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.
Pospisilik
John A
JA
Department of Physiology, University of British Columbia, Vancouver, British Columbia, Canada. Probiodrug AG, Halle (Saale), Germany.
Stafford
Sara G
SG
Demuth
Hans-Ulrich
HU
McIntosh
Christopher H S
CH
Pederson
Raymond A
RA
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