The authors of this manuscript investigate the effects of preimplantation factor (sPIF) on insulin secretion and glucose tolerance in diet-induced obese mice. PIF targets insulin-degrading enzyme (IDE), a protease that degrades insulin; loss of insulin contributes to the development of type 2 diabetes. Metabolic phenotyping assessed glucose tolerance, circulating insulin, C-peptide, and insulin secretion after treating high-fat diet-fed mice with sPIF. In addition, the effect of sPIF in MIN6 on GSIS and IDE activity was determined. The outcomes show that sPIF enhanced 2-fold increases in GSIS from human islets. In mice, it increased circulating insulin levels and improved glucose clearance. Furthermore, blocking the IDE by either shRNA or pharmacologically abolished sPIF-mediated effects on GSIS. To improve the mechanism, the impact of sPIF on beta cell mass and gene expression should be assessed.

Figure 1 A. The increase in insulin secretion (insulin per islet) upon sPIF treatment is relatively small compared to control-treated islets at 16 mM glucose. Also, there appears to be a slight reduction in insulin secretion in sPIF vs. control-treated islets at 1 mM glucose. Include the p-value between the sPIF vs. control at 1 mM glucose. Even though the insulin content remained unchanged, it will help if the data is presented as insulin secreted as a percent of total insulin. To improve the effect size of increases in insulin secretion, it is recommended that the dose-response of sPIF be performed in human/mouse islets.

Figure 2: Usage of MIN6 is good, but the effect of sPIF on insulin secretion from mouse islets should be included. Also, at least a few doses of sPIF should be tested while assessing the activity of IDE from mouse islets.

Figure 3: Is there an effect of 6bk on insulin contents in MIN6/islets?

The effect of sPIF on beta cell mass should be assessed. If changes are observed, then follow-up experiments should be performed to gain insights into the mechanism.

Is there an effect of sPIF treatment (>24 h) on the gene expression profile of beta-cells?