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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 4

Acute treatment with IL-1β increases the number of docked insulin granules.

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Acute treatment with IL-1β increases the number of docked insulin granul...
(A) Representative electron micrographs of mouse β cells treated with vehicle or IL-1β (10 ng/ml), as indicated (left), and quantification of the number of granules per micron of plasma membrane (right) (n = 51, 50, 56, 55, 51, 51, 57, 55, 52, 50, 57, 55 cells; 3 experiments). Experiments were performed in 2.8 mmol/l glucose, unless otherwise indicated (HG = 16.7 mmol/l glucose). Black dashed line indicates plasma membrane. Scale bar represents 500 nm. (B) Exocytosis responses of single mouse β cells treated with IL-1β (10 ng/ml) measured as an increase in cell membrane capacitance during a train of membrane depolarizations from –70 to 0 mV (left). Average capacitance response to each step-wise depolarization (middle) and total capacitance responses (right) (n = 29, 29 cells; 3 experiments). (C) Synaptosomal-associated protein 25 (SNAP-25)/syntaxin-1 complex formation in INS 832/13 cells treated with vehicle or IL-1β (10 ng/ml; 30 minutes) assessed by IP of IgG or syntaxin-1 and IB of SNAP-25 or syntaxin-1 (left). Quantification by densitometry relative to vehicle-treated control is shown (right) (n = 3, 3; 3 experiments). n values correspond to data points from left to right, respectively. Data are mean ±SEM and were compared with (A) 2-way ANOVA followed by Tukey post-test, (B) repeated-measures ANOVA followed by Sidak post-test, or (C) a 2-tailed Student’s t test. *P < 0.05, ***P < 0.001 versus vehicle-treated control. HG, high glucose.

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