Calpain-10 Research Articles

THE LACK OF CORRELATION IN TYPE 2 DIABETES MELLITUS BETWEEN NON-CPG METHYLATION AND DIABETES RISK FACTORS, LIPID PROFILE, KIDNEY FUNCTION TEST, HBA1C, AND RANDOM BLOOD SUGAR

Background: Chronic hyperglycemia and insulin resistance are two hallmarks of type 2 diabetes mellitus (T2DM), a complicated metabolic disease. The purpose of the current investigation was to identify Non-CPG methylation in the ABCC8 and CAPN10 promoter regions. Method: Fifty people were divided into two groups: thirty-five were diagnosed with type 2 diabetes mellitus, and fifteen were control group. Utilizing direct bisulfite sequencing to identify Non-CPG methylation in the promoter region and determine the extent of DNA methylation. To ascertain whether a result was statistically significant at the level of significance 0.05, the T-independent test, Spearman's correlation, and Chi square tests were performed. Results: Hypermethylation of DNA has been found in the diabetes promoter region of the CAPN10 and ABCC8 genes compared to the healthy group. Furthermore, Non-CPG methylation in both genes and the statistically significant CAPN10 gene has not been linked to risk factors or biochemical indicators. Conclusion: This study concluded that the biochemical biomarkers and risk factors did not influence Non-CPG methylation of selected genes in type 2 diabetes mellitus

Whole Exome Sequencing Revealed Paternal Inheritance of Obesity-related Genetic Variants in a Family with an Exclusively Breastfed Infant.

Obesity is a serious health problem, that progressively affects individuals' lives with comorbidities involving heart disease, stroke, and diabetes mellitus. Since its prevalence increases particularly in children under age-of-five years, its genetic and environmental causes should be determined for prevention and control of the disease. This study aimed to detect underlying genetic risk factors in a family with an exclusively breastfed obese infant. A three-generation family was recruited to be evaluated for obesity. Detailed examinations along with body mass indexcalculations were performed on available family members. Whole exome sequencing was performed on 7-month-oldobese infant utilizing Illumina-NextSeq550. Bioinformatic analyses were performed on the Genomize SEQ platform with variant filtering at minor allele frequencies (MAF)<1% for all normal populations. Sanger sequencing was applied in variant confirmation and family segregation. Neuro-motor developmental features were normal and genetic syndromes were excluded from the index. Early-onset severe obesity (4.25SDS weight-for-height) was obvious in index case, where his father and grandmother were also obese (BMIs: 38.1kg/m2 and 31.3kg/m2, respectively). WES analysis revealed deleterious variants in SH2B1, PDE11A, ADCY3, and CAPN10 genes previously associated with obesity. All variants were evaluated as novel candidates for obesity except PDE11A and family segregation confirmed paternal inheritance. This study confirmed the paternal inheritance of all potentially deleterious obesity-related variants. The cumulative effect of individual variants might explain the obesity phenotype in this family. The infant is recommended to be under periodic follow-up due to increased risk for later childhood obesity.

Meta-Analysis of Association of SNP 19 In-del Polymorphism at the CAPN 10 Gene with Type2 Diabetes Mellitus

The CAPN 10 gene encoding the larger subunit of the ubiquitously expressing calpain protein has been found to play a role in the incidence of Type2 diabetes mellitus (T2DM). Several intronic polymorphisms of the CAPN10 gene and the linked haplotypic combinations have been implicated in T2DM. The SNP 19 locus of the gene lying within intron 6 exhibits an in-del polymorphism and has been found to be associated with T2DM in several studies. However, the results have not been constant. Keeping this in view, the present work was carried out to understand the association of the intronic SNP 19 in-del polymorphism at the CAPN 10 gene with T2DM through meta-analysis of the case-control studies. All statistical tests based on PRISMA and PROSPERO were performed on R studio (4.2.3). However, the pooled odds ratio (OR) estimates did not reveal any significant association between polymorphism at the SNP 19 locus of CAPN 10 gene and T2DM. Therefore, it is concluded that polymorphism at the SNP19 locus of CAPN 10 gene alone has no role to play in the etiology of T2DM.

