Enormous Economic Consequences of Diabetes in the United States

1. Enormous Economic Consequences of Diabetes in the United States Direct Costs: $92 Billion Diabetes/ diabetes supplies: $23 billion Indirect Costs: $40 Billion Annual Total: $132 Billion* Indirect costs due to disability and early mortality: $40 billion Excess prevalence of chronic complications: $25 billion Excess prevalence of general medical conditions: $44 billion *Approximate 2002 US Dollars Hogan P, et al. Diabetes Care. 2003;26:917–932.

2. Impact of Type 1 and Type 2 Diabetes 6th leading cause of death Individuals diagnosed by 1.3 million each year Increasingly affects all age groups Diabetes Shortens average life expectancy by up to 15 years Especially prevalent in African and Hispanic Americans Adapted from http://www.cdc.gov/diabetes/pubs/factsheet.htm#contents. Accessed 2/10/04. Diabetes Research Working Group. NIH Pub #99-4398;1999:1–129.

3. Type 2 Accounts for the Vast Majority of Diabetes Mellitus Cases • Type 2 diabetes • About >75% of the diabetes population • Dual impairment: Insulin deficiency & Insulin resistance • No longer a disease of adults only • Obesity • Genetic link • Type 1 diabetes • Approximately 10% of diabetes population • Absolute insulin requirement • Autoimmune mediated CDC. National Diabetes Fact Sheet. 2003; Atlanta, GA. US Dept. HHS, Center for Disease Control and Prevention 2003.

4. Prediabetes • Historically has been called impaired glucose tolerance, or borderline diabetes • Very high probability of leading to diabetes • Broadly defined as a fasting glucose of 110-125mg/dl or impaired glucose tolerance of 140-199 mg/dl 2 hours after a 75 gram glucose load

5. Metabolic syndrome(syndrome X) • This syndrome is a relatively recently recognized group of characteristics that puts a patient at risk for type 2 diabetes. They include • Central obesity • Hypertension • Hyperlipidemia • Insulin resistance or glucose intolerance • Proinflammatory state

6. 1990 1995 No Data < 4% 4%-6% 6%-8% 8%-10% > 10% Prevalence of Diabetes Is Escalating 2001 (Includes Gestational Diabetes) Source: Mokdad A, et al. Diabetes Care. 2000;23:1278-1283; Mokdad A, et al. J Am Med Assoc. 2001;286:10; Mokdad A, et al. JAMA. 2003;289:76-79.

7. The Role of the Pancreas in Blood Sugar Regulation • Alpha Cells • Glucagon • Acts on liver to release glycogen • Increases blood sugar • Delta Cells • Somatostatin • Stops glucagon and growth hormone • Decreases blood sugar • Beta Cells • Insulin • Decreases blood sugar Colorado State University. http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/pancreas/anatomy.html. Accessed December 3, 2003.

8. Normal PhysiologicInsulin Sensitivity and ­Cell Function Produce Euglycemia Normal Insulin Sensitivity Normal ­Cell Function Decreased Lipolysis Pancreas Liver Decreased Plasma FFA ↑ Glucose Uptake ↓ Glucose Production Islet ­Cell Degranulation;Insulin Released in Response to Elevated Plasma Glucose Muscle Adipose Tissue Decreased Glucose Output Normal Physiologic Plasma Insulin Increased Glucose Transport Euglycemia

9. Type 1 Diabetes Inflammation FasL IFNg TNFa • Betacell destruction • Usually leading to absolute insulin deficiency • Immune mediated • Idiopathic T cell Autoimmune Reaction Macrophage TNFa Class IMHC Class IIMHC IL-1 Beta cell NO CD8+ T cell Dendritic cell Betacell Destruction American Diabetes Association. Diabetes Care. 2003;26:S33–S50.

10. Progression of Type 1 Diabetes Precipitating event Progressive loss of insulin release Genetic predisposition Antibody formation Normal insulin release Glucose normal Beta Cell Mass Overt diabetes C-peptide present No C-peptide present Time Atkinson MA and Eisenbarth GS. Lancet. 2001;358:221–229.

