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The role of diabetes in developing microvascular and macrovascular complications has been subject to extensive research. Despite multiple observational and genetic studies, the causal inference of diabetes (and associated risk factors) on those complications remains incomplete. In this review, we focused on type 2 diabetes, as the major form of diabetes, and investigated the evidence of causality provided by observational and genetic studies. We found that genetic studies based on Mendelian randomization provided consistent evidence of causal inference of type 2 diabetes on macrovascular complications; however, the evidence for causal inference on microvascular complications has been somewhat limited. We also noted high BMI could be causal for several diabetes complications, notable given high BMI is commonly upstream of type 2 diabetes and the recent calls to target weight loss more aggressively. We emphasize the need for further studies to identify type 2 diabetes components that mostly drive the risk of those complications. Even so, the genetic evidence summarized broadly concurs with the need for a multifactorial risk reduction approach in type 2 diabetes, including addressing excess adiposity. [ABSTRACT FROM AUTHOR]

Abstract Background This study investigated whether single nucleotide polymorphisms (SNPs) reported by previous genome-wide association studies (GWAS) to be associated with impaired insulin secretion, insulin resistance, and/or type 2 diabetes are associated with disposition index, the homeostasis model assessment of insulin resistance (HOMA-IR), and/or development of diabetes following a pregnancy complicated by gestational diabetes mellitus (GDM). Methods Seventy-two SNPs were genotyped in 374 women with previous GDM from Southern Sweden. An oral glucose tolerance test was performed 1–2 years postpartum, although data on the diagnosis of diabetes were accessible up to 5 years postpartum. HOMA-IR and disposition index were used to measure insulin resistance and secretion, respectively. Results The risk A-allele in the rs11708067 polymorphism of the adenylate cyclase 5 gene (ADCY5) was associated with decreased disposition index (beta = − 0.90, SE 0.38, p = 0.019). This polymorphism was an expression quantitative trait loci (eQTL) in islets for both ADCY5 and its antisense transcript. The risk C-allele in the rs2943641 polymorphism, near the insulin receptor substrate 1 gene (IRS1), showed a trend towards association with increased HOMA-IR (beta = 0.36, SE 0.18, p = 0.050), and the T-allele of the rs4607103 polymorphism, near the ADAM metallopeptidase with thrombospondin type 1 motif 9 gene (ADAMTS9), was associated with postpartum diabetes (OR = 2.12, SE 0.22, p = 0.00055). The genetic risk score (GRS) of the top four SNPs tested for association with the disposition index using equal weights was associated with the disposition index (beta = − 0.31, SE = 0.29, p = 0.00096). In addition, the GRS of the four SNPs studied for association with HOMA-IR using equal weights showed an association with HOMA-IR (beta = 1.13, SE = 0.48, p = 9.72874e−11). All analyses were adjusted for age, body mass index, and ethnicity. Conclusions This study demonstrated the genetic susceptibility of women with a history of GDM to impaired insulin secretion and sensitivity and, ultimately, to diabetes development.

Aims/hypothesis: South Asians in general, and Asian Indians in particular, have higher risk of type 2 diabetes compared with white Europeans, and a younger age of onset. The reasons for the younger age of onset in relation to obesity, beta cell function and insulin sensitivity are under-explored. Methods: Two cohorts of Asian Indians, the ICMR-INDIAB cohort (Indian Council of Medical Research-India Diabetes Study) and the DMDSC cohort (Dr Mohan's Diabetes Specialties Centre), and one of white Europeans, the ESDC (East Scotland Diabetes Cohort), were used. Using a cross-sectional design, we examined the comparative prevalence of healthy, overweight and obese participants with young-onset diabetes, classified according to their BMI. We explored the role of clinically measured beta cell function in diabetes onset in Asian Indians. Finally, the comparative distribution of a partitioned polygenic score (pPS) for risk of diabetes due to poor beta cell function was examined. Replication of the genetic findings was sought using data from the UK Biobank. Results: The prevalence of young-onset diabetes with normal BMI was 9.3% amongst white Europeans and 24–39% amongst Asian Indians. In Asian Indians with young-onset diabetes, after adjustment for family history of type 2 diabetes, sex, insulin sensitivity and HDL-cholesterol, stimulated C-peptide was 492 pmol/ml (IQR 353–616, p<0.0001) lower in lean compared with obese individuals. Asian Indians in our study, and South Asians from the UK Biobank, had a higher number of risk alleles than white Europeans. After weighting the pPS for beta cell function, Asian Indians have lower genetically determined beta cell function than white Europeans (p<0.0001). The pPS was associated with age of diagnosis in Asian Indians but not in white Europeans. The pPS explained 2% of the variation in clinically measured beta cell function, and 1.2%, 0.97%, and 0.36% of variance in age of diabetes amongst Asian Indians with normal BMI, or classified as overweight and obese BMI, respectively. Conclusions/interpretation: The prevalence of lean BMI in young-onset diabetes is over two times higher in Asian Indians compared with white Europeans. This phenotype of lean, young-onset diabetes appears driven in part by lower beta cell function. We demonstrate that Asian Indians with diabetes also have lower genetically determined beta cell function. [ABSTRACT FROM AUTHOR]

