title: Alterations in β-Cell Calcium Dynamics and Efficacy Outweigh Islet Mass Adaptation in Compensation of Insulin Resistance and Prediabetes Onset.
abstract: Emerging insulin resistance is normally compensated by increased insulin production of pancreatic β-cells, thereby maintaining normoglycemia. However, it is unclear whether this is achieved by adaptation of β-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 β-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 β-cell function, while islet mass only gradually expands. Hereby, functional adaptation is mediated by increased calcium efficacy, which involves Epac signaling. Prior to prediabetes, β-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 β-cell function as primary goals for prevention and treatment of diabetes and provide insight into potential therapeutic targets.
authors.affiliation: Paul Langerhans Institute Dresden, Helmholtz Center Munich, University Clinic Carl Gustav Carus, Technische Universität Dresden, Helmholtz Zentrum München, Neuherberg, Germany German Research Foundation-Center for Regenerative Therapies Dresden (CRTD), Faculty of Medicine, Technische Universität Dresden, Dresden, Germany German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Chunguang
authors.initials: C
authors.lastname: Chen
authors.affiliation: Paul Langerhans Institute Dresden, Helmholtz Center Munich, University Clinic Carl Gustav Carus, Technische Universität Dresden, Helmholtz Zentrum München, Neuherberg, Germany German Research Foundation-Center for Regenerative Therapies Dresden (CRTD), Faculty of Medicine, Technische Universität Dresden, Dresden, Germany German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Helena
authors.initials: H
authors.lastname: Chmelova
authors.affiliation: Paul Langerhans Institute Dresden, Helmholtz Center Munich, University Clinic Carl Gustav Carus, Technische Universität Dresden, Helmholtz Zentrum München, Neuherberg, Germany German Research Foundation-Center for Regenerative Therapies Dresden (CRTD), Faculty of Medicine, Technische Universität Dresden, Dresden, Germany German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Cohrs
authors.affiliation: Paul Langerhans Institute Dresden, Helmholtz Center Munich, University Clinic Carl Gustav Carus, Technische Universität Dresden, Helmholtz Zentrum München, Neuherberg, Germany German Research Foundation-Center for Regenerative Therapies Dresden (CRTD), Faculty of Medicine, Technische Universität Dresden, Dresden, Germany German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Chouinard
authors.affiliation: Paul Langerhans Institute Dresden, Helmholtz Center Munich, University Clinic Carl Gustav Carus, Technische Universität Dresden, Helmholtz Zentrum München, Neuherberg, Germany German Research Foundation-Center for Regenerative Therapies Dresden (CRTD), Faculty of Medicine, Technische Universität Dresden, Dresden, Germany German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Jahn
authors.affiliation: Paul Langerhans Institute Dresden, Helmholtz Center Munich, University Clinic Carl Gustav Carus, Technische Universität Dresden, Helmholtz Zentrum München, Neuherberg, Germany German Research Foundation-Center for Regenerative Therapies Dresden (CRTD), Faculty of Medicine, Technische Universität Dresden, Dresden, Germany German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Stertmann
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Uphues
authors.affiliation: Paul Langerhans Institute Dresden, Helmholtz Center Munich, University Clinic Carl Gustav Carus, Technische Universität Dresden, Helmholtz Zentrum München, Neuherberg, Germany German Research Foundation-Center for Regenerative Therapies Dresden (CRTD), Faculty of Medicine, Technische Universität Dresden, Dresden, Germany German Center for Diabetes Research (DZD), München-Neuherberg, Germany stephan.speier@tu-dresden.de.
authors.forename: Stephan
authors.initials: S
authors.lastname: Speier
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D011236:Prediabetic State / Q000378:metabolism*
chemical_list: D007328:Insulin; D002118:Calcium