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

• Published in: Diabetes, obesity & metabolism Vol. 13; no. 4; pp. 326 - 336
• Main Authors: Uhles, S, Wang, H, Bénardeau, A, Prummer, M, Brecheisen, M, Sewing, S, Tobalina, L, Bosco, D, Wollheim, C.B, Migliorini, C, Sebokova, E
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.04.2011; Wiley Subscription Services, Inc
• Subjects: animal pharmacology; Animals; Apoptosis; Beta cells; Cell culture; Cell proliferation; Cells, Cultured; Cytokines; Deoxyuridine - analogs & derivatives; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - pathology; GLP-1 analogue; Glucagon; Glucagon-Like Peptide 1 - administration & dosage; Glucagon-Like Peptide 1 - analogs & derivatives; Glucagon-Like Peptide 1 - pharmacology; Glucagon-Like Peptide-1 Receptor; Humans; Immunohistochemistry; Insulin; Insulin secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - pathology; Insulin-Secreting Cells - physiology; Insulinoma; Labeling; Male; Palmitic acid; Pancreas; Peptides - administration & dosage; Peptides - pharmacology; Rats; Rats, Zucker; Receptors, Glucagon - administration & dosage; Structure-function relationships; Zucker diabetic fatty rat; β-cells
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/j.1463-1326.2010.01352.x

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-1β, 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.