en
Scientific article
English

Interleukin-6 regulates pancreatic alpha-cell mass expansion

Publication date2008
Abstract

Interleukin-6 (IL-6) is systemically elevated in obesity and is a predictive factor to develop type 2 diabetes. Pancreatic islet pathology in type 2 diabetes is characterized by reduced beta-cell function and mass, an increased proportion of alpha-cells relative to beta-cells, and alpha-cell dysfunction. Here we show that the alpha cell is a primary target of IL-6 actions. Beginning with investigating the tissue-specific expression pattern of the IL-6 receptor (IL-6R) in both mice and rats, we find the highest expression of the IL-6R in the endocrine pancreas, with highest expression on the alpha-cell. The islet IL-6R is functional, and IL-6 acutely regulates both pro-glucagon mRNA and glucagon secretion in mouse and human islets, with no acute effect on insulin secretion. Furthermore, IL-6 stimulates alpha-cell proliferation, prevents apoptosis due to metabolic stress, and regulates alpha-cell mass in vivo. Using IL-6 KO mice fed a high-fat diet, we find that IL-6 is necessary for high-fat diet-induced increased alpha-cell mass, an effect that occurs early in response to diet change. Further, after high-fat diet feeding, IL-6 KO mice without expansion of alpha-cell mass display decreased fasting glucagon levels. However, despite these alpha-cell effects, high-fat feeding of IL-6 KO mice results in increased fed glycemia due to impaired insulin secretion, with unchanged insulin sensitivity and similar body weights. Thus, we conclude that IL-6 is necessary for the expansion of pancreatic alpha-cell mass in response to high-fat diet feeding, and we suggest that this expansion may be needed for functional beta-cell compensation to increased metabolic demand.

Keywords
  • Animals
  • Apoptosis/drug effects
  • Cell Proliferation/drug effects
  • Dietary Fats/pharmacology
  • Feeding Behavior/drug effects
  • Gene Expression Regulation/drug effects
  • Glucagon/genetics/metabolism
  • Glucagon-Secreting Cells/cytology/drug effects
  • Glucose Tolerance Test
  • Humans
  • Insulin-Secreting Cells/cytology/drug effects
  • Interleukin-6/metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphorylation/drug effects
  • Protein Precursors/genetics/metabolism
  • RNA, Messenger/genetics/metabolism
  • Rats
  • Rats, Wistar
  • Receptors, Interleukin-6/genetics/metabolism
  • STAT3 Transcription Factor/metabolism
Citation (ISO format)
ELLINGSGAARD, Helga et al. Interleukin-6 regulates pancreatic alpha-cell mass expansion. In: Proceedings of the National Academy of Sciences of the United States of America, 2008, vol. 105, n° 35, p. 13163–13168. doi: 10.1073/pnas.0801059105
Main files (1)
Article (Accepted version)
accessLevelRestricted
Secondary files (1)
Identifiers
ISSN of the journal0027-8424
488views
0downloads

Technical informations

Creation05/28/2009 3:45:00 PM
First validation05/28/2009 3:45:00 PM
Update time03/14/2023 3:05:57 PM
Status update03/14/2023 3:05:56 PM
Last indexation01/15/2024 6:30:42 PM
All rights reserved by Archive ouverte UNIGE and the University of GenevaunigeBlack