Correlation between TCF7L2 and CAPN10 gene polymorphisms and gestational diabetes mellitus in different geographical regions: a meta-analysis

BackgroundThe association between TCF7L2 and CAPN10 gene polymorphisms and gestational diabetes mellitus (GDM) has been explored in diverse populations across different geographical regions. Yet, most of these studies have been confined to a limited number of loci, resulting in inconsistent findings. In this study, we conducted a comprehensive review of published literature to identify studies examining the relationship between TCF7L2 and CAPN10 gene polymorphisms and the incidence of GDM in various populations. We specifically focused on five loci that were extensively reported in a large number of publications and performed a meta-analysis.MethodsWe prioritized the selection of SNPs with well-documented correlations established in existing literature on GDM. We searched eight Chinese and English databases: Cochrane, Elton B. Stephens. Company (EBSCO), Embase, Scopus, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang, and China Science and Technology Journal Database and retrieved all relevant articles published between the inception of the database and July 2022. The Newcastle Ottawa Scale (NOS) was used to evaluate the selected articles, and the odds ratio (OR) was used as the combined effect size index to determine the association between genotypes, alleles, and GDM using different genetic models. Heterogeneity between the studies was quantified and the I2 value calculated. Due to large heterogeneities between different ethnic groups, subgroup analysis was used to explore the correlation between genetic polymorphisms and the incidence of GDM in the different populations. The stability of the results was assessed using sensitivity analysis. Begg’s and Egger’s tests were used to assess publication bias.ResultsA total of 39 articles reporting data on 8,795 cases and 16,290 controls were included in the analysis. The frequency of the rs7901695 genotype was statistically significant between cases and controls in the European population (OR = 0.72, 95% CI: 0.65–0.86) and the American population (OR = 0.61, 95% CI: 0.48–0.77). The frequencies of rs12255372, rs7901695, rs290487, and rs2975760 alleles were also considerably different between the cases and controls in the populations analyzed.Conclusionsrs7903146, rs12255372, rs7901695, rs290487, and rs2975760 were associated with the incidence of GDM in different populations.

Molecular role of non-exonic variants in CALPAIN 10 gene in polycystic ovarian syndrome in Saudi women.

Non-diabetic women with polycystic ovarian syndrome (PCOS) often have abnormal insulin regulation. Calpain 10 (CALP10) is a biomarker of type 2 diabetes mellitus, with some of its single-nucleotide polymorphisms (SNPs) influencing PCOS development. In this case-control study on 90 women each with and without PCOS, we explored the molecular role of five CALP10 SNPs using biochemical parameters and Sanger sequencing analyses. Different genetic models, genotypes, and allele frequencies were significantly associated with UCSNP-19 (rs3842570; p=0.01), UCSNP-44 (rs2975760; p=0.009), UCSNP-56 (rs2975762; p<0.0001), and UCSNP-63 (rs5030952; p=0.0003) in women with PCOS. The multiple logistic regression model showed a strong association of CALP10 SNPs with fasting blood glucose (p<0.001). ANOVA showed significant associations with various biochemical parameters such as FSH (p=0.0001) in UCSNP-19 (rs3842570), FI (p=0.002), TG (p=0.01) in UCSNP-56 (rs2975762) and FBG (p=0.001), FI (p=0.004), FSH (p=0.02) & LDLc (p=0.04) in UCSNP-63 (rs5030952) SNPs. Haplotype analysis also revealed significant associations between different combinations of alleles in the studied 5 SNPs in women with PCOS (p<0.05). Generalized multifactor dimensionality reduction analysis showed the best gene-gene interactions among the five SNPs in CALP10I (p<0.05). However, dendrogram and graphical depletion models found no strong association in women with PCOS. In conclusion, this study confirms rs3842570, rs2975760, rs2975767, and rs5030952 SNPs in CALP10 gene is associated in diagnosed PCOS women in the Saudi Arabia.

Association of CAPN10 gene (rs3842570) polymorphism with the type 2 diabetes mellitus among the population of Noakhali region in Bangladesh: a case-control study.

