IL-6 is a pleiotropic cytokine with complex roles in inflammation and metabolic disease. The role of IL-6 as a pro- or anti-inflammatory cytokine is still unclear. Within the pancreatic islet, IL-6 stimulates secretion of the prosurvival incretin hormone glucagon-like peptide 1 (GLP-1) by α cells and acts directly on β cells to stimulate insulin secretion Uncovering physiologic mechanisms promoting β-cell survival under conditions of inflammation and stress can identify important pathways for diabetes prevention and treatment. Given the established role of GLP-1 in promoting β-cell survival, we hypothesized that IL-6 may also directly protect β cells from apoptosis. Herein, we show that IL-6 robustly activates signal transducer and activator of transcription 3 (STAT3), a transcription factor that is involved in autophagy. IL-6 stimulates LC3 conversion and autophagosome formation in cultured β cells. IL-6 infusion stimulates a robust increase in lysosomes in the pancreas that is restricted to the islet. Autophagy is critical for β-cell homeostasis, particularly under conditions of stress and increased insulin demand. The stimulation of autophagy by IL-6 is regulated multiple complementary mechanisms including inhibition of mammalian target of rapamycin complex 1 (mTORC1) and activation of Akt, ultimately leading to increases in autophagy enzyme production. Pretreatment with IL-6 renders β cells resistant to apoptosis induced by proinflammatory cytokines, and inhibition of autophagy with chloroquine prevents the ability of IL-6 to protect from apoptosis. Importantly, we find that IL-6 can activate STAT3 and the autophagy enzyme GABARAPL1 in human islets. We also see evidence of decreased IL-6 pathway signaling in islets from donors with type 2 diabetes. On the basis of our results, we propose direct stimulation of autophagy as a novel mechanism for IL-6-mediated protection of β cells from stress-induced apoptosis.-Linnemann, A. K., Blumer, J., Marasco, M. R., Battiola, T. J., Umhoefer, H. M., Han, J. Y., Lamming, D. W., Davis, D. B. Interleukin 6 protects pancreatic β cells from apoptosis by stimulation of autophagy.

Lavine JA, Kibbe CR, Baan M, Sirinvaravong S, Umhoefer HM, Engler KA, Meske LM, Sacotte KA, Erhardt DP, Davis DB. Cholecystokinin expression in the ␤-cell leads to increased ␤-cell area in aged mice and protects from streptozotocin-induced diabetes and apoptosis. Am J Physiol Endocrinol Metab 309: E819 -E828, 2015. First published September 22, 2015; doi:10.1152/ajpendo.00159.2015.-Cholecystokinin (CCK) is a peptide hormone produced in the gut and brain with beneficial effects on digestion, satiety, and insulin secretion. CCK is also expressed in pancreatic ␤-cells, but only in models of obesity and insulin resistance. Whole body deletion of CCK in obese mice leads to reduced ␤-cell mass expansion and increased apoptosis. We hypothesized that islet-derived CCK is important in protection from ␤-cell apoptosis. To determine the specific role of ␤-cell-derived CCK in ␤-cell mass dynamics, we generated a transgenic mouse that expresses CCK in the ␤-cell in the lean state (MIP-CCK). Although this transgene contains the human growth hormone minigene, we saw no expression of human growth hormone protein in transgenic islets. We examined the ability of MIP-CCK mice to maintain ␤-cell mass when subjected to apoptotic stress, with advanced age, and after streptozotocin treatment. Aged MIP-CCK mice have increased ␤-cell area. MIP-CCK mice are resistant to streptozotocin-induced diabetes and exhibit reduced ␤-cell apoptosis. Directed CCK overexpression in cultured ␤-cells also protects from cytokineinduced apoptosis. We have identified an important new paracrine/ autocrine effect of CCK in protection of ␤-cells from apoptotic stress. Understanding the role of ␤-cell CCK adds to the emerging knowledge of classic gut peptides in intraislet signaling. CCK receptor agonists are being investigated as therapeutics for obesity and diabetes. While these agonists clearly have beneficial effects on body weight and insulin sensitivity in peripheral tissues, they may also directly protect ␤-cells from apoptosis.cholecystokinin; islet; ␤-cell; apoptosis; aging; streptozotocin TYPE 1 AND TYPE 2 DIABETES MELLITUS are both diseases of reduced ␤-cell mass. In type 1 diabetes, autoimmune destruction of ␤-cells results in an absolute ␤-cell mass deficit. In type 2 diabetes, obesity increases insulin resistance, resulting in a relative insulin deficiency. In patients with type 2 diabetes, ␤-cell mass is lost via increased ␤-cell apoptosis (7, 16). Therefore, there has been wide interest in the development of diabetes therapeutics that preserve ␤-cell mass and prevent ␤-cell apoptosis.Cholecystokinin (CCK) is a gastrointestinal peptide produced by duodenal I cells and secreted in response to fat and protein (31). CCK signals through two G protein-coupled receptors, the CCK1(A) receptor [CCK1(A)R] and the CCK2(B) receptor [CCK2(B)R]. In healthy and diabetic patients, CCK infusion increases insulin secretion and decreases glucose excursion after a meal, suggesting that CCK is a potential diabetes therapeutic (1, 2). CCK also increases satiety by ...

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Loss of functional pancreatic β-cell mass and increased β-cell apoptosis are fundamental to the pathophysiology of both type 1 and type 2 diabetes. Pancreatic islet transplantation has the potential to cure type 1 diabetes but is often ineffective due to the death of the islet graft within the first few years after transplant. Therapeutic strategies to directly target pancreatic β-cell survival are needed to prevent and treat diabetes and to improve islet transplant outcomes. Reducing β-cell apoptosis is also a therapeutic strategy for type 2 diabetes. Cholecystokinin (CCK) is a peptide hormone typically produced in the gut after food intake, with positive effects on obesity and glucose metabolism in mouse models and human subjects. We have previously shown that pancreatic islets also produce CCK. The production of CCK within the islet promotes β-cell survival in rodent models of diabetes and aging. Now, we demonstrate a direct effect of CCK to reduce cytokine-mediated apoptosis in a β-cell line and in isolated mouse islets in a receptor-dependent manner. However, whether CCK can protect human β-cells was previously unknown. Here, we report that CCK can also reduce cytokine-mediated apoptosis in isolated human islets and CCK treatment in vivo decreases β-cell apoptosis in human islets transplanted into the kidney capsule of diabetic NOD/SCID mice. Collectively, these data identify CCK as a novel therapy that can directly promote β-cell survival in human islets and has therapeutic potential to preserve β-cell mass in diabetes and as an adjunct therapy after transplant.One Sentence SummaryCholecystokinin ameliorates pancreatic β-cell death under models of stress and after transplant of human islets.