Hope and fear for new classes of type 2 diabetes drugs: is there preclinical evidence that incretin-based therapies alter pancreatic morphology?

Abstract

Incretin-based therapies appear to offer many advantages over other approaches for treating type 2 diabetes. Some preclinical studies have suggested that chronic activation of glucagon-like peptide 1 receptor (GLP1R) signalling in the pancreas may result in the proliferation of islet b-cells and an increase in b-cell mass. This provided hope that enhancing GLP1 action could potentially alter the natural progression of type 2 diabetes. However, to date, there has been no evidence from clinical trials suggesting that GLP1R agonists or dipeptidyl peptidase-4 (DPP4) inhibitors can increase b-cell mass. Nevertheless, while the proliferative capacity of these agents remains controversial, some studies have raised concerns that they could potentially contribute to the development of pancreatitis and hence increase the risk of pancreatic cancer. Currently, there are very limited clinical data to directly assess these potential benefits and risks of incretin-based therapies. However, a review of the preclinical studies indicates that incretin-based therapies probably have only a limited capacity to regenerate pancreatic b-cells, but may be useful for preserving any remaining b-cells in type 2 diabetes. In addition, the majority of preclinical evidence does not support the notion that GLP1R agonists or DPP4 inhibitors cause pancreatitis.

Contribution of the hypothalamus and gut to weight gain susceptibility and resistance in mice

“…The reduction in Gpr expression in the present study may also explain why we saw a reduction in Glp1 mRNA expression in our DIO mice. It is clear that Glp1 affects satiety by acting centrally (Lamont & Andrikopoulos 2014), and the reduced gut expression of this incretin may well contribute to the increased energy intake of the DIO mice. Although it is not entirely clear why Gpr40 is markedly elevated in DIO mice, there may be a compensatory mechanism in place that activates this Gpr when the others are reduced.…”

Effect of placental restriction and neonatal exendin-4 treatment on postnatal growth, adult body composition, and in vivo glucose metabolism in the sheep

“…Exendin-4 is a long-acting analog of the hormone glucagon-like peptide 1 (GLP-1), which stimulates ␤-cell proliferation and function in rodents and human islets in vitro, with evidence of increased ␤-cell mass following short-and medium-term treatment (days to weeks) in rodents (reviewed in Ref. 29). Chronic treatment with exendin-4 and other GLP-1 receptor agonists improves insulin secretion in diabetic rats (61) and in human T2D patients, where current evidence from clinical trials suggests that GLP-1 receptor agonists increase ␤-cell function and may preserve existing ␤-cells but probably do not increase ␤-cell mass (reviewed in Ref.…”

“…Chronic treatment with exendin-4 and other GLP-1 receptor agonists improves insulin secretion in diabetic rats (61) and in human T2D patients, where current evidence from clinical trials suggests that GLP-1 receptor agonists increase ␤-cell function and may preserve existing ␤-cells but probably do not increase ␤-cell mass (reviewed in Ref. 29). Daily administration of exendin-4 for the first 6 days of neonatal life (1 nmol/kg body wt) successfully prevents development of diabetes in the IUGR rat without altering glucose metabolism in control progeny (52).…”

The Proliferative Gene Cyclin D1 and Gluconeogenesis—Could Suppressing Glucose Production Also Promote Cancer?

“…However, would this increase the risk of cancer further? Given the recent concern of incretin-based therapies in diabetes and cancer (17), further investigation and caution are warranted. and Cdk4 can regulate hepatic glucose production.…”