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  1. Tang H, Jiang L, Stolzenberg-Solomon RZ, Arslan AA, Beane Freeman LE, Bracci PM, et al.
    Cancer Epidemiol Biomarkers Prev, 2020 Sep;29(9):1784-1791.
    PMID: 32546605 DOI: 10.1158/1055-9965.EPI-20-0275
    BACKGROUND: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level.

    METHODS: We conducted a gene-environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m2) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case-control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics.

    RESULTS: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 × 10-6) was observed in the meta-analysis (P GxE = 1.2 ×10-6, P Joint = 4.2 ×10-7).

    CONCLUSIONS: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans.

    IMPACT: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.

    Matched MeSH terms: Diabetes Mellitus/genetics*
  2. Haghvirdizadeh P, Sadat Haerian M, Haghvirdizadeh P, Sadat Haerian B
    Gene, 2014 07 25;545(2):198-204.
    PMID: 24768178 DOI: 10.1016/j.gene.2014.04.040
    Diabetes mellitus (DM) is a major health problem worldwide and it will rapidly increase. This disease is characterized by hyperglycemia caused by defects in insulin secretion, insulin action or both. DM has three types: T1DM, T2M and gestational DM (GDM), of them T2DM is more frequent. Multiple genes and their interactions are involved in insulin secretion pathway. Sulfonylurea receptor encoded by ABCC8 gene, together with inward-rectifier potassium ion channel (Kir6.2) regulates insulin secretion by ATP-sensitive K(+) (KATP) channel located in the plasma membranes. Disruption of these molecules by different mutations is responsible for risk of DM. Several single nucleotide polymorphisms (SNPs) of ABCC8 gene and their interaction are involved in pathogenicity of DM. This review summarizes the current evidence of contribution of ABC8 genetic variants to the development of DM.
    Matched MeSH terms: Diabetes Mellitus/genetics*
  3. Cheah JS, Yeo PP, Thai AC, Lui KF, Wang KW, Tan YT, et al.
    Ann Acad Med Singap, 1985 Apr;14(2):232-9.
    PMID: 4037681
    Singapore is a tropical island city-state with a population of 2.4178 million consisting of Chinese (76.7%), Malays (14.7%), Indians (6.4%) and other races (2.2%). A diabetic survey of the adult population, aged 15 years and above, carried out in 1975, shows that the prevalence of diabetes is 1.99%; it is higher in males (2.36%) than in females (1.64%). It occurs mainly in the age group 40 years and above (5.08%) and is uncommon in the age group 15-39 years (0.40%). In males, the highest prevalence of diabetes (7.0%) is in the age group 45-49 years while in females the highest prevalence (7.2%) is in the age group 55-59 years. 43.3% of the diabetics are of normal weight while 44.3% are overweight and 12.4% are underweight. 59.6% of the diabetics are newly diagnosed while 40.4% are known diabetics; 64.3% of the newly diagnosed diabetics have no symptoms. The prevalence of diabetes among the Indians (6.07%) is significantly higher than that in Malays (2.43%) and Chinese (1.55%). Indian diabetics have a slightly higher positive family history of diabetes (12.7%) than Malays (10.9%) and Chinese (6.5%). Obesity is commoner in Malay diabetics (64.7%) than in Chinese (41.6%) and Indians (35.7%). The possible factors leading to the significantly higher prevalence of diabetes among the Indians compared to the other ethnic groups in Singapore are discussed. It is suggested that the Indian gene is susceptible to diabetes (diabetic genotype) and increased food consumption, altered lifestyle and greater obesity leads to the expression of diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)
    Matched MeSH terms: Diabetes Mellitus/genetics
  4. Liew SC, Gupta ED
    Eur J Med Genet, 2015 Jan;58(1):1-10.
    PMID: 25449138 DOI: 10.1016/j.ejmg.2014.10.004
