First generation insulin sensitizers improve both hyperglycemia and hyperinsulinemia and can preserve beta cell mass and function. GLP-1 receptor agonists work by augmenting glucose-stimulated insulin secretion. Our objective was to assess potential additive effects of the new insulin sensitizer, MSDC-0602K (0602K) when combined with a GLP-1 receptor agonist in db/db mice. Mice were gavaged daily with 30 mg/kg 0602K or vehicle, injected subcutaneously every other day with 200 μg/kg Liraglutide (Lira) or vehicle, or received both drugs. Lira reduced glycemia and plasma fructosamine levels, while 0602K or 0602K+Lira normalized glycemia and fructosamine to lean db/+ mouse levels. Both drugs alone improved glucose tolerance compared to vehicle db/db, while the combination of 0602K+Lira further improved glucose tolerance even compared to lean db/+ mice. Vehicle treated db/db mice displayed elevated insulin and C-peptide levels, which were both reduced by 0602K treatment. C-peptide levels were lowered to a greater degree than insulin, indicating that 0602K treatment exerted a major effect on insulin secretion. In contrast, Lira increased the insulin and C-peptide levels in db/db mice, while the combination of 0602K+Lira displayed reduced levels of insulin and C-peptide similar to 0602K-alone treatment. Pancreas immunohistochemistry of vehicle treated db/db mice showed little islet insulin content, but islet insulin was significantly increased by 0602K or 0602K+Lira treatment. Isolated islets from lean, naïve mice showed no defect in glucose-stimulated insulin secretion with 0602K treatment, suggesting that the lowered insulinemia in vivo is due to corrected insulin resistance rather than direct inhibition of insulin secretion.
In conclusion, the new insulin sensitizer MSDC-0602K improves insulinemia and helps to restore islet insulin content when used alone or in combination with Liraglutide. Glucose tolerance displayed additive effects with combined 0602K+Lira treatment.
K.D. Pyles: None. D. Kamm: None. J.R. Colca: Stock/Shareholder; Self; Cirius Therapeutics, Metabolic Solutions Development Company. K.S. McCommis: None.
National Institutes of Health (R01HL136658)