Hypoglycaemia without diabetes

While the internet is full of stories about 'spontaneous' hypoglycaemia, true hypoglycaemia is in fact extremely rare in in those without diabetes and without glucose-lowering drugs. Given the importance of glucose as an essential fuel for organs such as the brain, it is hardly surprising that the body has many ways to try and avoid hypoglycaemia occurring. The flip-side of this coin is that once hypoglycaemia has objectively been established and glucose-lowering agents have been ruled out as a cause, the underlying disease is usually serious.

When assessing hypoglycaemia in an adult without diabetes, Whipple's triad should be carefully observed. Thus, patients should have a low glucose (preferably below the lower limit of normal, i.e. below 2.8 mmol/l) accompanied by symptoms that resolve upon the administration of glucose. While in some cases the clinical history, symptoms and setting will point to the diagnosis right away, in those with less clear histories and no obvious illness the occurrence of hypoglycaemia is best assessed in the standardized setting of a 72-hour fast in hospital.[1]Once hypoglycaemia has been unequivocally established, further diagnostic tests should be undertaken.

Endogenous hyperinsulinemia: insulinoma and nesidioblastosis

Inappropriately high endogenous insulin levels will cause hypoglycaemia. True endogenous hyperinsulinemia can usually be discerned from factitious exogenous hyperinsulinemia because C-peptide is high in the first, but suppressed in the latter. Insulinomas are insulin secreting, usually benign, solitary tumours of the pancreas. Patients with insulinoma will typically present with a longer history of neuroglycopenic symtoms such as seizures provoked by fasting/missing a meal or exercise; some will present with fairly rapid weight increase because of compensatory eating behaviour. Nesidioblastosis is a more diffuse form of beta-cell hyperplasia. This has been described in neonates in association with certain genetic defects, but of late has increasingly been reported in adults following gastric bypass surgery.

Iatrogenic hypoglycaemia

Obviously, accidental or intentional overdosing of insulin or sulfonylurea derivatives will cause hypoglycaemia. However, there are various other drugs associated with an increased risk of hypoglycaemia, usually in already vulnerable patients. Best known for this side effect are sulfamethoxazol-trimethoprim, quinine, pentamidine and salicylates, but a variety of other drugs have been associated with hypoglycaemia.

Liver failure

The liver plays a central role in metabolism and, through glycogenolysis and gluconeogenesis, is the main endogenous source of glucose. This is the main explanation for the risk of hypoglycaemia in the setting of liver failure, although liver failure can be associated with hyperglycaemia as well. Functional inhibition of liver gluconeogenesis and/or liver cell destruction also explain the risk of hypoglycaemia associated with excessive alcohol use.


While inflammatory processes in general induce insulin resistance and can therefore lead to hyperglycaemia, in severe sepsis hypoglycaemia may occurr. This is related to the increased demand of this hypermetabolic state on one hand, and the failure of glucose-producing organs (the liver and to a lesser extent the kidneys) on the other. Since organ failure occurs only in severe illness, finding hypoglycaemia in this setting is associated with worse outcomes.

Mesenchymal tumours

While rare, large tumours may have such a high consumption of fuels that this exceeds gluconeogenic cacapity. In tumours of mesenchymal origin such as fibromas and sarcomas, the production of insulin-like factors further contributes to the risk of hypoglycaemia.

Inborn errors of metabolism

Certain inborn errors of metabolism interfere with glucose metabolism. Thus, glycogen storage disease, hereditary fructose intolerance and a variety of disorders of protein or lipid metabolism can cause hypoglycaemia.[2]


  1. ^ Service FJ. Hypoglycemic disorders. N Engl J Med 1995;332;1144-1152.

  2. ^ "Douillard C. Hypoglycaemia related to inherited metabolic diseases in adults. Orphanet Journal of Rare Diseases 2012, 26 "


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