Pleiotropic effects of GIP on islet function involve osteopontin

Valeriya Lyssenko; Lena Eliasson; Olga Kotova; Kasper Pilgaard; Nils Wierup; Albert Salehi; Anna Wendt; Anna Elisabet Jonsson; Yang Z De Marinis; Lisa M Berglund; Jalal Taneera; Alexander Balhuizen; Ola Hansson; Peter Osmark; Pontus Dunér; Charlotte Brøns; Alena Stancáková; Johanna Kuusisto; Marco Bugliani; Richa Saxena; Emma Ahlqvist; Timothy J Kieffer; Tiinamaija Tuomi; Bo Isomaa; Olle Melander; Emily Sonestedt; Marju Orho-Melander; Peter Nilsson; Sara Bonetti; Riccardo Bonadonna; Roberto Miccoli; Stefano Delprato; Piero Marchetti; Sten Madsbad; Pernille Poulsen; Allan Vaag; Markku Laakso; Maria F Gomez; Leif Groop

doi:10.2337/db10-1532

Pleiotropic effects of GIP on islet function involve osteopontin

Valeriya Lyssenko, Lena Eliasson, Olga Kotova, Kasper Pilgaard, Nils Wierup, Albert Salehi, Anna Wendt, Anna Elisabet Jonsson, Yang Z De Marinis, Lisa M Berglund, Jalal Taneera, Alexander Balhuizen, Ola Hansson, Peter Osmark, Pontus Dunér, Charlotte Brøns, Alena Stancáková, Johanna Kuusisto, Marco Bugliani, Richa SaxenaEmma Ahlqvist, Timothy J Kieffer, Tiinamaija Tuomi, Bo Isomaa, Olle Melander, Emily Sonestedt, Marju Orho-Melander, Peter Nilsson, Sara Bonetti, Riccardo Bonadonna, Roberto Miccoli, Stefano Delprato, Piero Marchetti, Sten Madsbad, Pernille Poulsen, Allan Vaag, Markku Laakso, Maria F Gomez, Leif Groop

66 Citations (Scopus)

Abstract

OBJECTIVE - The incretin hormone GIP (glucose-dependent insulinotropic polypeptide) promotes pancreatic β-cell function by potentiating insulin secretion and β-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 β-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 β-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 β-cell mass in humans.

Original language	English
Journal	Diabetes
Volume	60
Issue number	9
Pages (from-to)	2424-33
Number of pages	10
ISSN	0012-1797
DOIs	https://doi.org/10.2337/db10-1532
Publication status	Published - Sept 2011

Keywords

Alleles
Diabetes Mellitus, Type 2
Gastric Inhibitory Polypeptide
Genome-Wide Association Study
Glucagon-Like Peptide 1
Humans
Insulin
Insulin-Secreting Cells
Islets of Langerhans
Male
Osteopontin

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.2337/db10-1532

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Lyssenko, V., Eliasson, L., Kotova, O., Pilgaard, K., Wierup, N., Salehi, A., Wendt, A., Jonsson, A. E., De Marinis, Y. Z., Berglund, L. M., Taneera, J., Balhuizen, A., Hansson, O., Osmark, P., Dunér, P., Brøns, C., Stancáková, A., Kuusisto, J., Bugliani, M., ... Groop, L. (2011). Pleiotropic effects of GIP on islet function involve osteopontin. Diabetes, 60(9), 2424-33. https://doi.org/10.2337/db10-1532

Lyssenko, V, Eliasson, L, Kotova, O, Pilgaard, K, Wierup, N, Salehi, A, Wendt, A, Jonsson, AE, De Marinis, YZ, Berglund, LM, Taneera, J, Balhuizen, A, Hansson, O, Osmark, P, Dunér, P, Brøns, C, Stancáková, A, Kuusisto, J, Bugliani, M, Saxena, R, Ahlqvist, E, Kieffer, TJ, Tuomi, T, Isomaa, B, Melander, O, Sonestedt, E, Orho-Melander, M, Nilsson, P, Bonetti, S, Bonadonna, R, Miccoli, R, Delprato, S, Marchetti, P, Madsbad, S, Poulsen, P, Vaag, A, Laakso, M, Gomez, MF & Groop, L 2011, 'Pleiotropic effects of GIP on islet function involve osteopontin', Diabetes, vol. 60, no. 9, pp. 2424-33. https://doi.org/10.2337/db10-1532

