Alterations in β-Cell Calcium Dynamics and Efficacy Outweigh Islet Mass Adaptation in Compensation of Insulin Resistance and Prediabetes Onset
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作者:
Chen, Chunguang
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Tech Univ Dresden, Helmholtz Zentrum Munchen, Univ Clin Carl Gustav Carus, Paul Langerhans Inst Dresden, Neuherberg, Germany
Tech Univ Dresden, Fac Med, CRTD, German Res Fdn, Dresden, Germany
German Ctr Diabet Res DZD, Munich, GermanyTech Univ Dresden, Helmholtz Zentrum Munchen, Univ Clin Carl Gustav Carus, Paul Langerhans Inst Dresden, Neuherberg, Germany
Chen, Chunguang
[1
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]
Chmelova, Helena
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Tech Univ Dresden, Helmholtz Zentrum Munchen, Univ Clin Carl Gustav Carus, Paul Langerhans Inst Dresden, Neuherberg, Germany
Tech Univ Dresden, Fac Med, CRTD, German Res Fdn, Dresden, Germany
German Ctr Diabet Res DZD, Munich, GermanyTech Univ Dresden, Helmholtz Zentrum Munchen, Univ Clin Carl Gustav Carus, Paul Langerhans Inst Dresden, Neuherberg, Germany
Chmelova, Helena
[1
,2
,3
]
Cohrs, Christian M.
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Tech Univ Dresden, Helmholtz Zentrum Munchen, Univ Clin Carl Gustav Carus, Paul Langerhans Inst Dresden, Neuherberg, Germany
Tech Univ Dresden, Fac Med, CRTD, German Res Fdn, Dresden, Germany
German Ctr Diabet Res DZD, Munich, GermanyTech Univ Dresden, Helmholtz Zentrum Munchen, Univ Clin Carl Gustav Carus, Paul Langerhans Inst Dresden, Neuherberg, Germany
Cohrs, Christian M.
[1
,2
,3
]
Chouinard, Julie A.
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Tech Univ Dresden, Helmholtz Zentrum Munchen, Univ Clin Carl Gustav Carus, Paul Langerhans Inst Dresden, Neuherberg, Germany
Tech Univ Dresden, Fac Med, CRTD, German Res Fdn, Dresden, Germany
German Ctr Diabet Res DZD, Munich, GermanyTech Univ Dresden, Helmholtz Zentrum Munchen, Univ Clin Carl Gustav Carus, Paul Langerhans Inst Dresden, Neuherberg, Germany
Chouinard, Julie A.
[1
,2
,3
]
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Jahn, Stephan R.
[1
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,3
]
Stertmann, Julia
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Tech Univ Dresden, Helmholtz Zentrum Munchen, Univ Clin Carl Gustav Carus, Paul Langerhans Inst Dresden, Neuherberg, Germany
Tech Univ Dresden, Fac Med, CRTD, German Res Fdn, Dresden, Germany
German Ctr Diabet Res DZD, Munich, GermanyTech Univ Dresden, Helmholtz Zentrum Munchen, Univ Clin Carl Gustav Carus, Paul Langerhans Inst Dresden, Neuherberg, Germany
Stertmann, Julia
[1
,2
,3
]
Uphues, Ingo
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Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, GermanyTech Univ Dresden, Helmholtz Zentrum Munchen, Univ Clin Carl Gustav Carus, Paul Langerhans Inst Dresden, Neuherberg, Germany
Uphues, Ingo
[4
]
Speier, Stephan
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Tech Univ Dresden, Helmholtz Zentrum Munchen, Univ Clin Carl Gustav Carus, Paul Langerhans Inst Dresden, Neuherberg, Germany
Tech Univ Dresden, Fac Med, CRTD, German Res Fdn, Dresden, Germany
German Ctr Diabet Res DZD, Munich, GermanyTech Univ Dresden, Helmholtz Zentrum Munchen, Univ Clin Carl Gustav Carus, Paul Langerhans Inst Dresden, Neuherberg, Germany
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
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.
