When you steal from one author, it's plagiarism; if you steal from many, it's research

1. When you steal from one author, it's plagiarism; if you steal from many, it's research Wilson Mizner

2. Normal Pancreatic Function • Exocrine pancreas aids digestion • Bicarbonate • Lipase • Amylase • Proteases • Endocrine pancreas (islets of Langerhans) • Beta cells secrete insulin • Alpha cells secrete glucagon • Other hormones

3. Insulin Insulin Insulin Insulin Stimulates Cellular Glucose Uptake Adipocytes Skeletal Muscle Liver Intestine & Pancreas

8. Type 1 Diabetes:Hallmarks • Progressive destruction of beta cells • Decreased or no endogenous insulin secretion • Dependence on exogenous insulin for life

9. Absence of Insulin • Glucose cannot be utilized by cells • Glucose concentration in the blood rises • Blood glucose concentrations can exceed renal threshold • Glucose is excreted in urine

10. Presenting Symptoms of Type 1 Diabetes • Polyuria: Glucose excretion in urine increases urine volume • Polydipsia: Excessive urination leads to increased thirst • Hyperphagia: “Cellular starvation” increases appetite

11. Type 1 Diabetes Mellitus:Background • Affects ~1 million people • Juvenile onset • Genetic component • Autoimmune/environmental etiology

12. Insulin Glycerol Lipolysis Free fatty acids Triglyceride Synthesis Free fatty acids Glucose LPL Insulin Normal

13. Triglyceride LPL Type 1 Diabetes Mellitus Glycerol Lipolysis Free fatty acids Synthesis Free fatty acids Glucose

14. Normal Fasting blood glucose < 100 mg/dL Serum free fatty acids ~ 0.30 mM Serum triglyceride ~100 mg/dL Uncontrolled Type 1 Fasting blood glucose up to 500 mg/dL Serum free fatty acids up to 2 mM Serum triglyceride > 1000 mg/dL Clinical Chemistry

15. Insulin Regulation of Hepatic Fatty Acid Partitioning FA-CoA TG ATP, CO2 -hydroxybutyrate acetoacetate Mitochondrion

16. In Liver:FFA Entry into Mitochondria is Regulated by Insulin/Glucacon Malonyl CoA carnitine carnitine FA-CoA CPT-II FA-CoA CPT-I ATP, CO2 HB, AcAc inner outer TG Mitochondrial membranes CPT= Carnitine Palmitoyl Transferase

17. Malonyl CoA is a Regulatory Molecule • Condensation of CO2 with acetyl CoA forms malonyl CoA • First step in fatty acid synthesis • Catalyzed by acetyl CoA carboxylase • Enzyme activity increased by insulin

18. Ketone Bodies • Hydroxybutyrate, acetoacetate • Fuel for brain • Excreted in urine • At 12-14 mM reduce pH of blood • Can cause coma (diabetic ketoacidosis)

19. Natural History Of “Pre”–Type 1 Diabetes Putative trigger -Cell mass 100% Cellular autoimmunity Circulating autoantibodies (ICA, GAD65) Loss of first-phase insulin response (IVGTT) Clinical onset— only 10% of-cells remain Glucose intolerance (OGTT) Genetic predisposition Insulitis-Cell injury “Pre”-diabetes Diabetes Time Eisenbarth GS. N Engl J Med. 1986;314:1360-1368 14

20. Case 1R.T., a 15-year-old male with type 1 diabetes presented with a 5-day history of nausea and vomiting. He also reported a 2-week history of polyuria and polydipsia and a 10-lb weight loss. The patient was diagnosed with type 1 diabetes 2 years ago when he presented to a different hospital with symptoms of polyuria, polydipsia, and weight loss. The laboratory data showed an anion gap, metabolic acidosis, and hyperglycemia (pH of 7.14, anion gap of 24, bicarbonate 6 mmol/l, urinary ketones 150 mg/dl, glucose 314 mg/dl) consistent with the diagnosis of DKA. The patient's hemoglobin A1c (A1C) was 13.5%.

21. The Miracle of Insulin February 15, 1923 Patient J.L., December 15, 1922

24. Primary Defect in Type 2 • Study healthy 1st degree relatives of patients with type 2 • Measure ability of body to use glucose • Find defects in muscle glucose uptake before any symptoms develop

25. Why is Glucose Transport Reduced? • Mitochondrial phosphorylation decreased 30% • Intramyocellular lipid is increased 80% • Ectopic fat may hinder insulin-stimulation of glucose transport.

26. What is consequence of muscle insulin resistance? • Pancreas compensates > hyperinsulinemia • Hyperinsulinemia exacerbates insulin resistance in adipose tissue.

27. Consequences of Insulin Resistance in Adipose Tissue • Similar to insulin deficiency • Reduced TG synthesis • Enhanced lipolysis • Net increase in FA availability to non-adipose tissues

28. Consequences of Insulin Resistance FFA in Muscle • Increased intramyocellular lipid • Hypothetical: inhibition of insulin signaling by diglyceride • Reduction in glucose uptake by muscle

29. Consequences of Insulin ResistanceFFA in Liver • Increased triglyceride synthesis • Increased oxidation • Increased gluconeogenesis • Hepatic glucose output contributes to hyperglycemia

30. Consequences of Insulin ResistanceFFA in Pancreas • Animal models of diabetes • Lipid droplets accumulate in beta cells • Beta cells undergo apoptosis • Reduced beta cell mass • Decreased circulating insulin

34. KEY POINTS ■ Resistance to the actions of insulin is strongly associated with the microvascular complications of diabetes, independently of metabolic control and hypertension ■ Insulin resistance is an important marker of risk and a key target for intervention, as those patients who achieve a greater improvement of insulin sensitivity achieve better microvascular outcomes ■ Diabetes and obesity are associated with pathway-selective insulin resistance in the phosphatidylinositol-3-kinase signaling pathway, while signaling via extracellular signal-regulated kinase dependent pathways is comparatively unaffected, tipping the balance of insulin’s actions in favor of abnormal vasoreactivity, angiogenesis, and other pathways implicated in microangiopathy ■ Insulin resistance is able to enhance key pathways involved in hyperglycemia-induced microvascular damage and to exacerbate hypertension ■ The strong association between insulin resistance and microvascular disease might also reflect a common genotype or phenotype