Glycaemic response to metformin and sulphonylureas is heritable – with ~34%–37% of variation explainable by common genetic variation. The premise of this review is that by understanding how genetic variation contributes to drug response we can gain insights into the mechanisms of action of diabetes drugs. Here, I focus on two old drugs, metformin and sulphonylureas, where I would suggest we still have a lot to learn about their mechanism of action or their optimal use in clinical care. The fact that reduced function variants of the key transporter that takes metformin into the liver (OCT1) do not alter glycaemic response to metformin suggests that metformin does not need to get into the liver to work. A subsequent GWAS of metformin response identifies a robust variant that alters GLUT2 expression – which may support increasing evidence that metformin works primarily in the gut. For sulphonylureas, observation from patients with neonatal diabetes due to activating KATP channel mutations treated with sulphonylureas identified a novel role for sulphonylureas to enable β‐cell incretin response. This work led to recent studies of low‐dose sulphonylurea (20 mg gliclazide) in T2DM, which identified that at this dose sulphonylureas augment the incretin effect and increase β‐cell glucose sensitivity, without increasing hypoglycaemia risk. This work, prompted by studies in monogenic diabetes, suggests that we have historically been using sulphonylureas at too high a dose. With increasing availability of genetic data pharmacogenomic studies in patients with diabetes should reveal mechanistic insights into old and new diabetes drugs, with the potential for optimized use and novel therapies. [ABSTRACT FROM AUTHOR]

Background: This study investigated whether single nucleotide polymorphisms (SNPs) reported by previous genome-wide association studies (GWAS) to be associated with impaired insulin secretion, insulin resistance, and/or type 2 diabetes are associated with disposition index, the homeostasis model assessment of insulin resistance (HOMA-IR), and/or development of diabetes following a pregnancy complicated by gestational diabetes mellitus (GDM). Methods: Seventy-two SNPs were genotyped in 374 women with previous GDM from Southern Sweden. An oral glucose tolerance test was performed 1–2 years postpartum, although data on the diagnosis of diabetes were accessible up to 5 years postpartum. HOMA-IR and disposition index were used to measure insulin resistance and secretion, respectively. Results: The risk A-allele in the rs11708067 polymorphism of the adenylate cyclase 5 gene (ADCY5) was associated with decreased disposition index (beta = − 0.90, SE 0.38, p = 0.019). This polymorphism was an expression quantitative trait loci (eQTL) in islets for both ADCY5 and its antisense transcript. The risk C-allele in the rs2943641 polymorphism, near the insulin receptor substrate 1 gene (IRS1), showed a trend towards association with increased HOMA-IR (beta = 0.36, SE 0.18, p = 0.050), and the T-allele of the rs4607103 polymorphism, near the ADAM metallopeptidase with thrombospondin type 1 motif 9 gene (ADAMTS9), was associated with postpartum diabetes (OR = 2.12, SE 0.22, p = 0.00055). The genetic risk score (GRS) of the top four SNPs tested for association with the disposition index using equal weights was associated with the disposition index (beta = − 0.31, SE = 0.29, p = 0.00096). In addition, the GRS of the four SNPs studied for association with HOMA-IR using equal weights showed an association with HOMA-IR (beta = 1.13, SE = 0.48, p = 9.72874e−11). All analyses were adjusted for age, body mass index, and ethnicity. Conclusions: This study demonstrated the genetic susceptibility of women with a history of GDM to impaired insulin secretion and sensitivity and, ultimately, to diabetes development. [ABSTRACT FROM AUTHOR]

Aims/hypothesisWhile genome-wide association studies (GWASs) have been successful in identifying novel variants associated with various diseases, it has been much more difficult to determine the biological mechanisms underlying these associations. Expression quantitative trait loci (eQTL) provide another dimension to these data by associating single nucleotide polymorphisms (SNPs) with gene expression. We hypothesised that integrating SNPs known to be associated with type 2 diabetes with eQTLs and coexpression networks would enable the discovery of novel candidate genes for type 2 diabetes.MethodsWe selected 32 SNPs associated with type 2 diabetes in two or more independent GWASs. We used previously described eQTLs mapped from genotype and gene expression data collected from 1,008 morbidly obese patients to find genes with expression associated with these SNPs. We linked these genes to coexpression modules, and ranked the other genes in these modules using an inverse sum score.ResultsWe found 62 genes with expression associated with type 2 diabetes SNPs. We validated our method by linking highly ranked genes in the coexpression modules back to SNPs through a combined eQTL dataset. We showed that the eQTLs highlighted by this method are significantly enriched for association with type 2 diabetes in data from the Wellcome Trust Case Control Consortium (WTCCC, p = 0.026) and the Gene Environment Association Studies (GENEVA, p = 0.042), validating our approach. Many of the highly ranked genes are also involved in the regulation or metabolism of insulin, glucose or lipids.Conclusions/interpretationWe have devised a novel method, involving the integration of datasets of different modalities, to discover novel candidate genes for type 2 diabetes.

