Endocrine Abstracts

Glucokinase (GCK) serves as the blood glucose ‘sensor’ in pancreatic β-cells, being critically involved in transducing elevated blood glucose into increased insulin secretion. Inactivating GCK mutations cause a subtype of maturity onset diabetes of the young (MODY), whereas activating mutations are a rare cause of hyperinsulinaemic hypoglycaemia, usually presenting in infancy.

We now describe the case of a 60-year-old woman who first presented with symptomatic hypoglycaemia in her fifth decade. Despite biochemical evidence of hyperinsulinaemic hypoglycaemia, extensive investigation failed to identify an insulin-secreting tumour. An extended oral glucose tolerance test demonstrated fasting hypoglycaemia that was exacerbated following a glucose challenge, consistent with dysregulated glucose-stimulated insulin release. Mutational analysis of the human GCK gene revealed a heterozygous activating mutation, p.Val389Leu, in the patient and four other family members. Of these, two were undergoing extensive investigation elsewhere for recurrent hypoglycaemia presenting in adulthood, whilst the other two adult relatives were asymptomatic despite profound hypoglycaemia.

GCK is also expressed in non-pancreatic tissues including liver and GI tract, where it is expressed in enteroendocrine L cells that secrete GLP-1. In the liver, GCK mediates glucose clearance and has been implicated in lipogenesis and the pathogenesis of non-alcoholic fatty liver disease. Indeed, concerns have been raised that small molecule glucokinase activators used in the treatment of type 2 diabetes may drive hepatic steatosis and dyslipidaemia. However three members of the family studied with the GCK p.Val389Leu activating mutation had normal lipid profiles, hepatic triglyceride commensurate with their degree of adiposity, and normal rates of de novo lipogenesis. Consistent with previous reports two subjects with the p.Val389Leu mutation did not have significantly different levels of GLP-1 compared with controls.

In conclusion, activating GCK mutations are a rare cause of hyperinsulinaemic hypoglycaemia in adults and provide unique opportunities to study concepts relating to glucose sensing and therapeutic manipulation of GCK in man.