    The Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with various diseases (vascular, cancers, neurology, diabetes, psoriasis, etc) with the epidemiology of the polymorphism of the C677T that varies dependent on the geography and ethnicity. The 5,10-Methylenetetrahydrofolate reductase (MTHFR) locus is mapped on chromosome 1 at the end of the short arm (1p36.6). This enzyme is important for the folate metabolism which is an integral process for cell metabolism in the DNA, RNA and protein methylation. The mutation of the MTHFR gene which causes the C677T polymorphism is located at exon 4 which results in the conversion of valine to alanine at codon 222, a common polymorphism that reduces the activity of this enzyme. The homozygous mutated subjects have higher homocysteine levels while the heterozygous mutated subjects have mildly raised homocysteine levels compared with the normal, non-mutated controls. Hyperhomocysteinemia is an emerging risk factor for various cardiovascular diseases and with the increasing significance of this polymorphism in view of the morbidity and mortality impact on the patients, further prevention strategies and nutritional recommendations with the supplementation of vitamin B12 and folic acid which reduces plasma homocysteine level would be necessary as part of future health education. This literature review therefore focuses on the recent evidence-based reports on the associations of the MTHFR C677T polymorphism and the various diseases globally.
    Matched MeSH terms: Diabetes Mellitus/genetics
  5. Haghvirdizadeh P, Mohamed Z, Abdullah NA, Haghvirdizadeh P, Haerian MS, Haerian BS
    J Diabetes Res, 2015;2015:908152.
    PMID: 26448950 DOI: 10.1155/2015/908152
    Diabetes mellitus (DM) is a major worldwide health problem and its prevalence has been rapidly increasing in the last century. It is caused by defects in insulin secretion or insulin action or both, leading to hyperglycemia. Of the various types of DM, type 2 occurs most frequently. Multiple genes and their interactions are involved in the insulin secretion pathway. Insulin secretion is mediated through the ATP-sensitive potassium (KATP) channel in pancreatic beta cells. This channel is a heteromeric protein, composed of four inward-rectifier potassium ion channel (Kir6.2) tetramers, which form the pore of the KATP channel, as well as sulfonylurea receptor 1 subunits surrounding the pore. Kir6.2 is encoded by the potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) gene, a member of the potassium channel genes. Numerous studies have reported the involvement of single nucleotide polymorphisms of the KCNJ11 gene and their interactions in the susceptibility to DM. This review discusses the current evidence for the contribution of common KCNJ11 genetic variants to the development of DM. Future studies should concentrate on understanding the exact role played by these risk variants in the development of DM.
    Matched MeSH terms: Diabetes Mellitus/genetics*
  6. Ch'ng SL, Chandrasekharan N
    Ann Acad Med Singap, 1985 Apr;14(2):223-8.
    PMID: 4037680
    The pattern of plasma and urine sugar changes after 50g glucose load in 1900 Malaysians (522 males and 1378 females) consisting predominantly of Malays, Chinese and Indians were studied. The data were analysed using Statistical Package for Social Sciences (SPSS). The results show bimodal distribution of 120 min. plasma sugar values in the age groups 21 years and above and trimodal distribution in most groups above 40 years. The mean 120 minutes plasma sugar cut-off values for nondiabetics (ND), impaired glucose tolerance (IGT), and diabetics (DM) of 8.4 and 11.1 mmol/l respectively were close to the values recommended by the National Diabetic Data Group (NDDG). Fifty two percent of all subjects showed peaked plasma sugar values at 60 minutes (14% of them had IGT, 12% DM), 25% peaked at 30 minutes (98% of them were ND). The rest showed peaked values at 90 minutes (17%), 120 minutes (4%) and 150 minutes (2%) and from this group forty two percent were DM and 23% had IGT. Reliance on urine sugar qualitative tests could misclassify 7.3% of subjects (predominantly elderly females) with hyperglycaemia of greater than 11 mmol/l. This study shows that in the 50 g glucose tolerance test, the NDDG criteria for ND, IGT, DM is still applicable to the Malaysian population. The sampling time could be reduced to four points at 0, 60, 90, and 120 minutes. Blood analysis is the preferred method for the diagnosis of hyperglycaemia in elderly females.
    Matched MeSH terms: Diabetes Mellitus/genetics*
  7. Shahcheraghi SH, Aljabali AAA, Al Zoubi MS, Mishra V, Charbe NB, Haggag YA, et al.
    Life Sci, 2021 Aug 01;278:119632.
    PMID: 34019900 DOI: 10.1016/j.lfs.2021.119632
