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Pathophysiology of Type 2 Diabetes Deric Morrison October 14, 2009 Objectives Discuss the Pathophysiology of T2DM including: Insulin Secretion Genetic Factors Monogenic Polygenic Environmental factors Insulin Resistance Genetic Factors Environmental factors Introduction Type 2 Diabetes Hyperglycemia Insulin resistance (Skeletal muscle, liver, adipose tissue) - Early Insufficient pancreatic β cell compensation due to irreversible loss of β cell mass – Late Increased hepatic glucose production Genetic and environmental factors Normal IGT* Type 2 diabetes Insulin resistance Increased insulin resistance Insulin secretion Hyperinsulinemia, then -cell failure Post-prandial glucose Abnormal glucose tolerance Fasting glucose Hyperglycemia *IGT = impaired glucose tolerance Adapted from Type 2 Diabetes BASICS. International Diabetes Center (IDC), Minneapolis, 2000. Epidemiology T2DM ~90% of DM burden worldwide ~150 million people in 2005 Estimated ~300 million in 2025 Associated Conditions Hypertension High LDL Low HDL Obesity Metabolic Syndrome Cause? Effect? Pathophysiology The precise way genetic, environmental, and pathophysiologic factors interact to lead to the clinical onset of T2DM is not known Most T2DM is polygenic Some specific monogenic defects largely confined to the pathways that regulate insulin action or β cell function cause DM Monogenic Monogenic - IR Type A insulin resistance Leprechaunism insulin resistance acanthosis nigricans hyperandrogenism intrauterine growth retardation fasting hypoglycemia death within the first 1 to 2 years of life Rabson-Mendenhall syndrome short stature protuberant abdomen abnormalities of teeth and nails Monogenic - IR Lipoatrophic diabetes paucity of fat insulin resistance hypertriglyceridemia Face-sparing partial lipoatrophy (Dunnigan Syndrome) Lamin A/C gene mutation (AD) Congenital generalized lipoatrophy (the SeipBerardinelli syndrome - AR) Monogenic - IS Mutant Insulin Syndromes Hyperinsulinemia Mild DM, but no resistance to exogenous insulin Mitochondrial Diabetes Maternally transmitted Diabetes Sensorineural hearing loss Maturity Onset Diabetes of the Young Gene Molecular Basis MODY-1 HNF-4α MODY-2 Glucokinase Defect in transcription → ↓insulin secretion/β-cell mass ↓ Sn of β-cell to glucose/ ↓ glucose → glycogen MODY Gene Molecular Basis MODY-3 HNF-1α MODY-4 IPF-1 Defect in transcription → ↓insulin secretion/β-cell mass Defect in transcription → Abnormal β-cell development and function MODY Gene Molecular Basis MODY-5 HNF-1β MODY-6 NeuroD1 or β2 Defect in transcription → ↓insulin secretion/β-cell mass Defect in transcription → Abnormal β-cell development and function MODY May account for 1-5% of DM Often mild (especially the most common MODY-2 Glucokinase) Family Hx in successive generations Onset often childhood/adolescence DM2 Genetics High risk in certain ethnic groups Pima Indians ~21% 3.5x risk in 1st degree relatives Monozygotic vs. dizygotic twins 70 vs. 10% concordance DM2 Genetics Common variant-common disease hypothesis (i.e. not Mendelian) Simultaneous occurrence of common DNA sequence variations in many genes that in their sum confer an increased susceptibility toward adverse environmental factors. At least 27 (confirmed and potential) T2DM susceptibility genes have been identified Genome Wide Association Genetics and Insulin Secretion Insulin secretion is stimulated by Glucose Incretins Glucagon Like Peptide (GLP-1) Gastric Inhibitory Polypeptide (GIP) Glucose Taken up via glucose transporters Phosphorylated by glucokinase, metabolized ATP is generated that causes closure of the ATP sensitive potassium channel This provokes membrane depolarization and subsequent opening of a voltage-dependent calcium channel Calcium influx raises the cytosolic calcium concentration, and promotes exocytosis of insulin granules Incretins In the presence of glucose incretins enhance insulin secretion Binding to G protein-coupled transmembrane receptors activates adenylyl cyclase → cAMP cAMP activates protein kinase A, which mediates induction of the insulin gene and exocytosis of insulin granules Insulin Secretion Genetics Hypothesis: individual differences in insulin secretion capacity are predominantly determined by genetics Strengthened by the finding that 18 among those 27 genes mentioned affect β-cell function CAPN10, CDC123/CAMK1D, CDKAL1, CDKN2A/B, ENPP1, FOXO1, HHEX, IGF2BP2, JAZF1, KCNJ11, KCNQ1, MTNR1B, PPARGC1A, SGK1, SLC30A8, TCF7L2, TSPAN8/LGR5 and WFS1 Insulin Secretion Some Single Nucleotide Polymorphisms affect: β-cell response to GLP-1 GIP/GLP-1 levels Proinsulin conversion Free Fatty Acid Levels Leading to decreased β-Cell function β Cell Failure Oversecretion of insulin to compensate for insulin resistance1,2 Glucotoxicity2 Chronic hyperglycemia Lipotoxicity3 High circulating free fatty acids Pancreas Genetic Mutations -cell dysfunction 3Finegood 1Boden G & Shulman GI. Eur J Clin Invest 2002; 32:14–23. 