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

Abstract

In 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, with reports ranging from no receptors [10] to 20% of alpha cells expressing them [11]. A cautious guess might be that the expression level is low [12]. It is equally uncertain how GLP-1 lowers glucagon secretion (GLP-1 was even reported to stimulate secretion in isolated alpha cells [13, 14]), but several observations indicate that the inhibition is indirect, resulting from the inhibitory actions of hormones or agents released from neighbouring islet cells