2084-P: Hepatic Fat Accumulation Underlies the Inability of Glucokinase Activator to Achieve a Sustained Hypoglycemic Effect in db/db Mice

Background: Previous clinical trials have demonstrated that glucokinase activators (GKAs) do not achieve a sustained hypoglycemic effect; however, the mechanism for this has not been determined. Aims: We aimed to clarify the mechanisms for the loss of GKA hypoglycemic effect. Method: Six-week-old db/db mice were fed standard chow and divided into three groups as follows: Untreated (UT), 0.04% GKA (G), or 0.005% ipragliflozin, a sodium-glucose cotransporter 2 inhibitor that has a long-term hypoglycemic effect in db/db mice (S). After measuring body weight (BW) and blood glucose (BG) for 28 days, pancreatic beta-cell mass and hepatic triglyceride (TG) content were analyzed. Results: The three groups did not differ in BW. A hypoglycemic effect persisted until Day 28 in S; however, in G it lasted only 6 days (Day 6: UT 454 ± 84 mg/dL, G 257 ± 85 mg/dL, S 224 ± 55 mg/dL, Day 28: UT 588 ± 102 mg/dL, G 508 ± 129 mg/dL, S 217 ± 30 mg/dL). Insulin sensitivity on insulin tolerance testing did not differ between Days 9 and 23. Glucose tolerance was improved in G and S on Days 4 and 11; however, this improvement had disappeared by Day 25. Only S exhibited increased fasting insulin-to-BG ratio on Days 11 and 25. On Day 28, pancreatic beta-cell mass and proliferation were increased in S, but not in G. Although the three groups did not differ in visceral or subcutaneous fat weight, liver weight was increased in G on Days 6 and 28. Hepatic TG content was increased in G on Day 6 (UT 130 ± 18 mg/g liver, G 226 ± 20 mg/g liver, S 39 ± 7 mg/g liver), and mRNA expression related to lipogenesis, including Fas, Elovl6 and Scd1, was upregulated in G. Conclusion: Our results indicate that GKA does not increase insulin secretion or pancreatic beta-cell mass in db/db mice. However, GKA does increase hepatic TG in db/db mice, suggesting that GKA increases glucose utilization in the liver. However, it might also promote lipogenesis and hepatic fat accumulation, leading to its hypoglycemic effect being unsustained.