperplastic Altered insulin secretion and insulin resistance Associated with obesity (or visceral fat) Most common type (~90%) More genetic influence (identical twin concordance = 60-90% vs % for type 1) Mild hyperglycemia, non-ketotic form of diabetes Treatment requires diet (low sugar, low fat), exercise, drugs and insulin.

7 Gestational Diabetes Appears during pregnancy in women with no previous history of type 1 or 2 diabetes Disappear after delivery Leads to type 2 diabetes (~40% within 15 years) About 135,000 women develop GD each year. Screening between the 24 th and 28 th weeks of pregnancy.

8 Secondary Diabetes Severe pancreatic destruction (pacreatitis, total pancreatectomy) Acquired insulin resistance (acromegaly, Cushing s syndrome) Steroids, nicotinic acid, etc

9 Clinical Manifestations Early symptoms: polyuria polydipsia polyphasia (hyperphagia) weakness altered vision weight loss

10 Diabetic complication Large vessel atherosclerosis Small vessel disease Kidney failure (nephropathy) Blindness (retinopathy) Neuropathy (e.g., foot ulcer)

11 Causes of Type 1 Diabetes Autoimmune Disease - Autoantibodies (islet cell antigens, insulin, GAD) Genetic (HLA-DR on chromosome 6) Viruses Chemicals/drugs (e.g, pentamidine, L-asparaginase)

12 Causes of Gestational Diabetes Placental hormones (hcg, hcs) Genetic influence Obesity

13 Type 2 Diabetes Greater genetic influence vs. type 1 Polygenic, heterogeneous disorders Associated with obesity, aging, and physical inactivity

14 Regulation of Blood Glucose Fasting (or Postabsorptive) State Liver Blood Glucose Brain Other Tissues

15 Regulation of Blood Glucose After Meal Gut Liver Blood Glucose Brain Other Tissues INSULIN

16 Negative Feedback Control of Blood Glucose Blood Glucose Type 2 Diabetes Insulin Resistance INSULIN Type 1 Diabetes Insulin deficiency

17 Plasma Glucose (mg/dl) Three Clinical Stages Diabetes Impaired Normal 120 Oral Glucose Minutes

18 Pathogenesis of Insulin Resistance Increased Insulin Secretion Pancreas Insulin PI3K/Akt Adipose PI3K/Akt Liver Increased Hepatic Glucose Production Glucose PI3K/Akt Impaired Glucose Utilization Muscle

19 Definition of Insulin Resistance Insulin resistance is a physiological condition in which cells fail to respond to the normal actions of the hormone insulin. The body produces insulin, but the cells in the body become resistant to insulin and are unable to use it as effectively, leading to hyperglycemia. Beta cells in the pancreas subsequently increase their production of insulin, further contributing to hyperinsulinemia.

20 I. Glucose Stimulated Insulin Secretion Glucose Insulin Insulin Glucose ADP ATP CO 2 +H 2 O -90 mv Pancreatic β-cell Basal Stimulated K + K + Ca ++ Ca ++

21 II. Regulation of Glucose Production by Insulin Glycogen Glycogenolysis Lactate Amino Acids Glycerol Gluconeogenesis G-6-P Glucose Glucose INSULIN

22 III. Regulation of Glucose Transport by Insulin Insulin Insulin receptor Glucose PIP2 PIP3 Glut4 PI3-kinase IRS-1

23 How insulin resistance can lead to type 2 diabetes Normal IGT Type 2 diabetes Insulin resistance Insulin secretion Blood glucose Adapted from: Edelman SV, In Advances in Internal Medicine 1998; 43: Time

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25 Muscle is the major tissue responsible for insulin-mediated glucose uptake in vivo

26 Etiology of obesity-associated insulin resistance Insulin Insulin receptor Glucose PIP2 PIP3 Glut4 PI3-kinase IRS-1 IRE1 Mitochondrial dysfunction Fat metabolites Inflammation ER stress Accumulation of misfolded protein Alteration in ER homeostasis Nutrient excess Oxidative stress Fat accumulation

