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Physiology SDL

Q. A 20 year old diabetic patient is brought to the emergency with


severe dehydration. The patient had severe vomiting prior to his arrival
at the hospital. His pulse rate was 120 bpm .BP 90 /60. Blood glucose
was 240 mg/dl .Blood pH was 7.1 Urine was positive for ketone bodies

a) Explain the pathophysiological mechanisms that are responsible for


the pH findings, blood pressure and blood glucose levels seen in this
patient’s condition.

• The blood pH is 7.1 which indicates Acidosis. This is due the presence of
excess ketone bodies in plasma which starts to appear in the urine.
Acetoacetate and 3-Hydroxybutyrate (ketone bodies) are fairly strong acids, the
hydrogen ions from these are buffered, but the buffering capacity is soon
exceeded when the production is high. This leads to an accumulation of protons
and a fall in pH.

• Severe vomiting and dehydration leads to a decrease in plasma volume, hence


hypovolemia which causes a fall in blood pressure. In addition there is
glycosuria because the renal capacity for glucose reabsorption is exceeded.
Excretion of osmotically active glucose molecules entails the loss of large
amounts of water (Osmotic diuresis) and leads to hypovolemia and hypotension.

• The blood glucose levels are above normal, this is due to either decreased
production of Insulin (as in case of Diabetes type 1) or due to insulin resistance
in the tissues (as in case of Diabetes type 2). Insulin is a hypoglycaemic
hormone, absence of insulin leads to an increase in blood glucose and it also
decreases the peripheral glucose utilisation by tissues.

b) Why is this condition more likely to occur in type I than type II


diabetes mellitus ? Explain the importance of monitoring plasma
potassium levels during treatment of the patient’s condition?

• In case of Diabetes type I there is an absolute decrease in insulin production


due to the destruction / removal of beta cells of Islets of Langerhans, however in
type II insulin production is normal (or even increased) but the insulin receptors
are defective. Thus in type I diabetes, lipolysis will still occur and will lead to a
greater accumulation of ketone bodies in plasma leading to acidosis. On the
contrary in type II, insulin is present and thus the working insulin receptors will
still respond to the effects of insulin, and the condition may not be that severe.
• Insulin causes potassium ions to enter into the cell (Insulin increases Na/K
ATPase in cell membranes, so that more potassium is pumped into cells), which
lowers ECF concentration of potassium. Hypokalemia usually develops when
patients with diabetic acidosis are treated with insulin.

c) Give normal mechanism of insulin secretion from healthy beta cells in


response to hyperglycemia. Mention the other stimuli for insulin release.

The steps involved in insulin secretion are -

• Glucose enters the B cells via GLUT-2 transporters and is phosphorylated by


glucokinase then metabolised to pyruvate in the cytoplasm.
• The pyruvate enters the mitochondria and is metabolised to Carbon Dioxide and
Water via the TCA cycle with the formation of ATP by oxidative phosphorylation.
• The ATP then enters the cytoplasm, where it inhibits ATP-sensitive Potassium
channels, reducing Potassium efflux.
• This depolarises the B cell and Calcium enters via voltage gated Calcium
channels.
• This calcium influx causes exocytosis of readily releasable pool of insulin-
containing secretory granules, producing the initial spike of insulin secretion.
• Metabolism of pyruvate via the TCA cycle also causes an increase in intracellular
glutamate. Glutamate acts of second pool of secretory granules, committing
them to releasable form.
• The release of these granules produces the prolonged second phase of insulin
response to glucose. (Hence it primes secretory granules for secretion)

Other stimuli for insulin release are-

• Insulin promotes incorporation of amino acids into proteins and combats the
catabolism of fats that produces beta kept acids. Thus Arginine, Leucine and
other amino acids stimulate insulin secretion, as do beta kept acids such as
acetoacetate. (Compounds that generate ATP when metabolised and closes
ATP-sensitive Potassium channels in B cells)
• L-Arginine is a precursor of NO which stimulates Insulin secretion.
• Tolbutamide and other sulphonyl urea derivates such as acetohexamide,
tolazamide, glipizide and glyburide increase the secretion of insulin and act as
hypoglycaemic agents. (Bind to ATP-sensitive potassium channels and inhibit
channel activity.
• Stimuli that increase cAMP levels in B cells increase insulin secretion, including
Beta adrenergic agonists, glucagon and phosphodisesterase inhibitors such as
theophylline.
• Catecholamines have a dual effect on insulin secretion ; they inhibit secretion via
Alpha 2 adrenergic receptors and stimulate insulin secretion via beta adrenergic
receptors. The net effect is usually inhibition.
d) Explain how the diagnosis of diabetes mellitus is generally made.
Give the utility of C peptide and HbA1c measurements in diabetic
patients.

• Diabetes is characterised by-


- polyuria (passage of large volumes of urine)
- polydipsia (excessive drinking)
- weight loss inspite of polyphagia (increased appetite )
- hyperglycaemia
- glycosuria
- acidosis and coma (in severely uncontrolled diabetes)

Widespread biochemical abnormalities are present but fundamentally it is-


1) reduced entry of glucose into ‘various’ peripheral tissues
2) increased liberation of glucose into circulation from liver.
Therefore there is extracellular glucose excess and intracellular glucose deficiency.

• C peptide -
The peptide segment connecting A and B chains of insulin (connecting peptide /
C-peptide) is detached in the granule before secretion from B cells of Pancreas.
Thus insulin is released along with equimolar concentration of C peptide.
C peptide can be measured by radiommunoassay, and it’s level in blood provides
an index of B cell function in patients receiving exogenous insulin.

• HbA1c -
When plasma glucose is episodically elevated over time, small amounts of
Hemoglobin A are non enzymatically glycated to form HbA1c.
Normal HbA1c lies between 4% - 5.6%. Levels above 6.5% is indicative of
Diabetes.
HbA1c concentration is measured clinically as an integrated index of diabetic
control for the 4- to 6- weeks period before measurement. Careful control of the
diabetes with insulin reduces the amount of HbA1c formed.

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