11. BetaCell Dysfunction and Insulin Resistance Produce Hyperglycemia in Type 2 Diabetes Insulin Resistance BetaCell Dysfunction Increased Lipolysis Pancreas Liver Elevated Plasma FFA ↓Glucose Uptake ↑Glucose Production Islet BetaCell Degranulation;Reduced Insulin Content Muscle Adipose Tissue Increased Glucose Output Reduced Plasma Insulin Decreased Glucose Transport and Activity (expression) of GLUT4 Hyperglycemia Setter S, et al. In: Herfindal T, Gourley D, eds. Textbook of Therapeutics:Drug and Disease Management. 7th ed. 2000;377–406.

12. Prevalence of Diabetes Magnitude of the Disease

13. Age­Adjusted Total Prevalence of Diabetes in People Aged 20 Years or Older, by Race/Ethnicity—United States, 2002 American Indians/Alaskan Natives Hispanic/Latino Americans Non-Hispanic African Americans Non-Hispanic Caucasians 0 5 10 15 20 25 Percent Source: 1999-2001 National Health Interview Survey and 1999-2000 National Health and Nutrition Examination Survey estimates projected to year 2002. 2002 outpatient database of the Indian Health Service.

15. Prevalence of Diabetes at Age 45 to 74 Years

16. How and why diabetes affects major physiologic systems Objective 3

17. Metabolic Complication Pathways • Advanced Glycosylation Endproducts • Sorbitol (polyol) Pathway

18. Advanced Glycosylation Endproducts (AGE’s) • Circulation glucose attaches to various proteins via a process called glycosylation • Glucose attaches to the amino terminus of the protein forming aldimine (Schiff base) which later irreversibly changes through an amadori reaction to AGE’s

19. AGE’s • AGE’s are found in both extracellular and intracellular sites. • These AGE’s then form irreversible protein-protein crosslinks with other amino groups, that permanently attach to macromolecules such as arterial wall collagen

20. AGE’s – sites affected • Other sites affected by AGE’s are macrophages, endothelial cells, and smooth muscle. • AGE’s accumulate over the life of the patient. • AGE’s in arterial walls can increase binding for LDL cholesterol

21. AGE’s – sites affected • AGE formation also causes the thickening of capillary basement membranes. • This process is thought to be responsible for the microvascular complications in the eye, kidney, and nerve cells

22. Sorbitol pathway • Some cells are not dependent on insulin for entry of glucose (brain and eye) • Glucose enters these cells and is enzymaticaly converted to sorbitol and fructose

23. Sorbitol pathway-complications • Elevated glucose levels within the cell leads to an increase in formation of sorbitol and fructose. These two sugars accumulate within the cell and create a hyperosmolar state. This increases the amount of water being pulled within the cell which leads to swelling and cell damage.

24. Sorbitol pathway - complications • The cellular damage as a result of this process is what leads to damage of the fine blood vessels in the retina and peripheral nervous system.

25. Complications of Diabetes Cardiovascular complications Renal failure Blindness Diabetes Nerve damage Amputation http://www.cdc.gov/diabetes/pubs/factsheet.htm#contents. Accessed 2/10/04.

26. Chronic Complications • Complications due to chronic hyperglycemia are microvascular, macrovascular, and neuropathic • Microangiopathy – damage to smaller arteries by diffuse thickening of the capillary basement membranes • Macroangiopathy – damage to larger blood vessels

27. Physiologic systems affected • Vascular system • The three major types of macrovascular disease complications in diabetes are CAD (responsible for 50%-60% of deaths), cerebrovascular disease, and peripheral vascular disease (PVD). • Accelerated atherosclerosis in the major arteries increase risk of MI, cerebral stroke, aortic aneurysms, and gangrene of lower extremities

28. Physiologic systems • Diabetic nephropathy (microangiopathy) • Found in 20% - 30% or patients with diabetes • Renal failure accounts for many deaths in both type 1 and type 2 patients • Symptom include – microalbuminuria, proteinuria, chronic renal failure, and HTN • ACE inhibitors help prevent this damage in addition to tight glucose control

29. Physiologic systems • Ocular complications (microvascular) • Proliferative and nonproliferative retinopathy, cataracts and glaucoma • Damage due to weakened blood vessels • Osmotic damage can also occur to the lens of the eye and certain neurons, by the sorbitol pathway metabolism of glucose. • Risk factors – poor blood glucose control, high blood pressure, hyperlipidemia

30. Physiologic systems • Neuropathy (neurologic/microvascular) • Classified as somatic and autonomic • Affect 50% of patients • May affect nearly every system of the body • Occurs due to accumulation of sorbitol, and decrease in myoinositol, nerve glyosylation, • Somatic • The most common. • Lead to decreased sense of touch, position, and vibration sensations. Painful sensations also occur such as tingling, pin pricks (parasthesias), burning, stabbing, tearing, even crushing pain • Sweat glands also affected. Decreased moisture/dry skin

31. Neuropathy cont. • Autonomic • Affects the involuntary nerves of the autonomic nervous system • Complications occur include gastroparesis, diarrhea, constipation, urinary tract dysfunction, sexual dysfunction, and cardiac abnormalities.

