Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011

CHANGES OF THE ENDOCRINE SYSTEM AND METABOLISMPART II

Márta Balaskó-Erika PéterváriMolecular and Clinical Basics of Gerontology – Lecture 14

Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011

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FrailtyDiminished lean body mass (protein metabolism) and bone mass promoting weakness, fragility, pathological fractures. Multimetabolic syndrome• visceral obesity (waist/hip ratio above 0.9 males, 0.85

females)• insulin resistance, impaired glucose tolerance (IGT),

type 2 diabetes mellitus (DM) – glucose metabolism• dyslipidemia (triglyceride > 1.7 mmol/L, HDL

cholesterol below 0.9-1.0 males, 1.0-1.1 mmol/L female) – lipid metabolism

• hypertension• gout – purine metabolism• gall stones

Age-related metabolic alterations (outline)

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QOL issues

MenopauseEstrogen

(Progesterone?)

Andro“pause”Testosterone

DHT

SomatopauseGH

Sarcopenia leanbody mass

(appetite: CCK)

Adreno“pause”DHEA DHEAS Cortisol

ACTH

FSH LH

Failing libidodepression

osteoporosisQOL issues

Immuno-neuro-endocrine

correlationscertain

autoimmune processes

Metabolicalterations

Insulin resistance, IGT

Metabolic syndrome

(Carcinogenesis)

“Synchropause”MelatoninSleep(?)

(inflammaging)

Not “normal” ageing process, but common:subclinical hypo- and hyperthyroidism in elderly

Common endocrine alterations in the elderly

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• Somatopause: decline in GH and IGF-I production leads to protein catabolism, loss of lean body mass, accumulation of fat

• Adrenopause: decline in adrenal cortex-derived DHEA, DHEAS contribute to protein catabolism , loss of lean body mass and adiposity

• Andro/Menopause: decline in sex steroids lead to protein catabolism, loss of lean body mass, diminished metabolic rate, accumulation of fat

• Enhanced release and efficacy of peripheral anorexigenic, catabolic cholecystokinin promote insufficient food intake (e.g. protein deficiency) and loss of lean body mass

• Insulin resistance and hyperinsulinemia induces deficient protein anabolism and enhanced fat accumulation

Age-related endocrine alterations that promote frailty

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Frailty

Inflammatory state

Hormonal changes

cardio-pulmonal

hematologicalmusculoskelet

alneurological

Major musculoskeletal factors in frailty:Sarcopenia

Joint disease

Osteoporosis

Aging

Genetic

Pathologicalchanges

Factors leading to frailty

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• Numerous studies attest to the interactive influences between the GH/IGF-I and gonadal steroid axes.

• Combined GH and sex steroid supplementation would increase or improve:- protein anabolism, skeletal muscle mass and

strength;- decrease total and abdominal fat;- improve aerobic capacity and cardiovascular

function;- various endocrine, metabolic, and other outcomes

(e.g. sarcopenia, osteoporosis)• Dangerous side effects may include

carcinogenesis, thrombosis, diabetes mellitus, etc.

The potential role of hormone replacement in the prevention of frailty

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• Caloric restriction decreases fat accumulation, insulin- and leptin-resistance, free radical production, inflammation.

• Caloric restriction is the best way to delay both aging and cancer, affecting genes controlling these processes.

• Geroprotector antioxidants (e.g. resveratrol) some hormones (DHEA), peptides and drugs are mimetics of calorie restriction to a certain degree.

• Thus, caloric restriction presents an adequate and safe intervention for healthy aging and prevention of age-associated diseases, cancer included.

Caloric restriction in the prevention of metabolic and endocrine complications

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Energydeficit

Energyexcess

The spectrum of caloric intake from insufficient to excessive calories

Hypothetical U-shaped curve over the spectrum of caloric intake from insufficient to excessive calories, emphasizing negative physiologic effects at both extremes and positive or hormetic effects within a range of restricted caloric intake.

Longevity Cancer Autoimmune disease Oxidative stressPositive

effects

Negativeeffects

Longevity Cancer Autoimmune disease Oxidative stress

Parenchymal cell numberLoss of functionStarvationDeath

Regulated diet↑

Calories

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• Fasting glucose (FG) increases modestly but significantly from early adulthood to the middle-aged years and then tends to remain constant. (Normal value: 3.8-6.0 mmol/L, impaired FG: 6.1-6.9 mmol/L, diabetes mellitus: from 7.0 mmol/L.)

