Pancreatic deletion of the interleukin-1 receptor disrupts whole body glucose homeostasis and promotes islet β-cell de-differentiation

Abstract

ObjectivePancreatic tissue, and islets in particular, are enriched in expression of the interleukin-1 receptor type I (IL-1R). Because of this enrichment, islet β-cells are exquisitely sensitive to the IL-1R ligands IL-1α and IL-1β, suggesting that signaling through this pathway regulates health and function of islet β-cells.MethodsHerein, we report a targeted deletion of IL-1R in pancreatic tissue (IL-1RPdx1−/−) in C57BL/6J mice and in db/db mice on the C57 genetic background. Islet morphology, β-cell transcription factor abundance, and expression of the de-differentiation marker Aldh1a3 were analyzed by immunofluorescent staining. Glucose and insulin tolerance tests were used to examine metabolic status of these genetic manipulations. Glucose-stimulated insulin secretion was evaluated in vivo and in isolated islets ex vivo by perifusion.ResultsPancreatic deletion of IL-1R leads to impaired glucose tolerance, a phenotype that is exacerbated by age. Crossing the IL-1RPdx1−/− with db/db mice worsened glucose tolerance without altering body weight. There were no detectable alterations in insulin tolerance between IL-1RPdx1−/− mice and littermate controls. However, glucose-stimulated insulin secretion was reduced in islets isolated from IL-1RPdx1−/− relative to control islets. Insulin output in vivo after a glucose challenge was also markedly reduced in IL-1RPdx1−/− mice when compared with littermate controls. Pancreatic islets from IL-1RPdx1−/− mice displayed elevations in Aldh1a3, a marker of de-differentiation, and reduction in nuclear abundance of the β-cell transcription factor MafA. Nkx6.1 abundance was unaltered.ConclusionsThere is an important physiological role for pancreatic IL-1R to promote glucose homeostasis by suppressing expression of Aldh1a3, sustaining MafA abundance, and supporting glucose-stimulated insulin secretion in vivo.

The role of macrophages in obesity-associated islet inflammation and β-cell abnormalities

“…Box 1 | Physiological and pathophysiological roles of islet macrophages noninflammatory state • Intra-islet macrophages and peri-islet macrophages 12,17 • Supports islet (β-cell) development and regeneration [15][16][17] • Promotes glucose-stimulated insulin secretion 12 • Low concentration of IL-1β 10,17,104,109 obesity and type 2 diabetes mellitus • Increased number of intra-islet macrophages 10,12,24,27,32 • Promotes compensatory β-cell proliferation 12 • Suppresses glucose-stimulated insulin secretion with decreased expression of β-cell-specific genes 10,12,61,62 • Elevated production of IL-1β 10,51,61 Nature reviews | Endocrinology Transcriptional profile of islet macrophages. Obesity affects islet macrophage transcriptomes, which results in altered functions.…”

“…Proinflammatory cytokines, such as TNF and IL-1β, are key components of the islet inflammatory microenvironment 31 , and the role of IL-1β has been extensively studied 103 . Knockout of β-cell IL-1R in vivo causes β-cell dedifferentiation 104 . In addition, low concentrations (0.01-0.02 ng/ml) of IL-1β can induce β-cell proliferation in vitro by activating the FAS-FLIP antiapoptotic pathway 105 .…”

Cachexia and fibrosis are costs of chronic IL-1R-mediated disease tolerance inT. gondiiinfection

“…The mechanism(s) by which IL-1 is controlling chronic cachexia in T. gondii infection remains to be addressed. Mice deficient in the IL-1R antagonist have reduced fat mass and increased energy which prompted us to first investigate shifts in metabolic homeostasis as drivers of T. gondii infectioninduced cachexia (Matsuki et al, 2003;Burke et al, 2018). However, we did not observe major increases in lipolysis or markers of non-shivering thermogenesis in our experiments.…”

Investigation on Intestinal Proteins and Drug Metabolizing Enzymes in Simulated Microgravity Rats by a Proteomics Method

“…Under 14 d SMG, the decreased expression of ADH1 will reduce the synthesis of erythritol, which may lead to elevated blood glucose. At the same time, as a marker of β-cell dedifferentiation, the increase of ALDH1A3 expression will lead to the decrease of insulin secretion [ 52 ]. It can be speculated that SMG may induce polydipsia, polyphagia, polyuria, weight loss, and other symptoms if the intestinal glucose metabolism was seriously disturbed [ 53 ].…”