Dysfunction of Persisting β Cells Is a Key Feature of Early Type 2 Diabetes Pathogenesis
Christian M. Cohrs,
Julia K. Panzer,
Denise M. Drotar,
Stephen J. Enos,
Nicole Kipke,
Chunguang Chen,
Robert Bozsak,
Eyke Schöniger,
Florian Ehehalt,
Marius Distler,
Ana Brennand,
Stefan R. Bornstein,
Jürgen Weitz,
Michele Solimena,
Stephan Speier
Affiliations
Christian M. Cohrs
Paul Langerhans Institute Dresden (PLID) of the Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Physiology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
Julia K. Panzer
Paul Langerhans Institute Dresden (PLID) of the Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Physiology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
Denise M. Drotar
Paul Langerhans Institute Dresden (PLID) of the Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Physiology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
Stephen J. Enos
Paul Langerhans Institute Dresden (PLID) of the Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Physiology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
Nicole Kipke
German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Molecular Diabetology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
Chunguang Chen
Paul Langerhans Institute Dresden (PLID) of the Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Physiology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
Robert Bozsak
Paul Langerhans Institute Dresden (PLID) of the Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Physiology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
Eyke Schöniger
Paul Langerhans Institute Dresden (PLID) of the Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, Neuherberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Molecular Diabetology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
Florian Ehehalt
Department of GI-, Thoracic- and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
Marius Distler
Department of GI-, Thoracic- and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
Ana Brennand
Department of Diabetes, School of Life Science & Medicine, Faculty of Life Sciences & Medicine, King’s College London, London, UK
Stefan R. Bornstein
Department of Diabetes, School of Life Science & Medicine, Faculty of Life Sciences & Medicine, King’s College London, London, UK; Department of Medicine III, University Hospital Carl Gustav Carus, Dresden, Germany
Jürgen Weitz
Paul Langerhans Institute Dresden (PLID) of the Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, Neuherberg, Germany; Department of GI-, Thoracic- and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
Michele Solimena
Paul Langerhans Institute Dresden (PLID) of the Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, Neuherberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Molecular Diabetology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany; Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
Stephan Speier
Paul Langerhans Institute Dresden (PLID) of the Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Physiology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Corresponding author
Summary: Type 2 diabetes is characterized by peripheral insulin resistance and insufficient insulin release from pancreatic islet β cells. However, the role and sequence of β cell dysfunction and mass loss for reduced insulin levels in type 2 diabetes pathogenesis are unclear. Here, we exploit freshly explanted pancreas specimens from metabolically phenotyped surgical patients using an in situ tissue slice technology. This approach allows assessment of β cell volume and function within pancreas samples of metabolically stratified individuals. We show that, in tissue of pre-diabetic, impaired glucose-tolerant subjects, β cell volume is unchanged, but function significantly deteriorates, exhibiting increased basal release and loss of first-phase insulin secretion. In individuals with type 2 diabetes, function within the sustained β cell volume further declines. These results indicate that dysfunction of persisting β cells is a key factor in the early development and progression of type 2 diabetes, representing a major target for diabetes prevention and therapy. : Cohrs et al. utilize pancreas tissue slices of metabolically phenotyped subjects undergoing pancreatectomy to assess β cell pathogenesis in type 2 diabetes development. They reveal β cell dysfunction as an early hallmark in type 2 diabetes pathogenesis, manifesting as increased basal and missing first-phase insulin secretion, although β cell mass is maintained. Keywords: Type 2 diabetes, human pancreas, beta cell mass, beta cell function, insulin secretion
