Distinct effects of dipeptidyl peptidase-4 inhibitor and glucagon-like peptide-1 receptor agonist on islet morphology and function

Abstract

Although the two anti-diabetic drugs, dipeptidyl peptidase-4 inhibitors (DPP4is) and glucagon-like peptide-1 (GLP-1) receptor agonists (GLP1RAs), have distinct effects on the dynamics of circulating incretins, little is known of the difference in their consequences on morphology and function of pancreatic islets. We examined these in a mouse model of β cell injury/regeneration. The model mice were generated so as to express diphtheria toxin (DT) receptor and a fluorescent protein (Tomato) specifically in β cells. The mice were treated with a DPP4i (MK-0626) and a GLP1RA (liraglutide), singly or doubly, and the morphology and function of the islets were compared. Prior administration of MK-0626 and/or liraglutide similarly protected β cells from DT-induced cell death, indicating that enhanced GLP-1 signaling can account for the cytoprotection. However, 2-week intervention of MK-0626 and/or liraglutide in DT-injected mice resulted in different islet morphology and function: β cell proliferation and glucose-stimulated insulin secretion (GSIS) were increased by MK-0626 but not by liraglutide; α cell mass was decreased by liraglutide but not by MK-0626. Although liraglutide administration nullified MK-0626-induced β cell proliferation, their co-administration resulted in increased GSIS, decreased α cell mass, and improved glucose tolerance. The pro-proliferative effect of MK-0626 was lost by co-administration of the GLP-1 receptor antagonist exendin-(9-39), indicating that GLP-1 signaling is required for this effect. Comparison of the effects of DPP4is and/or GLP1RAs treatment in a single mouse model shows that the two anti-diabetic drugs have distinct consequences on islet morphology and function.

Liraglutide, a human glucagon‐like peptide‐1 analogue, stimulates AKT‐dependent survival signalling and inhibits pancreatic β‐cell apoptosis

“…Experimental evidence indicated that GLP-1 receptor agonists enhance b-cell proliferation and prevent b-cell apoptosis. [18,24,26,43]. Moreover, it was reported that liraglutide did not affect islet endocrine non-b-cells.…”

Baseline Characteristics of Patients with Type 2 Diabetes Initiating Second-Line Treatment in Japan: Findings from the J-DISCOVER Study

“…In the current study, the majority of patients received second-line treatment with a mode of action different from the first as recommended by Japanese treatment guidelines [4]. The higher use of DPP4is as the first-or the second-line agent in the current study (84.7%) may reflect various favorable characteristics of this class of agent in the clinical practice of diabetes care, including low risk of hypoglycemia and weight gain [2,19], safety (at reduced doses) in patients with renal failure [21], cytoprotective effects on pancreatic b-cells [22], and improved glycemic stability [23]. In addition, compared with Caucasians, Japanese patients with T2DM appear to be more predisposed to impaired insulin secretion rather than increased insulin resistance [6,24], Therefore, Japanese patients may receive greater benefit from DPP4is, which increase the endogenous incretin levels and promote insulin secretion in a glucose-dependent manner.…”

Role of Dipeptidyl Peptidase 4 Inhibitors in Antidiabetic Treatment

“…In a retrospective study in Korea, metformin and DPP4i was found to be effective in reducing HbA1c below 7%, with a low incidence of hypoglycemia [ 92 ].In tacrolimus-induced SD rat model and nephrotoxicity test, DPP4i and sodium–glucose transporter 2 inhibitors (SGLT2i) reduced blood glucose level and HbA1C level, and increased plasma insulin level and islet size of rats, and improved renal function and reduced interstitial fibrosis and pro-fibrotic cytokines, which providing a theoretical basis for the combination of SGLG2i and DPP4i in the treatment of tacrolimus-induced DM and nephrotoxicity [ 93 ]. The dual effect of DPP4i on α- and β- cells means that they also bind well to the islet independence of SGLT2i [ 94 ]. In addition, when DPP4i is combined with insulin secretin or insulin itself, DPP4i provides a complementary effect due to its inhibition of glucagon secretion and reduction in hepatic glucose production, which also means that a beneficial effect on glucose control can be achieved even with reduced β cell function [ 94 ].…”

“…The dual effect of DPP4i on α- and β- cells means that they also bind well to the islet independence of SGLT2i [ 94 ]. In addition, when DPP4i is combined with insulin secretin or insulin itself, DPP4i provides a complementary effect due to its inhibition of glucagon secretion and reduction in hepatic glucose production, which also means that a beneficial effect on glucose control can be achieved even with reduced β cell function [ 94 ]. In Chinese trials with T2DM, the addition of linagliptin and insulin improved glycemic control and was well tolerated with no increased risk of hypoglycemia or weight gain [ 95 ].…”