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Glucose homeostasis, pathophysiology of diabetes & ADA Guidelines

Glucose homeostasis, pathophysiology of diabetes & ADA Guidelines. JC Lynch PHPT 726 2007. Glucose homeostasis. Glycogenolysis Catabolism of glycogen. Gluconeogenesis Production of glucose from carbohydrates or proteins. Glycogenolysis & Glucoeogenesis Hepatic Glucose Output.

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Glucose homeostasis, pathophysiology of diabetes & ADA Guidelines

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

  2. Glucose homeostasis

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

  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 • Lipoprotein metabolism • Ketone metabolism • Protein metabolism

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

  8. Glucose Metabolism

  9. Lipoprotein Metabolism

  10. Ketone Metabolism

  11. Protein Metabolism

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

  13. Amylin • Secreted by pancreatic beta-cells • An anorectic hormone • Works on the brain to stimulate the feeling of satiety. • 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 • Stimulates insulin secretion • Decreases glucagon secretion • Slows gastric emptying • Reduces fuel intake (increases satiety) • Improves insulin sensitivity • Increases b-cell mass and improves b-cell function (animal studies)

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

  16. Diabetes Pathophysiology

  17. Diabetes is a Multi-Hormonal Disease • Pancreatic hormones • Insulin (b-cell) • Glucagon (a-cell) • Amylin (b-cell) • Intestinal Hormones (Incretins) • GLP-1 (L-cells) • GIP (K-cells)

  18. Type 1 Diabetes: Pathophysiology • Impaired insulin secretion • Absolute insulin deficiency

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

  20. 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. • Allows the heart and skeletal muscles primarily to use ketone bodies for energy, thereby preserving the limited glucose for use by the brain

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

  22. T2DMDiagnosis characteristics • Insidious • Obesity (almost always), or weight gain • Related to other IRS signs • Hyperlipidemia, acanthosis nigricans • Older (↑Obesity = ↓Age; fatter = younger) • Ethnic links • Family history of T2DM • No ketones

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

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

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

  26. Natural History of T2DM Symptomatic Obesity IGT* Diabetes Hyperglycemia Post-meal Glucose Plasma Glucose Fasting Glucose 120 (mg/dL) Insulin Resistance Relative -Cell Function Diabetes 100 (%) -20 -10 0 10 20 30 Years of Diabetes *IGT = impaired glucose tolerance

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

  28. C Response to Insulin Resistance:The Pancreatic b Cell (early T2DM) Genes Environment INSULIN RESISTANCE Normal b cells Abnormal b cells Hyperinsulinemia (normal glucose) Hyperglycemia (relative insulin deficiency)

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

  30. Relative Organ Contribution to Decreased Glucose Uptake 7 6 5 4 3 2 1 0 Splachnic Adipose Insulin-stimulated Glucose Uptake (mg/kg/min) Muscle Brain Control T2DM Adapted from DeFronzo RA. Diabetes 1988;37:667–687.

  31. C Insulin Resistance:Inherited and Acquired Influences Inherited Acquired Rare Mutations l Insulin receptorl Glucose transporterl Signalling proteins Common Forms l Largely unidentified l Inactivity l Obesity l Stress l Medications l Glucose toxicity l Lipotoxicity INSULIN RESISTANCE

  32. Atypical diabetes

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

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

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

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

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

  38. Diagnosis of GDM with a 100-g oral glucose load

  39. A1C monitoring

  40. For every 1% point of increase in A1c add 35mg/dl of glucose.

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

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

  43. Case #1

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