Type 2 diabetes mellitus (T2DM) is a multifactorial, polygenic, and metabolically complicated disease. A large number of genes are responsible for the biogenesis of T2DM and calpain10 (CAPN10) is one of them. The association of numerous CAPN10 genetic polymorphisms in the development of T2DM has been widely studied in different populations and noticed inconclusive results. The present study is an attempt to evaluate the plausible association of CAPN10 polymorphism SNP-19 (rs3842570) with T2DM and T2DM-related anthropometric and metabolic traits in the Noakhali region of Bangladesh. This case-control study included 202 T2DM patients and 75 healthy individuals from different places in Noakhali. A significant association (p < 0.05) of SNP-19 with T2DM in co-dominant 2R/3R vs. 3R/3R (odds ratio [OR], 2.7; p=0.0014) and dominant (2R/3R) + (2R/2R) vs. 3R/3R (OR, 2.47; p=0.0011) genetic models was observed. High-risk allele 2R also showed a significant association with T2DM in the allelic model (OR, 1.67; p=0.0109). The genotypic frequency of SNP-19 variants showed consistency with Hardy-Weinberg equilibrium (p > 0.05). Additionally, SNP-19 genetic variants showed potential associations with the anthropometric and metabolic traits of T2DM patients in terms of body mass index, systolic blood pressure, diastolic blood pressure, total cholesterol, and triglycerides. Our approach identifies the 2R/3R genotype of SNP-19 as a significant risk factor for biogenesis of T2DM in the Noakhali population. Furthermore, a large-scale study could be instrumental to correlate this finding in overall Bangladeshi population.

Molecular studies of CAPN-10 gene (rs2975760) and its association with Insulin Resistance in Polycystic Ovarian Syndrome of Iraqi women

Objectives: To explore an association between CAPN10, SNP-44 (rs2975760) with IR condition in women with PCOS.&#x0D; Methods: A study included 120 participants of which 68 women have PCOS subdivide according to their body mass index (BMI) into 45 obese (BMI≥30) and 23 non-obese (BMI&lt;30). The remaining 52 represent the control group who were apparently healthy women with normal weight and normal menstrual cycle. Patients with PCOS were selected from the Infertility Department, Gynecology and Obstetrics Teaching Hospital, Kerbala Health Directorate / Kerbala-Iraq between Nov., 2021 and June, 2022. Diagnosis of PCOS is based on 2 of 3 findings: oligo/anovulation, hyperandrogenism, polycystic ovaries in ultrasound (Rotterdam criteria). Patients were interviewed and examined for weight, height, waist circumference, and hip circumference. Venous blood samples were collected at 9 AM after an overnight fast. IR was assessed by calculating homeostatic model assessment of insulin resistance (HOMA-IR) using the formula (fasting glucose mg/dl x fasting insulin µU/ml)/405, taking normal value &lt;2.7. Genotypes of CAPN10, SNP-44 has been identified using Allele-specific polymerase chain reaction (AS-PCR) technique.&#x0D; Results: The prevalence of IR based on HOMA-IR was (80%) in obese PCOS and (48%) in non-obese PCOS women. CAPN10, SNP-44 has been reconstructed and analyzed in patients and controls. Genotypes of 45 obese PCOS subjects (TT, N=26; TC, N=12; and CC, N=7), 23 non-obese PCOS subjects (TT, N=15; TC, N=6; and CC, N=2) and control subjects (TT, N=39; TC, N=11; and CC, N=2) were identified. The genotype distribution was statistically different between obese PCOS women and controls (OR=5.25, P=0.048). The association of SNP-44 allele with IR status was detected. HOMA-IR was greater in CC (10.54 ± 1.29, 9.88 ± 1.41) than in TT (3.30 ± 1.52, P&lt;0.001; 2.82 ± 1.45, P&lt;0.001) and TC (3.76 ± 1.58, P&lt;0.001; 4.10 ±1.57, P&lt;0.05) in obese PCOS and non-obese PCOS subjects respectively.&#x0D; Conclusion: In obese PCOS, the C allele was associated with higher insulin secretion and HOMA-IR compared with the T allele. The increased HOMA-IR is an indicator of IR. In this scenario, the C allele might be involved in the pathophysiology of insulin resistance in PCOS.

Differential gene expression analysis for osteosarcoma lung metastases.

