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Long-term inhibition of dipeptidyl peptidase IV improves glucose tolerance and preserves islet function in mice.

Kvist Reimer, Martina LU ; Holst, J J and Ahrén, Bo LU (2002) In European Journal of Endocrinology1994-01-01+01:00 146(5). p.717-727
Abstract
OBJECTIVES: Inhibitors of the glucagon-like peptide-1 (GLP-1)-degrading enzyme, dipeptidyl peptidase IV (DPPIV), are being explored in the treatment of diabetes. We examined the long-term influence of a selective, orally active inhibitor of DPPIV (NVP DPP728), in normal female C57BL/6J mice and such mice rendered glucose-intolerant and insulin-resistant by feeding a high-fat diet. DESIGN: In mice fed a standard diet (11% fat) or a high-fat diet (58% fat), NVP DPP728 (0.12 micromol/g body weight) was administered in the drinking water for an 8 week period. RESULTS: DPPIV inhibition reduced plasma DPPIV activity to 0.01+/-0.03 mU/ml vs 3.26+/-0.19 mU/ml in controls (P<0.001). Glucose tolerance after gastric glucose gavage, as judged by... (More)
OBJECTIVES: Inhibitors of the glucagon-like peptide-1 (GLP-1)-degrading enzyme, dipeptidyl peptidase IV (DPPIV), are being explored in the treatment of diabetes. We examined the long-term influence of a selective, orally active inhibitor of DPPIV (NVP DPP728), in normal female C57BL/6J mice and such mice rendered glucose-intolerant and insulin-resistant by feeding a high-fat diet. DESIGN: In mice fed a standard diet (11% fat) or a high-fat diet (58% fat), NVP DPP728 (0.12 micromol/g body weight) was administered in the drinking water for an 8 week period. RESULTS: DPPIV inhibition reduced plasma DPPIV activity to 0.01+/-0.03 mU/ml vs 3.26+/-0.19 mU/ml in controls (P<0.001). Glucose tolerance after gastric glucose gavage, as judged by the area under the curve for plasma glucose levels over the 120 min study period, was increased after 8 weeks by NVP DPP728 in mice fed normal diet (P=0.029) and in mice fed a high-fat diet (P=0.036). This was accompanied by increased plasma levels of insulin and intact GLP-1. Glucose-stimulated insulin secretion from islets isolated from NVP DPP728-treated animals after 8 weeks of treatment was increased as compared with islets from control animals at 5.6, 8.3 and 11.1 mmol/l glucose both in mice fed normal diet and in mice fed a high-fat diet (both P<0.05). Islet insulin and glucagon immunocytochemistry revealed that NVP DPP728 did not affect the islet architecture. However, the expression of immunoreactive glucose transporter isoform-2 (GLUT-2) was increased by DPPIV inhibition, and in mice fed a high-fat diet, islet size was reduced after treatment with NVP DPP728 from 16.7+/-2.6 x 10(3) microm(2) in controls to 7.6+/-1.0 x 10(3) microm(2) (P=0.0019). CONCLUSION: Long-term DPPIV inhibition improves glucose tolerance in both normal and glucose-intolerant mice through improved islet function as judged by increased GLUT-2 expression, increased insulin secretion and protection from increased islet size in insulin resistance. (Less)
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Inbred C57BL, Mice, Islets of Langerhans : physiology, Islets of Langerhans : drug effects, Islets of Langerhans : anatomy & histology, Gastrointestinal, Intubation, Insulin Resistance : physiology, Insulin : blood, Glucose Intolerance : drug therapy, Glucose : pharmacology, Glucose : administration & dosage, Glucagon : blood, Female, Eating, Drinking, Dietary Fats : administration & dosage, Body Weight, Blood Glucose : analysis, CD26 : drug effects, Antigens, CD26 : blood, Animal, Nitriles : therapeutic use, Organ Weight : drug effects, Peptide Fragments : blood, Protease Inhibitors : therapeutic use, Protein Precursors : blood, Pyrrolidines : therapeutic use, Support, Non-U.S. Gov't
in
European Journal of Endocrinology1994-01-01+01:00
volume
146
issue
5
pages
717 - 727
publisher
Society of the European Journal of Endocrinology
external identifiers
  • wos:000178743200017
  • pmid:11980629
  • scopus:0036107064
ISSN
1479-683X
DOI
10.1530/eje.0.1460717
language
English
LU publication?
