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Pleiotropic Effects of GIP on Islet Function Involves Osteopontin
- Source :
- Diabetes; Vol 60, Diabetes
- Publication Year :
- 2011
-
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.
- Subjects :
- Male
endocrine system
medicine.medical_specialty
osteopontin
Endocrinology, Diabetes and Metabolism
medicine.medical_treatment
islet function
030209 endocrinology & metabolism
Gastric Inhibitory Polypeptide
Type 2 diabetes
Biology
beta cell function
Islets of Langerhans
03 medical and health sciences
0302 clinical medicine
Gastric inhibitory polypeptide
Glucagon-Like Peptide 1
Insulin-Secreting Cells
Internal medicine
Insulin Secretion
Genetics
Internal Medicine
medicine
Humans
Insulin
Osteopontin
Alleles
GIPR
030304 developmental biology
0303 health sciences
geography
GIP
geography.geographical_feature_category
medicine.disease
Islet
Glucagon-like peptide-1
pleiotropic effect of GIP
Endocrinology
Postprandial
Diabetes Mellitus, Type 2
Apoptosis
biology.protein
hormones, hormone substitutes, and hormone antagonists
Genome-Wide Association Study
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Diabetes; Vol 60, Diabetes
- Accession number :
- edsair.doi.dedup.....cdf4910e13f36b924b3c6cfde6bced02