1736-P: Effect of Glucokinase Haploinsufficiency on Pancreatic Beta-Cell Function and Mass in High-Fat, High-Sucrose Diet-Fed Mice

Background and Aim: We previously found in db/db mice that glucokinase haploinsufficiency reduces excessive glucose signaling in beta-cells and optimizes intracellular metabolic patterns, thereby preserving pancreatic beta-cell function and mass, ultimately improving glucose tolerance. In the present study, we investigated the effect of glucokinase haploinsufficiency on beta-cell function and mass in high-fat, high-sucrose diet (HFHS)-fed mice. Method: Four-week-old male wild-type (Gck+/+) and glucokinase haploinsufficient (Gck+/−) mice were fed normal chow (NC) or HFHS. Blood glucose levels were measured, and glucose tolerance, glucose-stimulated insulin secretion (GSIS), and pancreatic beta-cell mass were evaluated over time (16, 40, and 60 weeks of age). Results: At 16 weeks of age, no difference was found in glucose tolerance between NC and HFHS feeding in both Gck+/+ and Gck+/− mice. At 40 weeks of age, Gck+/+ HFHS-fed mice exhibited increases in GSIS and beta-cell mass versus Gck+/+ NC-fed mice (7.0 ± 1.2 mg vs. 3.3 ± 1.6 mg; P < 0.01), and glucose tolerance was preserved. Conversely, Gck+/− HFHS-fed mice displayed no increase in beta-cell mass (4.1 ± 0.5 mg vs. 3.9 ± 1.5 mg), a slight increase in GSIS, and worsening of glucose tolerance compared with Gck+/− NC-fed mice. At 60 weeks of age, Gck+/+ HFHS-fed mice displayed further increases in beta-cell mass (14.7 ± 2.0 mg) and GSIS with no worsening of glucose tolerance. In Gck+/− HFHS-fed mice, beta-cell mass (5.5 ± 1.4 mg) and GSIS were partially increased, and no further worsening of glucose tolerance was observed after 40 weeks of age. Conclusion: Gck+/− mice fed HFHS displayed insufficient increases in beta-cell mass and GSIS, resulting in worsening of glucose tolerance. In the longer term, however, these mice did not exhibit subsequent declines in beta-cell mass and GSIS nor progressive worsening of glucose tolerance unlike the non-compensatory phase in people with type 2 diabetes.