Backgrounds and Aims. Insulin-induced gene 2 (INSIG-2) is closely related to hypercholesteremia, which is a well-recognized risk factor of mild cognitive impairment (MCI) in type 2 diabetes mellitus (T2DM). We aim to investigate the association between promoter of the INSIG-2 rs7566605 single-nucleotide polymorphism (SNP) and T2DM with MCI. Methods. 233 T2DM patients with MCI or without MCI were recruited. Baseline data and genotype frequency were compared between MCI and non-MCI groups. Demographic parameters and neuropsychological tests results were analyzed among patients with different genotypes. Further correlation and regression analysis were conducted to find the association between cognition and cholesterol. Results. Despite no significant statistical difference was detected, we observed higher levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL) in patients with MCI than those without MCI. In addition, we observed higher TC and LDL levels in patients with GG or GC genotypes than those with CC genotype (P < 0.001 , P = 0.004 , or P < 0.001 , P = 0.002). Interestingly, increased MoCA and decreased TMTB scores were found in patients with CC genotype, compared to those with GG or CG genotype (P = 0.009 , P = 0.024 , or P = 0.005 , P = 0.109). Moreover, partial correlation (P = 0.030 and P = 0.004 , respectively) and multiple linear regression (P = 0.030 and P = 0.005 , respectively) showed that TC and LDL levels are associated with the TMTB score, indicating the executive function. Conclusions. CC genotype of INSIG-2 rs7566605 may be a protective factor of hypercholesteremia susceptible to MCI, especially to the executive function of T2DM. This trial is registered with ChiCTROCC15006060. [ABSTRACT FROM AUTHOR]

Objective: In treatment options for type 2 diabetes in adolescents and youth (TODAY), 4.5% of obese youth clinically diagnosed with type 2 diabetes (T2D) had genetic variants consistent with maturity onset diabetes of youth (MODY) diagnosis. The course of IS and β‐cell function in obese youth with MODY remains unknown. In this secondary analysis, we examined IS and β‐cell function in MODY vs. non‐MODY obese youth at randomization and over time. Methods: Genetic data in TODAY included 426 non‐MODY (T2D) and 22 MODY youth (7 glucokinase MODY mutation positive [GCK‐MODY], 12 hepatocyte nuclear factor MODY mutation positive [HNF‐MODY], 2 Insulin gene mutation [insulin (INS)‐MODY], and 1 Kruppel‐like factor 11 [KLF11‐MODY]). Oral glucose tolerance test (OGTT)‐derived IS, C‐peptide index, and β‐cell function relative to IS oral disposition index (oDI) was measured at randomization, and over 24 months in addition to total and high‐molecular‐weight adiponectin (HMWA). Results: At randomization, IS, total adiponectin, and HMWA were significantly higher in the two MODY groups than in non‐MODY. β‐cell function measured by C‐peptide oDI was 3‐fold higher in GCK‐MODY than in HNF‐MODY and 1.5‐fold higher than non‐MODY (P for both <.05). Glycemic failure rate was 75.0% in HNF‐MODY, 46.9% in non‐MODY, and zero in GCK‐MODY youth. While the changes in IS and oDI were not different among the three groups in the first 6 months, IS improved from 6 to 24 months in HNF‐MODY vs GCK‐MODY youth. Conclusions: In TODAY, β‐cell function at randomization was worse in obese HNF‐MODY youth compared with GCK‐MODY youth, while insulin sensitivity was worse in non‐MODY compared with the other two MODY groups. Over time, IS showed the greatest improvement in HNF‐MODY youth. This raises the possibility that TODAY therapeutic modalities of insulin sensitization in these obese HNF‐MODY youth may have played a beneficial role. [ABSTRACT FROM AUTHOR]

