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Pleiotropic Effects of GIP on Islet Function Involve Osteopontin

Lyssenko, Valeriya LU ; Eliasson, Lena; Kotova, Olga LU ; Pilgaard, Kasper; Wierup, Nils LU ; Salehi, S Albert LU ; Wendt, Anna; Jonsson, Anna; De Marinis, Yang Z. and Berglund, Lisa LU , et al. (2011) In Diabetes 60(9). p.2424-2433
Abstract
OBJECTIVE-The incretin hormone GIP (glucose-dependent insulinotropic polypeptide) promotes pancreatic beta-cell function by potentiating insulin secretion and beta-cell proliferation. Recently, a combined analysis of several genome-wide association studies (Meta-analysis of Glucose and Insulin-Related Traits Consortium [MAGIC]) showed association to postprandial insulin at the GIP receptor (GIPR) locus. Here we explored mechanisms that could explain the protective effects of GIP on islet function. RESEARCH DESIGN AND METHODS-Associations of GIPR rs10423928 with metabolic and anthropometric phenotypes in both nondiabetic (N = 53,730) and type 2 diabetic individuals (N = 2,731) were explored by combining data from 11 studies.Insulin... (More)
OBJECTIVE-The incretin hormone GIP (glucose-dependent insulinotropic polypeptide) promotes pancreatic beta-cell function by potentiating insulin secretion and beta-cell proliferation. Recently, a combined analysis of several genome-wide association studies (Meta-analysis of Glucose and Insulin-Related Traits Consortium [MAGIC]) showed association to postprandial insulin at the GIP receptor (GIPR) locus. Here we explored mechanisms that could explain the protective effects of GIP on islet function. RESEARCH DESIGN AND METHODS-Associations of GIPR rs10423928 with metabolic and anthropometric phenotypes in both nondiabetic (N = 53,730) and type 2 diabetic individuals (N = 2,731) were explored by combining data from 11 studies.Insulin secretion was measured both in vivo in nondiabetic subjects and in vitro in islets from cadaver donors. Insulin secretion was also measured in response to exogenous GIP. The in vitro measurements included protein and gene expression as well as measurements of beta-cell viability and proliferation. RESULTS-The A allele of GIPR rs10423928 was associated with impaired glucose- and GIP-stimulated insulin secretion and a decrease in BMI, lean body mass, and waist circumference. The decrease in BMI almost completely neutralized the effect of impaired insulin secretion on risk of type 2 diabetes. Expression of GIPR mRNA was decreased in human islets from carriers of the A allele or patients with type 2 diabetes. GIP stimulated osteopontin (OPN) mRNA and protein expression. OPN expression was lower in carriers of the A allele. Both GIP and OPN prevented cytokine-induced reduction in cell viability (apoptosis). In addition, OPN stimulated cell proliferation in insulin-secreting cells. CONCLUSIONS-These findings support beta-cell proliferative and antiapoptotic roles for GIP in addition to its action as an incretin hormone. Identification of a link between GIP and OPN may shed new light on the role of GIP in preservation of functional beta-cell mass in humans. Diabetes 60:2424-2433, 2011 (Less)
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Contribution to journal
publication status
published
subject
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Diabetes
volume
60
issue
9
pages
2424 - 2433
publisher
American Diabetes Association Inc.
external identifiers
  • wos:000294699600026
  • scopus:80052900597
ISSN
1939-327X
DOI
10.2337/db10-1532
language
English
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yes
id
e58b098d-f02d-497b-b1f5-e5c87f7c2fca (old id 2187102)
date added to LUP
2011-11-01 07:54:38
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2017-05-07 03:44:59
@article{e58b098d-f02d-497b-b1f5-e5c87f7c2fca,
  abstract     = {OBJECTIVE-The incretin hormone GIP (glucose-dependent insulinotropic polypeptide) promotes pancreatic beta-cell function by potentiating insulin secretion and beta-cell proliferation. Recently, a combined analysis of several genome-wide association studies (Meta-analysis of Glucose and Insulin-Related Traits Consortium [MAGIC]) showed association to postprandial insulin at the GIP receptor (GIPR) locus. Here we explored mechanisms that could explain the protective effects of GIP on islet function. RESEARCH DESIGN AND METHODS-Associations of GIPR rs10423928 with metabolic and anthropometric phenotypes in both nondiabetic (N = 53,730) and type 2 diabetic individuals (N = 2,731) were explored by combining data from 11 studies.Insulin secretion was measured both in vivo in nondiabetic subjects and in vitro in islets from cadaver donors. Insulin secretion was also measured in response to exogenous GIP. The in vitro measurements included protein and gene expression as well as measurements of beta-cell viability and proliferation. RESULTS-The A allele of GIPR rs10423928 was associated with impaired glucose- and GIP-stimulated insulin secretion and a decrease in BMI, lean body mass, and waist circumference. The decrease in BMI almost completely neutralized the effect of impaired insulin secretion on risk of type 2 diabetes. Expression of GIPR mRNA was decreased in human islets from carriers of the A allele or patients with type 2 diabetes. GIP stimulated osteopontin (OPN) mRNA and protein expression. OPN expression was lower in carriers of the A allele. Both GIP and OPN prevented cytokine-induced reduction in cell viability (apoptosis). In addition, OPN stimulated cell proliferation in insulin-secreting cells. CONCLUSIONS-These findings support beta-cell proliferative and antiapoptotic roles for GIP in addition to its action as an incretin hormone. Identification of a link between GIP and OPN may shed new light on the role of GIP in preservation of functional beta-cell mass in humans. Diabetes 60:2424-2433, 2011},
  author       = {Lyssenko, Valeriya and Eliasson, Lena and Kotova, Olga and Pilgaard, Kasper and Wierup, Nils and Salehi, S Albert and Wendt, Anna and Jonsson, Anna and De Marinis, Yang Z. and Berglund, Lisa and Taneera, Jalal and Balhuizen, Alexander and Hansson, Ola and Osmark, Peter and Dunér, Pontus and Brons, Charlotte and Stancakova, Alena and Kuusisto, Johanna and Bugliani, Marco and Saxena, Richa and Ahlqvist, Emma and Kieffer, Timothy J. and Tuomi, Tiinamaija and Isomaa, Bo and Melander, Olle and Sonestedt, Emily and Orho-Melander, Marju and Nilsson, Peter and Bonetti, Sara and Bonadonna, Riccardo and Miccoli, Roberto and DelPrato, Stefano and Marchetti, Piero and Madsbad, Sten and Poulsen, Pernille and Vaag, Allan and Laakso, Markku and Gomez, Maria and Groop, Leif},
  issn         = {1939-327X},
  language     = {eng},
  number       = {9},
  pages        = {2424--2433},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Pleiotropic Effects of GIP on Islet Function Involve Osteopontin},
  url          = {http://dx.doi.org/10.2337/db10-1532},
  volume       = {60},
  year         = {2011},
}