1. Pathophysiology Glucose Homeostasis & Diabetes Mellitus

2. Glucose Homeostasis  Insulin secretion  Counter-regulatory Hormones

3. Insulin Secretion  Daily basilar level –40-50 U/day  Stimulated secretion –BS 80-100mg/dl –Secreted through glucose metabolism mediated depolarization –Membrane changes promote Ca influx and insulin secretion

4. http://www.montana.edu/wwwai/imsd/alcohol/Vanessa/vwpancreas.htm

5. Pancreas Here is a normal Here is a normal pancreatic islet of langerhans surrounded by normal exocrine pancreatic acinar tissue. The islets contain alpha cells secreting glucagon, beta cells secreting insulin, and delta cells secreting somatostatin. pancreatic islet of langerhans surrounded by normal exocrine pancreatic acinar tissue. The islets contain alpha cells secreting glucagon, beta cells secreting insulin, and delta cells secreting somatostatin. http://library.med.utah.edu/WebPath/webpath.html#MENU

6. ProInsulin http://www.cebix.com/index.php/research/

7. Insulin Action  Insulin dependent glucose transporters  Storage of energy substrates –fats –amino acids –glucose to glycogen  Enhancement of growth factor activity  Increase cellular uptake of K, Phosphorus, and Mg

8. Counter Regulatory Hormones  Glucagon –opposes insulin  Epinephrine –mobilization of glucose stores  Glucocorticoids –decreases peripheral utilization of glucose  Growth Hormone –decreases glucose uptake by tissues

9. Incretins  Incretins – group of gastrointestinal hormones released in response to eating –Includes glucagon like peptide (GLP – 1) which decreases need for glucagon secretion  Result is increased insulin levels and decreased glucagon levels  Decrease gastric emptying and slow the rate of absorption of nutrients.

10. Diabetes  Group of metabolic disorders characterized by hyperglycemia  Epidemiology –25.8 million people in US –8.3% of the population –1.9 million cases diagnosed each year –Direct & Indirect costs exceed $174 Billion

11. Diabetes  Group of metabolic disorders characterized by hyperglycemia  Classified by etiology –Type 1 – Immune Mediated Diabetes –Type 2 - Insulin Resistance with altered insulin secretion –Other Endocrinopathies –Gestational diabetes

12.  Fasting Plasma Glucose (FPG) –100mg/dl to 125mg/dl –(5.6mmol/L to 6.9mmol/L  2 hour Post Prandial Glucose –After 75 g oral glucose tolerance test –140mg/dl to 199mg/dl –7.8mmol/L to 11.0mmol/L  Hgb A1c 5.7 to 6.4% Categories for Increased Risk for Diabetes

13. Diagnostic Criteria  Hgb A1c > 6.5%  FPG > 126 mg/dl (7.0mmol/L)  2 Hour post prandial glucose > 200mg/dl (11.1 mmol/L)  Symptoms of hyperglycemia in conjunction with random glucose >200 mg/dl

14. Diabetes  Insulin Secretion & Patterns of Administration –Link Link

15. Therapeutic Monitoring  Evaluation of Glycemic Control  BP < 130/80  Measurement of indices related to end organ effects –Neurologic assessment –Visual screening –BUN/Crt & Urine albumen levels –Estimate GFR –Lipid levels

16. ADA (2012) Standards of Medical Care in Diabetes - 2014 Goals of Treatment Hgb A1C Less than 7% Ideally less than 6% without symptoms of hypoglycemia Preprandial capillary plasma glucose 90–130 mg/dl (5.0–7.2 mmol/l) Peak postprandial capillary plasma glucose <180 mg/dl (<10.0 mmol/l)

17. ADA (2012) Standards of Medical Care in Diabetes - 2014 A1C (%) mg/dlmmol/l 61267.0 71548.6 818310.2 921211.8 1024013.4 1126914.9 1229816.5 Mean plasma glucose Correlation between A1C level and mean plasma glucose levels

18. Type 1 Diabetes  Molecular mimicry –Coxackie B virus –Bovine Serum Albumin  Genetic links –HLA antigens  Insulinitis

19. Type 2 Diabetes  Insulin Resistance  Reduction in Insulin secretion  Genetic & Environmental factors

20. Type 2 Diabetes  Genetic & Environmental Issues  Pathophysiology –Abnormalities in adipoctes (accelerated lipolysis) –Neuroprotective mechanisms (excessive appetite) –Excessive hepatic glucose production triggered by insulin resistance, insulinopenia, and increased glucagon secretion.

21. Acute Complications  Hyperglycemia –osmotic –osmotic diuresis  fluid  fluid & electrolytes –glucosuria  Candida –hyperphagia  DKA  HHNK

22. Hypoglycemia  Counter  Counter -regulatory hormone secretion  Enhanced  Enhanced Catecholamine secretion  Neuroglycopenia  Nocturnal  Nocturnal Hypoglycemia

23. Catecholamine Secretion

24. Neuroglycopenia

25. Nocturnal Hypoglycemia

26. Chronic Complications  Result of pathophysiologic changes  Ultimately lead to the development of end organ effects  End organ effects –Renal –Retinal –Cardiovascular –Neurologic

27. Chronic Complications  Complications –Link Link  Microvascular disease  Macrovascular disease  Neuropathy

28. Microvascular Disease  Thickening of basement membranes  Advanced Glycosylated end products  End organ effects –Retinopathy –Nephropathy

29. Microvascular Disease  Retinopathy –Microaneurysms, exudates, edema –Neovascularization promotes retinal detachment  Nephropathy –Alteration in glomerular function –Proteinuria, hypertension, renal insufficiency –Glomerular sclersosi

30. Macrovascular Disease  Acceleration of atherosclerosis  Increased VLDL  Increased foam cell activity  Imbalance in thrombotic and fibrinolytic factors

31. Neuropathy  Vascular insufficiency - ischemia  Neuronal tissues - Altered metabolism –non insulin dependent glucose transporters  Fructose & Sorbitol –Sorbitol excess –altered cellular osmolality –increased free radical formation

32. Autonomic Neuropathy  Tachycardia  Orthostatic hypotension  Incontinence  Headaches