Incretin Therapies Do Not Expand β-Cell Mass or Alter Pancreatic Histology in Young Male Mice

Abstract

The impact of incretins upon pancreatic β-cell expansion remains extremely controversial. Multiple studies indicate that incretin-based therapies can increase β-cell proliferation, and incretins have been hypothesized to expand β-cell mass. However, disagreement exists on whether incretins increase β-cell mass. Moreover, some reports indicate that incretins may cause metaplastic changes in pancreatic histology. To resolve these questions, we treated a large cohort of mice with incretin-based therapies and carried out a rigorous analysis of β-cell turnover and pancreatic histology using high-throughput imaging. Young mice received exenatide via osmotic pump, des-fluoro-sitagliptin, or glipizide compounded in diet for 2 weeks (short-term) on a low-fat diet (LFD) or 4.5 months (long-term) on a LFD or high-fat diet (HFD). Pancreata were quantified for β-cell turnover and mass. Slides were examined for gross anatomical and microscopic changes to exocrine pancreas. Short-term des-fluoro-sitagliptin increased serum insulin and induced modest β-cell proliferation but no change in β-cell mass. Long-term incretin therapy in HFD-fed mice resulted in reduced weight gain, improved glucose homeostasis, and abrogated β-cell mass expansion. No evidence for rapidly dividing progenitor cells was found in islets or pancreatic parenchyma, indicating that incretins do not induce islet neogenesis or pancreatic metaplasia. Contrasting prior reports, we found no evidence of β-cell mass expansion after acute or chronic incretin therapy. Chronic incretin administration was not associated with histological abnormalities in pancreatic parenchyma; mice did not develop tumors, pancreatitis, or ductal hyperplasia. We conclude that incretin therapies do not generate β-cells or alter pancreatic histology in young mice.

Effects of Linagliptin on Pancreatic α Cells of Type 1 Diabetic Mice

“…Many studies have shown GLP-1R agonists and DPP-4 inhibitors have mitogenic effects on β cells in rodents [ 35 – 37 ], but some showed otherwise. For instance, a newly published study using a large cohort of young male mice has shown that incretin (exenatide and sitagliptin) therapies have little impact on β -cell proliferation and mass expansion following long-term (4.5 months) treatment [ 38 ], although the authors indeed have observed moderate β -cell proliferation following short-term (2 weeks) treatment. Together, these studies suggest that the mitogenic potential of incretin therapies may be affected by drug dosage, administration route, treatment duration, and the nature of diabetes models [ 38 , 39 ].…”

GLP‐1 induces alpha cell proliferation and overrides leptin suppression induced by negative energy balance in vagotomized rats

“…57 In fact, in our study GLP-1 did not influence ki-67 staining in β-cell, similar to what was reported in more recent studies. 58 Conversely, chronic GLP-1 exposure, resulted in a lower ki-67 stained α-cells in rats with intact vagal pathway than in vagotomized rats. GLP-1R are present in α-cells 59 and have an active role in glycemic control.…”

Increases in bioactive lipids accompany early metabolic changes associated with β-cell expansion in response to short-term high-fat diet

“…Previous work from a different group showed that the addition of a dipeptidyl peptidase-IV (DPP-IV) inhibitor, TS-021, with metformin treatment had the opposite effect, increasing ␤-cell mass and lowering glucose, although ␤-cell proliferation directly was not examined (81). Furthermore, the incretin-effect of DPP-IV inhibition on mouse ␤-cell mass expansion following HFD feeding has not been validated by other studies (21). Similarly, although in an entirely different class of drugs, ␤-hydroxy-␤-methylglutaryl (HMG)-CoA reductase inhibitors (statins), which act by lowering endogenous cholesterol synthesis in the liver, have been linked with a 9% increased risk of Type 2 diabetes, particularly in older patients (73).…”