Interleukin-6 regulates pancreatic α-cell mass expansion

被引:218
作者
Ellingsgaard, Helga [1 ,2 ]
Ehses, Jan A. [1 ,2 ]
Hammar, Eva B. [3 ]
Van Lommel, Leentje [4 ]
Quintens, Roel [4 ]
Martens, Geert [5 ]
Kerr-Conte, Julie [6 ]
Pattou, Francois [6 ]
Berney, Thierry [3 ]
Pipeleers, Daniel [5 ]
Halban, Philippe A. [3 ]
Schuit, Frans C. [4 ]
Donath, Marc Y. [1 ,2 ]
机构
[1] Univ Zurich Hosp, Div Endocrinol & Diabet, CH-8091 Zurich, Switzerland
[2] Univ Zurich Hosp, Ctr Integrated Human Physiol, CH-8091 Zurich, Switzerland
[3] Ctr Med Univ Geneva, Dept Genet Med & Dev, CH-1211 Geneva 4, Switzerland
[4] Katholieke Univ Leuven, Gene Express Unit, Dept Mol Cell Biol, B-3000 Louvain, Belgium
[5] Free Univ Brussels, Diabet Res Ctr, B-1090 Brussels, Belgium
[6] Fac Med Lille, INSERM, ERIT M 0106, F-59045 Lille, France
基金
瑞士国家科学基金会;
关键词
alpha-cell mass; beta-cell function; high-fat diet; pancreatic islet;
D O I
10.1073/pnas.0801059105
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 a-cells relative to p-cells, and a-cell dysfunction. Here we show that the a 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 a-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 a-cell proliferation, prevents apoptosis due to metabolic stress, and regulates a-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 a-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 a-cell mass display decreased fasting glucagon levels. However, despite these a-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 a-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.
引用
收藏
页码:13163 / 13168
页数:6
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