机构:
Tech Univ Dresden, Fac Med Carl Gustav Carus, Inst Med Informat & Biometry, D-01062 Dresden, GermanyTech Univ Dresden, DFG, Res Ctr Regenerat Therapies Dresden CRTD, D-01062 Dresden, Germany
Kuhn, Matthias
;
Chen, Chunguang
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Tech Univ Dresden, DFG, Res Ctr Regenerat Therapies Dresden CRTD, D-01062 Dresden, Germany
Tech Univ Dresden, German Ctr Diabet Res DZD, Univ Clin Carl Gustav Carus, Paul Langerhans Inst Dresden,Helmholtz Ctr Munich, D-01062 Dresden, GermanyTech Univ Dresden, DFG, Res Ctr Regenerat Therapies Dresden CRTD, D-01062 Dresden, Germany
Chen, Chunguang
;
Roeder, Ingo
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Tech Univ Dresden, Fac Med Carl Gustav Carus, Inst Med Informat & Biometry, D-01062 Dresden, GermanyTech Univ Dresden, DFG, Res Ctr Regenerat Therapies Dresden CRTD, D-01062 Dresden, Germany
Roeder, Ingo
;
Kretschmer, Karsten
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Tech Univ Dresden, DFG, Res Ctr Regenerat Therapies Dresden CRTD, D-01062 Dresden, Germany
Tech Univ Dresden, German Ctr Diabet Res DZD, Univ Clin Carl Gustav Carus, Paul Langerhans Inst Dresden,Helmholtz Ctr Munich, D-01062 Dresden, GermanyTech Univ Dresden, DFG, Res Ctr Regenerat Therapies Dresden CRTD, D-01062 Dresden, Germany
Kretschmer, Karsten
;
Speier, Stephan
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Tech Univ Dresden, DFG, Res Ctr Regenerat Therapies Dresden CRTD, D-01062 Dresden, Germany
Tech Univ Dresden, German Ctr Diabet Res DZD, Univ Clin Carl Gustav Carus, Paul Langerhans Inst Dresden,Helmholtz Ctr Munich, D-01062 Dresden, GermanyTech Univ Dresden, DFG, Res Ctr Regenerat Therapies Dresden CRTD, D-01062 Dresden, Germany
机构:
Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48105 USA
Univ Michigan, Brehm Diabet Res Ctr, Ann Arbor, MI 48105 USANIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA
机构:
Tech Univ Dresden, Fac Med Carl Gustav Carus, Inst Med Informat & Biometry, D-01062 Dresden, GermanyTech Univ Dresden, DFG, Res Ctr Regenerat Therapies Dresden CRTD, D-01062 Dresden, Germany
Kuhn, Matthias
;
Chen, Chunguang
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机构:
Tech Univ Dresden, DFG, Res Ctr Regenerat Therapies Dresden CRTD, D-01062 Dresden, Germany
Tech Univ Dresden, German Ctr Diabet Res DZD, Univ Clin Carl Gustav Carus, Paul Langerhans Inst Dresden,Helmholtz Ctr Munich, D-01062 Dresden, GermanyTech Univ Dresden, DFG, Res Ctr Regenerat Therapies Dresden CRTD, D-01062 Dresden, Germany
Chen, Chunguang
;
Roeder, Ingo
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机构:
Tech Univ Dresden, Fac Med Carl Gustav Carus, Inst Med Informat & Biometry, D-01062 Dresden, GermanyTech Univ Dresden, DFG, Res Ctr Regenerat Therapies Dresden CRTD, D-01062 Dresden, Germany
Roeder, Ingo
;
Kretschmer, Karsten
论文数: 0引用数: 0
h-index: 0
机构:
Tech Univ Dresden, DFG, Res Ctr Regenerat Therapies Dresden CRTD, D-01062 Dresden, Germany
Tech Univ Dresden, German Ctr Diabet Res DZD, Univ Clin Carl Gustav Carus, Paul Langerhans Inst Dresden,Helmholtz Ctr Munich, D-01062 Dresden, GermanyTech Univ Dresden, DFG, Res Ctr Regenerat Therapies Dresden CRTD, D-01062 Dresden, Germany
Kretschmer, Karsten
;
Speier, Stephan
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h-index: 0
机构:
Tech Univ Dresden, DFG, Res Ctr Regenerat Therapies Dresden CRTD, D-01062 Dresden, Germany
Tech Univ Dresden, German Ctr Diabet Res DZD, Univ Clin Carl Gustav Carus, Paul Langerhans Inst Dresden,Helmholtz Ctr Munich, D-01062 Dresden, GermanyTech Univ Dresden, DFG, Res Ctr Regenerat Therapies Dresden CRTD, D-01062 Dresden, Germany
机构:
Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48105 USA
Univ Michigan, Brehm Diabet Res Ctr, Ann Arbor, MI 48105 USANIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA