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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 1

The stimulatory capacity of IL-1β is correlated with BMI and is absent in type 2 diabetic islets.

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The stimulatory capacity of IL-1β is correlated with BMI and is absent i...
(A and B) Insulin secretion normalized to percent insulin content from (A) mouse (n=15, 17, 17, 17; 6 experiments) or (B) human islets (n = 18, 18, 18, 18; 6 donors) following exposure to IL-1β (10 ng/ml), as indicated, and stimulated with 1.0 (1.0 G), 2.8 (2.8 G), or 16.7 (16.7 G) mmol/l glucose. (C–E) The potentiation index of 1-hour IL-1β treatment plotted against (C) BMI (kg/m2; n = 14 donors), (D) glucose stimulation index (n = 14 donors), and (E) glycated hemoglobin (HbA1C; n = 13 donors) in nondiabetic human islet donors. (F) Comparison of IL-1β potentiation index between type 2 diabetic (T2D) and control islets according to BMI tertiles (lean < 25; overweight 25–30; and obese > 35 kg/m2) (n = 3, 7, 4, 3 donors). (G and H) Insulin secretion normalized to percent insulin content from (G) nondiabetic (n = 41, 36, 39, 39; 14 donors) or (H) T2D human donors (n = 9, 8, 9, 8; 3 donors) treated for 1 hour with vehicle or IL-1β (10 ng/ml) and stimulated with either 1.0 or 16.7 mmol/l glucose. n values correspond to data points from left to right, respectively. Data are mean ±SEM and were compared with (A, B, G, and H) 2-way ANOVA followed by Tukey post-test, (C–E) Pearson correlation coefficients, or (F) 1-way ANOVA followed by Tukey post-test. *P < 0.05, **P < 0.01, ***P < 0.001, as indicated. G, glucose.

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