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Taspoglutide, a novel human once‐weekly GLP‐1 analogue, protects pancreatic β ‐cells in vitro and preserves islet structure and function in the Zucker diabetic fatty rat in vivo
Author(s) -
Uhles S.,
Wang H.,
Bénardeau A.,
Prummer M.,
Brecheisen M.,
Sewing S.,
Tobalina L.,
Bosco D.,
Wollheim C. B.,
Migliorini C.,
Sebokova E.
Publication year - 2011
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/j.1463-1326.2010.01352.x
Subject(s) - medicine , endocrinology , lipotoxicity , islet , apoptosis , in vivo , pancreatic islets , pancreas , insulin , glucagon like peptide 1 , cytokine , biology , insulinoma , diabetes mellitus , insulin resistance , type 2 diabetes , biochemistry , microbiology and biotechnology
Aim: Glucagon‐like peptide‐1 (GLP‐1) has protective effects on pancreatic β ‐cells. We evaluated the effects of a novel, long‐acting human GLP‐1 analogue, taspoglutide, on β ‐cells in vitro and in vivo . Methods: Proliferation of murine pancreatic β (MIN6B1) cells and rat islets in culture was assessed by imaging of 5‐ethynyl‐2′‐deoxyuridine‐positive cells after culture with taspoglutide. Apoptosis was evaluated with the transferase‐mediated 2′‐deoxyuridine 5′‐triphosphate nick‐end labelling assay in rat insulinoma (INS‐1E) cells and isolated human islets exposed to cytokines (recombinant interleukin‐1 β , interferon‐ γ , tumour necrosis factor‐ α ) or lipotoxicity (palmitate) in the presence or absence of taspoglutide. Islet morphology and survival and glucose‐stimulated insulin secretion in perfused pancreata were assessed 3–4 weeks after a single application of taspoglutide to prediabetic 6‐week‐old male Zucker diabetic fatty (ZDF) rats. Results: Proliferation was increased in a concentration‐dependent manner up to fourfold by taspoglutide in MIN6B1 cells and was significantly stimulated in isolated rat islets. Taspoglutide almost completely prevented cytokine‐ or lipotoxicity‐induced apoptosis in INS‐1E cells (control 0.5%, cytokines alone 2.2%, taspoglutide + cytokines 0.6%, p < 0.001; palmitate alone 8.1%, taspoglutide + palmitate 0.5%, p < 0.001) and reduced apoptosis in isolated human islets. Treatment of ZDF rats with taspoglutide significantly prevented β ‐cell apoptosis and preserved healthy islet architecture and insulin staining intensity as shown in pancreatic islet cross sections. Basal and glucose‐stimulated insulin secretion of in situ perfused ZDF rat pancreata was normalized after taspoglutide treatment. Conclusions: Taspoglutide promoted β ‐cell proliferation, prevented apoptosis in vitro and exerted multiple β ‐cell protective effects on islet architecture and function in vivo in ZDF rats.