To explore the exact molecular mechanisms underline osteosarcoma (OS) patients with lung metastases. The differentially expressed gene (DEG) as well as differentially expressed miRNAs (DEMs) for OS lung metastases were deeply investigated with two independent sources of databases (GEO dataset and clinical participants); The enriched biological processes and signaling pathways were explored; the miRNAs-mRNAs network was constructed; the functions of potential DEGs and DEMs were also verified with external analysis. The OS patients with lung metastases displayed 323 DEGs as C-C motif chemokine ligand 3 (CCL3), sorting nexin 10 (SNX10), alpha-2-macroglobulin (A2M), carboxypeptidase E (CPE), Rap guanine nucleotide exchange factor 4 (RAPGEF4), PDZ domain containing 2 (PDZD2), calpain 10 (CAPN10), four and a half LIM domains 2 (FHL2), alkaline phosphatase, biomineralization associated (ALPL), interleukin 6 (IL6), solute carrier family 26 member 1 (SLC26A1) as well as smoothened, frizzled class receptor (SMO) were significant differentially expressed. At the same time, 21 DEMs were potential for the progress of OS lung metastasis with hsa-miR-638, hsa-miR-451, hsa-miR-486-5p, hsa-miR-134 and hsa-miR-648 were significant distinct. It could been shown that hsa-miR-638 manipulated the largest number of target genes. The functions of hsa-miR-638 and target mRNAs for the development of lung metastasis in OS could be confirmed by quantitative Real-time PCR analysis. This integrated study hypothesized several miRNA dependent signaling pathway for OS patients with lung metastases and initiated a potential strategy for better understanding the lung metastases in clinic.

Association Study between T2DM and CAPN10 SNP-19 (rs3842570) Polymorphism in Navi Mumbai Population

Genetic research has brought a lot of new knowledge in the area of genetic predisposition of type 2 diabetes mellitus (T2DM). It has been proposed that excessive insulin resistance and obesity are also responsible for the higher incidence of type 2 diabetes. Calpain-10 (CAPN10) is a member of a large family of intracellular proteases. The polymorphism at deletion/insertion SNP19 of this gene influences susceptibility to T2DM. The aim of the study was to determine whether calpain-10 (ins/del SNP19) polymorphism contributes significantly to susceptibility to T2DM in population of Navi Mumbai. The study included randomly selected 75 patients of which 33 had T2DM and 42 served as control subjects. Mean waist-to-hip ratio, HDL, LDL, VLDL, cholesterol, and triglyceride showed no difference whereas mean of age, FBS, and body mass index showed significant differences between the control and diabetes subjects. Genotyping of calpain-10 (ins/del SNP19) polymorphism was performed by polymerase chain reaction method. Among 75 participants, for allele-specific SNP19, genotype frequencies of allele1 (2R-32 bp), heterozygous allele (2R-3R 32 bp), and allele 2 (3R-32 bp) were 20 (26.6%), 36 (48%), and 19 (25.3%) observed, respectively. The results from the present study have indicated that CAPN10 (SNP19) shows no significant association with T2DM and more extensive studies on T2DM using candidate gene approach may provide better preventive measures and potential disease diagnostic tools.

Chitosan-Encapsulated Nano-selenium Targeting TCF7L2, PPARγ, and CAPN10 Genes in Diabetic Rats

This study investigates the antidiabetic and antioxidant potential of chitosan-encapsulated selenium nanoparticles in streptozotocin-induced diabetic model. Glibenclamide was used as a reference antidiabetic drug. Forty-eight adult male Wistar rats were used along the study and divided equally into 6 groups of (I) normal control, (II) chitosan-encapsulated selenium nanoparticles (CTS-SeNPs), (III) glibenclamide, (IV) streptozotocin (STZ), (V) STZ + CTS-SeNPs, and (VI) STZ + Glib. The animals were sacrificed on the 35th day of the experiment. Serum glucose, insulin, IGF-1, ALT, AST, CK-MB, oxidative stress, lipid profile, and inflammatory parameters were subsequently assessed. Also, the expression level of TCF7L2, CAPN10, and PPAR-γ genes were evaluated using qPCR. In addition, histopathological studies on pancreatic tissue were carried out. The results revealed that STZ induced both diabetes and oxidative stress in normal rats, manifested by the significant changes in the studied parameters and in the physical structure of pancreatic tissue. Oral administration of CTS-SeNPs or Glib results in a significant amelioration of the levels of serum fasting blood glucose, insulin, IGF-1, AST, ATL, and CK-MB as compared with STZ-induced diabetic rats. CTS-SeNPs and Glib diminished the level of lipid peroxidation, increased total antioxidant capacity level, as well as possessed strong inhibition against serum α-amylase and α-glucosidase activities. Diabetic animals received CTS-SeNPs, or Glib demonstrated a significant (p < 0.05) decrease in the expression level of TCF7L2 and CAPN10 genes with a significant increase in the expression level of PPAR-γ gene, compared to STZ group. The above findings clarify the promising antidiabetic and antioxidant effect of CTS-SeNPs, recommending its inclusion in the currently used protocols for the treatment of diabetes and in the prevention of its related complications.Graphical abstract