    Diabetes epidemiological quantities are demonstrating one of the most important communities' health worries. The essential diabetic difficulties are including cardiomyopathy, nephropathy, inflammation, and retinopathy. Despite developments in glucose decreasing treatments and drugs, these diabetic complications are still ineffectively reversed or prohibited. Several signaling and molecular pathways are vital targets in the new therapies of diabetes. This review assesses the newest researches about the key molecules and signaling pathways as targets of molecular pharmacology in diabetes and diseases related to it for better treatment based on molecular sciences. The disease is not cured by current pharmacological strategies for type 2 diabetes. While several drug combinations are accessible that can efficiently modulate glycemia and mitigate long-term complications, these agents do not reverse pathogenesis, and in practice, they are not established to modify the patient's specific molecular profiling. Therapeutic companies have benefited from human genetics. Genome exploration, which is agnostic to the information that exists, has revealed tens of loci that impact glycemic modulation. The physiological report has begun to examine subtypes of diseases, illustrate heterogeneity and propose biochemical therapeutic pathways.
    Matched MeSH terms: Diabetes Mellitus/genetics
  8. Rasouli M, Allaudin ZN, Omar AR, Ahmad Z
    Curr Gene Ther, 2013 Aug;13(4):229-39.
    PMID: 23721205 DOI: 10.2174/15665232113139990002
    Poorly controlled diabetes mellitus can result in serious complications. Gene therapy is increasingly being considered as an alternative approach to treat diabetes, because of its ability to induce physiological insulin secretion and it allows patients to escape insulin injections. The properties of gut K and L-cells, including glucose sensitivity, the ability to process insulin and a regulated secretion pathway support their use as surrogate β-cells. Previous in vitro studies have provided sufficient evidence supporting the use of these cells for gene therapy studies. Therefore, we examined the ability of K and L-cells to produce insulin in diabetic mice. Chitosan nanoparticles were used to transfer the insulin gene into intestinal cells via oral administration. The efficiency of chitosan as a gene vehicle was investigated through the use of reporter gene. Insulin mRNA and protein expression levels were measured by RT-PCR and ELISA, respectively. Blood glucose testing revealed that this treatment reduced glucose levels in diabetic mice. The decrease in blood glucose level in the first week of treatment was greater in mice with K-cell specific insulin expression compared with mice with L-cell-specific insulin expression. These results indicate that inducing insulin secretion in K-cells conferred a quicker response to gene therapy.
    Matched MeSH terms: Diabetes Mellitus/genetics*
  9. Shen H, Qi L, Tai ES, Chew SK, Tan CE, Ordovas JM
    Obesity (Silver Spring), 2006 Apr;14(4):656-61.
    PMID: 16741267
    A polymorphism in the promoter region of uncoupling protein 2 gene -866G/A has been associated with its expression levels in adipose tissue, the risk of obesity, and metabolic abnormalities. Our purpose was to examine the associations of -866G/A with body fat and the risk of metabolic syndrome in a random sample of 4018 Asians (1858 men and 2160 women) from three ethnic groups (Chinese, Malay, and Indian). The minor allele frequency of -866G/A polymorphism in South Asians was similar to that in whites. After adjustment for covariates including age, cigarette smoking, and physical activity, the -866A/A genotype was associated with higher waist-to-hip ratio as compared with the wild-type genotype in Chinese and Indian men (p = 0.018 and p = 0.046, respectively). Moreover, Indian men with -866A/A genotype had a significantly increased risk of metabolic syndrome as compared with those homozygous for the wild-type (odds ratio, 2.66; 95% confidence interval, 1.21 to 5.88; p = 0.015). Such a risk was mainly caused by the excess presence of hypertriglyceridemia and central obesity. Our findings indicate that the uncoupling protein 2 gene -866G/A polymorphism may increase the risks of central obesity and metabolic syndrome, with greater effects on Asian men.
    Matched MeSH terms: Diabetes Mellitus/genetics
  10. Mustaffa BE
