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Candidate genes associated with the effect of rosiglitazone on glycemic control and cardiovascular system in the treatment of type 2 diabetes mellitus.

ABSTRACT: In the present study, candidate genes affected by rosiglitazone to exert glycemic control in the treatment of type 2 diabetes mellitus (T2DM) and associated with its adverse cardiovascular effects were identified using a bioinformatics analysis. The gene expression profiles of the dataset GSE36875 from the Gene Expression Omnibus database, including heart samples from 5 non-diabetic control mice (NC), 5 untreated diabetic mice (NH) and 5 rosiglitazone-treated diabetic mice (TH), were used to identify differentially expressed genes (DEGs) in the NC vs. NH, NC vs. TH and TH vs. NH groups. Subsequently, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriched by the DEGs were determined. Furthermore, genes associated with the action of rosiglitazone were identified using Short Time-series Expression Miner, which were then subjected to enrichment analysis in gene ontology (GO) terms in the category biological process (BP), and networks of the GO terms, KEGG pathways and genes associated with the action of rosiglitazone were constructed. Finally, biological abnormalities associated with these genes were identified using WebGestalt. A set of 791 DEGs in three groups (NC vs. NH, NC vs. TH and NH vs. TH) were identified. Subsequently, 72 DEGs [e.g., apolipoprotein (Apo)A1, ApoA5, cytochrome P450 (Cyp)2c37, Cyp2J5, Cyp2b9 and Cyp2b10] were identified as genes associated with the action of rosiglitazone. In addition, a network of 13 GO terms in the category BP, 6 KEGG pathways and 41 genes associated with the action of rosiglitazone was constructed, with major terms/pathways including oxidation/reduction, lipid transport, peroxisome proliferator-activated receptor signaling pathway and metabolism of xenobiotics by Cyp. Finally, 15 biological abnormalities (including abnormal triglyceride levels, abnormal cholesterol homeostasis, abnormal lipid homeostasis) associated with these genes were identified. ApoA1, ApoA5, Cyp2c37, Cyp2J5, Cyp2b9 and Cyp2b10 were differently expressed after rosiglitazone treatment, which may be accountable for affecting cardiovascular outcomes and glycemic control in T2DM. The present results may expand the current understanding of the mechanism of action of rosiglitazone to exert glycemic control in T2DM, as well as its effects on the cardiovascular system.

SUBMITTER: Wu X

PROVIDER: S-EPMC6364243 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Candidate genes associated with the effect of rosiglitazone on glycemic control and cardiovascular system in the treatment of type 2 diabetes mellitus.

Wu Xiaoli X

Experimental and therapeutic medicine 20190109 3

In the present study, candidate genes affected by rosiglitazone to exert glycemic control in the treatment of type 2 diabetes mellitus (T2DM) and associated with its adverse cardiovascular effects were identified using a bioinformatics analysis. The gene expression profiles of the dataset GSE36875 from the Gene Expression Omnibus database, including heart samples from 5 non-diabetic control mice (NC), 5 untreated diabetic mice (NH) and 5 rosiglitazone-treated diabetic mice (TH), were used to ide ...[more]

PMID: 30783475

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Project description:BACKGROUND:Poor glycemic control is associated with increased risk of cardiovascular disease (CVD) in type 1 diabetes mellitus (T1DM); however, little is known about mechanisms specific to T1DM. In T1DM, myocardial injury can induce persistent cardiac autoimmunity. Chronic hyperglycemia causes myocardial injury, raising the possibility that hyperglycemia-induced cardiac autoimmunity could contribute to long-term CVD complications in T1DM. METHODS:We measured the prevalence and profiles of cardiac autoantibodies (AAbs) in longitudinal samples from the DCCT (Diabetes Control and Complications Trial) in participants with mean hemoglobin A1c (HbA1c) ?9.0% (n=83) and ?7.0% (n=83) during DCCT. We assessed subsequent coronary artery calcification (measured once during years 7-9 in the post-DCCT EDIC [Epidemiology of Diabetes Interventions and Complications] observational study), high-sensitivity C-reactive protein (measured during EDIC years 4-6), and CVD events (defined as nonfatal myocardial infarction, stroke, death resulting from CVD, heart failure, or coronary artery bypass graft) over a 26-year median follow-up. Cardiac AAbs were also measured in matched patients with type 2 diabetes mellitus with HbA1c ?9.0% (n=70) and ?7.0% (n=140) and, as a control for cardiac autoimmunity, patients with Chagas cardiomyopathy (n=51). RESULTS:Apart from HbA1c levels, the DCCT groups shared similar CVD risk factors at the beginning and end of DCCT. The DCCT HbA1c ?9.0% group showed markedly higher cardiac AAb levels than the HbA1c ?7.0% group during DCCT, with a progressive increase and decrease in AAb levels over time in the 2 groups, respectively ( P<0.001). In the HbA1c ?9.0% group, 46%, 22%, and 11% tested positive for ?1, ?2, and ?3 different cardiac AAb types, respectively, similar to patients with Chagas cardiomyopathy, compared with 2%, 1%, and 0% in the HbA1c ?7.0% group. Glycemic control was not associated with AAb prevalence in type 2 diabetes mellitus. Positivity for ?2 AAbs during DCCT was associated with increased risk of CVD events (4 of 6; hazard ratio, 16.1; 95% CI, 3.0-88.2) and, in multivariable analyses, with detectable coronary artery calcification (13 of 31; odds ratio, 60.1; 95% CI, 8.4-410.0). Patients with ?2 AAbs subsequently also showed elevated high-sensitivity C-reactive protein levels (6.0 mg/L versus 1.4 mg/L in patients with ?1 AAbs; P=0.003). CONCLUSIONS:Poor glycemic control is associated with cardiac autoimmunity in T1DM. Furthermore, cardiac AAb positivity is associated with an increased risk of CVD decades later, suggesting a role for autoimmune mechanisms in the development of CVD in T1DM, possibly through inflammatory pathways.

