Alterations in β-Cell Calcium Dynamics and Efficacy Outweigh Islet Mass Adaptation in Compensation of Insulin Resistance and Prediabetes Onset

被引:56
作者
Chen, Chunguang [1 ,2 ,3 ]
Chmelova, Helena [1 ,2 ,3 ]
Cohrs, Christian M. [1 ,2 ,3 ]
Chouinard, Julie A. [1 ,2 ,3 ]
Jahn, Stephan R. [1 ,2 ,3 ]
Stertmann, Julia [1 ,2 ,3 ]
Uphues, Ingo [4 ]
Speier, Stephan [1 ,2 ,3 ]
机构
[1] Tech Univ Dresden, Helmholtz Zentrum Munchen, Univ Clin Carl Gustav Carus, Paul Langerhans Inst Dresden, Neuherberg, Germany
[2] Tech Univ Dresden, Fac Med, CRTD, German Res Fdn, Dresden, Germany
[3] German Ctr Diabet Res DZD, Munich, Germany
[4] Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany
关键词
HIGH-FAT DIET; IN-VIVO; DIABETES ONSET; MOUSE MODEL; GLUCOSE; MICE; SECRETION; OBESITY; RATS; SENSITIVITY;
D O I
10.2337/db15-1718
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Emerging insulin resistance is normally compensated by increased insulin production of pancreatic beta-cells, thereby maintaining normoglycemia. However, it is unclear whether this is achieved by adaptation of beta-cell function, mass, or both. Most importantly, it is still unknown which of these adaptive mechanisms fail when type 2 diabetes develops. We performed longitudinal in vivo imaging of beta-cell calcium dynamics and islet mass of transplanted islets of Langerhans throughout diet-induced progression from normal glucose homeostasis, through compensation of insulin resistance, to prediabetes. The results show that compensation of insulin resistance is predominated by alterations of beta-cell function, while islet mass only gradually expands. Hereby, functional adaptation is mediated by increased calcium efficacy, which involves Epac signaling. Prior to prediabetes, beta-cell function displays decreased stimulated calcium dynamics, whereas islet mass continues to increase through prediabetes onset. Thus, our data reveal a predominant role of islet function with distinct contributions of triggering and amplifying pathway in the in vivo processes preceding diabetes onset. These findings support protection and recovery of beta-cell function as primary goals for prevention and treatment of diabetes and provide insight into potential therapeutic targets.
引用
收藏
页码:2676 / 2685
页数:10
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