Expert Blog

Incretin Therapy and Beta Cell Mass

Patricia Brubaker, PhD
Basic Scientist

Analyses of human pancreata have demonstrated that type 2 diabetes is associated not only with a loss of beta cell function, but also with a marked decrease in beta cell volume.[1] Intriguingly, data from rodent studies have convincingly shown that GLP-1 and long-acting GLP-1 receptor agonists, including exenatide and liraglutide, increase both beta cell function and beta cell mass under physiological conditions as well as in models of diabetes. These growth effects of GLP-1 are mediated through stimulation of beta cell proliferation, inhibition of beta cell apoptosis, and/or enhancement of islet neogenesis, depending upon the model being tested.[2] Although less well established, DPP IV inhibitors (e.g., sitagliptin and vildagliptin), which increase endogenous levels of the incretin hormones (e.g., GLP-1 and GIP), have also been reported to increase beta cell mass in some animal studies.[3]

In contrast, although the incretin effects of GLP-1 are observed in both animal and humans, there is a relative dearth of information available as to whether the growth effects of GLP-1 seen in animal models are recapitulated in humans. One study conducted by Farilla et al.[4] demonstrated that GLP-1 decreases apoptosis in freshly-isolated human islets, while exendin-4 reduces tacrolimus-induced apoptosis in human beta cells.[5] A report from Suarez-Pinzon et al.[6] has further indicated that treatment with GLP-1 plus gastrin induces beta cell neogenesis from ductal cells contained in human islet preparations following transplantation into immunodeficient, diabetic mice.

However intriguing these findings, it must be recognized that many of the rodent studies on the growth effects of GLP-1 were conducted in young animals, and it is now known that beta cell proliferative capacity decreases with age, in both rodents and humans.[7] Furthermore, the ability of exendin-4 to induce beta cell proliferation is profoundly reduced in 8-12 month-old, “middle-aged” mice,[8] suggesting that, even if GLP-1 does enhance beta cell growth in humans, the effects may be restricted to younger patients. Finally, it remains possible that treatment with GLP-1 mimetics, whilst clearly enhancing beta cell function,[9] may not be associated with any effects on beta cell mass in patients with type 2 diabetes.

Ultimately, development of imaging methods to quantitate human beta cell mass in vivo or, alternatively, ex vivo analysis of cadaver pancreata from patients who had been chronically treated with GLP-1 mimetics or DPP IV inhibitors, will be necessary to establish whether these agents can enhance beta cell mass and/or prevent loss of beta cells in humans. Readers with comments on this topic are invited to share them here.