Metabolism week 13_2.pdf

Type 2 Diabetes, Obesity & Insulin Resistance Dr. Rose Tkacova BMS 150 Week 13 Diabetes - epidemiology Prevalence = 25 million in US § 1/3 don’t know they have it § 54 million have “pre-diabetes” Abnormal findings on OGTT suggest impairment of insulin f...

Type 2 Diabetes, Obesity & Insulin Resistance Dr. Rose Tkacova BMS 150 Week 13 Diabetes - epidemiology Prevalence = 25 million in US § 1/3 don’t know they have it § 54 million have “pre-diabetes” Abnormal findings on OGTT suggest impairment of insulin function 5-10% will progress to overt diabetes per year § 1.5 million new cases every year Other countries are developing an increased prevalence of the disease (India, China) Races at higher risk: Aboriginal people, Hispanics, African ancestry § 1.5 – 2X higher risk (certain subgroups, i.e. Pima aboriginals, very high risk) Type II Diabetes 90%+ of cases § Usually diagnosed in those > 30 years often preceded by insulin resistance and glucose intolerance for some time, even in childhood § Characterized by initial insulin resistance, followed (in many) by inadequate or almost absent insulin secretion Progression takes years to decades 80% are obese § Twin concordance rate between 70 and 90% - strong genetic as well as environmental influences Type II DM - etiology Just bad (enjoyable?) living? § Although proper diet and adequate activity reduce the progression of T2DM (and neglecting these lifestyle factors will hasten it)… § there is a phenomenal genetic component to type II DM – more than type I monozygotic twin concordance is 70 - 90% for Type II vs. about 30-50% for Type I 70+ genes have been identified, many of them involved in insulin secretion Genes implicated in Type II DM Over 70 discovered so far… § each one has a rough ability to increase the relative risk of expressing diabetes by ~ 5% (RR 1.05) § Notables: TCF7L2 gene (transcription factor that works on a WIDE variety of genes, including Wnt pathway genes) PPAR receptor (transcription factor/nuclear receptor that binds free fatty acids and/or prostaglandins) IRS genes However, the 70 discovered are thought to only contribute to 10% of the genetic risk Type II DM - etiology Most important environmental risk factor: obesity leading to insulin resistance § central obesity seems to be more crucial § a separate risk factor from obesity is lack of exercise Why does insulin resistance occur? § rarely monogenic problems in insulin transduction § usually a combination of factors, involving numerous genes and environmental risk factors  Obesity & Insulin Resistance Obesity, particularly visceral or central (as evidenced by the hip-waist ratio), is very common in type 2 DM (≥80% of patients are obese). Reduced glucose utilization in skeletal muscle Abnormal fat metabolism Systemic low-grade inflammation Type 2 Diabetes: Pathogenesis Healthy Type 2 Diabetes Insulin Resistance Type II Diabetes pathophysiology Obesity FAQs Is obesity really genetic? ▪ Sometimes “very genetic”, usually “not super genetic” ▪ Thought that less than 5% of population-wide variance in body weight is due to “genetics”, but environment- gene interactions make this very difficult to study Do obese people eat more? ▪ Often, but not always In studies that do not record exact caloric intake, often there is a poor association between body weight and questionnaire-reported caloric intake In studies that record caloric intake, the association is better Obese people and those with glucose intolerance often have impaired satiety mechanisms – i.e. poorly- characterized “leptin resistance” Obesity FAQs Do obese people “burn less energy”? ▪ This is a complicated question: In states where weight loss is not occurring, the obese person seems to use more calories than someone who is lean In states where weight loss is occurring, the obese person seems to use less calories than someone who is lean Consensus is that many obese people do have reduced BMR, though most don’t  Regulation of body weight and appetite Satiety signals: Leptin, GLP1, CCK, PYY, vagal afferents “Hunger” signals: Ghrelin (released by the stomach during fasting) All of these act on different nuclei in the hypothalamus Controllers of appetite  Obesity & chronic inflammation Why is visceral obesity so bad for you? ▪ excessive lipid build-up can stress the adipocyte (ROS) ▪ free fatty acids in high concentrations may bind to PAMP-R within the adipocyte both of the above can lead As shown above, pro- to the production of IL-6 inflammatory cytokines lead and TNF-alpha by the adipocyte to insulin resistance, and eventually type II diabetes Type II Diabetes pathophysiology Role of insulin resistance First, impaired insulin action (sensitivity) = insulin resistance § Insulin resistance and abnormal fat and skeletal muscle metabolism Second, impaired insulin secretion § Absolute or relative insulin deficiency (relative = should be secreting more insulin for the level of hyperglycemia) § This is usually accompanied by an imbalance in the insulin/ glucagon “activity ratio” ! increased glucagon action at the