Glucagon receptor antagonism improves islet function in mice with insulin resistance induced by a high-fat diet.
(2007) In Diabetologia 50. p.1453-1462- Abstract
- 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... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/168432
- author
- Sörhede Winzell, Maria LU ; Brand, C ; Wierup, Nils LU ; Sidelmann, U ; Sundler, Frank LU ; Nishimura, E and Ahrén, Bo LU
- organization
- publishing date
- 2007
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- diabetes, type 2, islet, insulin sensitivity, glucagon, glucose tolerance, glycaemia, insulin secretion, diabetes treatment, beta cell, alpha cell
- in
- Diabetologia
- volume
- 50
- pages
- 1453 - 1462
- publisher
- Springer
- external identifiers
-
- wos:000247210800014
- scopus:34249930188
- pmid:17479245
- ISSN
- 1432-0428
- DOI
- 10.1007/s00125-007-0675-3
- language
- English
- LU publication?
- yes
- id
- f3edce37-a4c5-47be-bbd6-a1b2d5aee231 (old id 168432)
- alternative location
- http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17479245&dopt=Abstract
- date added to LUP
- 2016-04-01 11:38:14
- date last changed
- 2024-01-07 14:47:14
@article{f3edce37-a4c5-47be-bbd6-a1b2d5aee231,
abstract = {{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.}},
author = {{Sörhede Winzell, Maria and Brand, C and Wierup, Nils and Sidelmann, U and Sundler, Frank and Nishimura, E and Ahrén, Bo}},
issn = {{1432-0428}},
keywords = {{diabetes; type 2; islet; insulin sensitivity; glucagon; glucose tolerance; glycaemia; insulin secretion; diabetes treatment; beta cell; alpha cell}},
language = {{eng}},
pages = {{1453--1462}},
publisher = {{Springer}},
series = {{Diabetologia}},
title = {{Glucagon receptor antagonism improves islet function in mice with insulin resistance induced by a high-fat diet.}},
url = {{http://dx.doi.org/10.1007/s00125-007-0675-3}},
doi = {{10.1007/s00125-007-0675-3}},
volume = {{50}},
year = {{2007}},
}