@article{75b9e8286a374a289d937737e9a189d9,

title = "Pleiotropic effects of GIP on islet function involve osteopontin",

abstract = "OBJECTIVE - The incretin hormone GIP (glucose-dependent insulinotropic polypeptide) promotes pancreatic β-cell function by potentiating insulin secretion and β-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 β-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 β-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 β-cell mass in humans.",

keywords = "Alleles, Diabetes Mellitus, Type 2, Gastric Inhibitory Polypeptide, Genome-Wide Association Study, Glucagon-Like Peptide 1, Humans, Insulin, Insulin-Secreting Cells, Islets of Langerhans, Male, Osteopontin",

author = "Valeriya Lyssenko and Lena Eliasson and Olga Kotova and Kasper Pilgaard and Nils Wierup and Albert Salehi and Anna Wendt and Jonsson, {Anna Elisabet} and {De Marinis}, {Yang Z} and Berglund, {Lisa M} and Jalal Taneera and Alexander Balhuizen and Ola Hansson and Peter Osmark and Pontus Dun{\'e}r and Charlotte Br{\o}ns and Alena Stanc{\'a}kov{\'a} and Johanna Kuusisto and Marco Bugliani and Richa Saxena and Emma Ahlqvist and Kieffer, {Timothy J} and Tiinamaija Tuomi and Bo Isomaa and Olle Melander and Emily Sonestedt and Marju Orho-Melander and Peter Nilsson and Sara Bonetti and Riccardo Bonadonna and Roberto Miccoli and Stefano Delprato and Piero Marchetti and Sten Madsbad and Pernille Poulsen and Allan Vaag and Markku Laakso and Gomez, {Maria F} and Leif Groop",

year = "2011",

month = sep,

doi = "10.2337/db10-1532",

language = "English",

volume = "60",

pages = "2424--33",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association",

number = "9",

}

TY - JOUR

T1 - Pleiotropic effects of GIP on islet function involve osteopontin

AU - Lyssenko, Valeriya

AU - Eliasson, Lena

AU - Kotova, Olga

AU - Pilgaard, Kasper

AU - Wierup, Nils

AU - Salehi, Albert

AU - Wendt, Anna

AU - Jonsson, Anna Elisabet

AU - De Marinis, Yang Z

AU - Berglund, Lisa M

AU - Taneera, Jalal

AU - Balhuizen, Alexander

AU - Hansson, Ola

AU - Osmark, Peter

AU - Dunér, Pontus

AU - Brøns, Charlotte

AU - Stancáková, Alena

AU - Kuusisto, Johanna

AU - Bugliani, Marco

AU - Saxena, Richa

AU - Ahlqvist, Emma

AU - Kieffer, Timothy J

AU - Tuomi, Tiinamaija

AU - Isomaa, Bo

AU - Melander, Olle

AU - Sonestedt, Emily

AU - Orho-Melander, Marju

AU - Nilsson, Peter

AU - Bonetti, Sara

AU - Bonadonna, Riccardo

AU - Miccoli, Roberto

AU - Delprato, Stefano

AU - Marchetti, Piero

AU - Madsbad, Sten

AU - Poulsen, Pernille

AU - Vaag, Allan

AU - Laakso, Markku

AU - Gomez, Maria F

AU - Groop, Leif

PY - 2011/9

Y1 - 2011/9

N2 - OBJECTIVE - The incretin hormone GIP (glucose-dependent insulinotropic polypeptide) promotes pancreatic β-cell function by potentiating insulin secretion and β-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 β-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 β-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 β-cell mass in humans.

AB - OBJECTIVE - The incretin hormone GIP (glucose-dependent insulinotropic polypeptide) promotes pancreatic β-cell function by potentiating insulin secretion and β-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 β-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 β-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 β-cell mass in humans.

KW - Alleles

KW - Diabetes Mellitus, Type 2

KW - Gastric Inhibitory Polypeptide

KW - Genome-Wide Association Study

KW - Glucagon-Like Peptide 1

KW - Humans

KW - Insulin

KW - Insulin-Secreting Cells

KW - Islets of Langerhans

KW - Male

KW - Osteopontin

U2 - 10.2337/db10-1532

DO - 10.2337/db10-1532

M3 - Journal article

C2 - 21810601

SN - 0012-1797

VL - 60

SP - 2424

EP - 2433

JO - Diabetes

JF - Diabetes

IS - 9

ER -

Pleiotropic effects of GIP on islet function involve osteopontin

Abstract

Keywords

UN SDGs

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