Chronic inhibition of circulating dipeptidyl peptidase IV by FE 999011 delays the occurrence of diabetes in male zucker diabetic fatty rats.
Acute suppression of dipeptidyl peptidase IV (DPP-IV) activity improves glucose tolerance in the Zucker fatty rat, a rodent model of impaired glucose tolerance, through stabilization of glucagon-like peptide (GLP)-1. This study describes the effects of a new and potent DPP-IV inhibitor, FE 999011, which is able to suppress plasma DPP-IV activity for 12 h after a single oral administration. In the Zucker fatty rat, FE 999011 dose-dependently attenuated glucose excursion during an oral glucose tolerance test and increased GLP-1 (7-36) release in response to intraduodenal glucose. Chronic treatment with FE 999011 (10 mg/kg, twice a day for 7 days) improved glucose tolerance, as suggested by a decrease in the insulin-to-glucose ratio. In the Zucker diabetic fatty (ZDF) rat, a rodent model of type 2 diabetes, chronic treatment with FE 999011 (10 mg/kg per os, once or twice a day) postponed the development of diabetes, with the twice-a-day treatment delaying the onset of hyperglycemia by 21 days. In addition, treatment with FE 999011 stabilized food and water intake to prediabetic levels and reduced hypertriglyceridemia while preventing the rise in circulating free fatty acids. At the end of treatment, basal plasma GLP-1 levels were increased, and pancreatic gene expression for GLP-1 receptor was significantly upregulated. This study demonstrates that DPP-IV inhibitors such as FE 999011 could be of clinical value to delay the progression from impaired glucose tolerance to type 2 diabetes.
Sudre
Béatrice
B
Ferring Research Institute and Division of Biology of Growth and Reproduction, Department of Pediatrics, University of Geneva School of Medicine, Geneva, Switzerland.
Broqua
Pierre
P
White
Richard B
RB
Ashworth
Doreen
D
Evans
D Michael
DM
Haigh
Robert
R
Junien
Jean-Louis
JL
Aubert
Michel L
ML
D000818:Animals; D001786:Blood Glucose; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000097:blood*; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000097:blood; D015870:Gene Expression / Q000502:physiology; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology*; D009765:Obesity; D010179:Pancreas / Q000502:physiology; D010446:Peptide Fragments / Q000097:blood; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011498:Protein Precursors / Q000097:blood; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D018027:Receptors, Glucagon / Q000235:genetics; D014280:Triglycerides / Q000097:blood; D015430:Weight Gain / Q000187:drug effects
C121834:1-(((2-((5-cyanopyridin-2-yl)amino)ethyl)amino)acetyl)-2-cyano-(S)-pyrrolidine; C454816:1-(2'-amino-3',3'-dimethylbutanoyl)pyrrolidine-2-carbonitrile; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; C000593833:GLP1R protein, human; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D009570:Nitriles; D010446:Peptide Fragments; D011480:Protease Inhibitors; D011498:Protein Precursors; D011759:Pyrrolidines; D018027:Receptors, Glucagon; D014280:Triglycerides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D018819:Dipeptidyl Peptidase 4