PI3Kγ ablation does not promote diabetes in db/db mice, but improves insulin sensitivity and reduces pancreatic β‐cell apoptosis

Abstract

PI3Kγ has emerged as a promising target for the treatment of obesity and insulin resistance; however, previous studies have indicated that PI3Kγ activity in pancreatic β cells is required for normal insulin secretion in response to glucose. Hence, a possible deterioration of insulin secretion capacity in patients who are predisposed to the failure of pancreatic β-cell function is a major concern for the pharmacologic inhibition of PI3Kγ. To address this issue, we investigated the effects of PI3Kγ ablation in diabetic mice, a genetic model of obesity-driven β-cell failure and diabetes. Mice that lacked PI3Kγ were backcrossed into mice C57BL/KS (>10 generations) to obtain γ mice. γ mice and control mice were phenotyped for glucose homeostasis, insulin sensitivity, insulin secretion, steatosis, metabolic inflammation, pancreatic islet morphometry, islet cellular composition, and inflammation. Pancreatic β-cell apoptosis and proliferation were also evaluated.γ mice and control mice developed similar body weight, steatosis, glycemia, and insulin levels after a glucose load; however, γ mice displayed improved insulin tolerance, higher levels of fasting serum insulin, and lower pancreatic insulin content. In γ mice, the number of adipose tissue macrophages was similar to control, but displayed reduced adipose tissue neutrophils and M2-polarized adipose tissue gene expression. Finally, γ mice have more pancreatic β cells and larger islets than mice, despite displaying similar islet inflammation. This phenotype could be explained by reduced β-cell apoptosis inγ mice compared with control mice. Our results are consistent with the concept that the beneficial action of PI3Kγ ablation in obesity-driven glucose intolerance is largely a result of its leptin-dependent effects on adiposity and, to a lesser extent, the promotion of adipose tissue neutrophil recruitment and M1 polarization of gene expression. Of importance, our data challenge the concept that PI3Kγ is required for insulin secretion in response to glucose, and indicate that PI3Kγ ablation protects mice from β-cell apoptosis and improves fasting insulin levels. We conclude that PI3Kγ inhibition in obese patients who are predisposed to β-cell failure is not expected to produce adverse effects on insulin secretion.-Breasson, L., Sardi, C., Becattini, B., Zani, F., Solinas, G. PI3Kγ ablation does not promote diabetes in mice, but improves insulin sensitivity and reduces pancreatic β-cell apoptosis.

Memory-Like Inflammatory Responses of Microglia to Rising Doses of LPS: Key Role of PI3Kγ

“…Together, our results propose PI3Kγ as an essential mediator of cytokine responses of microglia dependent on the specific immune context (68). Both pro- and anti-inflammatory signaling functions of PI3Kγ become apparent, supporting recent reports on ambivalent regulatory functions of PI3Kγ in inflammatory processes (69, 70).…”

Function, Regulation and Biological Roles of PI3Kγ Variants

“…These findings suggest an antidiabetic role for PI3Kγ that apparently contradicts reports demonstrating pro-diabetic effects in diet-induced obesity and thermogenesis, hepatic steatosis, metabolic inflammation, and insulin resistance [41,184]. In addition, PI3Kγ deficiency reduces pancreatic β-cell apoptosis [185]. Given the role of PI3Kγ in inflammation, and the role of inflammation in obesity-induced insulin resistance [186], it is well understandable that PI3Kγ affect insulin signaling through the immune system [185].…”

“…In addition, PI3Kγ deficiency reduces pancreatic β-cell apoptosis [185]. Given the role of PI3Kγ in inflammation, and the role of inflammation in obesity-induced insulin resistance [186], it is well understandable that PI3Kγ affect insulin signaling through the immune system [185]. However, the two groups reached opposite conclusions as to this point; adoptive transfer experiments with wild-type or PI3Kγ KO bone marrow suggested that the lean phenotype was due to PI3Kγ signaling in non-hematopoietic cells [41], whereas bone marrow-specific PI3Kγ KO suggested a key role for PI3Kγ in hematopoietic cells [184].…”

JNK1 ablation improves pancreatic β‐cell mass and function in db/db diabetic mice without affecting insulin sensitivity and adipose tissue inflammation

“…39 Total RNA quality and quantity was evaluated on a denaturing agarose gel. RNA was retro-transcribed using a commercial kit (Promega), and cDNA used to perform real-time quantitative PCR using a commercial SYBR-Green mix (Biorad) and specific primer sequences 11,40,41 listed in Table S1. For immunostaining, after fixation in 4% buffered formaldehyde, liver and fat tissues were embedded in paraffin, and cut into 5 µm thick sections.…”

“…Paraffin embedded sections of pancreas from all three mice groups were stained using specific antibodies against insulin (Dako, #IR002), glucagon (Sigma-Aldrich, #G2654), and Nkx6.1 (DSHB, #F55A10) and slides were stained with DAPI as described. 40 Images of pancreatic sections were acquired at a 5× and 20× magnification respectively to evaluate the number and size of pancreatic islets. Two random fields per section for each mouse were acquired and islets were counted and measured with the ImageJ software.…”