• In contrast, there is a striking increase in the 2-h glucose concentration during an oral glucose tolerance test (OGTT) throughout the adult years. In the course of OGTT the normal value for 2-h glucose concentration: below 7.8 mmol/L, IGT: 7.8-11.0 mmol/L, diabetes mellitus above 11.0 mmol/L.

• The percentage of impaired glucose tolerance (IGT) and thus, the number of individuals with type 2 diabetes mellitus (relative insulin deficiency with hyperinsulinemia and progressive insulin resistance) increases markedly with age.

Age-related changes in glucose metabolism

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Glucose tolerance tests*in different age-groups

Time (min)

Bloo

d su

gar (

mM

)

0

5

6

7

8

9

10

11

12

203040

5060

70

Age (years)

200 60 90 120 150

* 50 g glucose p.o.

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Age-related changes in glucose metabolism• Gradual development of insulin resistance with age, particularly in obese (resistin

and inflammatory cytokine production in abnormal fat tissue suppresses insulin effects) patients.

• Suppression of cellular metabolism (neither oxygen, nor glucose can be utilized normally).

• With muscle wasting and inactivity the insulin independent glucose utilization is limited.

Mild age-related hyperglycemia (insulin-resistance) is not to be treated by drugs. Treatment-associated hypoglycemia presents higher risk for the patient.

TÁMOP-4.1.2-08/1/A-2009-0011Complications of age-related disorders in carbohydrate metabolism• Acute complications include hyperglycemic hyperosmolar

syndrome involving such cerebrovascular and metabolic mechanisms that lead to severe impairment of neuronal functions and even to coma with high mortality.

• Long-term consequences include nonspecific complications, e.g. progressive atherosclerosis and hypertension (AMI, stroke, peripheral artery disease).

• Specific long-term complications of DM affect the microcirculation (first enhancing dilution and permeability, later causing obstructions and tissue ischemia) and neurons. Chronic DM lead to the development diabetic retinopathy (blindness), diabetic nephropathy (from initial microalbuminuria to glomerulosclerosis, peritubular interstitial fibrosis, papilla necrosis and finally chronic renal failure) and diabetic neuropathy. The latter involves microcirculatory damage of individual nerves or hyperglycemia-induced peripheral autonomic, sensory and motor neuropathy.

TÁMOP-4.1.2-08/1/A-2009-0011Prevention and treatment of age-related disorders in carbohydrate metabolism• Maintenance (or regain) of healthy BMI and body composition

(prevention of adiposity) with help of low-calorie diet (avoiding refined sugars and fat) and physical activity (the latter reduces the need for insulin also via increasing insulin-independent glucose uptake of active muscles).

• Inhibition of gastrointestinal glucose absorption• Inhibition of gluconeogenesis (biguanids)• Enhancement of insulin release (sulphanylureas) with side-

effect of hyperinsulinemia and progressive burn-out of pancreatic beta-cells.

• Enhancement of insulin sensitivity via stimulation of PPAR- receptors (thiazolidindiones with side-effect of adiposity, or angiotensine II receptor inhibitors, the metabolites of which also stimulates PPAR-).

• Stimulation of glucagon-like peptide-1 (GLP-1) and/or inhibition of its metabolism via dipeptidyl peptidase IV (DPP-4) inhibitors

• Insulin (large doses)

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Age-related changes in lipid metabolism• Visceral obesity: In the course of aging prevalence of

multimetabolic or metabolic X syndrome increases.• Ectopic fat accumulation – lipotoxicity: Increased fat

accumulation in various tissues (muscle, liver, myocardium, pancreas). Tissue functions deteriorate as a consequence: lower insulin efficacy, impaired contractility, diminished insulin release in response to elevated serum glucose level.

• Dyslipidemia – atherosclerosis: High serum cholesterol and dyslipidemia promote atherosclerosis.

• Diminished lipid utilization/fat metabolism due to impaired mitochondrial functions, lower energy consumption

Prevention includes low-fat, low-calorie diet, physical activity, intake of omega-3 polyunsaturated fatty acids, administration of cholesterol synthesis inhibitor statins.

