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Gastric inhibitory polypeptide receptor methylation in newly diagnosed, drug-naive patients with type 2 diabetes: a case-control study.

ABSTRACT: GIP action in type 2 diabetic (T2D) patients is altered. We hypothesized that methylation changes could be present in GIP receptor of T2D patients. This study aimed to assess the differences in DNA methylation profile of GIPR promoter between T2D patients and age- and Body Mass Index (BMI)-matched controls. We included 93 T2D patients (cases) that were uniquely on diet (without any anti-diabetic pharmacological treatment). We matched one control (with oral glucose tolerance test negative, non diabetic), by age and BMI, for every case. Cytokines and hormones were determined by ELISA. DNA was extracted from whole blood and DNA methylation was assessed using the Sequenom EpiTYPER system. Our results showed that T2D patients were more insulin resistant and had a poorer ? cell function than their controls. Fasting adiponectin was lower in T2D patients as compared to controls (7.0±3.8 µgr/mL vs. 10.0±4.2 µgr/mL). Levels of IL 12 in serum were almost double in T2D patients (52.8±58.3 pg/mL vs. 29.7±37.4 pg/mL). We found that GIPR promoter was hypomethylated in T2D patients as compared to controls. In addition, HOMA-IR and fasting glucose correlated negatively with mean methylation of GIPR promoter, especially in T2D patients. This case-control study confirms that newly diagnosed, drug-naïve T2D patients are more insulin resistant and have worse ? cell function than age- and BMI-matched controls, which is partly related to changes in the insulin-sensitizing metabolites (adiponectin), in the proinflammatory profile (IL12) and we suggest in the methylation pattern of GIPR. Our study provides novel findings on GIPR promoter methylation profile which may improve our ability to understand type 2 diabetes pathogenesis.

SUBMITTER: Canivell S

PROVIDER: S-EPMC3781044 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Gastric inhibitory polypeptide receptor methylation in newly diagnosed, drug-naïve patients with type 2 diabetes: a case-control study.

Canivell Silvia S Ruano Elena G EG Sisó-Almirall Antoni A Kostov Belchin B González-de Paz Luis L Fernandez-Rebollo Eduardo E Hanzu Felicia F Párrizas Marcelina M Novials Anna A Gomis Ramon R

PloS one 20130923 9

GIP action in type 2 diabetic (T2D) patients is altered. We hypothesized that methylation changes could be present in GIP receptor of T2D patients. This study aimed to assess the differences in DNA methylation profile of GIPR promoter between T2D patients and age- and Body Mass Index (BMI)-matched controls. We included 93 T2D patients (cases) that were uniquely on diet (without any anti-diabetic pharmacological treatment). We matched one control (with oral glucose tolerance test negative, non di ...[more]

PMID: 24086540

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Project description:BackgroundCognitive impairment is a common non-motor symptom in patients with Parkinson's disease (PD). Mild cognitive impairment (MCI) is also prevalent in nondemented PD patients, even in newly diagnosed PD patients. The possible impacts of MCI on brain function activities for PD patients need more investigation, and the potential of emerging technologies for detecting underlying pathophysiology of cognitive signs in PD can be further improved.MethodForty-seven newly diagnosed drug-naïve PD patients (28 PD-MCI patients and 19 PD patients with cognitively unimpaired (PD-CU)) and 28 healthy controls (HCs) underwent resting-state functional MRI. The connectivity patterns of specific networks were investigated through the independent component analysis among PD-MCI, PD-CU and HCs groups.ResultsThe independent component analysis revealed significantly decreased functional connectivity (FC) of the default mode network, visual network and sensorimotor network in the PD-MCI subgroup compared with the HC group. Furthermore, FC of the default mode network was positively correlated with memory scores from the brief visuospatial memory test-revised, and FC of the visual network was positively correlated with visuospatial scores from the clock copying test in the PD-MCI group. In all patients with PD, FC of the sensorimotor network negatively correlated with motor severity scores from the Unified PD Rating Scale (UPDRS) part III. On the other hand, the potential damage was more likely to occur in FC between the sensorimotor network and limbic network, and between the ventral attention network and visual network in all PD patients.ConclusionsNewly diagnosed drug-naïve PD-MCI patients showed characteristic damage of FC within the default mode network, visual network and sensorimotor network, and all PD patients presented impaired FC between the sensorimotor network and limbic network, and FC between the ventral attention network and visual network. These network-wide functional aberrations may underline the pathophysiology of PD.

Project description:BACKGROUND AND PURPOSE: Antagonism of the gastric inhibitory polypeptide (GIP) receptor with daily injection of proline-3 gastric inhibitory polypeptide ((Pro(3))GIP) can reverse or prevent many of the metabolic abnormalities associated with diet-induced obesity-diabetes (diabesity). This study has examined the ability of a novel and longer-acting form of (Pro(3))GIP, (Pro(3))GIP mini-polyethylene glycol ((Pro(3))GIP[mPEG]), to counter diet-induced diabesity in mice, using a daily and intermittent dosing regime. EXPERIMENTAL APPROACH: We studied the actions of (Pro(3))GIP[mPEG] at the GIP receptor in vitro and in vivo in both dietary and genetic diabesity. KEY RESULTS: (Pro(3))GIP[mPEG] was completely resistant to degradation by dipeptidyl peptidase IV. (Pro(3))GIP[mPEG] inhibited GIP-induced cAMP and insulin production in vitro. A greater and prolonged antagonism of GIP-induced glucose-lowering action was followed (Pro(3))GIP[mPEG] administration, compared with (Pro(3))GIP. In contrast with (Pro(3))GIP, mice injected once every 3 days for 48 days with (Pro(3))GIP[mPEG] displayed reduced body weight gain and hyperinsulinemia with improved glucose tolerance and insulin secretory responses, compared with high-fat-fed controls. Daily i.p. injection of (Pro(3))GIP, (Pro(3))GIP[mPEG] or (Pro(3))GIP b.i.d. for 21 days also decreased body weight, circulating plasma insulin levels and improved glucose tolerance, compared with high-fat controls. Plasma triglycerides were decreased by (Pro(3))GIP[mPEG] and (Pro(3))GIP b.i.d. treatment groups. The observed changes were accompanied by enhancement of insulin sensitivity in all treatment regimes. (Pro(3))GIP[mPEG] was also effective over 16 days treatment of genetically obese-diabetic ob/ob mice. CONCLUSIONS AND IMPLICATIONS: These data demonstrate the utility of GIP receptor antagonism for the treatment of diabesity and the potential offered by (Pro(3))GIP[mPEG] as a long-acting stable GIP receptor antagonist.

Dataset Information

Gastric inhibitory polypeptide receptor methylation in newly diagnosed, drug-naive patients with type 2 diabetes: a case-control study.

Publications

Gastric inhibitory polypeptide receptor methylation in newly diagnosed, drug-naïve patients with type 2 diabetes: a case-control study.

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