Interleukin-1 signaling contributes to acute islet compensation
Catherine Hajmrle, Nancy Smith, Aliya F. Spigelman, Xiaoqing Dai, Laura Senior, Austin Bautista, Mourad Ferdaoussi, Patrick E. MacDonald
Catherine Hajmrle, Nancy Smith, Aliya F. Spigelman, Xiaoqing Dai, Laura Senior, Austin Bautista, Mourad Ferdaoussi, Patrick E. MacDonald
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Research Article Inflammation Metabolism

Interleukin-1 signaling contributes to acute islet compensation

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.