1. Lecture 26 Non-insulin dependent diabetes mellitus (NIDDM) Maturity onset diabetes Type 2 diabetes

2. Statistics 150 million people with diabetes worldwide –will rise to 300 million by 2025. In Australia about 10% of the population aged 25 or over had diabetes –>20% of the population aged over 60 –Prevalence more than doubled in Australia since 1980s 16% have of impaired glucose metabolism Huge increase in cardiovascular risk factors Major ethnic differences in susceptibility to type 2 diabetes –Micronesian, Polynesian, Aboriginal and Torres Strait Islander, Indian or Chinese background at substantially increased risk. Increased in lower socioeconomic groups in developed countries but higher socioeconomic groups in developing countries

3. Insulin Resistance Inability of tissues to respond to normal levels of insulin –Insulin normally: Increases muscle and adipocyte glucose uptake (via GLUT-4 translocation) Increases glycogenesis, lipogenesis and other anabolic processess Decreases glycogenolysis, lipolysis, proteolysis, gluconeogenesis –Insulin acts via tetrameric receptor Tyrosine phosphorylation IRS-I, various protein kinases/phosphatases, etc All processes malfunctioning in IR –Receptor phosphorylation, receptor number, GLUT-4, IRS-1 phosphorylation, etc, etc

4. Measurement of IR In vitro –Just incubate tissues with insulin and measure responses In vivo –Euglycemic Clamp Infusion of insulin to achieve constant, desired plasma [insulin] Glucose infused simultaneously to keep plasma [glucose] at 5 mM Rate of glucose infusion required proportional to insulin sensitivity

5. Insulin Sensitivity & NIDDM Insulin Sensitivity fasting blood [glucose] (mM) high low 481216 sensitive resistant diabetic

6. Response to Glucose Load Blood [Glucose] mM Time (h) 10 5 00.51.01.5 resistant sensitive diabetic

7. Response to Glucose Load Blood [insulin] Time (h) high low 00.51.01.5 diabetic sensitive resistant

8. Most common hypothesis Insulin resistance occurs first.. Causes secretion of more insulin… Eventually pancreas can’t keep up –“Pancreatic exhaustion” Overt hyperglycemia develops Pancreas going at full speed – unable to accelerate –First phase secretion lost Time course insidious –Makes detection and research difficult –Symptoms indicative of disease presence for a while

9. Complications The secondary complications of hyperglycemia –Glycosylation: Retinopathy, blood vessel disease, nephropathy –Polyol pathway: neuropathy  Blindness, impotence, kidney disease, amputation, atherosclerosis –Complications appear BEFORE you know you’re diabetic

10. Cause of IR Strong genetic component –Identical twins >90% concordant –Indigenous populations Environment Important –Increased incidence over last century –Genotype clearly hasn’t changed!! What’s changed? –Lifestyle, exercise, habits, –Most commonly associated with obesity (>80% of cases) –DIET!

11. Diet & Insulin Resistance Increased fat consumption –Specifically saturated fat Widely used animal model –Rapid development of IR Perhaps not mimicked in humans Changed carbohydrate quality –Amylopectin vs Amylose Amylose – slowly absorbed, low glycemic index –Preserves insulin sensitivity Amylopectin – rapidly absorbed, high GI –May elicit or promote insulin resistance

12. Treatment Exercise –Brilliant, but unpopular! Diet –Low calorie, low saturated fat, low GI –Great, but unpopular Insulin –To combat the insulin resistance –Danger of hypoglycemia –Anabolic – so increases weight! –Popular!!

13. Drugs –Very popular! –Sulphonylureas Increase insulin secretion Restore 1 st phase insulin secretion Risk of hypoglycemia, weight gain –Thiazoledinediones Increase insulin sensitivity Agonists of PPAR-gamma –Transcription factor involved in adipocyte development