Pancreatic safety of GLP-1-based therapeutic agents: further insights from rodent studies?

Abstract

Abbreviations DPP-4 Dipeptidyl peptidase-4 GLP-1 Glucagon-like peptide-1In this issue of Diabetologia, Ellenbroek and colleagues present a study of the effects of the glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, on beta cell function and mass in normoglycaemic mice [1]. The mice were treated with liraglutide at 0.1 mg/kg twice daily (a high but reasonable dose) for either 1 or 6 weeks while they received either a control diet or a high fat diet. Compared with controls, liraglutide improved insulin resistance and attenuated resistance induced by high fat feeding. In the pancreas, a lower beta cell mass was observed in the liraglutide-treated group, which was associated with decreased proliferation of beta cells at 1 week. Despite this, islets isolated from treated mice showed enhanced glucose-stimulated insulin secretion. There was a similar reduction in alpha cell mass such that the alpha to beta cell ratio was preserved. In contrast, acinar cells showed a significantly higher number of proliferating cells following liraglutide treatment in both control and high fat fed mice (as measured using BrdU incorporation), and total pancreatic mass increased somewhat after 6 weeks. Duct cells did not show proliferation. There were no signs of inflammation and levels of pro-inflammatory cytokines were similar in all groups.These results are interesting in many ways. First, the reported effect on beta cell mass is consistent with the view that beta cell mass in rodents is predominantly regulated by glucose [2]. Thus, the proliferative effects of GLP-1 and GLP-1 agonists are mainly observed in hyperglycaemic animals. Bock et al [3] observed that the effect of liraglutide on beta cell mass (evaluated by stereology, the most reliable technique for morphometric analysis) in normoglycaemic rats was transient, supporting the view that glycaemic regulation overrides the effects of incretins. The lower beta cell mass observed by Ellenbroek et al is consistent with a glucose-lowering effect of GLP-1 even at basal levels [4]. The positive effects on insulin sensitivity and glucose tolerance are in line with those observed in human studies [5], although the mechanism in normoglycaemic animals is unclear. The question is whether or not GLP-1 directly affects peripheral insulin-sensitive tissues (muscle and fat); this has been reported in rodents [6], but is perhaps less likely to occur in humans [7,8], where improvements in patients with diabetes are generally thought to reflect improved metabolism and weight loss [5]. Weight loss may also play a role in the present study [1], as liraglutide treatment reduced body weight in control and high fat fed mice.A new finding in this study is that alpha cell mass was reduced similarly to beta cell mass [1]. Initially, this would appear consistent with the inhibitory effect of GLP-1 on alpha cell secretion [9]. However, the mechanism behind the inhibition is far from clear: in contrast to beta cells, it is highly controversial whether or not alpha cells express GLP-1 receptors...

Reanalysis of study of pancreatic effects of incretin therapy: methodological deficiencies

“…Although we would like to stress that it is important to investigate in depth any indication that incretin treatment may lead to inflammation or dysplasia in the pancreas, we find that the data presented in this paper have serious methodological deficiencies that preclude any meaningful conclusions. Others have already raised some of the issues: some inherent in a human postmortem study (small number of cases; lack of detailed premortem history), others specific to this study, including the heterogeneity in subject age, and differences in the incretin drugs used, dosage employed and duration of diabetes. Harja et al in re‐examining the clinical information of the cases in the nPOD database detailed even more differences between the study groups.…”

Studying Pancreatic Risks Caused by Incretin-Based Therapies

“…and their interpretation (reason for a serious change in the risk-benefit assessment for GLP-1 receptor agonists and/or DPP-4 inhibitors?) have raised a highly controversial debate, with letters-to-the editor [4][5][6] from pharmaceutical companies marketing incretin-based drugs or commentaries from the academic world in the journal originally publishing the latest results, Diabetes 7,8 as well as in other journals, 9,10 indicating that widely contrasting views have been held on the issues raised by Butler et al's article. 3 Journalists have adopted the position that long-term consequences of using incretin-based drugs may include pancreatitis and pancreatic cancer, and that hints from relevant studies have not been made public in due time to protect financial interests related to drug sales.…”