Valine pyrrolidide preserves intact glucose-dependent insulinotropic peptide and improves abnormal glucose tolerance in minipigs with reduced beta-cell mass.
The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are important in blood glucose regulation. However, both incretin hormones are rapidly degraded by the enzyme dipeptidyl peptidase IV (DPPIV). The concept of DPPIV inhibition as a treatment for type 2 diabetes was evaluated in a new large animal model of insulin-deficient diabetes and reduced beta-cell mass, the nicotinamide (NIA) (67 mg/kg) and streptozotocin (STZ) (125 mg/kg)-treated minipig, using the DPPIV inhibitor, valine pyrrolidide (VP) (50 mg/kg). VP did not significantly affect levels of intact GLP-1 but increased levels of intact GIP (from 4543 +/- 1880 to 9208 +/- 3267 pM x min; P <.01), thus improving glucose tolerance (area under the curve [AUC] for glucose reduced from 1904 +/- 480 to 1582 +/- 353 mM x min; P =.05). VP did not increase insulin levels during the oral glucose tolerance test (OGTT) but increased the insulinogenic index in normal animals (from 83 +/- 42 to 192 +/- 108; P <.05), but not after NIA + STZ, possibly because of less residual insulin secretory capacity in these animals. GIP seems to contribute to the antihyperglycemic effect of VP in this model; however, additional mechanisms for the effect of DPPIV inhibition cannot be excluded. The authors conclude that DPPIV inhibitors may be useful to treat type 2 diabetes, even when this is due to reduced beta-cell mass.
Larsen
Marianne Olholm
MO
Department of Pharmacological Research I, Novo Nordisk A/S, Bagsvaerd, Denmark. mmla@novonordisk.com
Rolin
Bidda
B
Ribel
Ulla
U
Wilken
Michael
M
Deacon
Carolyn F
CF
Svendsen
Ove
O
Gotfredsen
Carsten F
CF
Carr
Richard David
RD
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002405:Catheterization, Central Venous; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000378:metabolism*; D004361:Drug Tolerance; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology; D018149:Glucose Intolerance / Q000503:physiopathology* / Q000517:prevention & control; D005951:Glucose Tolerance Test; D007515:Islets of Langerhans / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology*; D013552:Swine; D013556:Swine, Miniature; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology*
D001786:Blood Glucose; D011759:Pyrrolidines; D005749:Gastric Inhibitory Polypeptide; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C100151:dipeptidyl peptidase II; D014633:Valine; D005947:Glucose