| Glucagon receptor antagonism improves islet function in mice with insulin resistance induced by a high-fat diet. | |
| | |
MedLine Citation:
|
PMID: 17479245 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
AIMS/HYPOTHESIS: Increased glucagon secretion predicts deterioration of glucose tolerance, and high glucagon levels contribute to hyperglycaemia in type 2 diabetes. Inhibition of glucagon action may therefore be a potential novel target to reduce hyperglycaemia. Here, we investigated whether chronic treatment with a glucagon receptor antagonist (GRA) improves islet dysfunction in female mice on a high-fat diet (HFD). MATERIALS AND METHODS: After 8 weeks of HFD, mice were treated with a small molecule GRA (300 mg/kg, gavage once daily) for up to 30 days. Insulin secretion was studied after oral and intravenous administration of glucose and glucagon secretion after intravenous arginine. Islet morphology was examined and insulin secretion and glucose oxidation were measured in isolated islets. RESULTS: Fasting plasma glucose levels were reduced by GRA (6.0 +/- 0.2 vs 7.4 +/- 0.5 mmol/l; p = 0.017). The acute insulin response to intravenous glucose was augmented (1,300 +/- 110 vs 790 +/- 64 pmol/l; p < 0.001). The early insulin response to oral glucose was reduced in mice on HFD + GRA (1,890 +/- 160 vs 3,040 +/- 420 pmol/l; p = 0.012), but glucose excursions were improved. Intravenous arginine significantly increased the acute glucagon response (129 +/- 12 vs 36 +/- 6 ng/l in controls; p < 0.01), notably without affecting plasma glucose. GRA caused a modest increase in alpha cell mass, while beta cell mass was similar to that in mice on HFD + vehicle. Isolated islets displayed improved glucose-stimulated insulin secretion after GRA treatment (0.061 +/- 0.007 vs 0.030 +/- 0.004 pmol islet(-1) h(-1) at 16.7 mmol/l glucose; p < 0.001), without affecting islet glucose oxidation. CONCLUSIONS/INTERPRETATION: Chronic glucagon receptor antagonism in HFD-fed mice improves islet sensitivity to glucose and increases insulin secretion, suggesting improvement of key defects underlying impaired glucose tolerance and type 2 diabetes. |
| | |
Authors:
|
M Sörhede Winzell; C L Brand; N Wierup; U G Sidelmann; F Sundler; E Nishimura; B Ahrén |
Related Documents
:
|
403115 - Comparison of trf, propranolol-glucagon, insulin and glucose stimulation tests in acrom... 4909765 - Insulin release from isolated human fetal pancreatic islets. 10497625 - Enhancement of b-cell secretion by blood glucose normalization in type 2 diabetes is as... 11880925 - The role of leucine-enkephalin on insulin and glucagon secretion from pancreatic tissue... 17981665 - Dipeptidyl peptidase iv inhibitors and diabetes therapy. 9775435 - Antidiabetic principles of natural medicines. iii. structure-related inhibitory activit... |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2007-05-04 |
Journal Detail:
|
Title: Diabetologia Volume: 50 ISSN: 0012-186X ISO Abbreviation: Diabetologia Publication Date: 2007 Jul |
Date Detail:
|
Created Date: 2007-06-06 Completed Date: 2007-11-07 Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 0006777 Medline TA: Diabetologia Country: Germany |
Other Details:
|
Languages: eng Pagination: 1453-62 Citation Subset: IM |
Affiliation:
|
Department of Clinical Sciences, Lund, Division of Medicine, BMC, B11, Lund University, 221 84, Lund, Sweden. Maria.Sorhede_Winzell@med.lu.se |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animal Feed* Animals Blood Glucose / metabolism Diet Female Glucagon / metabolism Glucose Tolerance Test Insulin / metabolism Insulin Resistance Islets of Langerhans / metabolism* Mice Mice, Inbred C57BL Oxygen / metabolism Receptors, Glucagon / antagonists & inhibitors*, metabolism Time Factors |
| Chemical | |
Reg. No./Substance:
|
0/Blood Glucose; 0/Receptors, Glucagon; 11061-68-0/Insulin; 7782-44-7/Oxygen; 9007-92-5/Glucagon |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Increased serum levels of advanced glycation endproducts predict total, cardiovascular and coronary ...
Next Document: Human Krüppel-like factor 11 inhibits human proinsulin promoter activity in pancreatic beta cells.