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 Statenecessary for maintenance of optimal

body function (homeostasis)

Homeostasis is maintained by a complex of

neuroendocrine adjustments

Neuroendocrine Adjustmentsfocus on the

Hypthalamic-Pituitary-Adrenal (HPA) Axis

Physiological Responses to StressBlood PressureSpeed of ConductionAccelerated Cardiac RhythmRedistribution of Blood

from most active to less active organs

CVS

Respiratory Speed & Volume of Pulmonary Respiration

Metabolic Breakdown of GlycogenBlood GlucoseBreakdown of LipidsBlood Lipids

Gastro-Intestinal function

Physiological Responses to Stress (cont.)

HPA axis:CRHACTHCortisolDHEAEpinephrineNorepinephrine

GHRHGnRHGHFSHLH

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 lifespanhermaphrodite19,000 genes

959 cells

IN FLIES (Drosophila melanogaster):

Genetic ManipulationInactivation of IGF-1

receptor analog

Decreased growthDelayed maturation

Shift of metabolismfrom aerobicto anaerobic

Greater resistanceto stress

Increased longevityDecreased mortality

IN MAMMALS (Rodents):

Genetic ManipulationInactivation of IGF-1, I, GH,PL, & TSH receptor analog

Increased longevity 18-40% Delayed aging & mortality

Decreased growthDelayed maturation

Most functions normal

Shift of metabolismfrom aerobic to anaerobic

Decreased free radical accumulation

Greater resistanceto 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 fragmentsProtein aggregates

Intracellular peptides that helpother proteins to fold

WITHOUT CHAPERONES

Miss a fold, prompt a disease Amyloidosis Lung, blood, liver diseasesDiabetes, cancer, infections

Severe stress?

Stress Proteins or Heat Shock Proteins (HSP)

Theyare synthesized in response

To a sudden rise in temperatureOr 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 onIncreased HSPs and their actions as chaperones

Interventions to prevent or treat deleterious effects of stress

According Grandmother Pharmacologic/Genetic Psychotherapy

•Good nutrition•Regular exercise•Good habits •Regular medical visits•Good education in youthand continuing into oldage•Avoiding isolation, livingwith family and in community

•Hypnotics & sedatives•Tranquilizers &Anti-anxiety drugs•Hormones •others

•Psychiatric counseling•Meditation•Yoga •Continuing interactionwith family & community

Coping Skills to Withstand Stress

Knowledgee.g. years

of education

Inner Resourcese.g. beliefs,assumptions

Spiritualitye.g. religious

beliefs

Social supporte.g. interpersonal

relations

Risk Factors (Allostatic Load)Endangering Health and Shortening Life Span

Elevated Physiologic Indices (at risk) Systolic blood pressure: 148 mm Hg

Diastolic blood pressure: 83 mm Hg

Waist-hip ration: 0.94

Tot al cholesterol-High Density Lipoprotein ratio: 5.9

Tot al glycosylated hemoglobin level: 7.1%

Urinary cortisol level: 25.7 mg/g creatinine

Urinary epinephrine level: 5 mg/ g creatinine

Urinary norepinephrine level: 48 mg/g creatinine

Lowered Physiologic Indices (at risk) HDL cholesterol level: 1.45 mmol/ L

DHEA (Dehydroepiandrosterone) level: 2.5 mol/ L

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 13.3Major Actions of Thyroid

Hormones• Calorigenesis

• Metabolism

• Brain maturation

• Behavior

• Growth & development

Figure 13-3

CNS

HYPOTHALAMUS

TRH

PITUITARY

TSH

THYROID GLAND

T3 T4 rT3

TARGET CELLS

T4 T3

INTRACELLULAR (NUCLEAR) BINDING

METABOLIC RESPONSE

CLEARANCE

FREE &BOUND

(-)

(-)

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

Characteristics Graves’ Disease Hashimoto’s Thyroiditis

Thyroid Status Hyperthyroid Hypothyroid

TSH Generally undetectable Normal to elevated

T4, T3 (serum) Above normal Below 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 Generally present

Lymphocytic Invasion Limited Marked

Female:Male Ratio As high as 10:1 As 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?