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Long-term inhibitio...
Long-term inhibition of dipeptidyl peptidase IV improves glucose tolerance and preserves islet function in mice.
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- Kvist Reimer, Martina (författare)
- Lund University,Lunds universitet,Medicin, Lund,Sektion II,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Medicine, Lund,Section II,Department of Clinical Sciences, Lund,Faculty of Medicine
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Holst, J J (författare)
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- Ahrén, Bo (författare)
- Lund University,Lunds universitet,Medicin, Lund,Sektion II,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Medicine, Lund,Section II,Department of Clinical Sciences, Lund,Faculty of Medicine
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(creator_code:org_t)
- Oxford University Press (OUP), 2002
- 2002
- Engelska.
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Ingår i: European Journal of Endocrinology. - : Oxford University Press (OUP). - 1479-683X .- 0804-4643. ; 146:5, s. 717-727
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
Nyckelord
- 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
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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