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Calpain-10 and Adiponectin Gene Polymorphisms in Korean Type 2 Diabetes Patients

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Calpain-10 and Adiponectin Gene Polymorphisms in Korean Type 2 Diabetes Patients Original Endocrinol Metab 2018;33:364-371 https://doi.org/10.3803/EnM.2018.33.3.364 Article pISSN 2093-596X · eISSN 2093-5978 Calpain-10 and Adiponectin Gene Polymorphisms in Korean Type 2 Diabetes Patients Ji Sun Nam1,2, Jung Woo Han1, Sang Bae Lee1, Ji Hong You1, Min Jin Kim1, Shinae Kang1,2, Jong Suk Park1,2, Chul Woo Ahn1,2 1Department of Internal Medicine, 2Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul, Korea Background: Genetic variations in calpain-10 and adiponectin gene are known to influence insulin secretion and resistance in type 2 diabetes mellitus. Recently, several single nucleotide polymorphisms (SNPs) in calpain-10 and adiponectin gene have been report- ed to be associated with type 2 diabetes and various metabolic derangements. We investigated the associations between specific cal- pain-10 and adiponectin gene polymorphisms and Korean type 2 diabetes patients. Methods: Overall, 249 type 2 diabetes patients and 131 non-diabetic control subjects were enrolled in this study. All the subjects were genotyped for SNP-43 and -63 of calpain-10 gene and G276T and T45G frequencies of the adiponectin gene. The clinical char- acteristics and measure of glucose metabolism were compared within these genotypes. Results: Among calpain-10 polymorphisms, SNP-63 T/T were more frequent in diabetes patients, and single SNP-63 increases the susceptibility to type 2 diabetes. However, SNP-43 in calpain-10 and T45G and intron G276T in adiponectin gene were not signifi- cantly associated with diabetes, insulin resistance, nor insulin secretion. Conclusion: Variations in calpain-10, SNP-63 seems to increase the susceptibility to type 2 diabetes in Koreans while SNP-43 and adiponectin SNP-45, -276 are not associated with impaired glucose metabolism. Keywords: Calpain 10; Adiponectin; Diabetes mellitus, type 2 INTRODUCTION as the development and progression of type 2 diabetes [3]. CAPN10 is a calcium activated protein expressed ubiquitously There has been a rapid rise in the incidence of type 2 diabetes in human bodies including heart, skeletal muscles, liver, and mellitus (DM) in Korea due to a recent economic development pancreatic islet cells [4]. It contributes to glucose metabolism and industrialization [1]. Insulin resistance (IR) and impaired by regulating insulin secretion from pancreatic β-cells and insu- insulin secretion (IIS) are two main pathogenesis of type 2 dia- lin action at the adipocyte level [4]. Accordingly, it has been re- betes, and they are related to both the environmental and genetic ported that CAPN10 gene is a crucial factor for obesity and dia- factors. However, very few genes have been identified [1,2]. betes, and combinations of single nucleotide polymorphisms Recently, calpain-10 (CAPN10) gene polymorphism has been (SNPs) (such as SNP-44, -43, -19, and -63) predominantly lo- reported to be associated with the IIS and insulin action as well cated in the intron of CAPN10 gene are involved in the develop- Received: 30 November 2017, Revised: 18 May 2018, Accepted: 11 June 2018 Copyright © 2018 Korean Endocrine Society Corresponding author: Chul Woo Ahn This is an Open Access article distributed under the terms of the Creative Com- Division of Endocrinology, Department of Internal Medicine, Gangnam mons Attribution Non-Commercial License (http://creativecommons.org/ Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribu- Gangnam-gu, Seoul 06273, Korea tion, and reproduction in any medium, provided the original work is properly Tel: +82-2-2019-4377, Fax: +82-2-3463-3882, E-mail: [email protected] cited. 364 www.e-enm.org Calpain-10 Polymorphism and Type 2 Diabetes Endocrinol Metab 2018;33:364-371 https://doi.org/10.3803/EnM.2018.33.3.364 pISSN 2093-596X · eISSN 2093-5978 ment of diabetes [5,6]. stolic blood pressures were measured by an experienced techni- Adiponectin is a well-known adipocytokine that is closely re- cian by placing the left arm at heart level after a 5-minute rest. lated to IR, obesity, atherosclerosis, and type 2 diabetes [7]. It is abundantly expressed in white adipocytes and structurally simi- Biochemical parameters lar to collagen VIII and X, complement C1q17-20, and tumor Blood samples were taken from all subjects after an overnight necrosis factor-α (TNF-α) [7]. Adiponectin gene is located in fast. Standard methods were used for biochemistry. Fasting chromosome 3q27 and composed of 3 exons and 2 introns. It plasma glucose, total cholesterol, high density lipoprotein cho- has been reported that SNPs, including a silent T to G substitu- lesterol (HDL-C), and triglycerides (TGs) levels were deter- tion (+45T>G) in exon 2 and a G to T substitution (+276G>T) mined using enzymatic methods with a Hitachi 7600-120 