SummaryContext Glucokinase (GCK) phosphorylates and thereby "traps" glucose in cells, thus serving as a gatekeeper for cellular glucose metabolism, particularly in hepatocytes and pancreatic beta cells. In humans, activating GCK mutations cause familial hyperinsulinaemic hypoglycaemia (GCK-HH), leading to keen interest in the potential of small-molecule glucokinase activators (GKAs) as treatments for diabetes mellitus. Many such agents have been developed; however, observation of side effects including hypertriglyceridaemia and hepatic steatosis has delayed their clinical development. Objective To describe the clinical presentation and metabolic profiles of affected family members in a kindred with familial hyperinsulinism of adult presentation due to a known activating mutation in GCK. Design Clinical, biochemical and metabolic assessment, and GCK sequencing in affected family members. Results In the 60-year-old female proband, hyperinsulinaemic hypoglycaemia (blood glucose 2Á1 mmol/mol, insulin 18 pM) was confirmed following 34 h of fasting; however, abdominal computed tomography (CT), pancreatic MRI, endoscopic ultrasound, octreotide scintigraphy and selective arterial calcium stimulation failed to localize an insulinoma. A prolonged OGTT revealed fasting hypoglycaemia that was exacerbated after glucose challenge, consistent with dysregulated glucose-stimulated insulin release. A heterozygous activating mutation, p.Val389Leu, in the glucokinase gene (GCK) was found in the proband and four other family members. Of these, two had been investigated elsewhere for recurrent hypoglycaemia in adulthood, while the other two adult relatives were asymptomatic despite profound hypoglycaemia. All three of the available family members with the p.Val389Leu mutation had normal serum lipid profiles, normal rates of fasting hepatic de novo lipogenesis and had hepatic triglyceride levels commensurate with their degree of adiposity. Conclusion Activating GCK mutations may present in late adulthood with hyperinsulinaemic hypoglycaemia and should be considered even in older patients being investigated for insulinoma. Normal circulating lipids, rates of hepatic de novo lipogenesis and appropriate hepatic triglyceride content for degree of adiposity in the patients we describe suggest that even lifelong GCK activation in isolation is insufficient to produce fatty liver and metabolic dyslipidaemia.

The aim of this study was to compare whole-body glucose uptake in cycling and running performed during physiological hyperinsulinaemia. On three occasions, seven male subjects underwent a hyperinsulinaemic (30 mU m(-2) min(-1)), euglycaemic (5 mmol l(-1)) clamp for 120 min. On one occasion, subjects rested for the duration of the trial (CON). On the other two occasions, after an initial resting period of 30 min, subjects either cycled (CYC) or ran (RUN) for 90 min at 65% of maximal O(2) uptake (VO(2max)). Insulin infusion resulted in physiological hyperinsulinaemia that was maintained for the duration of each trial [CON: 61 (3) mU l(-1); CYC: 77 (7) mU l(-1); RUN: 77 (5) mU l(-1)]. The rate of glucose uptake was greater during RUN than during CYC [last 30 min of exercise: 140 (4) vs 109 (8) micromol kg(-1) min(-1), respectively; P <0.01]. A differential amount of active muscle mass and/or muscle fibre type recruitment might account for the observed differences in glucose disposal between cycling and running.

Underfeeding for 6 days has no significant effect on UCP3 mRNA expression in skeletal muscle in non-obese men but is associated with changes in carbohydrate fuel partitioning, REE and the thermogenic response to the glucose clamp. Mild underfeeding had no effect on insulin sensitivity, but more severe energy restriction reduced insulin-stimulated glucose oxidation without affecting glucose storage.

Aim: This study investigated whether changing fuel use, by increasing pyruvate dehydrogenase complex (PDC) flux, independently of plasma substrate availability and insulin signalling, would alter metabolic gene expression. Methods: The PDC activator, dichloroacetate (DCA), was administered as an intravenous infusion in healthy male subjects at a rate of 50 mg kg^–1 min^–1, for 90 min. Saline was infused as a control (CON) on a separate occasion in a randomised sequence. Muscle biopsies were taken from the vastus lateralis at 0 and 30 min into the infusion and 90 min after infusion. Gene expression was quantified using RT-qPCR, and immunoblotting was used to confirm that there were no changes in insulin signalling via the PI3K/Akt pathway. Results: Blood glucose concentrations fell during both trials but 3 h after the start of the infusion they were lower in DCA (p < 0.05) than CON. Blood lactate concentrations also declined in both trials (p < 0.01), however, this decrease was also more pronounced in DCA than CON (p < 0.001). Carbohydrate oxidation was increased by DCA, 0.037 ± 0.017 g min^–1 (p < 0.05) at 3 h with no change observed in CON. UCP3 and PGC1α mRNA expression were induced in CON (as a response to continued fasting) but this was attenuated by DCA. Akt phosphorylation and the expression of other metabolic genes and transcription factors were unchanged throughout the intervention. Conclusion: It is concluded that PDC flux can be increased independently of plasma substrate availability, without causing downstream alterations to metabolic gene expression in the short term.

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