Elsevier

Metabolism

Volume 62, Issue 5, May 2013, Pages 638-641
Metabolism

Brief Report
The R230C variant of the ATP binding cassette protein A1 (ABCA1) gene is associated with a decreased response to glyburide therapy in patients with type 2 diabetes mellitus

https://doi.org/10.1016/j.metabol.2012.11.006Get rights and content

Abstract

Objective

To test the hypothesis that persons with the R230C allele of ABCA1 show a decreased glycemic response to glyburide. This polymorphism is exclusively found in Ameri-indian populations and is associated with type 2 diabetes.

Research design and methods

This is a single blind controlled study including participants with type 2 diabetes (fasting glucose levels 126-250 mg/dl and HbA1c 7%–10%) managed with metformin and a lifestyle program. Each person with the risk allele (R230C) was matched by age, gender and BMI to three others with the wild type variant (R230R). Following a four week stabilization period, only participants with a greater than 70% adherence to metformin and a stable body weight were prescribed glyburide therapy for a further 16 weeks. The main outcome variable was the glyburide dose required to achieve treatment goals.

Results

No significant difference was observed in the glucose lowering effect of glyburide between subjects with the R230C and R230R alleles. However, the dose of sulfonylurea was significantly higher in the R230C participants compared with the R230R subjects (3.3 ± 2.1 vs 6.3 ± 5 mg/day, p < 0.001). A higher percentage of R230C participants required at least 5 mg of glyburide per day to achieve treatment goals. The glyburide dose was determined by the presence of the risk allele, among other factors.

Conclusions

Patients with type 2 diabetes who have the R230C allele of ABCA1 needed a higher dose of glyburide in order to achieve the same glucose lowering effect as that in persons with the wild type variant.

Introduction

The ABCA1 transporter transfers cholesterol from the cell membrane to plasma apolipoprotein A-I. This action constitutes the initial step in the synthesis of high-density lipoproteins [1]. There are over 20 known ABCA1 polymorphisms [2]. One such variant, the R230C allele (rs9282541) is common in the Mexican population; a population-based survey, reported a prevalence of 18.7% among participants [3], [4]. The magnitude of the effect of the C230 variant (− 5.73 ± 1.4 mg/dl) on the concentration of HDL-C is greater than that observed with other polymorphisms (usually less than 2 mg/dl). In addition, two cross-sectional studies have shown that the R230C variant of ABC-A1 is associated with type 2 diabetes. This transporter appears to play a role in the regulation of insulin secretion [5], [6]. A beta cell specific abc-a1 knockout mouse has impaired glucose tolerance due to decreased insulin secretion [7]. The lack of β-cell ABCA1 results in impaired depolarization-induced exocytotic fusion of insulin granules, disturbances in membrane microdomain organization and abnormal Golgi and insulin granule morphology [8], [9]. Furthermore, impaired insulin secretion has been reported in persons with ABCA1 loss-of-function mutations [10].

Sulfonylureas stimulate insulin secretion from pancreatic beta cells, and are among the first line treatments of hyperglycemia. The response to these drugs shows inter-individual variability but little is known regarding sulfonylurea pharmacogenomics; variants of ABCC8, KCNJ11, IRS1, TCF7L2, and NOS1AP have been associated with changes in the sulfonylurea response [11].

In this report, our hypothesis is that persons with type 2 diabetes who have the R230C variant of ABCA1 may have a decreased hypoglycemic response to a sulfonylurea, compared to participants with the wild type variant (R230R).

Section snippets

Materials and methods

This was a single blind controlled study in which the hypoglycemic response to glyburide is compared between two groups of persons with type 2 diabetes during a 16 week treatment period. One group had the R230C variant of ABC-A1 and the other had the R230R variant. Both groups were matched for gender, age (± 5 years) and BMI (± 2 kg/m2). Each person with the risk allele was matched to three others with the wild type variant. Participants were Mexican mestizos aged 20–79 years, with a BMI between 18

Results

Our study sample included 17 individuals with the R230C variant and 68 subjects with the R230R variant. Both groups were successfully matched by age, gender and body mass index (Table 1). One subject in the R230R group died unexpectedly; the cause of death was unrelated to the study intervention. No further subjects were lost during the study. No severe hypoglycemic events were reported. Adherence to therapy was above 70% in all participants regardless of allelic variant.

