Pancreatic, but not myeloid-cell, expression of interleukin-1alpha is required for maintenance of insulin secretion and whole body glucose homeostasis

The expression of the interleukin-1 receptor type I (IL-1R) is enriched in pancreatic islet β-cells, signifying that ligands activating this pathway are important for the health and function of the insulin-secreting cell. Using isolated mouse, rat, and human islets, we identified the cytokine IL-1α as a highly inducible gene in response to IL-1R activation. In addition, IL-1α is elevated in mouse and rat models of obesity and Type 2 diabetes. Since less is known about the biology of IL-1α relative to IL-1β in pancreatic tissue, our objective was to investigate the contribution of IL-1α to pancreatic β-cell function and overall glucose homeostasis in vivo. We generated a novel mouse line with conditional IL-1α alleles and subsequently produced mice with either pancreatic- or myeloid lineage-specific deletion of IL-1α. Using this in vivo approach, we discovered that pancreatic (IL-1αPdx1−/−), but not myeloid-cell, expression of IL-1α (IL-1αLysM−/−) was required for the maintenance of whole body glucose homeostasis in both male and female mice. Moreover, pancreatic deletion of IL-1α led to impaired glucose tolerance with no change in insulin sensitivity. This observation was consistent with our finding that glucose-stimulated insulin secretion was reduced in islets isolated from IL-1αPdx1−/− mice. Alternatively, IL-1αLysM−/− mice (male and female) did not have any detectable changes in glucose tolerance, respiratory quotient, physical activity, or food intake when compared with littermate controls. Taken together, we conclude that there is an important physiological role for pancreatic IL-1α to promote glucose homeostasis by supporting glucose-stimulated insulin secretion and islet β-cell mass in vivo. •Pancreatic IL-1α is required for normal glucose tolerance in male and female mice.•Pancreatic IL-1α supports islet beta-cell growth and function.•Myeloid lineage-derived IL-1α does not contribute to changes in glucose tolerance.•Neither pancreatic nor myeloid lineage-derived IL-1α contributes to insulin sensitivity.