Combination of the Dipeptidyl Peptidase IV Inhibitor LAF237 [(S)-1-[(3-Hydroxy-1-adamantyl)ammo]acetyl-2-cyanopyrrolidine] with the Angiotensin II Type 1 Receptor Antagonist Valsartan [N-(1-Oxopentyl)-N-[[2′-(1 H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl]methyl]-l-valine] Enhances Pancreatic Islet Morphology and Function in a Mouse Model of Type 2 Diabetes

Abstract

LAF237 [(S)-1-[(3 -hydroxy-1-adamantyl)ammo]acetyl-2-cyanopyrrolidine] is an inhibitor of dipeptidyl peptidase IV that delays the degradation of glucagonis an antagonist of the angiotensin II type 1 receptor (AT1R) that reduces the incidence of type 2 diabetes mellitus. LAF237 and valsartan act on a common target through separate pathways to improve pancreatic islet cell function. We hypothesize that the combination of these two drugs acts in a synergistic or additive manner on islet function and structure. To test this hypothesis, we performed in vitro and in vivo studies. To measure the acute effect of the treatment, pancreatic islets of db/db mice were isolated and stimulated in vitro with glucose in the presence of valsartan (1 M) and exendin-4 (100 nM), a GLP-1 receptor agonist. Combination treatment with valsartan and exendin-4 significantly enhanced glucose-stimulated insulin secretion from isolated islets. For studies of chronic effect, db/db mice received LAF237 (1 mg/kg/day) and/or valsartan (10 mg/kg/day). Islet cell reactive oxygen species (ROS), proliferation, apoptosis, fibrosis, ␤-cell area, and glucose homeostasis were evaluated after 8 weeks of treatment, which showed that combination treatment resulted in a significant increase in pancreatic islet ␤-cell area compared with monotherapy. This beneficial effect correlated with an increase in ␤-cell proliferation and a decrease in ROS-induced islet apoptosis and fibrosis. These in vitro and in vivo data indicate that combination treatment with LAF237 and valsartan has significant beneficial additive effects on pancreatic ␤-cell structure and function compared with their respective monotherapeutic effects.

Exendin-4 Pretreated Adipose Derived Stem Cells Are Resistant to Oxidative Stress and Improve Cardiac Performance via Enhanced Adhesion in the Infarcted Heart

“…Independent studies demonstrated that increased ROS in HUVECs and rat Goto-Kakizaki islets was decreased by treatment with GLP-1 and GLP-1R agonists [17], [18], which were analogous to our study. In addition, this effect was also observed in diabetic db/db mouse islets by treatment with an inhibitor of dipeptidyl peptidase IV that inhibits endogenous GLP-1 clearance [31]. In particular, a recent study showed that Exenatide suppressed ROS generation in the diabetic obese patient's peripheral blood mononuclear cells (MNC) [32].…”

Effects of combination therapy with vildagliptin and valsartan in a mouse model of type 2 diabetes

“…The combination therapy of vildagliptin and valsartan in db/db mice leads to improvement of islet ROS production, apoptotic events, beta-cell mass, and whole body glucose homeostasis [22]. The expression of NAD(P)H oxidase subunits is also significantly decreased by a similar combination resulting in decreased ROS production with GLP-1 up-regulation [30].…”

“…The levels of ViL and VaL used in this study were chosen based on previous studies [21,22] and represent relevant physiological doses for a human clinical situation.…”

Methyl 2-Benzamido-2-(1H-benzimidazol-1-ylmethoxy)acetate

“…Both telmisartan (TST) and candesartan (CST) are potent angiotensin II type 1 (AT1) receptor blockers (ARBs), which have been widely used in the treatment of hypertension and also found to display some other pharmacologic effects in treating diabetes [9] and heart disease [10], while DB921 with diamidine in terminal can strongly bind to the DNA groove and cause rapid destruction of the mitochondrial kinetoplast [11].…”