Background: Vitamin D deficiency is associated with glycemic dysregulation in many observational studies. However, the causality between them has not been fully established, especially in Asian origin. We used bidirectional Mendelian randomization (MR) analysis to explore the causal relationship between 25-hydroxyvitamin D [25(OH)D] and glycemic status and indices. Methods: Participants were included from a survey in East China from 2014 to 2016 (10,338 and 10,655 participants having diabetes and vitamin D-related genotyping information). We calculated weighted genetic risk scores (GRS) as the instrumental variables for 25(OH)D concentration and diabetes based on related single nucleotide polymorphisms. Diagnosis of type 2 diabetes and prediabetes was based on American Diabetes Association criteria. Results: The MR-derived odds ratios of genetically determined 25(OH)D for risk of type 2 diabetes (1565/10655) and prediabetes (3915/10655) was 0.985 (95% CI 0.940, 1.032) and 0.982 (95% CI 0.948, 1.016), respectively. The MR-derived estimates for fasting plasma glucose and HbA1c were also not significant. Moreover, the MR-derived regression coefficients of genetically determined diabetes and prediabetes for 25(OH)D was 0.448 (95% CI − 0.395, 1.291) and 1.303 (95% CI − 1.210, 3.816). Conclusions: Our results support the conclusion that there is no causal association between vitamin D and type 2 diabetes and prediabetes using a bidirectional MR approach in a Chinese population. [ABSTRACT FROM AUTHOR]

Objective. Long noncoding RNA (lncRNA) and circular RNA (circRNA) are receiving increasing attention in diabetes research. However, there are still many unknown lncRNAs and circRNAs that need further study. The aim of this study is to identify new lncRNAs and circRNAs and their potential biological functions in type 2 diabetes mellitus (T2DM). Methods. RNA sequencing and differential expression analysis were used to identify the noncoding RNAs (ncRNAs) and mRNAs that were expressed abnormally between the T2DM and control groups. The competitive endogenous RNA (ceRNA) regulatory network revealed the mechanism of lncRNA and circRNA coregulating gene expression. The biological functions of lncRNA and circRNA were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The candidate hub mRNAs were selected by the protein-protein interaction (PPI) network and validated by using the Gene Expression Omnibus (GEO) database. Results. Differential expression analysis results showed that 441 lncRNAs (366 upregulated and 75 downregulated), 683 circRNAs (354 upregulated and 329 downregulated), 93 miRNAs (63 upregulated and 30 downregulated), and 2923 mRNAs (1156 upregulated and 1779 downregulated) were identified as remarkably differentially expressed in the T2DM group. The ceRNA regulatory network showed that a single lncRNA and circRNA can be associated with multiple miRNAs, and then, they coregulate more mRNAs. Functional analysis showed that differentially expressed lncRNA (DElncRNA) and differentially expressed circRNA (DEcircRNA) may play important roles in the mTOR signaling pathway, lysosomal pathway, apoptosis pathway, and tuberculosis pathway. In addition, PIK3R5, AKT2, and CLTA were hub mRNAs screened out that were enriched in an important pathway by establishing the PPI network. Conclusions. This study is the first study to explore the molecular mechanisms of lncRNA and circRNA in T2DM through the ceRNA network cofounded by lncRNA and circRNA. Our study provides a novel insight into the T2DM from the ceRNA regulatory network. [ABSTRACT FROM AUTHOR]

Background: P-selectin, encoded by SELP, has been implicated as an important molecule in the development of arterial stiffness, consequently leading to vascular complications in T2DM. SELP polymorphisms and increased levels of soluble P-selectin (sP-selectin) have been shown to be associated with several inflammatory diseases. The present work was designed to assess nine putative functional non-coding SELP variants in relation to sP-selectin levels and arterial stiffness in T2DM. Methods: The genetic distribution of rs3917655, rs3917657, rs3917739, rs2235302, rs3917843 was determined by restriction fragment length polymorphism–polymerase chain reaction (RFLP-PCR). Genotyping of rs3917779 was performed by tetra primer amplification-refractory mutation system (ARMS)- PCR. Three SNPs i.e. rs3917853, rs3917854, rs3917855 were genotyped by Sanger sequencing. Construction of haplotypes was performed using PHASE software. The data thus obtained was analyzed by appropriate statistical tools. Results: Two non-coding variants i.e. rs3917657 and rs3917854 of SELP were found to be associated with 2 and 1.7 -fold risk of disease development respectively. However, one non-coding variant rs2235302 was found to provide protection against disease development. Furthermore, variant allele of rs3917854 in T2DM patients was found to be associated with 2.07-fold very high vascular risk. Non-coding haplotype GCAGGCCGC was conferring 4.14-fold risk of disease development. Furthermore, overall sP-selectin levels were higher in T2DM patients when segregated according to genotypes as well as haplotypes. Significant genotype- phenotype correlation was observed for rs3917655 as well as rs3917739 variant in patients and for rs3917854 in controls. In vascular risk categories, a significant genotype- phenotype correlation was observed for rs3917655 and rs2235302. Furthermore, patients with CCGGGCCGC haplotype in high risk category were observed with higher levels of sP-selectin as compared to other haplotypes (p < 0.05). Conclusions: Non-coding SELP variants may significantly modulate sP-selectin levels, vascular risk and T2DM susceptibility. [ABSTRACT FROM AUTHOR]

