A patient with Addison's disease (primary adrenal insufficiency) is found to have hyperpigmentation, hyponatraemia, hyperkalaemia, and hypoglycaemia. What is the direct physiological mechanism linking loss of cortisol to hypoglycaemia?

• A Cortisol normally stimulates gluconeogenesis in the liver (by inducing PEPCK, fructose-1,6-bisphosphatase, and glucose-6-phosphatase) and promotes peripheral protein catabolism to provide gluconeogenic substrates; its absence reduces hepatic glucose output, causing fasting hypoglycaemia ✓
• B Loss of cortisol removes its direct inhibitory effect on pancreatic beta cells, causing excessive insulin secretion that produces hypoglycaemia
• C Cortisol deficiency impairs renal tubular glucose reabsorption through Na-coupled SGLT2, causing glycosuria and low blood glucose
• D Aldosterone deficiency (also lost in primary AI) causes hyperkalaemia-induced depolarisation of beta cells, triggering unregulated insulin release and hypoglycaemia

Explanation

Cortisol is a major counter-regulatory hormone. It stimulates hepatic gluconeogenesis by inducing key gluconeogenic enzymes (phosphoenolpyruvate carboxykinase, PEPCK; pyruvate carboxylase; glucose-6-phosphatase) and promotes proteolysis in peripheral tissues (muscle) to generate gluconeogenic amino acids (alanine, glutamine). In its absence, fasting hypoglycaemia results from inadequate hepatic glucose production. Cortisol also antagonises insulin signalling peripherally. Cortisol inhibits (not stimulates) insulin secretion; option B is physiologically backward. SGLT2 reabsorption is not regulated by cortisol. Hyperkalaemia-induced insulin release is a clinically minor effect and not the dominant mechanism here.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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