liver, increased hepatic production of glucose Pathophysiologic pearl: it seems like to progress to overt T2DM, you need impaired insulin secretion, which seems to arise after a long history of insulin resistance § concept of “islet cell burnout” after years of increased insulin Development of insulin resistance Increased free fatty acids and adipocyte endocrine dysfunction – see next slide § lack of insulin results in excessive activity of lipoprotein lipase ! increased FFA Reduced incretin release § incretins (GIP, GLP-1) are released by the GI tract in response to a meal – they: decrease gastric emptying ! satiety increase insulin release reduce glucagon secretion Insulin receptor desensitization due to chronically high levels of serum glucose Pathophysiology - A focus on fat… Non-esterified fatty acids (NEFA or FFA) increase insulin resistance § More released from central fat than peripheral fat ▪ NEFAs are released from adipose tissue through the process of lipolysis ▪ Stimulated by hormones such as glucagon and adrenaline during times when energy demand is high, such as fasting or exercise. ▪ Once released into the bloodstream, NEFAs can be taken up and oxidized by various tissues to produce energy. § Increased intracellular concentrations of NEFA cause serine phosphorylation of insulin receptor – which inactivates it (tyrosine phosphorylation activates it) Pathophysiology - A focus on fat… Adipokines modify sensitivity of insulin receptor § Adipose tissue is endocrine tissue – protein hormones from fat cells (adipokines) increase sensitivity of insulin receptor and increase activity of enzymes that oxidize NEFA Increased NEFA oxidation mediated by AMP-K, a protein kinase activated by metformin Anti-hyperglycemic adipokines: leptin, adiponectin (drops in T2DM) Hyperglycemic adipokines: resistin, retinol-binding-protein 4 Pro-inflammatory cytokines also secreted by fat cells, and decrease insulin receptor sensitivity 19 Insulin Resistance - A focus on fat… Non-esterified fatty acids (NEFA) increase insulin resistance ▪ More released from central fat than peripheral fat ▪ Increased intracellular concentrations of NEFA cause serine phosphorylation of insulin receptor – which inactivates it (tyrosine phosphorylation activates it) Adipokines modify sensitivity of insulin receptor ▪ Adipose tissue is endocrine tissue – protein hormones from fat cells (adipokines) increase sensitivity of insulin receptor and increase activity of enzymes that oxidize NEFA Increased NEFA oxidation mediated by AMP-K, a protein kinase activated by metformin Anti-hyperglycemic adipokines: leptin, adiponectin (drops in T2DM) Hyperglycemic adipokines: resistin, retinol-binding-protein 4 Pro-inflammatory cytokines also secreted by fat cells, and decrease insulin receptor sensitivity Insulin Resistance and Dyslipidemia More VLDL is produced in those that are insulin- resistant ▪ More circulating FFAs from insulin-resistance adipocytes ▪ The liver produces more VLDL, fatty acids, and triglycerides Lipoprotein lipase is down-regulated in a wide variety of tissues in those that are insulin-resistant ▪ Reduced production of LPL, especially in skeletal muscle and adipose tissue ▪ A type of ApoC protein (ApoC-III) is produced in insulin- resistant states by the liver – it inhibits LPL HDL is also reduced during insulin resistance ▪ Mechanism is unclear 22 Complications of long- term hyperglycemia Remember: DM is associated with - Small vessels disease - Large vessels disease Diabetes – large vessel disease Endothelial dysfunction predisposes to atherosclerosis Hallmark of diabetic macrovascular disease: accelerated atherosclerosis involving aorta and large- and medium- sized arteries § Diabetic atherosclerosis looks the same as non- diabetic atherosclerosis, but more severe and with an earlier onset § MI caused by atherosclerosis of the coronary arteries is most common cause of death in diabetics § Gangrene of lower extremities - result of advanced peripheral vascular disease 100 times more common in diabetics than in general population Atherosclerosis – in brief Development of atheromas results from: § endothelial dysfunction ! deposition of LDL in arterial wall ! oxidation of LDL (may happen before) ! phagocytosis of oxLDL ! activation of macrophages ! growth and necrosis in the atherosclerotic plaque Atherosclerosis will be discussed in much more detail next week DM II - Clinical Features Insidious, usually asymptomatic initially § 80% are obese § DKA is rare Some chronic diabetics develop hyper-osmolar non-ketotic crises (HONK) results in severe dehydration, impaired level of consciousness and hyperosmolarity due to massively elevated serum glucose § Slowly developing peripheral neuropathy, impaired wound healing, impaired vision acanthosis nigricans an early sign of insulin resistance in some § atherosclerosis is usually asymptomatic until angina or a heart attack occurs Also at higher risk of stroke § renal failure is usually asymptomatic Acanthosis Nigricans Hyperpigmented, velvety patches of skin in axillary regions and neck (typically).