Background/Objectives: Patients referred for HNF1B testing present very heterogeneous phenotypes. Despite suggestive characteristics, many do not harbor mutations in HNF1B. Our objective was to evaluate the clinical characteristics of probands referred for HNF1B genetic testing through a nationwide monogenic diabetes screening program. Methods: Probands tested for HNF1B mutations in the 2005‐2018 period (N = 50) were identified in the Polish Monogenic Diabetes Registry, which prospectively recruits primarily pediatric patients and their families on a nationwide scale. Variants that had been reported pathogenic were reassessed using criteria of the American College of Medical Genetics and Genomics (ACMG). A structured medical interview was performed with all available individuals, their parents, and/or their physicians. For each patient, HNF1B score was calculated based on available clinical information. Results: The study group numbered 36 unrelated probands (28% lost to follow‐up): 14 with pathogenic or likely‐pathogenic variants in HNF1B, one with a variant of uncertain significance, and 21 negative for HNF1B mutations. Presence of cystic kidneys (OR = 9.17, 95% CI:1.87‐44.92), pancreatic abnormalities (OR = 15, 95% CI:1.55‐145.23), elevated liver enzymes (OR = 15, 95% CI:1.55‐145.23) best discriminated HNF1B‐positive cases from the negative ones. Presence of impaired glucose tolerance coupled with kidney disease in the proband and one parent was also highly predictive for HNF1B mutations (OR = 11.11, 95% CI:1.13‐109.36). HNF1B‐score with recommended cutoff distinguished patients with and without HNF1B findings with 100% sensitivity and 47.6% specificity. Addition of four clinical variables to select patients based on HNF1B score improved specificity to 71.4% (95% CI:47.8%‐88.7%) while retaining 100% sensitivity. Conclusions: Detailed medical interview may enable more accurate patient selection for targeted genetic testing. [ABSTRACT FROM AUTHOR]

Aims: To examine the phenotypic features of people identified with ABCC8‐maturity‐onset diabetes of the young (MODY) who were included in the adult 'Mater MODY' cohort and to establish their response to sulfonylurea therapy. Methods: Ten participants with activating ABCC8 mutations were phenotyped in detail. A 2‐hour oral glucose tolerance test was performed to establish glycaemic tolerance, with glucose, insulin and C‐peptide measurements taken at baseline and 30‐min intervals. Insulin was discontinued and sulfonylurea therapy initiated after genetic diagnosis of ABCC8‐MODY. A blinded continuous glucose monitoring sensor was used to establish glycaemic control on insulin vs a sulfonylurea. Results: The mean age at diagnosis of diabetes was 33.8 ± 11.1 years, with fasting glucose of 18.9 ± 11.5 mmol/l and a mean (range) HbA1c of 86 (51,126) mmol/mol [10.0 (6.8,13.7)%]. Following a genetic diagnosis of ABCC8‐MODY three out of four participants discontinued insulin (mean duration 10.6 ± 1.69 years) and started sulfonylurea treatment. The mean (range) HbA1c prior to genetic diagnosis was 52 (43,74) mmol/mol (6.9%) and the post‐treatment change was 44 (30,57) mmol/mol (6.2%; P=0.16). Retinopathy was the most common microvascular complication in this cohort, occurring in five out of 10 participants. Conclusions: Low‐dose sulfonylurea therapy resulted in stable glycaemic control and the elimination of hypoglycaemic episodes attributable to insulin therapy. The use of appropriate therapy at the early stages of diabetes may decrease the incidence of complications and reduce the risks of hypoglycaemia associated with insulin therapy. What's new?: Activating mutations in ABCC8 are a rare cause of diabetes mellitus that manifests first in adolescence and early adulthood, with phenotype variability among family members.We report on the successful switch to sulfonylureas after chronic insulin use in participants with activating mutations in ABCC8.The individuals in our study cohort presented with dramatic hyperglycaemia with classic symptoms of diabetes.Diabetic retinopathy was the most common complication in the cohort.Early genetic confirmation of ABCC8‐maturity‐onset diabetes of the young (MODY) and appropriate sulfonylurea therapy would reduce episodes of hypoglycaemia and is likely to reduce diabetes complications.The study emphasizes the importance of the genetic characterization of ABCC8‐MODY to guide personalized treatment. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is a complex, lifelong condition that is disproportionately prevalent among minority populations. Haitian immigrants (HIs) living in the US with T2D have unique factors that influence diagnosis, treatment, and self-management. The purpose of this integrative review was to provide a synthesis of the research on T2D in the HI population. In a systematic literature search, 14 studies met the inclusion criteria. Three themes were identified: risk factors for less self-management and/or worse metabolic control; protective factors for better self-management and/or metabolic control; and mixed results. HIs had higher HbA1c, yet better self-management, different genetic profiles, and lower levels of vitamin D and hemoglobin concentration compared to other ethnic groups. HIs also reported better dietary quality, less healthcare utilization, and higher perceived emotional/psychological stress compared to other ethnic groups. This study has implications for practice for integrating the unique cultural factors when assessing and intervening with HIs. [ABSTRACT FROM AUTHOR]

