Diabetes and Aging MCB 135K Ryan Klimczak April 13th, 2007

1. Diabetes and Aging MCB 135K Ryan Klimczak April 13th, 2007

2. Where is the pancreas?

3. Pancreatic endocrine functions •  cells: insulin (stores glucose) •  cells: glucagon (mobilizes glucose) •  cells: Somatostatin (regulatory, inhibits endocrine pancreas) • PP cells: pancreatic polypeptide (regulatory, inhibits exocrine pancreas) • The pancreas also has exocrine functions, secreting enzymes needed in digestion (pancreatic amylase, trypsin, chymotrypsin, etc.)

5. Insulin Anabolic (building) hormone Increases glucose transport to muscles and adipose for use Stores excess glucose in liver and muscles as glycogen Lowers blood glucose Inhibits gluconeogenesis (endogenous glucose production) Promotes growth overall Glucagon Catabolic (breaking down) hormone Breaks down glycogen to increase blood glucose level Promotes gluconeogenesis Insulin vs. Glucagon

6. Table 14-2 Major actions of insulin Glucose transport into muscle & adipose cells overall body growth (general effect) • intracellular metabolic use of glucose blood glucose intracellular transport of amino acids & lipids & protein and triglyceride synthesis glycogen synthesis in liver and muscle cells gluconeogenesis (in liver)

7. Insulin’s function in detail • Insulin is stimulated to be secreted by high blood glucose levels (after a meal). • Glucose binds to GLUT 2 receptor on B cell. • Ultimately causes the exocytosis of insulin from B cells. • Insulin binds to target cell receptors and this complex is taken into the cell. • Insulin now stimulates GLUT 4 to bring glucose into the cells. • Glucose levels in the blood now decline

8. How does glucose cause insulin release? How does insulin lower blood sugar? Glucose from blood vessel Insulin primarily targets muscle cells / adipocytes

9. Pancreas changes with aging • Atrophy • Increased incidence of tumor • Presence of amyloid material and lipofuscin granules (signs of abnormal cell metabolism) • But these changes can’t account for the degree of metabolic change we see in elderly individuals. There are also changes in sensitivity to insulin in the body.

10. Glucose metabolism changes with aging • Studies show a slightly higher fasting blood glucose level in older individuals • Studies show elderly have inability to lower blood glucose as well as younger people. • These 2 things can be called glucose intolerance • What causes glucose intolerance?

11. What is responsible for glucose intolerance with aging? • The pancreas: Insulin secretion may be depressed • The peripheral tissue receptors may be resistant to insulin • The liver may not be responding properly to insulin It is widely believed that the glucose intolerance is due to insulin resistance at the peripheral tissues.

12. Insulin resistance: an explanation for glucose intolerance in elderly • Insulin resistance: failure of insulin to stimulate glucose uptake by peripheral tissue. • No problem with insulin secretion, metabolism in the elderly • Resistance due to • receptor problem? • Post-receptor pathway problem? Due to defect in the signaling pathway once insulin has attached to its receptor.

13. Why else do elderly have glucose intolerance? • Loss of hepatic sensitivity to insulin and reduced glycogenesis • Increased glucagon levels (thus opposing insulin’s effects) • Changes in diet/exercise • Impaired glucose uptake in muscles and loss of muscle mass • Increase in adipose tissue (obesity) which may contribute to impaired uptake in adipose tissue. • Cell enlargement reduces the concentration of receptors on cell surface • Overall decrease in absolute number of insulin receptors.

14. Defining diabetes type 2 • Insulin resistance that meets criteria for significantly impaired glucose tolerance, as measured by fasting and glucose tolerance tests. • Glucose of 126 mg/dL or higher after an overnight fast on more than one occasion. (Fasting test) • After 75 g oral glucose, diagnostic values are 200 mg/dL or more 2 hours after the oral glucose. (Tolerance test) • Insulin secretory capacity is partially preserved (contrast to Diabetes type 1 in which B cells are destroyed due to an autoimmune response)

15. Prevalence/Risk factors • 1999 study showed it affects 7% of US population; 16-20% of adults over age 65. • Risk factors: • Age • Reduced physical activity • Obesity: adipocytes secrete factors that modulate insulin activity in a negative way (e.g. adipsin, TNF-alpha, IL-6, MCP1, etc.) • Ethnicity differences • Need to screen high risk individuals because symptoms show up late

17. Obesity trends and diabetes in the United States 1990-2000

18. Impact: • Nearly 21 million Americans are believed to be diabetic, according to the CDC, and 41 million more are prediabetic. • Diabetes is thought to shave 5 to 10 years off a life. • Currently, it is the six leading cause of death in the United States, however the condition is vastly underreported. • Studies have found that only 35-40% of decedents have it listed anywhere on the death certificate, and only 10-15% have it listed as the underlying cause of death. The contributing role of diabetes in death is likely far higher. • As many war veterans lost lower limbs last year to the disease as American soldiers did to combat injuries in the entire Vietnam War.