    Ann Acad Med Singap, 1985 Apr;14(2):272-6.
    PMID: 4037685
    Estimated prevalence of diabetes mellitus in Malaysia was about 2%. Diabetes was most common in Indians especially males and least common in Chinese. There was a slight male preponderance seen in Malays and Indians. Positive family history was obtained in 14% of cases most commonly in Malays, almost 1/3 of whom had more than one family member with diabetes. Familial association was uncommon in Chinese. Over 50% of patients were overweight. Obesity was noted in nearly 70% of female Malays and Indians while the majority of Chinese were not overweight. More than 80% of patients were non insulin requiring. Youth onset diabetes was considered rare; those 10 years and below were estimated to be only 0.4% and below 20 years of age between 2%-4% of the diabetic population. Females were twice as common than males in this type of diabetes and familial association was greater. Malnutrition-related diabetes and pancreatic calcification were not well-documented but youth-onset non insulin requiring diabetics with mild symptoms but strong family history of diabetes were observed. More than half of hospital-based patients had evidence of complications, mainly amongst Malays and Indians. Hypertension was the most frequent associated disease followed by foot ulcers and ischaemic heart disease. Hypertension usually associated with chronic renal failure was most common amongst Malays while gangrenic ulcers and heart diseases were seen mainly in Indians. The major causes of death were chronic renal failure, myocardial infarction, ketoacidosis, stroke and septicaemia related to gangrene.(ABSTRACT TRUNCATED AT 250 WORDS)
    Matched MeSH terms: Diabetes Mellitus/genetics
  11. Jones JJ, Watkins PJ, Owyong LY, Loh PP, Kutty MK, Jogie B
    Trop Geogr Med, 1978 Dec;30(4):439-49.
    PMID: 749278
    One hundred and thirty-two newly diagnosed Asian diabetic patients (39 Malay, 30 Chinese and 63 Indians) have been studied in Kuala Lumpur. The highest proportion of diabetic patients were Indian and the lowest were Chinese. Vascular complications were equally common in Asian diabetic patients as in Europeans; coronary heart disease was relatively more common in Indians and cerebral vascular disease in Chinese. Twenty percent of all Asian diabetic patients requiring admission to hospital also had coronary heart disease, 9% had cerebral vascular disease and 8% had gangrene or ulceration of the feet. In Kuala Lumpur, diabetes is a very important risk factor for coronary heart disease: 17% of all patients admitted to the General Hospital with coronary heart disease were already diabetic.
    Matched MeSH terms: Diabetes Mellitus/genetics
  12. Ooi HL, Wu LL
    Singapore Med J, 2012 Jul;53(7):e142-4.
    PMID: 22815030
    Neonatal diabetes mellitus (DM) is defined as insulin-requiring DM in the first six months of life. Unlike type 1 DM, it is a monogenic disorder resulting from a de novo mutation in the genes involved in the development of the pancreas, β-cell mass or secretory function. The majority of neonatal DM cases are caused by a heterozygous activating mutation in the KCNJ11 or ABCC8 genes that encode the Kir6.2 and SUR1 protein subunits, respectively, in the KATP channel. Sulphonylurea, a KATP channel inhibitor, can restore insulin secretion, hence offering an attractive alternative to insulin therapy. We report three cases of neonatal DM and their genetic mutations. Two patients were successfully switched over to sulphonylurea monotherapy with resultant improvement in the quality of life and a more stable blood glucose profile. Patients with neonatal DM should undergo genetic evaluation. For patients with KCNJ11 and ABCC8 gene mutation, oral sulphonylurea should be considered.
    Matched MeSH terms: Diabetes Mellitus/genetics*
  13. Li X, Xu A, Sheng H, Ting TH, Mao X, Huang X, et al.
    Pediatr Diabetes, 2018 03;19(2):251-258.
    PMID: 28791793 DOI: 10.1111/pedi.12560
    BACKGROUND: Sulfonylurea therapy can improve glycemic control and ameliorate neurodevelopmental outcomes in patients suffering from neonatal diabetes mellitus (NDM) with KCNJ11 or ABCC8 mutations. As genetic testing results are often delayed, it remains controversial whether sulfonylurea treatment should be attempted immediately at diagnosis or doctors should await genetic confirmation.