Although Alzheimer's disease (AD) is a central nervous system disease and type 2 diabetes MELLITUS (T2DM) is a metabolic disorder, an increasing number of genetic epidemiological studies show clear link between AD and T2DM. The current approach to uncovering the shared pathways between AD and T2DM involves association analysis; however such analyses lack power to discover the mechanisms of the diseases. As an alternative, we developed novel causal inference methods for genetic studies of AD and T2DM and pipelines for systematic multi-omic casual analysis to infer multilevel omics causal networks for the discovery of common paths from genetic variants to AD and T2DM. The proposed pipelines were applied to 448 individuals from the ROSMAP Project. We identified 13 shared causal genes, 16 shared causal pathways between AD and T2DM, and 754 gene expression and 101 gene methylation nodes that were connected to both AD and T2DM in multi-omics causal networks. [ABSTRACT FROM AUTHOR]

Introduction: Diabetic nephropathy (DN) is the commonest single cause of end-stage renal failure, and dyslipidemia is a critical risk factor in the occurrence of DN. In the light of recent reports emphasizing the importance of angiotensin I-converting enzyme (ACE) in the modulation of plasma lipids, we sought to evaluate the influence of ACE I/D gene polymorphism with dyslipidemia status among type 2 diabetic (T2D) patients with and without nephropathy in the genetic predisposition and the progression to DN. Method: This study comprised of 600 subjects, which include patients with DN, T2D, and healthy controls (HC). Polymerase chain reaction based genotyping of ACE I/D polymorphism was performed and appropriate statistical analysis was done.Results: Out of the 600 subjects, 20 (10%) of the HC, 73 (36.5%) of the T2D group, and 125 (62.5%) of the DN subjects had dyslipidemia. The D allele (0.62) and DD (42.5) genotype frequencies were higher in the DN group in comparison with T2D and HC (P < 0.05). The genotypes also varied among patients with dyslipidemia (χ2 5.04; P < 0.05) but not in the non-dyslipidemia group. Under the co-dominant model, DD genotype conferred a risk of 1.26 (P < 0.001) toward DN, whereas the ID genotype offered protection from DN among the dyslipidemic subjects (OR = 0.05; P < 0.01). In addition, genotype-dependent difference was seen in the plasma lipid levels among study groups. A multiple logistic regression analysis revealed male gender, BMI, HbA1c, TG, HDL, and ACE DD genotype as independent risk factors for the development of DN. Conclusion: The study showed a significant predisposing association of ACE DD genotype with DN and protective effect of ID genotype on DN in the dyslipidemia subgroup. [ABSTRACT FROM AUTHOR]

The article discusses a study that determined the effects of severe obesity and type 2 diabetes on mitochondrial network morphology and expression of proteins that regulate mitochondrial quality control processes in cultured human myotubes. Results indicate that regulatory proteins in mitochondrial fission protein Drp1 phosphorylation and mitophagy protein Parkin are intrinsically dysregulated at the cellular level in skeletal muscle from severely obese nondiabetic and type 2 diabetic humans.

Background Whether genetic susceptibility to type 2 diabetes is modified by a healthy lifestyle among Chinese remains unknown. Objectives The aim of the study was to determine whether genetic risk and adherence to a healthy lifestyle contribute independently to the risk of developing type 2 diabetes. Methods We defined a lifestyle score using BMI, alcohol intake, smoking, physical activities, and diets in 461,030 participants from the China Kadoorie Biobank and 38,434 participants from the Singapore Chinese Health Study. A genetic risk score was constructed based on type 2 diabetes loci among 100,175 and 16,172 participants in each cohort, respectively. A Cox proportional-hazards model was used to estimate the interaction between genetic and lifestyle factors on the risk of type 2 diabetes. Results In 2 independent Asian cohorts, we consistently found a healthy lifestyle (the bottom quintile of lifestyle score) was associated with a substantially lower risk of type 2 diabetes than an unhealthy lifestyle (the top quintile of lifestyle score) regardless of genetic risk. In those at a high genetic risk, the risk of type 2 diabetes was 57% lower among participants with a healthy lifestyle than among those with an unhealthy lifestyle in the pooled cohorts. Among participants at high genetic risk, the standardized 10-y incidence of type 2 diabetes was 7.11% in those with an unhealthy lifestyle vs. 2.45% in those with a healthy lifestyle. Conclusions In 2 independent cohorts involving 558,302 Chinese participants, we did not observe an interaction between genetics and lifestyle with type 2 diabetes risk, but our findings provide replicable evidence to show lifestyle factors and genetic factors were independently associated with the risk of type 2 diabetes. Within any genetic risk category, a healthy lifestyle was associated with a significantly lower risk of type 2 diabetes among the Chinese population. [ABSTRACT FROM AUTHOR]

