A tale of two glucose transporters: how GLUT2 re-emerged as a contender for glucose transport into the human beta cell.

Finding novel causes for monogenic forms of diabetes is important as, alongside the clinical implications of such a discovery, it can identify critical proteins and pathways required for normal beta cell function in humans. It is increasingly apparent that there are significant differences between rodent and human islets. One example that has generated interest is the relative importance of the glucose transporter GLUT2 in rodent and human beta cells. The central role of GLUT2 in rodent beta cells is well established, but a number of studies have suggested that other glucose transporters, namely GLUT1 and GLUT3, may play an important role in facilitating glucose transport into human beta cells. In this issue of Diabetologia Sansbury et al (DOI: 10.1007/s00125-012-2595-0 ) report homozygous loss of function mutations in SLC2A2, which encodes GLUT2, as a rare cause of neonatal diabetes. Evidence for a beta cell defect in these subjects comes from very low birthweights, lack of endogenous insulin secretion and a requirement for insulin therapy. Neonatal diabetes is not a consistent feature of SLC2A2 mutations. It is only found in a small percentage of cases (~4%) and the diabetes largely resolves before 18 months of age. This discovery is significant as it suggests that GLUT2 plays an important role in human beta cells, but the interplay and relative roles of other transporters differ from those in rodents. This finding should encourage efforts to delineate the precise role of GLUT2 in the human beta cell at different developmental time points and is a further reminder of critical differences between human and rodent islets.

Heterogeneity in disease severity in a family with a novel G68V GCK activating mutation causing persistent hyperinsulinaemic hypoglycaemia of infancy.

BACKGROUND/AIM: Glucokinase (GCK)-activating mutations cause persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI). GCK-PHHI patients have regulated insulin secretion and can usually be treated with diazoxide. The six reported cases suggest that the severity of the mutation predicts the clinical phenotype. The aim of this study was to relate genotype to phenotype [clinical phenotype, glucose-stimulated insulin release (GSIR) and GCK functional analysis] in a large pedigree with eight affected individuals. METHODS: The genes encoding B-cell GCK and the K(ATP) channel subunits (ABCC8 and KCNJ11) were sequenced to identify mutations for functional analysis. Genetic variants influencing B-cell function were genotyped in affected individuals. Islet secretory capacity was determined by oral glucose tolerance test RESULTS: A novel GCK mutation (G68V) co-segregating with hypoglycaemia was identified in eight family members. Kinetic analysis revealed that G68V-GCK activity is ~16 times more than wild-type-GCK with an increased affinity for glucose [concentration at half maximal activation (S(0.5)) 1.94 +/- 0.16 vs. 7.43 +/- 0.12, mutant vs. wild type, mean +/- sem]. Mathematical modelling predicted a threshold for GSIR of 1.9 mmol/l in the mutant. Oral glucose tolerance tests showed regulated insulin secretion. The severity of hypoglycaemia and related symptoms in affected subjects were heterogeneous. Clinical presentations were asymptomatic (n = 1), extreme hunger (n = 3), seizures (n = 2) and loss of consciousness (n = 2); 7/8 were managed with diet but the proband was treated with diazoxide and octreotide. Phenotypic modification by a second mutation in the K(ATP) channel genes (ABCC8, KCNJ11) or by common genetic variants in KCNJ11, GCK and TCF7L2 was excluded. CONCLUSION: The novel activating GCK mutation G68V is associated with variable phenotypic severity, supporting modification of GSIR by genetic and/or environmental factors.