Familial adult onset hyperinsulinism due to an activating glucokinase mutation: implications for pharmacological glucokinase activation

Abstract

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.

Heterogeneity in phenotype of hyperinsulinism caused by activating glucokinase mutations: a novel mutation and its functional characterization

“…The age of presentation in our cases varied widely from the neonatal period (first days of life), to infancy (3·5 years), and adulthood (25 years). This variation in the age of GCK‐HI presentation has been described in the literature, and Challis et al . have recently described GCK‐HI even in older patients investigated for insulinoma (>60 years old).…”

“…All our probands were responsive to diazoxide treatment, although finally not all were treated with diazoxide. Although activating GCK mutations are not usually reported in HI, the cases described to date, including this report, indicate that a large variability in phenotype is common, and also highlight the importance of GCK screening in HI even if there is no positive family history or if it presents in adulthood…”

Clinical and enzymatic phenotypes in congenital hyperinsulinemic hypoglycemia due to glucokinase‐activating mutations: A report of two cases and a brief overview of the literature

“…To date, just 20 cases of naturally occurring GCK‐CHI mutations were reported, including the two variants in the present study (Table ), sorting by amino acid sequences as S64Y, T65I, G68V, K90R (case 2 of this study), V91L, W99R, W99L, W99C, T103S, N180D, M197I, M197T, M197V (case 1 of this study), Y214C, V389L, E442K, V452L, ins454A, V455M and A456V. Of the 20 GCK‐CHI mutations, the missense mutations account for 95% (19/20), and the remaining mutation was an insertional mutation (5%, 1/20).…”

“…For example, most living carriers of the V455M mutation developed diabetes later in life, suggesting an eventual β‐cell exhaustion. However, β‐cell exhaustion might not occur in all AD patients, as a carrier of the V389L mutation was reported to show persistent hypoglycemia when aged in his 90s.…”

Glucokinase activation is beneficial or toxic to cultured rat pancreatic islets depending on the prevailing glucose concentration

“…If GKAs undoubtedly trigger liver steatosis (4,6,34), their potential toxicity to ␤-cells remains unclear (4,35,38,43,44,46). Thus, although some GKAs proved beneficial to ␤-cell survival and GSIS under glucotoxic conditions and in islets from T2D patients (8,35,46), their secondary failure during long-term treatment (22,31,47) reopened the question of their toxicity to ␤-cells.…”