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Authors |
Ludovic Breasson Claudia Sardi Barbara Becattini Fabio Zani Giovanni Solinas |
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Published in | Faseb Journal |
Volume | 32 |
Issue | 1 |
Pages | 319-+ |
ISSN | 0892-6638 |
Publication year | 2018 |
Published at |
Wallenberg Laboratory Institute of Medicine, Department of Molecular and Clinical Medicine |
Pages | 319-+ |
Language | en |
Links |
dx.doi.org/10.1096/fj.201700372RR |
Keywords | phosphoinositide 3-kinase, macrophage activation, neutrophils, phosphoinositide 3-kinase, resistance, secretion, inflammation, obesity, phosphorylation, inhibition, p110-gamma, elevation, blockade, Biochemistry & Molecular Biology |
Subject categories | Biochemistry and Molecular Biology |
PI3K gamma has emerged as a promising target for the treatment of obesity and insulin resistance; however, previous studies have indicated that PI3K gamma activity in pancreatic beta 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 beta-cell function is a major concern for the pharmacologic inhibition of PI3K gamma. To address this issue, we investigated the effects of PI3K gamma ablation in db/db diabetic mice, a genetic model of obesity-driven beta-cell failure and diabetes. Mice that lacked PI3K gamma were backcrossed into db/+ mice C57BL/KS (>10 generations) to obtain db/db-PI3K gamma(-/-) mice. db/db-PI3K gamma(-/-) mice and control db/db mice were phenotyped for glucose homeostasis, insulin sensitivity, insulin secretion, steatosis, metabolic inflammation, pancreatic islet morphometry, islet cellular composition, and inflammation. Pancreatic beta-cell apoptosis and proliferation were also evaluated. db/db-PI3K gamma(-/-) mice and control db/db mice developed similar body weight, steatosis, glycemia, and insulin levels after a glucose load; however, db/db-PI3K gamma(-/-) mice displayed improved insulin tolerance, higher levels of fasting seruminsulin, and lower pancreatic insulin content. In db/db-PI3K gamma(-/-) 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, db/db-PI3K gamma(-/-) mice have more pancreatic beta cells and larger islets than db/db mice, despite displaying similar islet inflammation. This phenotype could be explained by reduced beta-cell apoptosis in db/db-PI3K gamma(-/-) mice compared with control db/db mice. Our results are consistent with the concept that the beneficial action of PI3K gamma 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 PI3K gamma is required for insulin secretion in response to glucose in vivo, and indicate that PI3K gamma ablation protects db/db mice from beta-cell apoptosis and improves fasting insulin levels. We conclude that PI3K gamma inhibition in obese patients who are predisposed to beta-cell failure is not expected to produce adverse effects on insulin secretion.