1. Glucose homeostasis, pathophysiology of diabetes & ADA Guidelines JC Lynch PHPT 726 2007

2. Glucose homeostasis

3. Glycogenolysis & Glucoeogenesis Hepatic Glucose Output Glycogenolysis Glycogenolysis –Catabolism of glycogen. Gluconeogenesis Gluconeogenesis –Production of glucose from carbohydrates or proteins.

4. (this is the simple slide: know this first)

5. Comparison of normal glucose patterns to patient with diabetes (probably type 1).

6. Direct Effects of Insulin Glucose metabolism Glucose metabolism Lipoprotein metabolism Lipoprotein metabolism Ketone metabolism Ketone metabolism Protein metabolism Protein metabolism

7. Insulin Action: Definitions Insulin Sensitivity Ability of insulin to lower circulating glucose concentrations Ability of insulin to lower circulating glucose concentrations Insulin Resistance Condition of low insulin sensitivity

8. Glucose Metabolism Major Metabolic Effects of Insulin Consequences of Insulin Deficiency Stimulates glucose uptake into muscle and adipose cells Stimulates glucose uptake into muscle and adipose cells Inhibits hepatic glucose production Inhibits hepatic glucose production Hyperglycemia  osmotic diuresis and dehydration Hyperglycemia  osmotic diuresis and dehydration

9. Lipoprotein Metabolism Major Metabolic Effects of Insulin Consequences of Insulin Deficiency Inhibits breakdown of triglycerides (lipolysis) in adipose tissue Inhibits breakdown of triglycerides (lipolysis) in adipose tissue Elevated FFA levels Elevated FFA levels

10. Ketone Metabolism Major Metabolic Effects of Insulin Consequences of Insulin Deficiency Inhibits ketogenesis Inhibits ketogenesis Ketogenesis: is the process by which ketone bodies are produced as a result of fatty acid breakdown. Ketogenesis: is the process by which ketone bodies are produced as a result of fatty acid breakdown. Ketoacidosis Ketoacidosis

11. Protein Metabolism Major Metabolic Effects of Insulin Consequences of Insulin Deficiency Stimulates amino acid uptake and protein synthesis Stimulates amino acid uptake and protein synthesis Inhibits protein degradation Inhibits protein degradation Regulates gene transcription Regulates gene transcription Muscle wasting Muscle wasting Others Others

12. Insulin and Amylin Co-secreted Amylin Insulin Without Diabetes n = 6 Plasma insulin (pM)Plasma amylin (pM) 30 25 20 15 10 5 7 amMidnight5 pm12 noon Time 600 400 200 0 Meal Koda et al, Diabetes. 1995; 44 (s1): 23BA. Data on file. (Fineman)

13. Amylin Secreted by pancreatic beta-cells Secreted by pancreatic beta-cells An anorectic hormone An anorectic hormone Works on the brain to stimulate the feeling of satiety. Works on the brain to stimulate the feeling of satiety. This results in decreased G.I. motility, slowed carbohydrate absorption, and decreased appetite. This results in decreased G.I. motility, slowed carbohydrate absorption, and decreased appetite.

14. GLP-1 “Incretin” hormone secreted by jejunal and ileal L cells in response to a meal “Incretin” hormone secreted by jejunal and ileal L cells in response to a meal Stimulates insulin secretion Stimulates insulin secretion Decreases glucagon secretion Decreases glucagon secretion Slows gastric emptying Slows gastric emptying Reduces fuel intake (increases satiety) Reduces fuel intake (increases satiety) Improves insulin sensitivity Improves insulin sensitivity Increases  -cell mass and improves  - cell function (animal studies) Increases  -cell mass and improves  - cell function (animal studies)

15. GLP-1 release following meal: comparison of control, T2DM & IGT

17. Diabetes Pathophysiology

18. Diabetes is a Multi-Hormonal Disease Pancreatic hormones Pancreatic hormones –Insulin (  -cell) –Glucagon (  -cell) –Amylin (  -cell) Intestinal Hormones (Incretins) Intestinal Hormones (Incretins) –GLP-1 (L-cells) –GIP (K-cells)

19. Type 1 Diabetes: Pathophysiology Impaired insulin secretion Impaired insulin secretion –Absolute insulin deficiency

20. T1DM Typically autoimmune (~90%) Typically autoimmune (~90%) Beta-cells destroyed by multiple antibodies. Beta-cells destroyed by multiple antibodies. Can occur at any age (but more in kids) Can occur at any age (but more in kids) Fast progression (the older the slower) Fast progression (the older the slower) Related to ketones @ Related to ketones @ –Urine ketones –Ketoacidosis  Weight loss, N&V, lethargy

21. Ketogenesis Normal physiological responses to carbohydrate shortages cause the liver to increase the production of ketone bodies from the acetyl-CoA generated from fatty acid oxidation. Normal physiological responses to carbohydrate shortages cause the liver to increase the production of ketone bodies from the acetyl-CoA generated from fatty acid oxidation. Allows the heart and skeletal muscles primarily to use ketone bodies for energy, thereby preserving the limited glucose for use by the brain Allows the heart and skeletal muscles primarily to use ketone bodies for energy, thereby preserving the limited glucose for use by the brain

22. Honeymooning The ability of the failing b-cells to become hyper-productive and compensate for failing insulin response.

