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Glucose-dependent insulinotropic polypeptide (GIP) and GIP receptor (GIPR) genes: An association analysis of polymorphisms and bone in young and elderly women.

ABSTRACT: The gastro-intestinal hormone glucose-dependent insulinotropic polypeptide (GIP) potentiates glucose-induced insulin secretion, with bone anabolic effects through GIP receptor (GIPR) in animal models. We explore its potential in humans by analyzing association between polymorphisms (SNPs) in the GIP and GIPR genes with bone phenotypes in young and elderly women.Association between GIP (rs2291725) and GIPR (rs10423928) and BMD, bone mineral content (BMC), bone microarchitecture, fracture and body composition was analyzed in the OPRA (75y, n = 1044) and PEAK-25 (25y; n = 1061) cohorts and serum-GIP in OPRA.The GIP receptor AA-genotype was associated with lower ultrasound values in young women (BUA p = 0.011; SI p = 0.030), with no association to bone phenotypes in the elderly. In the elderly, the GIP was associated with lower ultrasound (GG vs. AA; SOS padj = 0.021) and lower femoral neck BMD and BMC after adjusting for fat mass (padj = 0.016 and padj = 0.03). In young women, neither GIPR nor GIP associated with other bone phenotypes including spine trabecular bone score. In the elderly, neither SNP associated with fracture. GIP was associated with body composition only in Peak-25; GIPR was not associated with body composition in either cohort. Serum-GIP levels (in elderly) were not associated with bone phenotypes, however lower levels were associated with the GIPR A-allele (β = - 6.93; padj = 0.03).This first exploratory association study between polymorphisms in GIP and GIPR in relation to bone phenotypes and serum-GIP in women at different ages indicates a possible, albeit complex link between glucose metabolism genes and bone, while recognizing that further studies are warranted.

SUBMITTER: Garg G

PROVIDER: S-EPMC4926814 | biostudies-other | 2016 Jun

REPOSITORIES: biostudies-other

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Glucose-dependent insulinotropic polypeptide (<i>GIP</i>) and GIP receptor (<i>GIPR</i>) genes: An association analysis of polymorphisms and bone in young and elderly women.

Garg Gaurav G McGuigan Fiona E FE Kumar Jitender J Luthman Holger H Lyssenko Valeriya V Akesson Kristina K

Bone reports 20151217

<h4>Introduction</h4>The gastro-intestinal hormone glucose-dependent insulinotropic polypeptide (GIP) potentiates glucose-induced insulin secretion, with bone anabolic effects through GIP receptor (GIPR) in animal models. We explore its potential in humans by analyzing association between polymorphisms (SNPs) in the <i>GIP</i> and <i>GIPR</i> genes with bone phenotypes in young and elderly women.<h4>Methods</h4>Association between <i>GIP</i> (rs2291725) and <i>GIPR</i> (rs10423928) and BMD, bone ...[more]

PMID: 28326339

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Project description:Context:In healthy individuals, glucose-dependent insulinotropic polypeptide (GIP) enhances insulin secretion and reduces bone resorption by up to 25% estimated by absolute placebo-corrected changes in carboxy-terminal type 1 collagen crosslinks (CTX) during GIP and glucose administration. In patients with type 2 diabetes (T2D), GIP's insulinotropic effect is impaired and effects on bone may be reduced. Objective:To investigate GIP's effect on bone biomarkers in patients with T2D. Design:Randomized, double-blinded, crossover study investigating 6 interventions. Patients:Twelve male patients with T2D. Interventions:A primed continuous 90-minute GIP infusion (2 pmol/kg/min) or matching placebo (saline) administered at 3 plasma glucose (PG) levels (i.e., paired days with "insulin-induced hypoglycemia" (PG lowered to 3 mmol/L), "fasting hyperglycemia" (mean PG ~8 mmol/L), or "aggravated hyperglycemia" (mean PG ~12 mmol/L). Main Outcome Measures:Bone biomarkers: CTX, procollagen type 1 N-terminal propeptide (P1NP) and PTH. Results:On days with insulin-induced hypoglycemia, CTX was suppressed by up to 40?±?15% during GIP administration compared with 12?±?11% during placebo infusion (P?<?0.0001). On days with fasting hyperglycemia, CTX was suppressed by up to 36?±?15% during GIP administration, compared with 0?±?9% during placebo infusion (P?<?0.0001). On days with aggravated hyperglycemia, CTX was suppressed by up to 47?±?23% during GIP administration compared with 10?±?9% during placebo infusion (P?=?0.0005). At all glycemic levels, P1NP and PTH concentrations were similar between paired days after 90 minutes. Conclusions:Short-term GIP infusions reduce bone resorption by more than one-third (estimated by absolute placebo-corrected CTX reductions) in patients with T2DM, suggesting preserved bone effects of GIP in these patients. Précis:Short-term GIP infusions reduce the bone resorption marker CTX by one-third in patients with type 2 diabetes independent of glycemic levels.

Project description:Aims/introductionThe involvement of glucose-dependent insulinotropic polypeptide (GIP) on inflammation was explored in atherosclerosis and adipose tissue. Periodontal disease is a chronic inflammatory disease, and is considered one of the diabetic complications. In the present study, to examine the effect of GIP on periodontitis, we induced experimental periodontitis in glucose-dependent insulinotropic polypeptide receptor-knockout mice (GIPRKO). We also investigated the anti-inflammatory effect of GIP in a culture system.Materials and methodsExperimental periodontitis was induced by ligature wire in GIPRKO and C57BL/C mice. Two weeks after the ligature, immunohistological evaluation and inflammatory messenger ribonucleic acid expression in the gingiva was examined. To elucidate the role of GIP in inflammation, the effects of GIP on lipopolysaccharide-induced gene expressions in THP-1 cells were evaluated.ResultsPeriodontitis increased inflammatory cell infiltration, macrophage accumulation and tumor necrosis factor-? and nitric oxide synthase gene expressions in the gingiva. Periodontitis in GIPRKO showed a marked increase of inflammatory cells in the gingivomucosal tissue. Mac-1-positive macrophages and the inflammatory gene expressions were significantly increased in periodontitis in GIPRKO compared with C57BL/C mice periodontitis. Immunohistochemical staining confirmed that GIP receptors were expressed in residual and infiltrated Mac-1-positive macrophages. The in vitro study showed that GIP suppressed lipopolysaccharide-induced tumor necrosis factor-? and nitric oxide synthase gene expression in a dose-dependent manner. Furthermore, the inhibitory effect of GIP on lipopolysaccharide-induced inflammatory gene expressions was at least partially through cyclic adenosine monophosphate/protein kinase A pathway.ConclusionsThese results suggest the beneficial effects of GIP on periodontal disease. In diabetic patients, GIP is expected to have a direct anti-inflammatory effect on periodontitis in addition to its glucose-lowering effect.

Dataset Information

Glucose-dependent insulinotropic polypeptide (GIP) and GIP receptor (GIPR) genes: An association analysis of polymorphisms and bone in young and elderly women.

Publications

Glucose-dependent insulinotropic polypeptide (<i>GIP</i>) and GIP receptor (<i>GIPR</i>) genes: An association analysis of polymorphisms and bone in young and elderly women.

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