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

Abstract

Objective 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 . Methods 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. Results Using this in vivo approach, we discovered that pancreatic (IL-1α Pdx1−/− ), but not myeloid-cell, expression of IL-1α (IL-1α LysM−/− ) 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-1α Pdx1−/− mice. Alternatively, IL-1α LysM−/− 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. Conclusions 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 .

IL-1beta promotes the age-associated decline of beta cell function

“…More recently, a physiological role of IL-1beta on insulin secretion has emerged during fasting-refeeding, endotoxin treatment, adaptation to short-term high-fat diet feeding (Dror et al, 2017;Hajmrle et al, 2016), and in mouse models with constitutive pancreatic deletion of the IL-1R1 or IL-1alpha (Burke et al, 2018;Collier et al, 2021). At first glance this beneficial and adaptive role of IL-1beta appears to be at odds with the deleterious chronic effects of IL-1beta on insulin secretion.…”

“…The beneficial role of IL-1beta on insulin secretion was mostly observed in acute and short-term exposure (single injection of IL-1beta or LPS, fasting-refeeding, or 4-day high-fat diet feeding) in vivo as well as in vitro (Spinas et al, 1988). Recently, deleterious long-term effects (in 9-months-old male mice) on glucose tolerance in mice with pancreatic deletion of either the IL-1R1 or IL-1alpha (Burke et al, 2018;Collier et al, 2021) were reported, and it was concluded that IL-1R1 signaling and IL-1alpha are needed for proper metabolic control in older mice. Because a constitutive Pdx-Cre driver mouse line that targets the whole pancreas, entero-endocrine cells, and the hypothalamus was used for knockout induction, it is possible that there is a role for IL-1R1 and IL-1alpha in the development of these tissues, which only manifests later in life.…”

Pharmacological inhibition of lipolysis prevents adverse metabolic outcomes during glucocorticoid administration

“…Metabolomics analyses were conducted as previously described [ 12 , 16 , 25 ]. RNA from adipose tissue and gene expression was assessed as described [ 26 ]. Primer sequences are provided in Supplemental Table 1 and genes tested by RT-PCR were normalized using ribosomal protein S9 ( Rps9 ) as a housekeeping gene.…”

The alpha‐7 nicotinic acetylcholine receptor agonist GTS‐21 engages the glucagon‐like peptide‐1 incretin hormone axis to lower levels of blood glucose in db/db mice

“…After fixation in 10% neutral buffered formalin for 24‐48 hours, pancreatic tissue isolated from 17‐18 week‐old db/db mice was embedded in paraffin. Five‐micron sections were cut and placed onto positively charged glass slides for immunohistochemical (IHC) analysis 15 . Detection of insulin was performed using a Bond‐Max Automated IHC Staining System and a Bond Polymer Refine detection kit (DS9800; Leica Biosystems Inc., Buffalo Grove, IL).…”

“…Five-micron sections were cut and placed onto positively charged glass slides for immunohistochemical (IHC) analysis. 15 Detection of insulin was performed using a Bond-Max Automated IHC Staining System and a Bond Polymer Refine detection kit (DS9800; Leica Biosystems Inc., Buffalo Grove, IL). The primary polyclonal antiserum was guinea pig anti-insulin (1:800 dilution, 180067, Invitrogen, Grand Island, NY).…”