Cryptic splicing events result in unexpected protein products from calpain-10 (CAPN10) cDNA

Calpain-10 (CAPN10) belongs to the calpain superfamily. Genetic polymorphisms of the CAPN10 gene are associated with susceptibility to develop type 2 diabetes mellitus. Although the role of CAPN10 in the pathophysiology of diabetes has been extensively investigated, its biochemical properties are largely unknown. In this report, we made the surprising discovery that CAPN10 cDNA transcripts are subject to cryptic splicing and unexpected protein products were expressed. The same set of splicing products was reproducibly detected in four types of cultured cells including the primary culture of mouse myoblast. At least, one of the products was identical to a natural splicing variant. Sequence analysis of the splicing potential of CAPN10 cDNA, together with mutagenesis studies, resulted in the identification of a powerful splicing acceptor site at the junction of the sequences encoded by exons 9 and 10. We successfully extended the analysis to create expression construct resistant to splicing for both human and mouse CAPN10. The construct allowed us to analyze two major CAPN10 isoforms and reveal their difference in substrate proteolysis and potential cell functions.These results demonstrate that proteins produced from cDNA do not necessarily reflect the original nucleotide sequence. We provide insight into the property of recombinantly expressed CAPN10 proteins in cultured cells circumventing unexpected protein products.

SNP-43 polymorphism in CAPN10 gene is associated with Type 2 Diabetes risk in Konya region population

Amaç: Kalpain-10 (CAPN10), Ca+2 bağımlı intrasellüler sistein proteazlar ailesinin atipik bir üyesidir. Birçok dokuda eksprese edilir ve başta insülin sekresyonu ve aktivitesi olmak üzere çok çeşitli hücresel fonksiyonlar için gereklidir. Tanımlanan ilk Tip 2 diyabet (T2D) yatkınlık genidir. Çalışmamızda bir Türk popülasyonunda CAPN10 gen polimorfizmleri (SNP-44, -43 ve -137) ile artmış T2D riski arasındaki ilişkinin analiz edilmesi amaçlandı. Gereç ve Yöntem: Çalışmaya 149 T2D’li hasta ve 48 sağlıklı birey dahil edildi. Genotiplendirme PCR-SSCP tekniği kullanılarak yapıldı, dizi analizi ile doğrulandı. CAPN10 genotiopleri ile T2D gelişimi ve klinik özellikler arasındaki ilişki istatistiksel olarak analiz edildi. Bulgular: Hastalıkla genotip arasındaki ilişkiyi belirlemek için yapılan odds analizi sonuçlarına göre; SNP-44 ile hastalık arasında ilişki gözlenmezken (OR: 1.417 CI:0.452-4.436, P=0.740), SNP-43 ile hastalık arasında anlamlı ilişki bulundu (OR: 0.455 CI:0.235-0.881, P=0.028). SNP-137 genotip dağılımı bakımından tüm hasta ve kontrol bireylerde C/C olarak tespit edildi. Taranan SNP’ler ile klinik parametreler arasında herhangi bir ilişki bulunmadı (P&amp;gt;0.05). Sonuç: Sonuçlarımıza göre; CAPN10 genindeki SNP-43, Türk populasyonunda T2D gelişimi açısından bir risk faktörüdür.

ADCY5, CAPN10 and JAZF1 Gene Polymorphisms and Placental Expression in Women with Gestational Diabetes

