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Interleukin-1 signaling contributes to acute islet compensation
Catherine Hajmrle, … , Mourad Ferdaoussi, Patrick E. MacDonald
Catherine Hajmrle, … , Mourad Ferdaoussi, Patrick E. MacDonald
Published April 7, 2016
Citation Information: JCI Insight. 2016;1(4):e86055. https://doi.org/10.1172/jci.insight.86055.
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Research Article Inflammation Metabolism

Interleukin-1 signaling contributes to acute islet compensation

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Abstract

IL-1β is a well-established inducer of both insulin resistance and impaired pancreatic islet function. Despite this, findings examining IL-1 receptor deficiency or antagonism in in vivo animal models, as well as in clinical studies of type 2 diabetic (T2D) patients, have led to conflicting results, suggesting that the actions of IL-1β on glycemic control may be pleiotropic in nature. In the present work, we find that the ability of IL-1β to amplify glucose-stimulated insulin secretion from human islets correlates with donor BMI. Islets from obese donors are sensitized to the insulinotropic effects of this cytokine, whereas the stimulatory effects of IL-1β are lost in islets from obese T2D patients, suggesting a role for IL-1 signaling in islet compensation. Indeed, mice deficient in IL-1 receptor type I become glucose intolerant more rapidly than their WT littermates and have impaired secretory responses during the acute stages of inflammatory and metabolic stress induced by LPS and high-fat diet, respectively. IL-1β directly enhances β cell insulin secretion by increasing granule docking and soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) complex formation at the plasma membrane. Together, our study highlights the importance of IL-1β signaling in islet compensation to metabolic and inflammatory stress.

Authors

Catherine Hajmrle, Nancy Smith, Aliya F. Spigelman, Xiaoqing Dai, Laura Senior, Austin Bautista, Mourad Ferdaoussi, Patrick E. MacDonald

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Figure 6

LPS-induced potentiation of insulin secretion is mediated by IL-1 receptor type I.

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LPS-induced potentiation of insulin secretion is mediated by IL-1 recept...
(A) Blood glucose measurements following i.p. glucose injections from WT (+/+) and Il1r1-KO (–/–) mice treated with LPS (2 mg/kg) or PBS (n = 4, 4; n = 4, 5 mice) and fasted for 6 hours. (B) Area under the curve (AUC) for glucose tolerance tests in A indicated by squares (n = 4, 4; n = 4, 5 mice), and fasting blood glucose concentrations in WT and KO mice following a 6-hour fast, indicated by circles (n = 4, 4; n = 4, 5 mice). (C) Fold increase in plasma insulin concentrations following i.p. injection of glucose, subsequent to a 6-hour fast and treatment with LPS or PBS, in WT and KO mice (n = 4, 4; n = 3, 5 mice). Comparison of secretory response in PBS-treated WT and KO mice (inset; n = 4, 4 mice). (D) Blood glucose measurements following i.p. insulin injections, subsequent to a 6-hour fast, from WT (+/+) and Il1r1-KO (–/–) mice treated with LPS or PBS (n = 4, 4; n = 3, 4 mice). n values correspond to data points from left to right, respectively. Data are mean ±SEM and were compared with (A, C, and D) repeated-measures ANOVA followed by Tukey post-test or (B) a 2-tailed Student’s t-test. *P < 0.05, **P < 0.01, ***P < 0.001 versus WT controls.

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