yes
id
52f8ffd9-963f-49d6-bc88-6fbf381e3bc1 (old id 107886)
alternative location
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11980629&dopt=Abstract
date added to LUP
2007-06-29 11:43:58
date last changed
2017-09-24 03:30:43
@article{52f8ffd9-963f-49d6-bc88-6fbf381e3bc1,
  abstract     = {OBJECTIVES: Inhibitors of the glucagon-like peptide-1 (GLP-1)-degrading enzyme, dipeptidyl peptidase IV (DPPIV), are being explored in the treatment of diabetes. We examined the long-term influence of a selective, orally active inhibitor of DPPIV (NVP DPP728), in normal female C57BL/6J mice and such mice rendered glucose-intolerant and insulin-resistant by feeding a high-fat diet. DESIGN: In mice fed a standard diet (11% fat) or a high-fat diet (58% fat), NVP DPP728 (0.12 micromol/g body weight) was administered in the drinking water for an 8 week period. RESULTS: DPPIV inhibition reduced plasma DPPIV activity to 0.01+/-0.03 mU/ml vs 3.26+/-0.19 mU/ml in controls (P&lt;0.001). Glucose tolerance after gastric glucose gavage, as judged by the area under the curve for plasma glucose levels over the 120 min study period, was increased after 8 weeks by NVP DPP728 in mice fed normal diet (P=0.029) and in mice fed a high-fat diet (P=0.036). This was accompanied by increased plasma levels of insulin and intact GLP-1. Glucose-stimulated insulin secretion from islets isolated from NVP DPP728-treated animals after 8 weeks of treatment was increased as compared with islets from control animals at 5.6, 8.3 and 11.1 mmol/l glucose both in mice fed normal diet and in mice fed a high-fat diet (both P&lt;0.05). Islet insulin and glucagon immunocytochemistry revealed that NVP DPP728 did not affect the islet architecture. However, the expression of immunoreactive glucose transporter isoform-2 (GLUT-2) was increased by DPPIV inhibition, and in mice fed a high-fat diet, islet size was reduced after treatment with NVP DPP728 from 16.7+/-2.6 x 10(3) microm(2) in controls to 7.6+/-1.0 x 10(3) microm(2) (P=0.0019). CONCLUSION: Long-term DPPIV inhibition improves glucose tolerance in both normal and glucose-intolerant mice through improved islet function as judged by increased GLUT-2 expression, increased insulin secretion and protection from increased islet size in insulin resistance.},
  author       = {Kvist Reimer, Martina and Holst, J J and Ahrén, Bo},
  issn         = {1479-683X},
  keyword      = {Inbred C57BL,Mice,Islets of Langerhans : physiology,Islets of Langerhans : drug effects,Islets of Langerhans : anatomy & histology,Gastrointestinal,Intubation,Insulin Resistance : physiology,Insulin : blood,Glucose Intolerance : drug therapy,Glucose : pharmacology,Glucose : administration & dosage,Glucagon : blood,Female,Eating,Drinking,Dietary Fats : administration & dosage,Body Weight,Blood Glucose : analysis,CD26 : drug effects,Antigens,CD26 : blood,Animal,Nitriles : therapeutic use,Organ Weight : drug effects,Peptide Fragments : blood,Protease Inhibitors : therapeutic use,Protein Precursors : blood,Pyrrolidines : therapeutic use,Support,Non-U.S. Gov't},
  language     = {eng},
  number       = {5},
  pages        = {717--727},
  publisher    = {Society of the European Journal of Endocrinology},
  series       = {European Journal of Endocrinology1994-01-01+01:00},
  title        = {Long-term inhibition of dipeptidyl peptidase IV improves glucose tolerance and preserves islet function in mice.},
  url          = {http://dx.doi.org/10.1530/eje.0.1460717},
  volume       = {146},
  year         = {2002},
}