Gestational diabetes mellitus (GDM) is carbohydrate intolerance that occurs during pregnancy. This disease may lead to various maternal and neonatal complications; therefore, early diagnosis is very important. Because of the similarity in pathogenesis of type 2 diabetes and GDM, the genetic variants associated with type 2 diabetes are commonly investigated in GDM. The aim of the present study was to examine the associations between the polymorphisms in the ADCY5 (rs11708067, rs2877716), CAPN10 (rs2975760, rs3792267), and JAZF1 (rs864745) genes and GDM as well as to determine the expression of these genes in the placenta. This study included 272 pregnant women with GDM and 348 pregnant women with normal glucose tolerance. The diagnosis of GDM was based on a 75 g oral glucose tolerance test (OGTT) at 24–28 weeks gestation, according to International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. There were no statistically significant differences in the distribution of the ADCY5 gene (rs11708067, rs2877716) and CAPN10 gene (rs2975760, rs3792267) polymorphisms between pregnant women with normal carbohydrate tolerance and pregnant women with GDM. We have shown a lower frequency of JAZF1 gene rs864745 C allele carriers among women with GDM CC + CT vs. TT (OR = 0.60, 95% CI = 0.41–0.87, p = 0.006), and C vs. T (OR = 0.75, 95% CI = 0.60–0.95, p = 0.014). In addition, ADCY5 and JAZF1 gene expression was statistically significantly increased in the placentas of women with GDM compared with that of healthy women. The expression of the CAPN10 gene did not differ significantly between women with and without GDM. Our results indicate increased expression of JAZF1 and ADCY5 genes in the placentas of women with GDM as well as a protective effect of the C allele of the JAZF1 rs864745 gene polymorphism on the development of GDM in pregnant women.

Association of Calpain-10 gene (rs2975760 and rs3792267) Polymorphism with Type 2 Diabetes Mellitus in the Iraqi Population

Background: Type II Diabetes Mellitus (T2DM) can be considered as the main diabetes’ type, which ispresent in all populations worldwide and all regions. Calpain-10 is a part of a vast intracellular proteasefamily. CAPN10 gene polymorphisms have been related to complex types of T2DM.Objective: the major goal of the presented work is evaluating the relation regarding CAPN10 genepolymorphisms (SNP44 rs2975760 and SNP43 rs3792267) with T2DM in the Iraqi population as well aschanges in serum lipid concentration and insulin concentration.Materials and Methods: Two groups of persons were recruited, 300 patients with type2 diabetes mellitus,and 300 healthy control individuals. Fasting serum glucose and serum lipid concentrations have beenevaluated via standard enzymatic approaches, while the concentrations of serum insulin were evaluated viaELISA assay. Genotyping of rs2975760 and rs3792267 SNPs is conducted via PCR-RFLP.Results: Those of the SNP-44 showed that patients of heterozygous genotype (TC) decreased significantlywith respect to the control group. Patients with the homozygous genotype (CC) elevated insignificantlyrelative to the control group. The minor allele C frequency in patients (12%) is decreased considerablyin the patients’ group relative to the group of controls (15%). The genotype results of SNP-43 illustratedthat patients of heterozygous (GA) genotypes decreased significantly with respect to the control group.Patients of the homozygous genotype (AA) appeared to be insignificantly higher than the controls. Theminor allele A frequency in patients (11.5%) is decreased considerably in the patients’ group relative to thegroup of controls (27%). Serum lipid concentrations, insulin, and insulin resistance are distributed in groupsof various genotypes of the 2 SNPs deferentially.Conclusion: SNP-44 and SNP-43 in Iraqi individuals are protective against the development of T2DM.They were implicated in serum lipid changes, insulin and insulin resistance values.

Single Nucleotide Polymorphisms Associated with Metformin and Sulphonylureas' Glycaemic Response among South African Adults with Type 2 Diabetes Mellitus.

Aims: To examine the association of polymorphisms belonging to SLC22A1, SP1, PRPF31, NBEA, SCNN1B, CPA6 and CAPN10 genes with glycaemic response to metformin and sulphonylureas (SU) combination therapy among South African adults with diabetes mellitus type 2 (T2DM). Methods: A total of 128 individuals of Swati (n = 22) and Zulu (n = 106) origin attending chronic care for T2DM were recruited. Nine SNPs previously associated with metformin and SUs were selected and genotyped using MassArray. Uncontrolled T2DM was defined as HbA1c > 7%. The association between genotypes, alleles and glycaemic response to treatment was determined using multivariate logistic regression model analysis. Results: About 85.93% (n = 110) of the study participants were female and 77.34% (n = 99) had uncontrolled T2DM (HbA1c > 7%). In the multivariate (adjusted) logistic regression model analysis, the CC genotype of rs2162145 (CPA6), GG and GA genotypes of rs889299 (SCNN1B) were significantly associated with uncontrolled T2DM. On the other hand, the C allele of rs254271 (PRPF31) and the GA genotype of rs3792269 (CAPN10) were associated with controlled T2DM. A significant interaction between rs2162145 and rs889299 in response to metformin and SU combination therapy was observed. Conclusions: In this study, we reported the association of rs2162145 (CC) and rs889299 (GG and GA) with uncontrolled T2DM. We also reported the association of rs254271 (C) and rs3792269 (GA) with controlled T2DM in response to metformin and SU combination therapy. Furthermore, an interaction between rs2162145 and rs889299 was established, where the genotype combination GA (rs889299) and TT (rs2162145) was associated with uncontrolled T2DM.