    OBJECTIVE: This study aimed to investigate the effectiveness and safety of sulfonylurea therapy in Chinese NDM patients during infancy before genetic testing results were available.

    METHODS: The medical records of NDM patients with their follow-up details were reviewed and molecular genetic analysis was performed. Sulfonylurea transfer regimens were applied in patients diagnosed after May 2010, and glycemic status and side effects were evaluated in each patient.

    RESULTS: There were 23 NDM patients from 22 unrelated families, 10 had KCNJ11 mutations, 3 harbored ABCC8 mutations, 1 had INS mutations, 4 had chromosome 6q24 abnormalities, 1 had a deletion at chromosome 1p36.23p36.12, and 4 had no genetic abnormality identified. Sixteen NDM infants were treated with glyburide at an average age of 49 days (range 14-120 days) before genetic confirmation. A total of 11 of 16 (69%) were able to successfully switch to glyburide with a more stable glucose profile. The responsive glyburide dose was 0.51 ± 0.16 mg/kg/d (0.3-0.8 mg/kg/d), while the maintenance dose was 0.30 ± 0.07 mg/kg/d (0.2-0.4 mg/kg/d). No serious adverse events were reported.

    CONCLUSIONS: Molecular genetic diagnosis is recommended in all patients with NDM. However, if genetic testing results are delayed, sulfonylurea therapy should be considered before such results are received, even in infants with newly diagnosed NDM.

    Matched MeSH terms: Diabetes Mellitus/genetics
  14. Carayol M, Leitzmann MF, Ferrari P, Zamora-Ros R, Achaintre D, Stepien M, et al.
    J Proteome Res, 2017 Sep 01;16(9):3137-3146.
    PMID: 28758405 DOI: 10.1021/acs.jproteome.6b01062
    Metabolomics is now widely used to characterize metabolic phenotypes associated with lifestyle risk factors such as obesity. The objective of the present study was to explore the associations of body mass index (BMI) with 145 metabolites measured in blood samples in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolites were measured in blood from 392 men from the Oxford (UK) cohort (EPIC-Oxford) and in 327 control subjects who were part of a nested case-control study on hepatobiliary carcinomas (EPIC-Hepatobiliary). Measured metabolites included amino acids, acylcarnitines, hexoses, biogenic amines, phosphatidylcholines, and sphingomyelins. Linear regression models controlled for potential confounders and multiple testing were run to evaluate the associations of metabolite concentrations with BMI. 40 and 45 individual metabolites showed significant differences according to BMI variations, in the EPIC-Oxford and EPIC-Hepatobiliary subcohorts, respectively. Twenty two individual metabolites (kynurenine, one sphingomyelin, glutamate and 19 phosphatidylcholines) were associated with BMI in both subcohorts. The present findings provide additional knowledge on blood metabolic signatures of BMI in European adults, which may help identify mechanisms mediating the relationship of BMI with obesity-related diseases.
    Matched MeSH terms: Diabetes Mellitus/genetics
  15. Guru A, Issac PK, Velayutham M, Saraswathi NT, Arshad A, Arockiaraj J
    Mol Biol Rep, 2021 Jan;48(1):743-761.
    PMID: 33275195 DOI: 10.1007/s11033-020-06036-8
    Obesity is growing at an alarming rate, which is characterized by increased adipose tissue. It increases the probability of many health complications, such as diabetes, arthritis, cardiac disease, and cancer. In modern society, with a growing population of obese patients, several individuals have increased insulin resistance. Herbal medicines are known as the oldest method of health care treatment for obesity-related secondary health issues. Several traditional medicinal plants and their effective phytoconstituents have shown anti-diabetic and anti-adipogenic activity. Adipose tissue is a major site for lipid accumulation as well as the whole-body insulin sensitivity region. 3T3-L1 cell line model can achieve adipogenesis. Adipocyte characteristics features such as expression of adipocyte markers and aggregation of lipids are chemically induced in the 3T3-L1 fibroblast cell line. Differentiation of 3T3-L1 is an efficient and convenient way to obtain adipocyte like cells in experimental studies. Peroxisome proliferation activated receptor γ (PPARγ) and Cytosine-Cytosine-Adenosine-Adenosine-Thymidine/Enhancer-binding protein α (CCAAT/Enhancer-binding protein α or C/EBPα) are considered to be regulating adipogenesis at the early stage, while adiponectin and fatty acid synthase (FAS) is responsible for the mature adipocyte formation. Excess accumulation of these adipose tissues and lipids leads to obesity. Thus, investigating adipose tissue development and the underlying molecular mechanism is important in the therapeutical approach. This review describes the cellular mechanism of 3T3-L1 fibroblast cells on potential anti-adipogenic herbal bioactive compounds.
    Matched MeSH terms: Diabetes Mellitus/genetics
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