Pancreatic safety of GLP1based therapeutic agent

Authors: Jens Juul Holst

Publish Date: 2013/07/03

Volume: 56, Issue: 9, Pages: 1869-1872

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Abstract

In this issue of Diabetologia Ellenbroek and colleagues present a study of the effects of the glucagonlike peptide1 GLP1 receptor agonist liraglutide on beta cell function and mass in normoglycaemic mice 1 The mice were treated with liraglutide at 01 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 liraglutidetreated group which was associated with decreased proliferation of beta cells at 1 week Despite this islets isolated from treated mice showed enhanced glucosestimulated 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 proinflammatory cytokines were similar in all groupsThese 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 GLP1 and GLP1 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 glucoselowering effect of GLP1 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 GLP1 directly affects peripheral insulinsensitive 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 miceA 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 GLP1 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 GLP1 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 GLP1 lowers glucagon secretion GLP1 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 such as somatostatin 15 and beta cell products 14The results obtained by Ellenbroek et al 1 appear at a time when new findings regarding the effects of GLP1based therapies have questioned the safety of these therapies In an online report in Diabetes a team of workers from Los Angeles and Florida reported pancreatic morphological changes in eight diabetes patients treated with GLP1based therapies seven with the dipeptidyl peptidase4 DPP4 inhibitor sitagliptin one with exenatide for less than a year 16 The pancreatic tissue specimens were obtained freshly post mortem through a collaboration with the Network for Pancreatic Organ Donors with Diabetes nPOD funded by the JDRF to promote type 1 diabetes research and compared with tissue from 12 diabetic patients not receiving GLP1based therapies and a group of nondiabetic donors As one can imagine the groups were extremely heterogeneous with widely differing circumstances leading to a final hospital stay eg in intensive care units and to death The main findings in incretintreated individuals were a 40 increase in pancreatic mass accompanied by increased proliferation of exocrine cells as well as dysplasia in the form of intraepithelial neoplasia hyperplasia of beta and alpha cells five to sixfold increases increased frequency of cells costaining for insulin and glucagon peri/intraductal luminal projections of glucagon immunoreactive cells and glucagonproducing microadenomas in three donors one of whom also had a glucagonproducing tumour There were no signs of pancreatitis in any of the pancreases examined The study has been heavily criticised particularly because of the heterogeneity of the groups 17 18 Particularly important is a mean 18 year age difference between incretin treated and nonincretin treated patients with diabetesHowever the studies by Ellenbroek et al 1 and Butler et al 16 have in common an increase in the mass of the exocrine pancreas Do GLP1 and GLP1 receptor agonists cause pancreatic growth And if they do what does that mean for treatment safetyPancreatic growth is generally not reported in the studies available to date It is also unclear whether or not GLP1 receptors are expressed in the acinar tissue However it should be noted that exenatide was originally isolated using a bioassay based on cAMP accumulation in guinea pig pancreatic acini 19 indicating that exenatide must somehow interact with this tissue although it may be possible that the acinus preparations could have been contaminated with islet cells It has also been reported that exenatide enhances cholecystokinininduced pancreatic enzyme secretion but has little effect alone 20 perhaps consistent with reports of slightly raised lipase levels during GLP1 agonist therapy 21 In preclinical studies provided by the pharmaceutical companies for registration of GLP1based therapeutics increases in pancreatic mass have not been reported 22 and in one study of exenatide pancreas mass was actually reduced 23 In extensive studies on the pancreatic effects of liraglutide Nyborg et al examined pancreases from 1438 animals of which more than 1000 were treated for 2 years lifetime at up to 60fold higher doses than the equivalent human therapeutic doses 22 increases in pancreas size were not noted and in monkeys followed for 87 weeks of therapy there was no growth of the pancreas However a study by Koehler et al of exenatide and liraglutide in mice 24 found increases in pancreatic size not associated with inflammation and in female but not in male monkeys given liraglutide for 52 weeks there was apparently an increase in pancreas mass mentioned in a news report in the British Medical Journal 25 contrasting with the lack of effect in the 87 week study in monkeys 22 Thus it is difficult to conclude anything from the preclinical studies In the cases where an increase was observed this was not associated with inflammation ie pancreatitis The human pancreas donor study by Butler et al 16 included only one patient treated with a GLP1 agonist exenatide whereas the others were treated with the DPP4 inhibitor sitagliptin for which there are no preclinical data derived from extensive studies 26 suggesting growth of the pancreas or any other pathology It should also be considered that GLP1 plasma levels during DPP4 inhibitor treatment are only slightly elevated and still fall within the normal range 27 Rather it should be noted that the diabetic control group in the donor study 16 probably included several or a majority of pancreases from patients with type 1 diabetes which are known to be smaller than those of controls 28 A similar reservation applies to the observed beta cell hyperplasia some years ago a trophic effect on beta cells would have been received with enthusiasm because it would support notions of protective or restitutive effects of the GLP1 therapies on beta cells but despite the potential to enhance beta cell mass in young rodents 29 no studies so far have revealed beta cell tumours insulinomas resulting from GLP1 therapies consistent with the concept that GLP1 therapy does not enhance beta cell mass in humans 30

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