auto- in intron 2, are related to low blood adiponectin concentration, mated chemistry analyzer (Hitachi, Tokyo, Japan). Low density IR, and type 2 diabetes [8,9]. lipoprotein cholesterol (LDL-C) was calculated according to the There are several studies that demonstrated the association Friedewald formula. Hemoglobin A1c (HbA1c) was determined between genetic variations in the genes coding adiponectin and by high performance liquid chromatography (Variant II, Bio- IR, metabolic syndrome as well as the risk of type 2 diabetes in Rad, Hercules, CA, USA). Fasting serum insulin was deter- Korean population [10,11]. However, not much is known about mined by chemiluminescence (RIA kit, Daiichi, Tokyo, Japan), the CAPN10 genetic polymorphism and metabolic derange- and IR was calculated using the homeostasis model assessment ments in Koreans. Therefore, the present study explored the as- of insulin resistance (HOMA-IR) index, using following formu- sociations between CAPN10 and adiponectin gene polymor- la: HOMA-IR=glucose (mmol/L)×insulin (μU/mL)/22.5. In- phism and various components of metabolic syndrome, IR and sulin secretion capacity was calculated using homeostasis model secretion, and the incidence of type 2 diabetes in Korean popu- assessment of β-cell function (HOMA-β) index using the fol- lation. lowing formula: HOMA-β=20×insulin (μU/mL)/[glucose (mmol/L)–3.5]. METHODS Genotyping of polymorphisms in CAPN10 and adiponectin Subjects gene This study was conducted on 249 Korean type 2 diabetes pa- CAP10 gene polymorphism tients at Diabetes Center of Gangnam Severance Hospital, Ko- Genomic DNA was isolated from 5 mL of whole blood collect- rea from January 2006 to June 2007. Previously diagnosed dia- ed in ethylenediaminetetraacetic acid (EDTA) tubes. The geno- betes patients based on self-reported responses and newly diag- type of all patients was classified depending on two CAPN10 nosed diabetes patients according to American Diabetes Associ- gene polymorphisms (SNP-43, -63), which were analyzed using ation criteria were all included. Type 1 diabetes patients and TaqMan (TaqMan fluorogenic 5´ nuclease assay; Applied Bio- those who received insulin therapy within 3 years after the diag- systems, Waltham, MA, USA) and SNaPshot method respec- nosis of type 2 diabetes were excluded. The control group was tively. Polymerase chain reaction (PCR) reaction solution was composed of 131 non-diabetic patients from Gangnam Sever- adjusted to a final volume of 5 µL containing 10 ng of template ance Check-up Center. The Institutional Review Board (3-2006- DNA, 0.13 µL of 40X assay mix (Assay ID C_27483762_10), 0005) of Yonsei University College of Medicine approved this and 2.5 µL of TaqMan Universal PCR master mix. Real-time study protocol, and written informed consent was obtained from PCR was performed in two stages using ABI Prism 7900HT all subjects. Fast Real-Time PCR System (Applied Biosystems, Waltham, MA, USA), thus 45 cycles of PCR were done at 95°C for 15 Anthropometric measurements seconds and at 60°C for 1 minute after an initial denaturation at Body weight and height were measured in the morning, with 95°C for 10 minutes. PCR analysis was performed using 7900HT light clothing without shoes, and body mass index (BMI) was SDS 2.3 software (Applied Biosystems). Meanwhile, SNaPshot calculated by dividing the weight (kg) by the square of the assay was employed to analyze SNP-63, and the SNP site was am- height (m2). Waist circumference was measure at the midway plified using 5´-AGCACCCAGTCCTACCAGTG-3´ (Forward) between the lower margin of the last palpable rib and the top of and 5´-CTGGCTGGAGTTTGGAGAAG-3´ (Reverse). PCR the iliac crest at the end of a normal expiration. Systolic and dia- contained solution was prepared containing 10 ng of 0.5 pM Copyright © 2018 Korean Endocrine Society www.e-enm.org 365 Nam JS, et al. template DNA, 0.5 pM forward/reverse primer, 1l of 10X PCR spectively measured in a diversity of models such as codomi- Gold buffer, 250 µM dNTP, 3 mM MgCl2, and 0.25 unit of nant, additive, dominant, and recessive model. These measure- DNA polymerase, and we added distilled water to make a final ments were adjusted for age, sex, and BMI value. All statistical volume of 10 µL. The solution was incubated at 7°C for 7 min- analyses were conducted using SAS version 9.1 (SAS Institute utes. PCR was carried out with one cycle of 95°C for 10 min- Inc., Cary, NC, USA). utes, and 30 cycles of 95°C for 30 seconds, 60°C for 1 minute, and 72°C for 1 minute. We added 1 µL of purified PCR products RESULTS to SNaPshot Ready Reaction mixture containing 0.15 pmol ge- notyping primer (5´-ASAGACGCGGCCCACCCCTC-3´) for Clinical characteristics of study subjects primer extension reaction, which was conducted in three stages The genetic polymorphisms were evaluated in 249 patients with with 25 cycles of 96°C for 10 seconds, 50°C for 5 seconds, and type 2 diabetes and 131 control subjects.
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