Physiology

Question 1

Regular physical activity may prevent or delay the onset, or aid in the management of chronic non-communicable diseases, such as cardio-vascular disease, diabetes mellitus, certain cancers and chronic lung disease. Outline five (5) different possible mechanisms underlying these benefits (5)

Answer 1

Specific and general cardiovascular effects
Endothelial function (some detail)
Insulin sensitivity (some detail- Glut 4 receptors, IRS-1, contraction-mediated glucose uptake, etc.)
Increased mitochondrial biogenesis
Immune function, bowel transit time, reduced body fat
Attenuation of muscle wasting in COPD etc.

Question 2

Obesity is associated with significant co-morbidities, including insulin resistance, diabetes and cardiovascular disease. There are a number of theories (based on evidence), which may explain the link between these pathologies. Briefly describe two (2) of these potential mechanisms and provide evidence to support your answer (2x3 = 6)

Answer 2

Fatty acid hypothesis: Proposes a central role for these molecules as the systemic signal for obesity-associated insulin resistance.

Fatty acid-portal hypothesis: ‘Suggests that the higher rates of lipolysis in visceral fat expose the liver directly to high concentrations of non-esterified fatty acids (NEFA). The consequence is hepatic insulin resistance, followed by peripheral hyper-insulinaemia and insulin resistance in skeletal muscle.’

Metabolic inflexibility: Absence of increased fat oxidation in skeletal muscle during fasting, and an impaired ability to switch from fat to CHO oxidation in response to insulin may lead to incomplete oxidation of fatty acids, insulin resistance, fat storage, etc.

Endocrine hypothesis: “Postulates that obesity may contribute to insulin resistance by altering the levels of these key adipose-derived circulating hormones.” Some examples should be provided.

Altered HPA axis hypothesis: Posits that the pathophysiology of obesity, particularly central obesity, is associated with dysregulation of the HPA axis, and in particular, the GR receptor, the accumulation of visceral adipose tissue, 11B-HSD activity, and the sequelae of the metabolic syndrome through increased local cortisol effects.

Question 3

Obesity, particularly central obesity, is associated with significant co-morbidities, including insulin resistance, diabetes and cardiovascular disease. Insulin resistance is characterized by pathophysiological changes in various tissues and organs.

Briefly summarise these changes.

Answer 3

Pathophysiological changes associated with obesity & insulin resistance

Muscle (2)
Adipose tissue (3)
Vasculature (2)
Liver (1½)
Brain (1½)

Question 4

Insulin resistance is characterized by changes in muscle, adipose tissue, the vasculature, the liver and even the brain. Briefly describe these changes for each system (7½)

Answer 4

Resistance to the suppressive effects of insulin on endogenous glucose production and the stimulatory effects of insulin on peripheral glucose uptake and glycogen synthesis.

Decreased suppression of adipose tissue lipolysis by insulin, resulting in elevated circulating non-esterified fatty acid (NEFA) levels.

Decreased vascular endothelial cell sensitivity to various actions of insulin, which include stimulating the expression and activation of eNOS with consequent vasodilatation.

Insulin impacts on capillary recruitment to  nutritive tissue perfusion, insulin resistance may inhibit capillary recruitment.

Brain insulin action is required for physiological glucose homeostasis. Targeted impairments in insulin receptors either in all neurons or specifically in the hypothalamus rapidly cause hyperphagia and diet-dependent obesity.

Question 5

Breath that smells of acetone.

Answer 5

Acetone is a ketone. Unable to use glucose for fuel the diabetic mobilizes fat stores and via beta oxidation produces ketones for fuel. Excess ketogenesis results in the acetone-smelling breath

Question 6

Increased urine output (polyuria)

Answer 6

If circulating glucose levels are high the renal threshold for glucose re-absorption is exceeded and glucose appears in the urine. Glucose is osmotically active and pulls water with it. Hence increased urine output.

Question 7

Thirst (polydipsia)

Answer 7

Dehydration as a result of increased urine output will activate ADH secretion (to increase water re-absorption in the collecting ducts) and also trigger the thirst centres in the hypothalamus. Cells in the hypothalamus are osmo-receptors and will trigger drinking behaviour in response to a minute changes in blood osmolarity

Question 8

Hypotension.

Answer 8

Dehydration results in a loss of circulating blood volume. As blood pressure is proportional to volume, this will lead to a reduced blood pressure. OR reduced blood volume results in decreased cardiac output and without a compensatory increased in peripheral resistance, blood pressure will drop (BP = CO x TPR)

Question 9

Fatigue and weight loss.

Answer 9

Fat breakdown (beta oxidation/ketogenesis) reduces fat stores and results in weight loss. There is also muscle breakdown. Fatigue as ketones are not as readily available or efficient a fuel source as carbohydrates

Question 10

Explain why type 1 diabetic patient with DKA had “deep sighing” respiration (Kussmaul breathing) (4)

Answer 10

She is acidotic (pH 7.05). Acidosis is due to keto (inability to utilize glucose so using ketogenic pathways for fuel, resulting in excess ketones (acidic) in the blood. Lacto-acidosis due to dehydration, inadequate perfusion of tissues and anaerobic respiration with production of lactate. The deep breathing is the respiratory compensation for acidosis – an attempt to ‘blow off’
carbon dioxide and thereby decrease H+ levels - i.e. move the Hendersson Hasselback equation back towards the left.