32. Physiologic systems • Infections • Decreased ability to fight infections • Prolonged healing times • Due to impaired leukocyte function and poor circulation • Infections in the mouth can lead to gum disease

33. May be asymptomatic at in type 2 3 P’s: polyuria, polydipsia, Polyphagia Ketoacidosis Weakness/fatigue Glycosuria Dry, itchy skin Visual changes Skin and mucous membrane infections Frequent Symptoms of Diabetes

34. Normal Plasma glucose range • Normal fasting plasma glucose is 70-110 mg/dl • Diagnostic criteria for diabetes • Fasting plasma glucose of > 126mg/dl or a 2 hour postload glucose of > 200mg/dl. Must be confirmed on a different day. • Diagnostic criteria for pre-diabetes • Fasting plasma glucose of 100-125mg/dl or a 2 hour postload glucose of 140-199 mg/dl

35. Importance of Postprandial Glucose (PPG) — Conclusions • Even in nondiabetic individuals, postprandial hyperglycemia carries a higher risk of death than elevated fasting evidence shows that elevated PPG levels increases the risk for cardiovascular disease • Earlier detection and management of postprandial hyperglycemia is crucial in reducing the risk of death Gerich J. Arch Int Med. Jun 2003;163:1306-1316

36. Conclusions • Approximately 13 million patients in the United States have diabetes, with another 5.2 million people undiagnosed • US health care costs associated with diabetes are $132 billion each year • Kidney failure, cardiovascular disease, blindness, and amputations are major complications of diabetes • Intensive insulin therapy is effective in reducing the risk of several diabetic complications • Use of intensive insulin therapy is steadily increasing

37. Risk factors associated with development of Type 2 diabetes • Family history • Children of individuals with type 2 diabetes have a 15% chance of developing the disease and 30% risk of developing IGT • > 90% concordance in twins • Obesity > 120% of ideal body weight • Age > 45yo • Race • History of gestational diabetes • Hypertension • Hyperlipidemia • Polycystic ovary disease

38. HbA1c • Hemoglobin is a protein in circulating red blood cells. The level of glycosylation to HbA1c of this protein is directly proportional to the level of glucose in the blood. Because gylcosylation is irreversible and the life span of a red blood cell is 120 days, measuring the level can tell us how well blood sugar has been controlled over the past 3 to 4 months. • Should be <6.5%

39. Approximate Comparison of HbA1c to Blood Glucose Glucose mg/dl HbA1c %

40. Blood glucose test vs. urine glucose test • Blood glucose testing tells you what your blood sugar is at that time. The kidney only spills glucose into the urine when blood glucose levels exceed 180mg/dl. So urine testing is not very accurate and the results only approximate what your blood sugar level was at an earlier time.

41. Hyperglycemia • High blood sugar. >200 mg/dl • Symptoms include: • Extreme thirst • Frequent urination • Dry skin • Hunger • Blurred vision • Drowsiness • Nausea • If not corrected can lead to diabetic ketoacidosis

42. Hypoglycemia • Low blood sugar <60-70 mg/dl (depends) • Symptoms include: • Shaky, light-headed or weak • Sweaty or clammy skin • Fast heartbeat • Irritability • Confusion • Sudden extreme hunger • Headache • Fast heartbeat

43. Treatment of hypoglycemia • “Rule of 15’s” • If blood sugar is low eat or drink 15 grams of carbohydrate • Wait 15 minutes • Check blood sugar again • If blood glucose is normal and your next meal is more than 60 to 90 minutes away eat a snack • If not back to normal then treat, wait and check again. If not back to normal after 3 tmts. Call 911

44. Hypoglycemia • 15 grams of carbohydrate • 4 glucose tablets • 1 tube glucose gel • 1/3 to ½ cup of fruit juice • 1 cup skim milk • 1/3 to ½ cup of regular soda • 6 small sugar cubes • 1 tbsp honey • 5 lifesavers