DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with beta-cell-specific overexpression of human islet amyloid polypeptide.

Summary, in English

Inhibition of dipeptidyl peptidase-4 (DPP-4) is currently explored as a novel therapy of type 2 diabetes. The strategy has been shown to improve glycemia in most, but not all, rodent forms of glucose intolerance. In this study, we explored the effects of DPP-4 inhibition in mice with [beta-cell overexpression of human islet amyloid polypeptide (IAPP). We therefore administered the orally active and highly selective DPP-4 inhibitor, vildagliptin (3 pmol/mouse daily) to female mice with [beta-cell overexpression of human IAPP. Controls were given plain water, and a series of untreated wildtype mice was also included. After five weeks, an intravenous glucose tolerance test showed improved glucose disposal and a markedly enhanced insulin response in mice treated with vildagliptin. After eight weeks, a gastric tolerance test showed that vildagliptin improved glucose tolerance and markedly (approximately ten-fold) augmented the insulin response in association with augmented (approximately five-fold) levels of intact glucagon-like peptide-1 (GLP-1). Furthermore, after nine weeks, islets were isolated. Islets from vildagliptin-treated mice showed augmented glucose-stimulated insulin response and a normalization of the islet insulin content, which was reduced by approximately 50% in transgenic controls versus wildtype animals. Double immunostaining of pancreatic islets for insulin and glucagon revealed that transgenic islets displayed severely disturbed intra-islet topography with frequently observed centrally located a-cells. Treatment with vildagliptin restored the islet topography. We therefore conclude that DPP-4 inhibition improves islet function and islet topography in mice with [beta-cell specific transgenic overexpression of human IAPP. (c) 2007 Elsevier B.V. All rights reserved.

• Författare: Bo Ahrén; Maria Sorhede Winzell; Nils Wierup; Frank Sundler; Bryan Burkey; Thomas E Hughes
• Avdelning/ar: Medicin/akutsjukvård, Lund; Institutionen för experimentell medicinsk vetenskap
• Publiceringsår: 2007
• Språk: Engelska
• Sidor: 97-103
• Publikation/Tidskrift/Serie: Regulatory Peptides
• Volym: 143
• Issue: 1-3
• Fulltext: - 201 kB; Download statistics
• Länkar: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17482289&dopt=Abstract; http://dx.doi.org/10.1016/j.regpep.2007.03.008
• Dokumenttyp: Artikel i tidskrift
• Förlag: Elsevier
• Ämne: Cell and Molecular Biology
• Nyckelord: islet amyloid polypeptide; DPP4; insulin secretion; mice; vildagliptin; glucose tolerance
• Status: Published
• ISBN/ISSN/Övrigt: ISSN: 1873-1686