23. T2DM Diagnosis characteristics Insidious Insidious Obesity (almost always), or weight gain Obesity (almost always), or weight gain Related to other IRS signs Related to other IRS signs –Hyperlipidemia, acanthosis nigricans Older ( ↑Obesity = ↓Age; fatter = younger ) Older ( ↑Obesity = ↓Age; fatter = younger ) Ethnic links Ethnic links Family history of T2DM Family history of T2DM No ketones No ketones

24. Acanthosis Nigricans Hyperpigmented, velvety patches of skin in axillary regions and neck (typically).

25. Type 2 Diabetes: Pathophysiology Impaired insulin secretion Impaired insulin secretion –Absolute or relative insulin deficiency Impaired insulin action (sensitivity) Impaired insulin action (sensitivity) –Insulin resistance

26. Dual Metabolic Abnormalities in Type 2 Diabetes Excessive Hepatic Glucose Output Decreased Glucose Uptake Insulin Deficiency Insulin Resistance Decreased Insulin Secretion Unrestrained Lipolysis

27. Natural History of T2DM *IGT = impaired glucose tolerance Years of Diabetes Symptomatic Obesity IGT* Diabetes Hyperglycemia Relative  -Cell Function 100 (%) -20-100102030 PlasmaGlucose Insulin Resistance Diabetes 120 (mg/dL) Fasting Glucose Post- meal Glucose

28. Insulin Resistance Glucose Intolerance Obesity Dyslipidemia (High TG, Low HDL) Cardiovascular Disease Hypertension PCOS Insulin Resistance Syndrome (Metabolic Syndrome)

29. Response to Insulin Resistance: The Pancreatic  Cell (early T2DM) EnvironmentGenes INSULIN RESISTANCE Hyperglycemia (relative insulin deficiency) Hyperinsulinemia (normal glucose) Normal  cells Abnormal  cells C

30. Hepatic Insulin Resistance (T2DM) Adapted from Consoli A. Diabetes 1989;38:550–557. Hepatic glucose output (µmol/kg/min) CON 25 20 15 10 5 0 T2DM Glycogenolysis Gluconeogenesis

31. Relative Organ Contribution to Decreased Glucose Uptake ControlT2DM Adapted from DeFronzo RA. Diabetes 1988;37:667–687. Brain Muscle Adipose 7654321076543210 Splachnic Insulin-stimulated Glucose Uptake (mg/kg/min)

32. Insulin Resistance: Inherited and Acquired Influences Rare Mutations Insulin receptor Glucose transporter Signalling proteins Common Forms Largely unidentified Inactivity Obesity Stress Medications Glucose toxicity Lipotoxicity INSULIN RESISTANCE AcquiredInherited C

33. AgentTarget Site(s) of action Insulins/Analogues Insulin receptor Liver, muscle, fat Sulfonylureas Phenylalanine Der. Meglitinides SFU receptor K-ATP Channel Pancreatic  cell MetorminUnknown Liver (muscle) Glucosidase inhibitors  -glucosidase Intestine Thiazolidinediones PPAR-  Muscle (liver, fat) Exenatide GLP-1 receptors Pancreas Vildagliptin DPP 4 (inhibition) Enzymatic

34. Atypical diabetes

35. Idiopathic type 1 diabetes Also known as “Flatbush diabetes” Also known as “Flatbush diabetes” African American and Asian men (18-25) African American and Asian men (18-25) Fluctuating insulin secretion Fluctuating insulin secretion No antibodies No antibodies Many honeymoons Many honeymoons

36. LADA Latent autoimmune diabetes of adulthood Latent autoimmune diabetes of adulthood Like type 1 but diagnosed after age 25. Like type 1 but diagnosed after age 25. ~20% of those with diagnosis of T2 may actually have LADA. ~20% of those with diagnosis of T2 may actually have LADA. Slower onset than type 1 dm. Slower onset than type 1 dm. Positive antibodies. Positive antibodies. Low or no c-peptide Low or no c-peptide No family history No family history

37. MODY Maturity Onset Diabetes of the Young Maturity Onset Diabetes of the Young A collection of many (at least 6) inherited diseases affecting insulin secretion. A collection of many (at least 6) inherited diseases affecting insulin secretion. Dominant inheritance characteristics Dominant inheritance characteristics Normal insulin sensitivity Normal insulin sensitivity Impaired insulin secretion (but still some). Impaired insulin secretion (but still some). Diagnosis confirmed by genetic testing. Diagnosis confirmed by genetic testing.

38. Pancreatic Diabetes Results from a failure of the pancreas as a whole. Results from a failure of the pancreas as a whole. May be secondary to ETOH abuse, trauma, repeat pancreatitis. May be secondary to ETOH abuse, trauma, repeat pancreatitis. Exocrine pancreas generally fails before endocrine pancreas. Exocrine pancreas generally fails before endocrine pancreas. Will need pancreatic enzyme replacement as well as insulin. Will need pancreatic enzyme replacement as well as insulin.

39. Gestational diabetes Any glucose intolerance first diagnosed during pregnancy Any glucose intolerance first diagnosed during pregnancy –Some definitions require return to normal following end of pregnancy. Closely related to T2DM Closely related to T2DM Treat only with insulin Treat only with insulin –Some data support the use of SUs & metformin.

40. mg/dlmmol/l Fasting955.3 1-h18010.0 2-h1558.6 3-h1407.8 Diagnosis of GDM with a 100-g oral glucose load

41. A1C monitoring

42. For every 1% point of increase in A1c add 35mg/dl of glucose. A1c (%)Mean Plasma glucose mg/dl 6135 7170 8205 9240 10275 11310 12345

43. False A1C Readings Elevated Elevated –Iron deficiency anemia –Splenectomy Decreased Decreased –Hemolytic anemia –Sickle cell anemia –Transfusion

44. ADA Guidelines http://www.diabetes.org/

45. Case #1