19. Costs • Without complications, the average medical costs are $1600, but for more severe conditions, the price quickly escalates: $30,000 for a heart attack or amputation, $40,000 for a stroke, $37,000 for end-stage kidney disease • Nationwide, the disease's cost just for 2002 - from medical bills to disability payments and lost workdays was estimated at $132 billion. (All cancers, taken together, cost the country an estimated $171 billion a year) [American Diabetes Association] • Increased incidence in future years may overwhelm healthcare system

20. Children and diabetes: - Two (2) million adolescents (or 1 in 6 overweight adolescents) aged 12-19 have pre-diabetes. - One in three children born in the United States five years ago are expected to become diabetic in their lifetimes, according to a projection by the Centers for Disease Control and Prevention. For Latinos: one in every two. - The C.D.C. has projected that a child found to have Type 2 diabetes at age 10 will see her life shortened by 19 years.

21. Issues in treatment: • Without symptoms or pain, most Type 2 diabetics find it hard to believe they are truly sick until it is too late to avoid the complications that can overwhelm them. • - Acute care is more emphasized relative to chronic care because of profitability for hospitals and the greater sense of urgency for patients and insurers • - Insurers will often refuse to cover a $150 for a diabetic to see a podiatrist or $75 to visit a nutritionist, while nearly all will cover the $30000 needed for an amputation or $315 for a single dialysis session

22. Pathogenesis • Caused by genetic and environmental influences • Impaired insulin sensitivity at peripheral cells • Impaired insulin secretion • Increased liver production of glucose because liver not responsive to insulin’s inhibitory effects on gluconeogenesis • Often insulin secretion becomes impaired after a period of insulin insensitivity, causing B cells to work too hard and thus fail

23. Consequences and Pathophysiology of Type 2 Diabetes: • Microvascular changes • Infections / Gangrene / Blindness / Atherosclerosis • Increased intra-luminal pressures, weakened capillary walls in part due to glycation- leading to vascular permeability, microaneurysms, hemorrhages, and ischemia • This can result in the release of vasoproliferative factors (e.g. VEGF), leading to neovascularization and further damage as in the case of proliferative diabetic retinopathy • For type 2 diabetics, 40% develop retinopathy after 5 years, 84% by 15-19yrs

24. Consequences and Pathophysiology of Type 2 Diabetes (con’t): • Macrovascular changes: • Increased likelihood of heart disease and stroke • Diabetes leads to hypercholesteremia, reduction in HDL levels • Microvascular changes compromise arterial wall • Neuropathy: • Loss of gut motility, sensation changes in feet, etc. • Glycation of nerves, comprised microvasculature, and autoimmune responses may effect nerve structure, leading to nerve damage, demyelination, and axonal atrophy • 7% of Type 2 diabetes develop neuropathies after 1 yr and 50% after 25yrs

25. Consequences and Pathophysiology of Type 2 Diabetes (con’t): • Diabetic nephropathy • Kidney disease caused by angiopathy in the capillaries in the kidney glomeruli causing increased extracellular matrix production, endothelial damage • Increased glomerular permeability leads to glomerular sclerosis • Leads to fluid filtration deficits and ultimately renal failure

26. Theories of Complications • High levels of glucose lead to formation of Advanced Glycosylation End products (AGEs). They cross-link proteins and accelerate atherosclerosis, kidney damage, artery wall damage • Excess Glucose is metabolized through a different pathway, the sorbitol pathway which more readily forms reactive oxidative species • Excess glucose activates Protein Kinase C and alters other cellular pathways, leading to deleterious changes in transcription/translation and thus causing damage • ?

27. Treatment Lifestyle modification • Diet • Weight loss • Exercise Pharmacologic • Reduce insulin resistance • Stimulate insulin secretion • Give insulin Transplantation -Replace entire pancreas or some pancreatic islets