TUG is a calpain-10 substrate involved in the translocation of GLUT4 in adipocytes.

The calpain-10 (CAPN10) protease is implicated in the translocation of the glucose transporter 4 (GLUT4), which is retained in the Golgi matrix via the Tether containing a UBX domain for GLUT4 (TUG) protein. Insulin stimulation induces the proteolytic processing of TUG, which leads to the translocation of GLUT4 to the cell membrane. We tested whether TUG is a CAPN10 substrate. Proteolysis of TUG by calpains was assessed using a cell-free system containing calpain-1 and TUG. In situ proteolysis of TUG by calpains was demonstrated in 3T3-L1 adipocytes in the presence of insulin or calpain inhibitors to modulate calpain activity. Proteolysis of TUG by CAPN10 was confirmed using transient or stable silencing of CAPN10 in 3T3-L1 adipocytes. Calpains proteolyzed the C-terminus of TUG in vitro. In adipocytes, insulin-induced cleavage of TUG was correlated with the activation of calpains. Treatment with calpain inhibitors reduced TUG cleavage, resulting in impaired GLUT4 translocation without altering Akt phosphorylation. Furthermore, CAPN10 but not calpain-1 or calpain-2 colocalized with GLUT4 in the absence of insulin, and their colocalization was reduced after stimulation with insulin. Finally, we demonstrated that CAPN10 knockdown reduced the proteolysis of TUG without altering the phosphorylation of Akt or the expression of the Usp25m protease. Thus, our results provide evidence that the TUG protein is cleaved by CAPN10 to regulate GLUT4 translocation.

Association of CAPN10 (SNP-19) genetic polymorphism and obesity with T2DM: a study on Bengali Hindu caste population

Type 2 diabetes mellitus (T2DM) is a multifactorial disease caused due to induced obesity and the influence of genetic polymorphism. Calpain-10 (CAPN10) gene and its genetic polymorphism (SNP-19) significantly alter insulin sensitivity assayed by the synthesis of a mutant protein and/or altered transcriptional regulation, which could contribute to the diabetes risk. The role of CAPN10 genetic polymorphism in T2DM has widely been studied in different populations and obtained variable results. Considering the variable results in different ethnic groups, the present study is an attempt to understand the association of CAPN10 (SNP-19) genetic polymorphism and obesity with T2DM in Bengali Hindu caste population. The present study consisted of 104 clinically diagnosed type 2 diabetes mellitus male patients (Age range = 23–80 years) and 176 apparently healthy males (Age range = 18–79 years) without T2DM and family history of T2DM from Bengali Hindu caste population. Genomic DNA was isolated from mouthwash using phenol-chloroform method with slight modifications. PCR method has been used to perform genotyping of (CAPN10 snp-19). Anthropometric and physiological variables have been collected by using standard method. Overall, the distribution CAPN10 (SNP-19) genotypes revealed no significant difference between T2DM patients and control group. However, T2DM patients with II genotype have significantly (p < 0.05) higher WHR compared to ID and DD genotypes. Individuals with DD genotype demonstrated significant (p < 0.05) higher risk associated with T2DM than (II+ID) genotype with increase in BMI, WC, and HC. The findings of the present study might incorporate as criterion for early prognosis of T2DM in Bengali Hindu caste.

