Pleiotropic Effects of GIP on Islet Function Involve Osteopontin
- Valeriya Lyssenko1⇓,
- Lena Eliasson2,
- Olga Kotova3,
- Kasper Pilgaard4,
- Nils Wierup5,
- Albert Salehi6,
- Anna Wendt2,
- Anna Jonsson1,
- Yang Z. De Marinis1,
- Lisa M. Berglund3,
- Jalal Taneera1,
- Alexander Balhuizen6,
- Ola Hansson1,
- Peter Osmark1,
- Pontus Dunér7,
- Charlotte Brøns4,
- Alena Stančáková8,
- Johanna Kuusisto8,
- Marco Bugliani9,10,
- Richa Saxena11,12,
- Emma Ahlqvist1,
- Timothy J. Kieffer13,
- Tiinamaija Tuomi14,15,
- Bo Isomaa14,16,
- Olle Melander17,18,
- Emily Sonestedt19,
- Marju Orho-Melander19,
- Peter Nilsson20,
- Sara Bonetti21,
- Riccardo Bonadonna21,
- Roberto Miccoli9,
- Stefano DelPrato9,
- Piero Marchetti9,10,
- Sten Madsbad22,
- Pernille Poulsen4,
- Allan Vaag4,
- Markku Laakso8,
- Maria F. Gomez7 and
- Leif Groop1
- 1Diabetes and Endocrinology, Department of Clinical Sciences, University Hospital Malmö, Lund University, Malmö, Sweden
- 2Islet Cell Exocytosis, Department of Clinical Sciences, University Hospital Malmö, Lund University, Malmö, Sweden
- 3Vascular ET-Coupling, Department of Clinical Sciences, University Hospital Malmö, Lund University, Malmö, Sweden
- 4Steno Diabetes Center, Gentofte, Denmark
- 5Neuroendocrine Cell Biology, Department of Experimental Medical Science, Lund University, Malmö, Sweden
- 6Division of Endocrine Pharmacology, Department of Clinical Sciences, University Hospital Malmö, Lund University, Malmö, Sweden
- 7Experimental Cardiovascular Research Unit, Department of Clinical Sciences, Lund University, University Hospital Malmö, Malmö, Sweden
- 8Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
- 9Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy
- 10Endocrinology and Metabolism of Organ and Cellular Transplantation, AOUP Pisa, Pisa, Italy
- 11Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts
- 12Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
- 13Laboratory of Molecular and Cellular Medicine, Departments of Cellular and Physiological Sciences and Surgery, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
- 14Folkhalsan Research Centre, Helsinki, Finland
- 15Department of Medicine, Helsinki University Central Hospital and Research Program of Molecular Medicine, University of Helsinki, Helsinki, Finland
- 16The Department of Social Services and Health Care, Jakobstad, Finland
- 17Center for Emergency Medicine, Malmö University Hospital, Malmö, Sweden
- 18Hypertension and Cardiovascular Disease, Department of Clinical Sciences, Lund University, Clinical Research Centre, Malmö University Hospital, Malmö, Sweden
- 19Diabetes and Cardiovascular Disease: Genetic Epidemiology, Department of Clinical Sciences, Lund University, Malmö, Sweden
- 20Medicine, Department of Clinical Sciences, Lund University, University Hospital Malmö, Malmö, Sweden
- 21Section of Endocrinology and Metabolism Diseases, Department of Medicine, University of Verona, Verona, Italy
- 22Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
- Corresponding author: Valeriya Lyssenko, .
V.L. and L.E. contributed equally to this study.
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db10-1532/-/DC1.
- Received November 4, 2010.
- Accepted June 16, 2011.
- © 2011 by the American Diabetes Association.
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