Diabetes and Aging MCB 135K Laura Epstein 4/14/06

Where is the pancreas?

Pancreas endocrine functions B cells: insulin (stores glucose) A cells: glucagon (mobilizes glucose) D cells: Somatostatin (regulatory function) F cells: pancreatic polypeptide (regulatory function) Don’t forget—the pancreas also has exocrine functions, secreting enzymes needed in digestion

Insulin vs. Glucagon 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

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

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

How does glucose cause insulin release? How does insulin lower blood sugar?

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 must be a change in sensitivity to insulin in the body!

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?

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.

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.

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 numbers of receptors concentration of receptors on cell surface –remember that there may be an overall decrease in number of insulin receptors.

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)

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 –Ethnicity differences Need to screen high risk individuals because sx show up late

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 become impaired after a period of insulin insensitivity, causing B cells to work too hard and thus fail

Consequences of Type 2 diabetes Microvascular changes –Infections/Gangrene –Blindness –atherosclerosis (due to changes in arterial wall) Macrovascular changes –Stroke –Heart Disease Nephropathy (Kidney disease) Neuropathies (changes in gut motility, sensation changes in feet)

Theories of Complications 1.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 2.Excess Glucose is metabolized through a different pathway, the sorbitol pathway which forms free radicals 3.Excess glucose activates Protein Kinase C and alters transcription/translation and thus causes damage

Treatment Lifestyle modification! –Diet –Weight loss –Exercise Pharmacologic –Reduce insulin resistance –Stimulate insulin secretion –Give insulin