27 Insulin Receptor IRSs Akt GSK3 Glucos Glucose-6-P e Glucose transport Glycogen Synthase Glycogen Synthesis Glycolysis

28 Human Insulin Resistance

29 (mg/kg/min) Insulin Resistance and Insulin Signaling Defects in Humans With Obesity and Type 2 Diabetes Glucose Disposal Rate (Whole body) * *# IR and IRS-1 Phosphorylation pir IR pirs-1 Lean Obese Type 2 Diabetes 0 Lean Obese Type 2 Diabetes IRS-1 Insulin:

30 PI3-kinase and Akt Activity in Human Skeletal Muscle AU/mg protein 30 PI3-kinase 100 Akt * Insulin: Lean Obese Type 2 Diabetes Lean Obese Type 2 Diabetes

31 FV (%) Glycogen Synthase Activity in Human Skeletal Muscle * 0 Insulin: Lean Obese Type 2 Diabetes

32 Diabetes (2003)

33 Weight loss Enhances Tyrosine Phosphorylation of IRS-1 and Activity of PI3K/PKCl/z in Muscle of Obese Subjects

34 Diabetes (2002) Thiazolidinediones (TZDs) are a class of insulin sensitizing agents being used for the treatment of type 2 diabetes. The molecular targets of these compounds are thought to include the nuclear receptor peroxisome proliferator-activator receptor-g (PPARg), which regulates the expression of numerous genes involved in glucose and lipid metabolism. Metformin is a member of the biguanide class of compounds, which are also effective at lowering glucose concentrations in patients with type 2 diabetes. Metformin inhibits gluconeogenesis, reduces glucose output, and lowers fasting blood glucose concentration.

35 Troglitazone Therapy Increases Insulin-Stimulated PI3K Activity In Type 2 Diabetic Subjects (% of preinsulin) 200 Troglitazone * 200 Metformin Insulin: Pre Post Pre Post

36 Molecular Mechanism of Human Insulin Resistance Glucose TZD VLCD Insulin receptor GLUT4 vesicle PI3K IRS-1 PKCl/z Akt X GSK3 GLUT4 vesicle Glycogen synthase

37 Fatty Acid-Induced Insulin Resistance

38 .. Lipid Infusion Causes Insulin Resistance mmol/kg/min 300 Glucose Infusion Rate Glycogen Synthesis * 100 * Glycerol Lipid 0 Glycerol Lipid

39 Insulin Stimulation of Glucose Metabolism Glucose Insulin receptor GLUT4 vesicle p110 p85 PDK-1 IRSs P ATP? PKCl/z? Akt/PKB X GLUT4 vesicle GLUT4 GSK3 Glycogen synthase

40 Lipid Infusion Impairs PI3K Activity in Muscle % of saline IRS1 IRS2 Phosphotyrosine * 200 * 200 * Saline Glycerol Lipid 0 Saline Glycerol Lipid 0 Saline Glycerol Lipid Insulin:

41 Lipid Infusion Impairs Insulin-Stimulated Activity of Akt1 but Not Akt2 in Muscle % of saline Akt1 Akt2 Akt * Saline Glycerol Lipid 0 Saline Glycerol Lipid 0 Saline Glycerol Lipid Insulin:

42 Lipid Infusion Impairs PKCl/z Activity in Muscle % of saline 250 PKCl/z Activity PKCl/z Protein * Saline Glycerol Lipid PKCl/z 100 Insulin: Saline Glycerol Lipid Insulin: - + +

43 Effects of Fatty Acids on Insulin Signal Transduction Glucose Insulin receptor GLUT4 vesicle PI 3-kinase PDK-1 IRSs P ATP PKCl/z Akt1 X GLUT4 vesicle GLUT4 GSK3 Glycogen synthase

44 PNAS (2001)

45 Epididymal Inguinal SubQ PTP1B-/- Interscapular BAT WT PTP1B-/- mice are resistant to diet-induced obesity; increased metabolic rate, tendency for increased food intake.

46 Insulin-stimulated glucose metabolism Insulin Insulin receptor Glucose PIP2 PIP3 Glut4 PI3-kinase IRS-1

47 Pathogenesis of Insulin Resistance Brain Pancreas Increased Insulin Secretion Insulin Adipose Increased Hepatic Glucose Production Glucose Impaired Glucose Utilization Liver Muscle