title: Modulation of the pancreatic islet-stress axis as a novel potential therapeutic target in diabetes mellitus.
abstract: Loss of pancreatic islet function and insulin-producing beta cell mass is a central hallmark in the pathogenesis of both type 1 and type 2 diabetes. While in type 1 diabetes this phenomenon is due to an extensive destruction of beta cells caused by an autoimmune process, the mechanisms resulting in beta cell failure in type 2 diabetes are different and less clear. Also, beta cell destruction in type 1 diabetes occurs early and is the initial step in the pathogenetic process, while beta cell loss in type 2 diabetes after an initial phase of hyperinsulinemia due to the underlying insulin resistance occurs relatively late and it is less pronounced. Since diabetes mellitus is the most frequent endocrine disease, with an increasing high prevalence worldwide, huge efforts have been made over the past many decades to identify predisposing genetic, environmental, and nutritional factors in order to develop effective strategies to prevent the disease. In parallel, extensive studies in different cell systems and animal models have helped to elucidate our understanding of the physiologic function of islets and to gain insight into the immunological and non-immunological mechanisms of beta cell destruction and failure. Furthermore, currently emerging concepts of beta cell regeneration (e.g., the restoration of the beta cell pool by regenerative, proliferative and antiapoptotic processes, and recovery of physiologic islet function) apparently is yielding the first promising results. Recent insights into the complex endocrine and paracrine mechanisms regulating the physiologic function of pancreatic islets, as well as beta cell life and death, constitute an essential part of this new and exciting area of diabetology. For example, understanding of the physiological role of glucagon-like peptide 1 has resulted in the successful clinical implementation of incretin-based therapies over the last years. Further, recent data suggesting paracrine effects of growth hormone-releasing hormone and corticotropin-releasing hormone on the regulation of pancreatic islet function, survival, and proliferation as well as on local glucocorticoid metabolism provide evidence for a potential role of the pancreatic islet-stress axis in the pathophysiology of diabetes mellitus. In this chapter, we provide a comprehensive overview of current preventive and regenerative concepts as a basis for the development of novel therapeutic approaches to the treatment of diabetes mellitus. A particular focus is given on the potential of the pancreatic islet-stress axis in the development of novel regenerative strategies.
authors.affiliation: Department of Medicine III, University Hospital Carl Gustav Carus, Dresden, Germany; The Paul Langerhans Institute, Dresden, Germany; Center for Regenerative Therapies Dresden, Dresden University of Technology, Dresden, Germany. Electronic address: barbara.ludwig@uniklinikum-dresden.de.
authors.forename: Barbara
authors.initials: B
authors.lastname: Ludwig
authors.affiliation: Department of Medicine III, University Hospital Carl Gustav Carus, Dresden, Germany; Endokrinologikum Ruhr, Bochum, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Barthel
authors.affiliation: Department of Medicine III, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reichel
authors.affiliation: Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Medicine, Division of Hematology-Oncology, University of Miami Miller School of Medicine, Miami, Florida, USA; Veterans Administration Medical Center, Miami, Florida, USA.
authors.forename: Norman L
authors.initials: NL
authors.lastname: Block
authors.affiliation: Department of Visceral, Thorax and Vascular Surgery, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Ludwig
authors.affiliation: Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Medicine, Division of Endocrinology, University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Medicine, Division of Hematology-Oncology, University of Miami Miller School of Medicine, Miami, Florida, USA; Veterans Administration Medical Center, Miami, Florida, USA.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
authors.affiliation: Department of Medicine III, University Hospital Carl Gustav Carus, Dresden, Germany; The Paul Langerhans Institute, Dresden, Germany; Center for Regenerative Therapies Dresden, Dresden University of Technology, Dresden, Germany.
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Bornstein
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D058990:Molecular Targeted Therapy; D013312:Stress, Physiological; D013315:Stress, Psychological / Q000503:physiopathology*
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin
keywords: Corticotrophin-releasing hormone; Diabetes mellitus type 1; Diabetes mellitus type 2; Endocrine receptors; Environmental factors; Genetic factors; Glucocorticoids; Insulin; Mineralocorticoids; Nutrition; Pancreas; Pancreatic islet cells; Stress; Stress response