After 16 weeks of

Discussion

Our data show that persons with type 2 diabetes who have the ABCA1 R230C polymorphism require a higher glyburide dose to achieve similar glucose lowering as matched subjects with the wild type variant. This observation suggests that ABCA1 is involved in the pharmacogenomics of type 2 diabetes. The R230C allele was independently associated with the glyburide dosage, even after adjusting for FPG, BMI and adherence to therapy.

ABC-A1 plays an important role in the regulation of insulin secretion in

Author contributions

C.A.A-S designed the study and wrote the manuscript. L.L.M-H researched data and contributed to the discussion. MC-B, M.R.R-M and M.L.O-S researched data. R.M. reviewed/edited the manuscript. R.M-S.and M.T.T-L. contributed to the discussion and reviewed/edited the manuscript. No conflict of interest is declared by the authors.

Funding

The study was conducted with support provided by Department of Research and Postgraduate Studies, Escuela Superior de Medicina, Instituto Politecnico Nacional, Mexico City, Mexico.

Conflict of interest

None of the authors have a financial interest related to this work.

Acknowledgments

We express our gratitude to the personnel of the Endocrinology and Metabolism department who provided technical and logistic support. We also express our gratitude to our patients.

References (17)

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    In contrast, decreased ABCA1 expression results in the impairment in cholesterol efflux and aggravates cholesterol accumulation in the liver, thereby exacerbating NAFLD [116,117]. In addition, ABCA1 mutations or its variants have been reported be closely associated with NAFLD-related risk factors, such as type 2 diabetes, obesity, and metabolic syndrome [118–121]. Consequently, these studies indicate that ABCA1-mediated cholesterol efflux may contribute to a decrease in lipid storage in hepatocytes although more data are required to establish its exact role in NAFLD.

  • ABCA1 genetic polymorphisms and type 2 diabetes mellitus and its complications

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    ABCA1 is a determinant of HDL levels. The rs9282541 is reported to be associated with susceptibility to T2DM (Villarreal-Molina et al., 2008; Aguilar-Salinas et al., 2013) or HDL levels in the patients from Mexico (Aguilar-Salinas et al., 2004; Lara-Riegos et al., 2004), but this variant was ineffective in subjects from Colombia (Campbell et al., 2012), Malaysia (Haghvirdizadeh et al., 2015) or other study from Mexico (Miranda-Lora et al., 2017) (Table 4). The CT carriers from Mexico were more susceptible to early onset of T2DM (Villarreal-Molina et al., 2008).

  • Novel Association of the R230C Variant of the ABCA1 Gene with High Triglyceride Levels and Low High-density Lipoprotein Cholesterol Levels in Mexican School-age Children with High Prevalence of Obesity

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    This finding may be related with our result because there are different body distribution between children and adults; nonetheless, additional studies are necessary. Although some reports have shown a tendency of higher triglycerides in those subjects with the risk variant genotype in a dominant model (R230C/C230C), their results failed to reach statistical significance (7,8,31,32). For this reason, more studies are needed with larger sample sizes to validate this finding.

  • ATP-binding cassette transporter A1: From metabolism to neurodegeneration

    2014, Neurobiology of Disease
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    A highly frequent non-synonymous variant of ABCA1 (R230C) was identified in a Mexican population and shown to associate with obesity and type 2 diabetes (Villarreal-Molina et al., 2008). Also in a Mexican population it was reported that diabetic patients harboring this mutation needed a higher dose of glyburide to control glucose level (Aguilar-Salinas et al., 2013). However, a recent study examining several genetic variants in ABCA1 and ABCG1 did not find an association with an increased risk of type 2 diabetes (Schou et al., 2012).

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The study is registered in ClinicalTrials.gov (NCT01456650).

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