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Glucokinase (Gck) is known to function as a glucose sensor for insulin secretion. Mice with β-cell-specific haploinsufficiency of glucokinase gene (Gck+/-) fed a standard-chow diet exhibit impaired insulin secretion to glucose. After 4 weeks on a high-fat (HF) diet wild-type mice maintained normal glucose tolerance, whereas Gck+/- developed severe diabetes, despite the presence of a similar degree of insulin resistance. We here investigated the effects of small-molecular glucokinase activator (GKA) on glucose metabolism in wild-type mice and Gck+/- in response to HF-diet-induced insulin resistance. We analyzed three mouse groups, namely wild-type mice on the HF diet (W), Gck+/- on the HF diet (G), and Gck+/- treated with GKA mixed in the HF diet (A). After 10 weeks on the above diets, we investigated body weight, fat mass, liver weight, liver triglyceride content, serum triglyceride and ALT levels in these mice. We also performed glucose tolerance test (OGTT and IVGTT) and histological analysis to assess β-cell mass. After 10 weeks on the above diets, there were no differences in body weight among the three mouse groups (W: 39.8 ± 1.5 g, G: 40.9 ± 1.3 g, A: 42.0 ± 1.8 g). Fat mass, liver weight, serum triglyceride and ALT levels were also indistinguishable among these mice. Fed glucose levels decreased shortly after the GKA treatment in A compared with G. In fact, after 10 weeks' GKA treatment, A had blood glucose level significantly lower than G (W: 129.2 ± 12.2 mg/dl, G: 202.8 ± 18.1 mg/di, A: 77.0 ± 6.6 mg/dl, A vs. G: p<0.01). Moreover, GTT revealed that A had better glucose tolerance and higher serum insulin level 1 min after an intravenous glucose load than G. Histological analysis revealed that A had maximum islet diameter similar to W and larger than G, although statistically not significant (W: 111.3 ± 3.3 µn, G: 105.6±2.5 µm, A: 112.9±3.3 µm, G vs. W: p=0.17, A vs. G: p=0.07). These results suggest that GKA is able to improve glucose metabolism on the HF diet in mice with β-cell-specific haploinsufficiency of glucokinase gene. [ABSTRACT FROM AUTHOR]

We investigated the effect of glucokinase activator (GKA) on glucose metabolism and beta-cell mass. We analyzed four mouse groups: wild-type mice and beta-cell-specific haploinsufficiency of glucokinase gene (Gck(+/-)) mice on a high-fat (HF) diet. Each genotype was also treated with GKA mixed in the HF diet. Rodent insulinoma cells and isolated islets were used to evaluate beta-cell proliferation by GKA. After 20 wk on the above diets, there were no differences in body weight, lipid profiles, and liver triglyceride content among the four groups. Glucose tolerance was improved shortly after the GKA treatment in both genotypes of mice. beta-Cell mass increased in wild-type mice compared with Gck(+/-) mice, but a further increase was not observed after the administration of GKA in both genotypes. Interestingly, GKA was able to up-regulate insulin receptor substrate-2 (Irs-2) expression in insulinoma cells and isolated islets. The administration of GKA increased 5-bromo-2-deoxyuridine (BrdU) incorporation in insulinoma cells, and 3 d administration of GKA markedly increased BrdU incorporation in mice treated with GKA in both genotypes, compared with those without GKA. In conclusion, GKA was able to chronically improve glucose metabolism for mice on the HF diet. Although chronic GKA administration failed to cause a further increase in beta-cell mass in vivo, GKA was able to increase beta cell proliferation in vitro and with a 3-d administration in vivo. This apparent discrepancy can be explained by a chronic reduction in ambient blood glucose levels by GKA treatment.