Continuous stimulation of human glucagon-like peptide-1 (7–36) amide in a mouse model (NOD) delays onset of autoimmune type 1 diabetes

Abstract

Aims/hypothesis We examined the effect of glucagon-like peptide-1 (GLP-1) on the development of diabetes and islet morphology in NOD mice by administering GLP-1 to prediabetic mice. Methods Eight-week-old female NOD mice were infused subcutaneously with human GLP-1 via a mini-osmotic pump for 4 or 8 weeks. In mice treated with GLP-1 for 4 weeks, blood glucose levels and body weight were measured. An intraperitoneal glucose tolerance test (IPGTT) and evaluation of insulitis score were also performed. Beta cell area, proliferation, apoptosis, neogenesis from ducts and subcellular localisation of forkhead box O1 (FOXO1) were examined by histomorphometrical, BrdU-labelling, TUNEL, insulin/cytokeratin and FOXO1/ insulin double-immunostaining methods, respectively.Results Mice treated with human GLP-1 for 4 weeks had lower blood glucose levels until 2 weeks after completion of treatment, showing improved IPGTT data and insulitis score. This effect continued even after cessation of the treatment. In addition to the increase of beta cell neogenesis, BrdU labelling index was elevated (0.24 vs 0.13%, p<0.001), while apoptosis was suppressed by 54.2% (p<0.001) in beta cells. Beta cell area was increased in parallel with the translocation of FOXO1 from the nucleus to the cytoplasm. The onset of diabetes was delayed in mice treated with GLP-1 for 4 weeks, while mice treated with GLP-1 for 8 weeks did not develop diabetes by age 21 weeks compared with a 60% diabetes incidence in control mice at this age. Conclusions/interpretation Continuous infusion of human GLP-1 to prediabetic NOD mice not only induces beta cell proliferation and neogenesis, but also suppresses beta cell apoptosis and delays the onset of type 1 diabetes.

Glucagon-like peptide-1 (GLP-1) receptor agonists, obesity and psoriasis: diabetes meets dermatology

“…Consistent with the results reported by Hogan et al, GLP-1R agonists have previously been shown to increase cAMP formation in multiple lymphocyte populations in a GLP-1R-and exendin (9-39)-dependent manner [5]. Furthermore, several reports have described disease remission and enhanced numbers of regulatory T cells in experimental murine models of autoimmune type 1 diabetes treated with GLP-1R agonists in the absence of concomitant therapy with immunomodulatory agents [6,7]. GLP-1R activation also modestly reduced stromal cell-derived factor-1-enhanced lymphocyte migration in human CD4 + lymphocytes [8], whereas genetic disruption of Glp1r produced detectable defects in thymocyte and lymphocyte proliferation following stimulation ex vivo [5].…”

Anti-inflammatory action of exendin-4 in human islets is enhanced by phosphodiesterase inhibitors: potential therapeutic benefits in diabetic patients

“…For example, chronic administration of exendin-4 to NOD mice leads to modest and significant decrease in insulitis [29]. Continuous infusion of GLP-1 also delayed the onset of diabetes in NOD mice [30]. Other studies have used exendin-4 in combination with anti-inflammatory agents to demonstrate a more significant blocking of insulitis and diabetes onset in NOD mice [31][32][33].…”

DsAAV8-mediated expression of glucagon-like peptide-1 in pancreatic beta-cells ameliorates streptozotocin-induced diabetes

“…47 GLP-1 has also been recently investigated for its potential benefit in the treatment of type-1 diabetes. Zhang et al 5 have demonstrated that continuous infusion of GLP-1 in pre-diabetic NOD mice results in significant delay in the onset of diabetes as a result of increased beta-cell proliferation coupled with decrease in beta-cell apoptosis. Furthermore, combination therapies using GLP-1 or exendin-4 with gastrin, 48 anti-lymphocyte serum 49 or anti-CD3 immunotherapy 50 have been shown to restore normoglycemia in acutely diabetic NOD mice by increasing insulin stores and reducing beta-cell apoptosis.…”

“…1 GLP-1 promotes the maintenance of beta-cell mass through stimulation of cell proliferation and neogenesis while inhibiting apoptosis, [2][3][4] and has been shown to be effective in reducing diabetes incidence in models of type-1 diabetes. 5 In addition to its effects on beta-cell survival and growth, GLP-1 acutely stimulates glucose-dependent insulin secretion and can increase insulin gene expression through several mechanisms including upregulation of the transcription factor pancreatic duodenal homeobox-1 (Pdx-1). [6][7][8] GLP-1 also reduces blood glucose levels by inhibiting glucagon secretion from alpha-cells, an effect likely mediated through increased somatostatin release from delta-cells.…”

“…17 In animal models of type-1 diabetes, administration of GLP-1-receptor agonists has been shown to improve glycemia, in part due to increases in beta-cell mass. 5,18,19 Native GLP-1, as well as currently available GLP-1-receptor agonists, have short biological half-lives. [20][21][22][23] Native GLP-1 is degraded within minutes by dipeptidylpeptidase (DPP)-IV, 20,21 rendering it unfit for use as a subcutaneously administered therapeutic.…”