2Kaiser N, et al. J Pediatr Endocrinol Metab 2003; 16:5–22. DT & Topp B. Diabetes Obes Metab 2001; 3 (Suppl. 1):S20–S27. Insulin Resistance Subnormal response to insulin Genetic β-cell defects only apparent when insulin requirements > insulin production Insulin resistance is strongly associated with obesity Environmental factors? Calculating insulin sensitivity BG and insulin levels OGTT Euglycemic clamp Isotope tracer methods Insulin Resistance There are obesity independent genetic factors of insulin resistance e.g. PPAR-γ 2 Isoforms PPAR-γ-1: expressed in a number of tissues and cell types at moderate levels PPAR-γ-2: largely restricted to adipose tissue, where it represents a master regulator of fat cell differentiation Insulin Resistance PPAR-γ-2 P12Avariant ? → ↓ adipose insulin sensitivity→ ↑ release of fatty acids→ ↓ muscle and liver insulin sensitivity PPAR-γ is the target of TZDs → ↑ insulin sensitivity Insulin Resistance May be best predictor of T2DM ↑ with age and weight ? Unmasking defect of β-cell function Leads to Hyperglycemia Hyperglycemia has toxic effects on β-cell Obesity Causes peripheral resistance to insulin-mediated glucose uptake May ↓ sensitivity of β-cells to glucose Potential Exacerbating Factors Abdominal > Peripheral fat β-3-adrenergic receptor mutation ↑ c-Jun amino-terminal kinase (JNK) activity Inflammatory Adipokines (leptin, adiponectin, TNF α, and resistin) ↑ Free fatty acids Leptin Produced by adipocytes, secreted in proportion to adipocyte mass Signals the hypothalamus about the quantity of stored fat Leptin deficiency and leptin resistance → obesity and insulin Leptin may be important for the regulation of beta cell mass/function depending upon diet and presence of insulin resistance Adiponectin Reduces levels of free fatty acids and associated with improved lipid profiles better glycemic control reduced inflammation in diabetic patients inversely associated with risk for diabetes in the nondiabetic population Adiponectin Lower adiponectin levels are more closely related to the degree of insulin resistance and hyperinsulinemia than to the degree of adiposity and glucose intolerance Adiponectin is downregulated in obesity ↓ Adiponectin → ↑ TNF-α and ↑ insulin resistance TNF-α ? major role in insulin action impairment A preliminary study found a strong correlation between the degree of obesity, hyperinsulinemia, and TNF-α mRNA in adipose tissue. In a study of a homogeneous Native Canadian population plasma TNF-α concentrations were positively correlated with insulin resistance Plasminogen activator inhibitor An inhibitor of fibrinolysis, is another protein related to adipocytes. It is also secreted from endothelial cells, mononuclear cells, hepatocytes, and fibroblasts May be associated with an increased risk for T2DM Resistin In obese mice adipocytes secrete resistin Administration of resistin decreases insulinmediated glucose uptake by adipocytes Neutralization of resistin increases insulinmediated glucose uptake by adipocytes Hypothalamic administration of resistin enhances glucose production, independent of changes in glucoregulatory hormones Retinol-binding protein 4 Released from adipocytes Correlates with the degree of insulin resistance in mice, ? humans Intrauterine Development Low birth weight “Thrifty" genotype hypothesis Insulin resistance might improve survival during states of caloric deprivation but would lead to diabetes in states of caloric excess or adequacy. Intrauterine Development Thrifty genotype might be induced by IUGR Inverse relationship between birth weight and DM in Nurses' Health Study (69,000 women) Relative risk of T2DM by ascending birth weight categories decreased progressively Thinness at birth vs. in adult life have opposing effects on insulin resistance Adult, kg/m2 Intrauterine Development Higher birth weight (>4.0 kg) may also be associated with an increased risk of diabetes A meta-analysis of 14 studies (132,180 babies) of birth weight and risk of T2DM U-shaped relationship between birth weight and diabetes risk High birth weight was associated with increased risk of diabetes in later life to the same extent as low birth weight Prematurity independent of birth weight may also be a risk factor for insulin resistance Summary Type 2 Diabetes Hyperglycemia Insulin resistance (Skeletal muscle, liver, adipose tissue) - Early Insufficient pancreatic β cell compensation due to irreversible loss of β cell mass – Late Increased hepatic glucose production Genetic and environmental factors Summary Insulin Resistance Intrauterine Low/High birth weight Prematurity Obesity/Inflammation Central, JNK, FFA, adipokines Genetic PPAR-γ Others Summary Insulin Secretion/β-cell Function Monogenic MODY Polygenic SNPs afffecting Response to glucose Response to incretins Selected References Williams UpToDate