Beta-cell expression of a dominant-negative HNF-1alpha compromises the ability of inhibition of dipeptidyl peptidase-4 to elicit a long-term augmentation of insulin secretion in mice.
Glucagon-like peptide-1 (GLP-1) has long-term effects on pancreatic islets by increasing the insulin secretory capacity and beta cell mass. The islet effects of GLP-1 are glucose dependent and therefore tied to glucose sensing and metabolism. We examined whether prevention of inactivation of GLP-1 by inhibiting dipeptidyl peptidase-4 (DPP-4) is sufficient to promote long-term augmentation of glucose-stimulated insulin secretion. We also explored whether a defective glucose sensing and metabolism could be overcome by DPP-4 inhibition. We administered the orally active and highly selective DPP-4 inhibitor (1-[[(3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidineP-4; vildagliptin; 3 mumol/mouse daily) to normal, wildtype, mice and to mice with a beta-cell targeted dominant-negative mutant hepatocyte nuclear factor-1alpha (HNF-1alpha); these mice have a defective islet response to glucose. After eight weeks, vildagliptin augmented the insulin response after gastric glucose (75 mg) by 5-fold in male mice (7.3+/-0.8 vs. 1.3+/-0.5 nmol/l, P<0.001) and 30-fold in female mice (26.5+/-5.8 vs. 0.9+/-0.3 nmol/l, P<0.001). Furthermore, glucose-stimulated insulin secretion from isolated islets was markedly enhanced by 9 weeks treatment with vildagliptin. In contrast, in transgenic mice, the severely suppressed insulin response was only marginally improved by vildagliptin in males, and not affected at all in females. We conclude that DPP-4 inhibition improves islet function and increases beta cell secretory responses on a long-term basis and that this is dependent on intact expression of HNF-1alpha.
Ahrén
Bo
B
Department of Medicine, Lund University, B11 BMC, SE 221 84 LUND, Sweden. Bo.Ahren@med.lu.se
Sörhede Winzell
Maria
M
Burkey
Bryan
B
Hughes
Thomas E
TE
D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005838:Genotype; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D007441:Intubation, Gastrointestinal; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009570:Nitriles; D011759:Pyrrolidines; D013997:Time Factors; D000077597:Vildagliptin
D004791:Enzyme Inhibitors; D051538:Hepatocyte Nuclear Factor 1-alpha; D007328:Insulin; D009570:Nitriles; D011759:Pyrrolidines; D018819:Dipeptidyl Peptidase 4; D000077597:Vildagliptin; D005947:Glucose; D000218:Adamantane