Protein kinase C pathway mediates the protective effects of glucagon-like peptide-1 on the apoptosis of islet β-cells

Abstract

The incidence of diabetes has been increasing over previous years. It is hypothesized that promoting the survival of islet β-cells is a key direction for the treatment of diabetes. Although gastric bypass surgery improves certain types of diabetes and attenuates its progression, there are certain associated disadvantages (including intestinal obstruction and anastomotic leakage), and quality of life and physical status (such as malnutrition) are significantly affected by gastric bypass surgery. Therefore, it is important to determine the mechanisms underlying the improvement of diabetes by gastric bypass surgery and identify novel gene targets for diabetes therapeutics. In the present study, glucagon‑like peptide‑1 (GLP‑1), whose secretion was markedly increased following gastric bypass surgery, increased the activity of protein kinase C (PKC) in islet β‑cells in a dose‑dependent manner. Additionally, treatment with GLP‑1 boosted cell viability and decreased cell death in starved islet β‑cells, and inhibited mitochondria‑dependent apoptosis by regulating the expression levels of Bcl‑2/Bax. These effects were reversed by inhibiting the PKC pathway using hypericin. Therefore, the present study concluded that GLP‑1 may promote the survival and inhibit the apoptosis of islet β‑cells at least in part by activating the PKC pathway, which is an important underlying mechanism and may be exploited in the treatment of diabetes.

NR5A2/LRH-1 regulates the PTGS2-PGE2-PTGER1 pathway contributing to pancreatic islet survival and function

“…Moreover, PKCε activators improve islet survival during isolation as well as function after transplantation in mice ( Hamilton et al., 2014 ; Kvezereli et al., 2008 ). In addition to substantiating the implication of PTGER1 in relaying the BL001/LRH-1/NR5A2/PTGS2/PGE 2 survival signal, GLP-1-mediated activation of PKC was shown to inhibit the intrinsic apoptotic pathway via modulation of BAX, whereas an activated variant of AKT prevented PARP cleavage, two events we report herein ( Kennedy et al., 1997 ; Zhang et al., 2015 ). Oddly, PTGER1 exhibits the lowest affinity for PGE 2 .…”

LRH-1/NR5A2 regulates the PTGS2-PGE2-PTGER1 signalling axis contributing to islet survival and antidiabetic actions of the agonist BL001

“…Moreover, PKCe activators improve islet survival during isolation as well as function after transplantation in mice 60,61 . Further substantiating the implication of PTGER1 in relaying the BL001/LRH-1/NR5A2/PTGS2/PGE2 survival signal, GLP-1-mediated activation of PKC was shown to inhibit the intrinsic apoptotic pathway via modulation of BAX while an activated variant of AKT prevented PARP cleavage, two events we report herein 62,63 . Oddly, PTGER1 exhibits the lowest affinity for PGE2.…”

Comparison of Exenatide and Metformin Monotherapy in Overweight/Obese Patients with Newly Diagnosed Type 2 Diabetes

“…Previous studies showed that metformin indirectly increased β -cell function through decreasing glucotoxicity, lowering insulin resistance, inhibiting the formation of advanced glycation end products, and reducing oxidative stress [ 23 , 26 ]. In addition to the similar capabilities of metformin, exenatide also displays some direct beneficial effects on islet β -cells [ 27 – 30 ]. A previous study showed that exenatide improved the insulin secretion of β -cells as compared to the insulin glargine in a similar glycemic control, and this effect was sustained after a 4-week off-drug period [ 28 ].…”

“…A previous study showed that exenatide improved the insulin secretion of β -cells as compared to the insulin glargine in a similar glycemic control, and this effect was sustained after a 4-week off-drug period [ 28 ]. Animal studies have demonstrated that GLP-1 promotes the proliferation of β -cells and inhibits their apoptosis [ 29 , 30 ]. Cell-based studies showed that GLP-1 enhanced the viability and inhibited the mitochondrial-dependent apoptosis in the PKC-dependent pathway [ 30 ].…”

“…Animal studies have demonstrated that GLP-1 promotes the proliferation of β -cells and inhibits their apoptosis [ 29 , 30 ]. Cell-based studies showed that GLP-1 enhanced the viability and inhibited the mitochondrial-dependent apoptosis in the PKC-dependent pathway [ 30 ].…”