Valine pyrrolidide preserves intact glucose-dependent insulinotropic peptide and improves abnormal glucose tolerance in minipigs with reduced beta-cell mass

Exp Diabesity Res. Apr-Jun 2003;4(2):93-105. doi: 10.1155/EDR.2003.93.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Catheterization, Central Venous
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / metabolism*
  • Drug Tolerance
  • Gastric Inhibitory Polypeptide / pharmacology*
  • Glucose / pharmacology
  • Glucose Intolerance / physiopathology*
  • Glucose Intolerance / prevention & control
  • Glucose Tolerance Test
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / physiopathology*
  • Male
  • Pyrrolidines / pharmacology*
  • Swine
  • Swine, Miniature
  • Valine / analogs & derivatives*
  • Valine / pharmacology*

Substances

  • Blood Glucose
  • Pyrrolidines
  • Gastric Inhibitory Polypeptide
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
  • dipeptidyl peptidase II
  • Valine
  • Glucose