Long-term treatment with dipeptidyl peptidase IV inhibitor improves hepatic and peripheral insulin sensitivity in the VDF Zucker rat: a euglycemic-hyperinsulinemic clamp study.
Upon release into circulation, the potent insulin secretagogues glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are rapidly cleaved and inactivated by the enzyme dipeptidyl peptidase IV (DP IV). Long-term administration of specific DP IV inhibitors, so as to enhance circulating active GIP and GLP-1 levels, has been shown to improve glucose tolerance and beta-cell glucose responsiveness and to reduce hyperinsulinemia in the Vancouver diabetic fatty (VDF) rat model of type 2 diabetes. Using the VDF model, the current study was undertaken to examine the effects of long-term DP IV inhibitor treatment on insulin sensitivity. Euglycemic-hyperinsulinemic clamps were performed on two sets of conscious VDF rats treated with or without the DP IV inhibitor P32/98 (20 mg. kg(-1). day(-1) for 12 weeks). The protocol consisted of three sequential 90-min periods with insulin infusion rates of 0, 5, and 15 mU. kg(-1). min(-1) and included a constant infusion of [ (3)H]glucose for measure of hepatic and peripheral insulin sensitivity. Relative to untreated littermates, the treated animals showed a left shift in the sensitivity of hepatic glucose output to insulin (average reduction approximately 6 micro mol. kg(-1). min(-1)) and a marked gain in peripheral responsiveness to insulin, with glucose disposal rates increasing 105 and 216% in response to the two insulin steps (versus 2 and 46% in controls). These results provide the first demonstration of improved hepatic and peripheral insulin sensitivity after DP IV inhibitor therapy, and coupled with apparent improvements in beta-cell function, they offer strong support for the utility of these compounds in the treatment of diabetes.
Department of Physiology, University of British Columbia, Vancouver, British Columbia, Canada. Probiodrug AG, Halle (Saale), Germany.
John A
JA
Pospisilik
Sara G
SG
Stafford
Hans-Ulrich
HU
Demuth
Christopher H S
CH
McIntosh
Raymond A
RA
Pederson
D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000503:physiopathology; D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects*; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D007328:Insulin / Q000502:physiology*; D008066:Lipolysis / Q000502:physiology; D008099:Liver / Q000378:metabolism / Q000503:physiopathology*; D009765:Obesity; D010421:Pentanoic Acids / Q000008:administration & dosage* / Q000627:therapeutic use; D051381:Rats; D011924:Rats, Zucker; D013844:Thiazoles / Q000008:administration & dosage* / Q000627:therapeutic use; D053778:Thiazolidines
D004791:Enzyme Inhibitors; D007328:Insulin; C453900:P32-98 compound; D010421:Pentanoic Acids; D013844:Thiazoles; D053778:Thiazolidines; D018819:Dipeptidyl Peptidase 4