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Glucagon receptor antagonism improves islet function in mice with insulin resistance induced by a high-fat diet.

Sörhede Winzell, Maria LU ; Brand, C; Wierup, Nils LU ; Sidelmann, U; Sundler, Frank LU ; Nishimura, E and Ahrén, Bo LU (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)
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author
organization
publishing date
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 Verlag
external identifiers
  • wos:000247210800014
  • scopus:34249930188
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
2007-07-10 16:20:11
date last changed
2017-11-19 03:25:57
@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 &lt; 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 &lt; 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 &lt; 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},
  keyword      = {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 Verlag},
  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},
  volume       = {50},
  year         = {2007},
}