Investigating the role of LEAP2 in glucose homeostasis and insulin secretion

Abstract

Prior research has shown that LEAP-2 stimulates insulin secretion in male mice. sympathetic activation of release of glucagon can be mediated to an extent through the indirect effect on somatostatin secretion where the inhibition of δ-cell somatostatin on α-cells is eliminated. The two questions answered in this study were: 1) Is somatostatin essential to mediate a possible effect of ghrelin and LEAP-2 on glucose-induced insulin release in male mice, and 2) does glucose intake stimulate LEAP-2 production in humans? Two studies were undertaken to address the research hypotheses. The first study investigated the changes in plasma concentration of LEAP-2 after glucose ingestion whereas the second study analysed the effect of glucose, ghrelin and LEAP-2 and amino acids on insulin, glucagon and somatostatin secretion in mice. Following the consumption of a 75g glucose drink, there was a statistically significant increase in glucose concentration levels at intervals up to 120 minutes post-meal when compared to fasting baseline. Contrarily, no significant change was observed in the plasma LEAP-2 concentration post-meal, with results only marginally insignificant (p=0.0502). Plasma ghrelin concentration significantly reduced after glucose ingestion, with the lowest observed levels 60 minutes post-intake. Moreover, there was a notable increase in plasma insulin concentration, peaking at 30 minutes post-intake, before gradually reducing, albeit remaining elevated compared to fasting levels. This rise in insulin post-glucose ingestion is consistent with its role in regulating blood glucose levels and mirrors patterns observed in prior studies. Furthermore, ghrelin and/ or LEAP-2 did not alter the glucose-induced insulin secretion from WT and KO. Interestingly, KO islets were found to release more insulin in response to glucose compared to the WT. LEAP-2 was found to block the action of ghrelin, which is consistent with the expectation in this study that LEAP-2 should act as an antagonist of AG. The experiments revealed that AG and LEAP-2 did not affect the secretion in WT islets. Therefore, it is difficult to conclude with confidence whether SST is important or not. When we remove SST (as was the case in Sst KO), no effect was observed. It was expected that an effect of LEAP-2 in the WT would be observed as noticed previously. However, if SST was important for this effect, it would not be expected to see an effect in the Sst KO islets. Overall, the results of this study lead to rejection of the hypothesis that somatostatin is essential to mediate a possible effect of ghrelin and LEAP-2 on glucose-induced insulin release in male mice. The results could have been statistically significant at 5% level if the sample size was higher. These findings should be confirmed by future studies, which should aim to increase the sample size and methodological rigour and power through overcoming the limitations of this study.