Today 4/17/06 1.Stress, Adaptation, and Regulation of Homeostasis 2.Hypothalamus, pituitary axis 3.Diabetes and aging

Stress, Adaptation, Homeostasis

Continually Changing Environment Challenges Steady State necessary for maintenance of optimal body function (homeostasis) Homeostasis is maintained by a complex of neuroendocrine adjustments Neuroendocrine Adjustments focus on the Hypthalamic-Pituitary-Adrenal (HPA) Axis

Physiological Responses to Stress Blood Pressure Speed of Conduction Accelerated Cardiac Rhythm Redistribution of Blood from most active to less active organs CVS Respiratory Speed & Volume of Pulmonary Respiration Metabolic Breakdown of Glycogen Blood Glucose Breakdown of Lipids Blood Lipids Gastro-Intestinal function

Physiological Responses to Stress (cont.) HPA axis: CRH ACTH Cortisol DHEA Epinephrine Norepinephrine GHRH GnRH GH FSH LH Hormonal

With age there is: Breakdown of self-organizing systems (dynamic instability) Declining capacity to adapt to the environment With consequence Failure of adaptation Increased pathology or Evolution, progress, creativity, hormesis=the stimulating or beneficial effect of small doses of a toxic substance that at higher doses has an inhibitory or adverse effect.

Beneficial effects of Hormesis may be due to: DNA repair Immune competence Neurologic acuity Neuromuscular activity Better memory Resistance / adaptation to stress

High energy consumption Active growth & development Active reproductive function Several lines of investigations have shown that manipulation of the genome will result in changes of the phenome. These changes involve alteration of the endocrine signaling with a shift Reduce energy consumption Arrest of growth, development, reproductive function High resistance to stress From To

Among invertebrates, the most used models have been the fly (Drosophila melanogaster) and the nematode (C. elegans) Suppression of the receptor for insulin/IGF hormone will produce a mutant nematode that will live 6x longer than corresponding controls and be more resistant to all stress, but they will not grow, undergo development, or reproduce. C. Elegans 2 week lifespan hermaphrodite 19,000 genes 959 cells

IN FLIES (Drosophila melanogaster): Genetic Manipulation Inactivation of IGF-1 receptor analog Decreased growth Delayed maturation Shift of metabolism from aerobic to anaerobic Greater resistance to stress Increased longevity Decreased mortality

IN MAMMALS (Rodents): Genetic Manipulation Inactivation of IGF-1, I, GH, PL, & TSH receptor analog Increased longevity 18-40% Delayed aging & mortality Decreased growth Delayed maturation Most functions normal Shift of metabolism from aerobic to anaerobic Decreased free radical accumulation Greater resistance to stress

If response to stress is severe & prolonged it may represent a major risk for the “diseases of adaptation” (e.g. cardiovascular, cognitive, emotional, metabolic diseases) & shorten the lifespan If the response to stress is moderate & of short duration, it may stimulate hormesis : –the functions of alertness, vigilance & motivation –a greater availability & utilization of metabolic energy –favor DNA repair –improve protein folding (chaperone stimulation) –prevent/decrease free radical accumulation –promote survival and may delay aging

CHAPERONES Prevent production of Inactive protein Protein fragments Protein aggregates Intracellular peptides that help other proteins to fold WITHOUT CHAPERONES Miss a fold, prompt a disease Amyloidosis Lung, blood, liver diseases Diabetes, cancer, infections Severe stress?

Stress Proteins or Heat Shock Proteins (HSP) They are synthesized in response To a sudden rise in temperature Or other types of stress

ON FLIES, WORMS, RODENTS: LONGEVITY is associated With stimulation (up-regulation) Of genes involved in response to stress including those of HSP HSPs act as chaperones and promote greater tolerance/resistance to stress (thermic and others) Hence, increased longevity and hormesis may depend on Increased HSPs and their actions as chaperones

Interventions to prevent or treat deleterious effects of stress According Grandmother Pharmacologic/GeneticPsychotherapy Good nutrition Regular exercise Good habits Regular medical visits Good education in youth and continuing into old age Avoiding isolation, living with family and in community Hypnotics & sedatives Tranquilizers & Anti-anxiety drugs Hormones others Psychiatric counseling Meditation Yoga Continuing interaction with family & community

Coping Skills to Withstand Stress Knowledge e.g. years of education Inner Resources e.g. beliefs, assumptions Spirituality e.g. religious beliefs Social support e.g. interpersonal relations

Table 10.9

Questions How does the body respond to stress? What are some ways to prevent deleterious effects of stress? What did we learn from the flies, worms, rodents examples? How is the response to stress different with aging?

Hypothalmo-Pituitary-Thyroid System

Table 13.3 Major Actions of Thyroid Hormones Calorigenesis Metabolism Brain maturation Behavior Growth & development

Table 13-2: Some MORPHOLOGIC Changes in the Thyroid Gland with Aging FOLLICLES: - Are distended - Change in color - Epithelium flattened w/ reduced secretion Fewer mitoses Increased connective tissue; Fibrosis Atherosclerotic changes

Table 13-2 (con’t.): Some SECRETORY Changes in the Thyroid Gland with Aging Simultaneously decreased secretion and metabolic clearance of T4 with resulting essentially normal levels Failure of up-regulation of T3 nuclear receptors peripheral conversion of T4 to T3 TSH levels in 10% of the elderly, associated in antithyroid antibodies, present even in the absence of manifestations of hypothyroidism circulating T3 levels but generally within the normal (lower) range

Table 13-1: Some Critical Aspects of Thyroid Hormone Regulation 1.Major source of circulating T3 from peripheral deiodination of T4 (NOT from thyroid gland secretion) 2.The negative feedback at the pituitary anterior lobe is mainly through T4 (taken from circulation & converted into T3) 3.The peripheral deiodination of T4 depends on the physiological state of the organism. It allows an autonomy of response of the tissues to the hormones. 4.Deiodination can convert T4 (a less biologically active hormone) to T3 (a more active hormone). This conversion depends on the activity of the various deiodinating enzymes.

Table 13-5 In the Elderly, Thermoregulatory Insufficiency Results from: Decreased heat production, Decreased body mass, Reduced muscle activity, Less efficient shivering, Reduced sweating response, Less efficient vasomotor responses, Decline in temperature perception.

Table 13-6 Autoimmune Diseases of the Thyroid Gland CharacteristicsGraves’ DiseaseHashimoto’s Thyroiditis Thyroid StatusHyperthyroidHypothyroid TSH Generally undetectable Normal to elevated T4, T3 (serum)Above normalBelow normal Antibodies(ABs)Stimulatory ABs compete with TSH at receptor sites Loss of TSH control over thyroid function Some ABs block TSH actions Autoantibodies against thyroglobulin, T3, T4, thyroid destroy thyroid microsomal and nuclear components Generally present Lymphocytic InvasionLimitedMarked Female:Male RatioAs high as 10:1

Questions What does thyroid hormone do? What are the morphological changes with aging? What are the secretory changes with aging?

Diabetes

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

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

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 (gut motility slowed, 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

Questions What is diabetes type 2? What is glucose intolerance? What is the proposed mechanism for glucose intolerance in the elderly? What are complications of diabetes? How does insulin work?