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DefinitionGout is a disease involving precipitation of crystals of uric acid in tissues of the body.Uric acid is a metabolite of purin break-down, a product of the enzyme xanthin-oxidase (XO). Serum urate levels vary with age and sex.• Children: serum urate concentrations of 3.0-4.0 mg/dL

(178-238 mmol/L). • Levels rise during puberty, remain low until

menopause. • Adult men: 6.8 mg/dL (404 mmol/L) ,

premenopausal women: 6 mg/dL (357 mmol/L) • In adulthood: concentrations rise steadily over time

and vary with height, body weight, blood pressure, renal function and alcohol intake.

Gout

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Causes of increased se urate levels:• Primary hyperuricemia: the cause is innate• Secondary hyperuricemia: is the result of an acquired disorder.

1 Increased production (40% of our urate production is of external, 60% is of internal origin)

2 Decreased excretion

Hyperuricemia 1

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• Normal serum level of urate is 6.4 mg/dL (375 mmol/l).• At this level gout very rarely occurs (0.5%). • Above 7 mg/dl (416 mmol/L) the incidence of gout increases, above 9 mg/dL (535

mmol/L) the risk of gout is 90%.• The solubility of urate is decreased with cold and acidemia. → It is precipitated in

the form of needle-like Na-urate crystals.Causes of increased se urate levels:1 Increased production2 Decreased excretion

Hyperuricemia 2

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External (food) sources of purines are • nuts (hazelnuts, peanuts, walnuts),• meat and liver (high content of cell nuclei). • Alcohol intake, overweight, hypertension,

susceptibility to type 2 diabetes mellitus, male gender and aging → risk for gout.

Internal urate production:• massive cell necrosis, cell proliferation • hypoxia (xanthine-dehydrogenase → XO )• alcohol ( XO), acidic metabolites → urate

precipitation.• Defect of the salvage pathway

1 Increased urate production

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• Hyperuricemia does not necessarily represent a disease, nor is it a specific indication for therapy.

• The decision to treat depends on the cause and the potential consequences of the hyperuricemia in each individual.

Evaluation of hyperuricemia

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90% of urate is excreted via the kidneysIn the kidneys proximal tubuli reabsorb 97% of the urate, in the distal tubuli urate is secreted. Altogether 6-7% of the urate is eliminated.Secretion is antagonized by organic acids (lactate, ketone bodies – DM!, starvation; salicylate intoxication), alcohol, thiazide diuretics and may be impaired in kidney damage (lead poisoning), in genetic disorders or by stress.

10% is excreted via the GI tract. Nicotinic acid administered to decrease serum lipid levels may block intestinal excretion.

2 Decreased urate excretion

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• Acute inflammation with fever, anorexia (the joint is swollen, red, with shiny skin and is extremely painful).

• Role of neutrophil granulocytes in acute attacks of gout– In the background of symptoms futile activation of

neutrophil granulocytes are presumed. – Following phagocytosis of Na-urate crystals, release

of lysosomal enzymes, free radicals (oxidative burst) and inflammatory cytokines induce inflammation and tissue damage without destruction of the urate crystals.

– Inhibition of neutrophil activation by colchicin efficiently suppresses acute symptoms.

– Acute attacks are reversible within a few days without treatment. Without suppression of serum urate level they become recurrent.

Pathomechanism of acute consequences

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• Chronic inflammation: fibrotic tissue and macrophages surround the crystals → foreign body granuloma = TOPHUS (in untreated, neglected cases).

• Joints that are distal, therefore their temperature is lower with pre-existing damage (mild arthrosis) facilitate the gouty arthritis.

• PODAGRA: inflammation of the first metatarso-phalangeal joint (big toe).

• Periodical acute recurrent episodes lead to the chronic phase, when joints are distorted, tophuses appear in the joints. Urate precipitates in the kidneys (urate stones, urate nephropathy) and in practically any tissue, except the brain (atherosclerosis, ischemic heart disease).

Pathomechanism ofchronic complications

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Urate precipitation• kidneys

- urolithiasis (hyperuricemia presents a 1,000× risk)- parenchymal damage (chronic sclerotising

interstitial nephritis)• joints, leading to arthrosis• arterial wall - atherosclerosis.• coronaries - producing ischemic heart disease

Other consequences

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• Diet A diet based on vegetables with little meat and nuts and no alcohol may help reduce hyperuricemia.

• Xanthine-oxidase inhibitorAllopurinol reduces serum urate levels

• Pain-killers Although salicylates tend to inhibit urate excretion as organic acids, in clinical practice they are used to suppress inflammation and pain in gout .

• Colchicin Despite toxic side effects, efficacy in relieving gouty pain justifies its use.

Treatment of hyperuricemia