The DPP4 Inhibitor Sitagliptin Increases Active Glp-1 Levels from Human Islets and May Increase Islet Cell Survival Prior to Transplantation

Abstract

Background: One of the goals of clinical islet transplantation is to achieve a single-donor transplant that is dependent on obtaining enough quality  cell mass from one donor pancreas. Human islets are routinely cultured prior to transplantation, and pro-survival factors such as GLP-1 analogues have been reported to maintain  cell mass and survival. Interestingly, human islets may secrete GLP-1 and they also express the enzyme DPP4 that proteolytically cleaves GLP-1 into an inactive form. The aim of this study is to investigate GLP-1 secretion from human islets and to test if the DPP4 inhibitor sitagliptin may increase levels of active GLP-1 to increase islet survival in culture. Methods: Active GLP-1, glucagon, and insulin were measured from non-diabetic and type 2 diabetic islets using a glucose suppression test. Human islet cultures were treated with sitagliptin, and active GLP-1 levels were taken at 48 hours. These levels were then correlated with islet isolation parameters (SI, viability, culture time, cold ischemia time, and DNA was used to measure cell death in human islet cultures treated with sitagliptin. Results: We found that both non-diabetic and type 2 diabetic islets secrete active GLP-1. Active GLP-1 levels from human islet cultures negatively correlated with the stimulation index for insulin and this correlation was maintained when active GLP-1 levels were increased with sitagliptin. No strong correlations were found for other islet or donor parameters. The fold change in active GLP-1 in sitagliptin treated islet cultures was correlated with increased islet survival. Conclusions: Human islets have a local paracrine source of the prosurvival peptide, active GLP-1. Although low levels of active GLP-1 are associated with greater  cell function, these levels may be increased with the DPP4 inhibitor sitagliptin. The increase in active GLP-1 levels may confer protection from islet cell death and pre-treatment of islets with DPP4 inhibitors prior to transplantation has the potential to improve post-transplant islet survival.

Dipeptidyl Peptidase-4 at the Interface Between Inflammation and Metabolism

“…Recent evidence in mice genetically engineered to reexpress Gcg has suggested that bioactive and glucoregulatory GLP-1 may be produced in the pancreas. 101 Dipeptidyl peptidase-4 protein expression has been observed in isolated human islets, 102 and GLP-1R antagonism blunts the DPP4i (linagliptin) improvement in mice with Gcg expression restricted to the pancreas, 103 suggesting a potential pancreatic, paracrine circuit to control glycemia. However, further use of these models to reexpress Gcg in the proximal and distal gut demonstrates gut-derived GLP-1 is indeed the dominant site of GLP-1, and pancreas perfusion studies with a DPP4i have demonstrated no impact on glycemia.…”

9 - Regulation of Glucose Metabolism via the Intra-Islet DPP4/Incretin Axis

“…shown that treatment of islets from T2D patients with DPP4 inhibitor sitagliptin led to increased GLP-1 secretion, which was associated with improved β-cell health and survival (Bugliani et al, 2018;Buteau et al, 2004;Campbell et al, 2019;Farilla et al, 2003;Li et al, 2003). As such, we hypothesized that the deletion of intra-islet Dpp4 could prevent the cleavage of GLP-1 by DPP4 within the islet, thus resulting in improved glucose tolerance via the augmented paracrine action on the β-cell.…”

Evidence for the existence and potential roles of intra-islet glucagon-like peptide-1

“…DPP4 inhibition protects beta cells from lipo- and glucotoxicity, 14 , 26 , 78 and improves islet survival in culture. 26 , 78 Intra-islet DPP4, whether endothelial or endocrine cell-derived, may reduce GLP-1 concentrations, limiting the GLP-1 mediated protection of beta cells. As discussed above, DPP4 inhibitors have the potential to increase active GLP-1 concentrations in the local islet microenvironment.…”

“…This finding suggests that sitagliptin, and other DPP4 inhibitors, may preserve healthy beta cell mass during the pre-transplant culture period and increase beta cell survival immediately post-transplant. 78 Finally, DPP4 inhibitors may increase GLP-1 secretion from the remaining alpha cells in T1D, as many T1D patients are identified with residual functional beta cell mass. 83 These patients may benefit from increased active GLP-1 levels local to the beta cell, with potentially less need for exogenous insulin and a reduced risk of hypoglycemia.…”