Question 8

Outline the physiological consequences of an inability to produce insulin.

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College Answer

Most candidates were able to detail how insulin allowed influx of glucose into insulin dependent cells, in combination with potassium. Good candidates were able to explain how the inability to produce insulin allowed hypovolaemia and electrolyte loss, with the ensuing tachycardia and hypotension. Few candidates mentioned insulin’s action on hormone sensitive lipase (HSL), and that deficiency of insulin leads to increased activity of this enzyme. The fact that when insulin is not produced, the liver cells carry out -oxidation of the fatty acid (released peripherally by the action of HSL) releasing acetyl CoA which is coalesced into acetoacetic acid was mentioned by only a
few. However, the fact that ketone bodies in the form of acetoacetic acid, -hydroxybutyric acid and acetone accumulate and cause a metabolic (anion gap) acidaemia, appeared to be well known. Few, went on to describe that a compensatory respiratory alkalosis will be generated and detail how and why this occurred.
Syllabus: N2a&b, E2,F1, C1g 2b
References: Guyton and Hall Textbook of Medical Physiology 10th Ed, pg 888


  • Decreased insulin availability leads to:
    • Decreased glucose uptake into skeletal muscle
    • Increased reliance on glycogenolysis and gluconeogenesis in liver and muscle
    • Increased hormone sensitive lipase activity, leading to an increased release of free fatty acids from adipose tissue
    • Lack of insulin regulation in the liver leads to increased fatty acid oxidation
    • Increased availability of acetyl CoA liberated through fatty acid oxidation causes increased ketone synthesis because of excess acetyl CoA being metabolised into acetoacetyl-CoA and ultimately into the ketones acetoacetate and β-hydroxybutyrate
  • The consequences of this are:
    • Hyperglycaemia
      • Thus:
        • osmotic diuresis
        • volume depletion
        • compensatory cardiovascular changes in response to volume loss (eg. tachycardia)
      • With volume loss, electrolytes are also lost, leading to a total body potassium and phosphate deficit
    • Metabolic acidosis
      • Thus, increased respiratory rate to compensate by lowering systemic CO2
      • Increased anion gap (ketones are unmeasured anions)


Petersen, Max C., and Gerald I. Shulman. "Mechanisms of insulin action and insulin resistance." Physiological reviews 98.4 (2018): 2133-2223.

Newsholme, E. A., and G. Dimitriadis. "Integration of biochemical and physiologic effects of insulin on glucose metabolism." Experimental and Clinical Endocrinology & Diabetes 109.Suppl 2 (2001): S122-S134.

White, Morris F. "Mechanisms of insulin action." Atlas of diabetes. Springer, Boston, MA, 2012. 19-38.