CAPN10 SNP-19 is Associated with Susceptibility of Type 2 Diabetes Mellitus: A Javanese Case-control Study

BACKGROUND: The health data of Central Java, Indonesia showed that diabetes mellitus (DM) was the second most increasing non-communicable disease in the province. More than 20 genes have been reported to be associated with DM. Calpain-10 (CAPN10) polymorphism has been reported to be associated with Type 2 Diabetes Mellitus (T2DM). However, the association between CAPN10 single nucleotide polymorphism (SNP)-19 and T2DM among Javanese ethnics has never been reported. Therefore, this study was conducted to investigate the association.METHODS: After fasting for 8 hours, blood samples were drawn from veins of 107 T2DM and 107 non diabetic subjects. A half of the drawn blood was collected for identification of CAPN10 SNP-19, and another half for measuring triglycerides and fasting blood glucose (FBG). Identification of CAPN10 SNP-19 was performed with polymerase chain reaction (PCR) method, while measurement of triglycerides and FBG with colorimetric enzymatic method.RESULTS: The number of T2DM Javanese subjects with 2R/3R and 3R/3R CAPN10 SNP-19 genotypes was significantly higher than the number of T2DM Javanese subjects with 2R/2R genotype (p=0.002). When each number of 2R/3R and 3R/3R T2DM subjects was compared with the number of 2R/2R T2DM subjects, the number of 2R/3R T2DM subjects was significantly higher than the number of 2R/2R T2DM subjects (p=0.000).CONCLUSION: Javanese subjects with 2R/3R and 3R/3R CAPN10 SNP19 genotypes might have susceptibility of T2DM.KEYWORDS: Calpain-10, CAPN10, polymorphism, type2 diabetes mellitus, triglycerides, fasting blood glucose

KCNQ1OT1 promotes ovarian cancer progression via modulating MIR-142-5p/CAPN10 axis.

BackgroundLong non‐coding RNA (lncRNA) has been regarded as crucial regulator for cancer progression. Roles of KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) in cancers including osteosarcoma and colon cancer have been previously reported. However, its role in ovarian cancer (OC) remains unclear.MethodsExpression level of KCNQ1OT1 on OC cells and normal cell was analyzed with quantitative real‐time PCR. Gain and loss‐of‐function experiments were performed to analyze the biological roles of KCNQ1OT1 in OC. Moreover, whether KCNQ1OT1 functions its role via mediating MICRORNA‐142‐5p (MIR‐142‐5p)/calpain 10 (CAPN10) axis was analyzed. In addition, effects of KCNQ1OT1, MIR‐142‐5p, and CAPN10 on overall survival of OC patients were analyzed at Kaplan–Meier plotter website.ResultsWe showed KCNQ1OT1 was elevated expression in OC cells and indicated poorer overall survival of OC patients. Besides, we found KCNQ1OT1 could promote OC cell proliferation and migration in vitro. Moreover, MIR‐142‐5p was found reduced expression, while CAPN10 was found elevated expression in OC cells compared with normal cell. Kaplan–Meier curve analysis showed low MIR‐142‐5p or high CAPN10 expression were indicators for poorer overall survival of OC patients. At length, we showed KCNQ1OT1 could regulate OC development via MIR‐142‐5p/CAPN10 axis.ConclusionsTaken together, KCNQ1OT1 upregulates CAPN10 expression via sponging MIR‐142‐5p, thus promoting the proliferation and migration of OC.

Calpain Activity in Leukocytes Is Associated with Diabetes Biochemical Markers

CAPN10 gene is associated with type 2 diabetes (T2D). Specific members of the calpain system (CAPN1, CAPN2 and CAPN10) are implicated in glucose metabolism. The aim of this study was to evaluate the calpain activity in leukocytes of control subjects and patients with T2D and its association with the calpain family members involved in glucose metabolism and with biochemical parameters that are altered in T2D. Calpain activity under extracellular glucose concentrations (70-280mg/dL) was evaluated in leukocytes from subjects with and without T2D. Protein and mRNA levels of CAPN1, CAPN2 and CAPN10 were evaluated. Calpain inhibitors assays were performed in leukocytes from subjects without T2D to evaluate glucose uptake. Calpain activity at 100mg/dL glucose was correlated with biochemical parameters by multivariate regression. Calpain activity in control subjects increased with extracellular glucose concentration in a dose-dependent manner, showing a negative association with HbA1c levels and total amount of CAPN10 protein. In contrast, calpain activity is decreased in patients with T2D and do not respond to changes in glucose concentration. A reduction of CAPN1 autolytic fragments were observed in the subjects with diabetes. Calpain inhibitors decreased calpain activity but did not altered glucose uptake in leukocytes. Calpain activity induced by glucose in leukocytes was associated with biochemical markers of glucose metabolism and with CAPN10 protein abundance. Calpain activity is low in subjects with T2D. Thus, calpain activity induced by extracellular glucose in leukocytes could be a potential marker for T2D early risk detection.