Project description:ImportanceIn older adults with multiple serious comorbidities and functional limitations, the harms of intensive glycemic control likely exceed the benefits.ObjectivesTo examine glycemic control levels among older adults with diabetes mellitus by health status and to estimate the prevalence of potential overtreatment of diabetes.Design, setting, and participantsCross-sectional analysis of the data on 1288 older adults (≥65 years) with diabetes from the National Health and Nutrition Examination Survey (NHANES) from 2001 through 2010 who had a hemoglobin A1c (HbA1c) measurement. All analyses incorporated complex survey design to produce nationally representative estimates.ExposuresHealth status categories: very complex/poor, based on difficulty with 2 or more activities of daily living or dialysis dependence; complex/intermediate, based on difficulty with 2 or more instrumental activities of daily living or presence of 3 or more chronic conditions; and relatively healthy if none of these were present.Main outcomes and measuresTight glycemic control (HbA1c level, <7%) and use of diabetes medications likely to result in hypoglycemia (insulin or sulfonylureas).ResultsOf 1288 older adults with diabetes, 50.7% (95% CI, 46.6%-54.8%), representing 3.1 million (95% CI, 2.7-3.5), were relatively healthy, 28.1% (95% CI, 24.8%-31.5%), representing 1.7 million (95% CI, 1.4-2.0), had complex/intermediate health, and 21.2% (95% CI, 18.3%-24.4%), representing 1.3 million (95% CI, 1.1-1.5), had very complex/poor health. Overall, 61.5% (95% CI, 57.5%-65.3%), representing 3.8 million (95% CI, 3.4-4.2), had an HbA1c level of less than 7%; this proportion did not differ across health status categories (62.8% [95% CI, 56.9%-68.3%]) were relatively healthy, 63.0% (95% CI, 57.0%-68.6%) had complex/intermediate health, and 56.4% (95% CI, 49.7%-62.9%) had very complex/poor health (P = .26). Of the older adults with an HbA1c level of less than 7%, 54.9% (95% CI, 50.4%-59.3%) were treated with either insulin or sulfonylureas; this proportion was similar across health status categories (50.8% [95% CI, 45.1%-56.5%] were relatively healthy, 58.7% [95% CI, 49.4%-67.5%] had complex/intermediate health, and 60.0% [95% CI, 51.4%-68.1%] had very complex/poor health; P = .14). During the 10 study years, there were no significant changes in the proportion of older adults with an HbA1c level of less than 7% (P = .34), the proportion with an HbA1c level of less than 7% who had complex/intermediate or very complex/poor health (P = .27), or the proportion with an HbA1c level of less than 7% who were treated with insulin or sulfonylureas despite having complex/intermediate or very complex/poor health (P = .65).Conclusions and relevanceAlthough the harms of intensive treatment likely exceed the benefits for older patients with complex/intermediate or very complex/poor health status, most of these adults reached tight glycemic targets between 2001 and 2010. Most of them were treated with insulin or sulfonylureas, which may lead to severe hypoglycemia. Our findings suggest that a substantial proportion of older adults with diabetes were potentially overtreated.

Dataset Information

Candidate genes associated with the effect of rosiglitazone on glycemic control and cardiovascular system in the treatment of type 2 diabetes mellitus.

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Candidate genes associated with the effect of rosiglitazone on glycemic control and cardiovascular system in the treatment of type 2 diabetes mellitus.

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