Background: Maturity Onset Diabetes of the Young (MODY) constitutes a genetically and clinically heterogeneous type of monogenic diabetes. It is characterized by early onset, autosomal dominant inheritance and a defect in pancreatic β‐cell insulin secretion. To date, various MODY subtypes have been reported, each one of a distinct genetic etiology. Objective: The aim of this study was to identify the molecular defects of 50 patients with MODY employing the methodology of next generation sequencing (NGS) targeted gene panel. Methods: A panel of seven MODY genes was designed and employed to screen 50 patients fulfilling the MODY diagnostic criteria. Patients with no pathogenic, likely pathogenic or uncertain significance variants detected, were further tested by multiplex ligation‐dependent probe amplification (MLPA) for copy number variations (CNVs). Results: Eight different pathogenic or likely pathogenic variants were identified in eight MODY patients (diagnostic rate 16%). Five variants of uncertain significance were also detected in seven MODY patients. Five novel pathogenic and likely pathogenic variants were detected in the genes GCK; p.Cys371X, HNF1A; p.Asn402Tyr, HNF4A; p.Glu285Lys, and ABCC8; p.Met1514Thr and p.Ser1386Phe. Two de novo heterozygous deletions of the entire HNF1B gene were detected in two patients, raising the diagnostic rate to 20%. Conclusions: Although many MODY patients still remain without exact MODY type identification, the application of NGS methodology provided rapid results, increased diagnostic accuracy, and was cost‐effective compared to Sanger sequencing. Accurate genetic diagnosis of the MODY subtype is important for treatment selection, disease prognosis, and family counseling. [ABSTRACT FROM AUTHOR]

Background: A positive family history of type 2 diabetes (T2D) has been associated with risk awareness and risk‐reducing behaviours among the unaffected relatives. Yet, little is known about how people with a positive family history for diabetes develop and manage their personal sense of risk. Objective: To characterize two key concepts, salience and vulnerability, within the familial risk perception (FRP) model among unaffected individuals, at increased familial risk for T2D. Design: We conducted a mixed method study. Descriptions of salience and vulnerability were collected through semi‐structured interviews. Participant's perception of self‐reported risk factors (family history, age, race/ethnicity, medical history, weight and exercise) was measured using the Perceived Risk Factors for T2D Tool and was compared to a clinical evaluation of the same risk factors. Results: We identified two components of salience: (a) concern for developing T2D and (b) risk awareness triggers, and two features of vulnerability: (a) statement of risk and (b) risk assessment devices. Although few participants (26%) were concordant between their perceived and clinical overall T2D risk, concordance for individual risk factors was higher, ranging from 42% (medical history) to 90% (family history). Discussion and conclusion: Both familial and non‐familial events lead people to contemplate their T2D risk, even among people who have a positive family history. Participants often downplayed their overall risk and underestimated their overall risk compared to a clinical risk assessment of the same self‐reported risk factors. Clinicians could leverage key components of the FRP process as way to engage patients in risk reduction strategies earlier. [ABSTRACT FROM AUTHOR]

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People who have a single first‐degree relative with type 2 diabetes (T2D) are at increased risk for developing T2D over their lifetime. A positive family history of T2D is also associated with developing risk awareness and engaging in risk‐reducing behaviors among the unaffected relatives. Yet, little is known about how people with a positive family history for disease personalize and process their familial risk to form perceptions about their own risk. In this mixed method study, we explored risk personalization among a diverse group of people between the ages of 18 and 60, with a positive family history of T2D, who were themselves unaffected (n = 109). We collected interview and survey data with respect to the familial risk perception personalization model. Using cluster analysis, qualitative and quantitative data were combined to inductively derive three distinct clusters representing three different familial risk perception personalization processes. These results can serve as a basis for tailored interventions aimed at reducing risk for T2D among people with increased risk due to familial history. [ABSTRACT FROM AUTHOR]

