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Glucose homeostasis, pathophysiology of diabetes & ADA Guidelines JC Lynch PHPT 726 2007 Glucose homeostasis Glycogenolysis & Glucoeogenesis Hepatic Glucose Output Glycogenolysis – Catabolism of glycogen. Gluconeogenesis – Production of glucose from carbohydrates or proteins. (this is the simple slide: know this first) Comparison of normal glucose patterns to patient with diabetes (probably type 1). Direct Effects of Insulin Glucose metabolism Lipoprotein metabolism Ketone metabolism Protein metabolism Insulin Action: Definitions Insulin Sensitivity Ability of insulin to lower circulating glucose concentrations Insulin Resistance Condition of low insulin sensitivity Glucose Metabolism Major Metabolic Effects of Insulin Stimulates glucose uptake into muscle and adipose cells Inhibits hepatic glucose production Consequences of Insulin Deficiency Hyperglycemia osmotic diuresis and dehydration Lipoprotein Metabolism Major Metabolic Effects of Insulin Consequences of Insulin Deficiency Inhibits Elevated breakdown of triglycerides (lipolysis) in adipose tissue FFA levels Ketone Metabolism Major Metabolic Effects of Insulin Inhibits ketogenesis Ketogenesis: is the process by which ketone bodies are produced as a result of fatty acid breakdown. Consequences of Insulin Deficiency Ketoacidosis Protein Metabolism Major Metabolic Effects of Insulin Stimulates amino acid uptake and protein synthesis Inhibits protein degradation Regulates gene transcription Consequences of Insulin Deficiency Muscle Others wasting Insulin and Amylin Co-secreted Meal Meal Meal 30 Plasma amylin (pM) Without Diabetes n=6 20 400 15 200 10 5 0 7 am 12 noon 5 pm Time Koda et al, Diabetes. 1995; 44 (s1): 23BA. Data on file. (Fineman) Midnight Plasma insulin (pM) 600 25 Insulin Amylin 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. 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 bcell function (animal studies) GLP-1 release following meal: comparison of control, T2DM & IGT Diabetes Pathophysiology 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) Type 1 Diabetes: Pathophysiology Impaired insulin secretion – Absolute insulin deficiency 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 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 Honeymooning The ability of the failing b-cells to become hyper-productive and compensate for failing insulin response. T2DM Diagnosis 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 Acanthosis Nigricans Hyperpigmented, velvety patches of skin in axillary regions and neck (typically). Type 2 Diabetes: Pathophysiology Impaired insulin secretion – Absolute or relative insulin deficiency Impaired insulin action (sensitivity) – Insulin resistance Dual Metabolic Abnormalities in Type 2 Diabetes Insulin Resistance Decreased Glucose Uptake Unrestrained Lipolysis Excessive Hepatic Glucose Output Insulin Deficiency Decreased Insulin Secretion Natural History of T2DM Obesity IGT* Diabetes Symptomatic Hyperglycemia Post-meal Glucose Plasma Glucose Fasting Glucose 120 (mg/dL) Insulin Resistance Relative b-Cell Function Diabetes 100 (%) -20 *IGT = impaired glucose tolerance -10 0 10 Years of Diabetes 20 30 Insulin Resistance Syndrome (Metabolic Syndrome) Glucose Intolerance Dyslipidemia Hypertension Insulin Resistance PCOS Obesity (High TG, Low HDL) Cardiovascular Disease Response to Insulin Resistance: The Pancreatic b Cell (early T2DM) Genes C Environment INSULIN RESISTANCE Normal b cells Hyperinsulinemia (normal glucose) Abnormal b cells Hyperglycemia (relative insulin deficiency) Hepatic Insulin Resistance (T2DM) Hepatic glucose output (µmol/kg/min) 25 20 Glycogenolysis 15 10 5 Gluconeogenesis 0 CON T2DM Adapted from Consoli A. Diabetes 1989;38:550–557. Relative Organ Contribution to Decreased Glucose Uptake 7 6 5 Adipose Splachnic 4 Muscle 3 2 1 Brain 0 Control T2DM Adapted from DeFronzo RA. Diabetes 1988;37:667–687. Insulin Resistance: Inherited and Acquired Influences Inherited Rare Mutations Insulin receptor Glucose transporter Signalling proteins Common Forms Largely unidentified C Acquired INSULIN RESISTANCE Inactivity Obesity Stress Medications Glucose toxicity Lipotoxicity Agent Target Site(s) of action Insulins/Analogues Insulin receptor Liver, muscle, fat Sulfonylureas Phenylalanine Der. Meglitinides SFU receptor K-ATP Channel Pancreatic b cell Metormin Unknown Liver (muscle) Glucosidase inhibitors a-glucosidase Intestine Thiazolidinediones PPAR-g Muscle (liver, fat) Exenatide GLP-1 receptors Pancreas Vildagliptin DPP 4 (inhibition) Enzymatic Atypical diabetes Idiopathic type 1 diabetes Also known as “Flatbush diabetes” African American and Asian men (18-25) Fluctuating insulin secretion No antibodies Many honeymoons 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 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. 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. 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. Diagnosis of GDM with a 100-g oral glucose load Fasting 1-h 2-h 3-h mg/dl mmol/l 95 180 155 140 5.3 10.0 8.6 7.8 A1C monitoring A1c (%) 6 Mean Plasma glucose mg/dl 135 7 170 8 205 9 240 10 275 11 310 12 345 For every 1% point of increase in A1c add 35mg/dl of glucose. False A1C Readings Elevated – Iron deficiency anemia – Splenectomy Decreased – Hemolytic anemia – Sickle cell anemia – Transfusion ADA Guidelines http://www.diabetes.org/ Case #1