Analogous to precision medicine, precision nutrition aims to tailor nutritional recommendations based on personal needs to optimize health. The field of nutritional genomics, which refers to the bidirectional interplay between dietary nutrients and the genome, is providing some of the necessary scientific evidence for precision nutrition. However, the extent of the clinical utility of nutritional genomics largely depends on the mode of disease/trait inheritance and remains unclear for prevalent, complex diseases, such as obesity, heart disease, and type 2 diabetes. Because genomic technology is now readily accessible through affordable personal DNA tests, it is now critical for nutritionists to establish a basic understanding in nutritional genomics to evaluate the validity of genetics-related "health claims" being provided by direct-to-consumer genetic testing companies. In this review, we provide examples of successful nutritional genomics studies, review current limitations, provide guidelines to evaluate health claims, and lastly discuss possible avenues and future outlooks for precision nutrition. [ABSTRACT FROM AUTHOR]

Polymorphisms at −176 in IL-6, and −238 and −308 in TNF-α have been described as risk factors for developing tuberculosis (TB) and type 2 diabetes mellitus (T2DM). However, it is not known how these changes influence the development of TB-T2DM comorbidity. The objective of this work was therefore to analyze the impact of these polymorphisms in the Mexican population. This is a cross-sectional study of cases and controls in which polymorphisms at −174 in IL-6 , −238 and −308 in TNF-α were identified in healthy subjects, those with TB, T2DM and carriers of the comorbidity, each group consisted of 30 individuals. Descriptions of the population, frequency of genotypes and risk association were calculated, and a reduction of multifactorial dimensionality between groups (MDR) was determined. Genotype 174 G/G-of IL-6 was observed in 78% of individuals, while −308 G/G and −238 G/G of TNF-α occurred in 90% and 91% of individuals, respectively. The −174 G/G IL-6 in individuals with T2DM increased five-fold (p =.02) the risk of developing the comorbidity. The MDR analysis showed that the association of −174 G/G IL-6 and −308 G/G TNF-α in healthy individuals increased the risk of developing the comorbidity up to six-fold (p =.019), while in individuals with T2DM, this risk augmented 14-fold (p =.0002). The −174 G/G IL-6 genotype increases the risk of developing comorbidity in the T2DM population and this risk is raised when associated with −308 G/G TNF-α. These findings have implications for understanding the epidemiological dynamics of the TB-T2DM comorbidity, promoting prevention strategies and inhibiting the development of this co-morbidity. • Genotype 174 G/G-of IL-6 was observed in 78% of individuals. • Genotype −308 G/G and −238 G/G of TNF-α occurred in 90% and 91% of individuals. • Association of −174 G/G IL-6 + −308 G/G TNF-α, increase 14-fold comorbidity risk [ABSTRACT FROM AUTHOR]

Background and Objective: Genetics play a very strong role in the development of pediatric‐onset type 2 diabetes (T2D); however, little information exists about specific common single nucleotide polymorphisms (SNPs) associated with T2D in this age group. The aim of the study was to analyze the association and parental transmission of 64 obesity‐related SNPs with pediatric‐onset T2D in Mexican families. Methods: A total of 57 pedigrees containing 171 probands with pediatric‐onset T2D and 119 unrelated controls older than 18 years were included. The participants were genotyped for 64 polymorphisms. Association of each variant with pediatric‐onset T2D was analyzed through a parent‐offspring transmission disequilibrium test (TDT) and in a case‐control comparison by χ2 analysis. Results: Five SNPs exhibited associations with pediatric‐onset T2D in the combined case‐parent trio and case‐control analysis: LINGO/rs10968576 (odds ratio [OR] 1.82, P = 0.003), POC5/rs2112347 (OR 1.96, P = 2.4E‐5), RPS10‐NUDT3/rs206936 (OR 1.40, P = 0.023), GLIS3/rs7034200 (OR 2.34, P = 1.2E‐6), and VEGFA/rs6905288 (OR 1.58, P = 0.015). The first three were also associated with obesity status. The SNPs POC5/rs2112347 and RPS10‐NUDT3/rs206936 were significantly associated through the maternal allele and GLIS3/rs7034200 through the paternal allele (P < 0.05). Conclusions: These findings suggest that certain SNPs associated with obesity and other metabolic traits may also be involved in risk of pediatric‐onset T2D in Mexican families. We also identified preferential transmission of parental alleles in some variants. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to study whether macronutrient intake could modify the association between ApoB Ins/Del and lipid profile, and serum leptin and ghrelin in type 2 diabetes mellitus (T2DM) patients. Methods: In this study, 700 T2DM patients were recruited. Anthropometric, biochemical and molecular data were collected, and Diet was assessed using a food frequency questionnaire. The interactions were tested using ANCOVA. Results: Del-allele carriers with high-MUFA and carbohydrate (≥ 12 and ≥ 54% of energy, respectively) had significantly higher TG (P = 0.04) and LDL-C (P = 0.02) compared to Ins/Ins homozygotes, and these were not significant in subjects with low-MUFA and -carbohydrate (< 12 and < 54%, respectively). A significant interaction was observed between ApoB Ins/Del and diet on TG in both unadjusted (P = 0.03) and adjusted models (model 2 and 3, P = 0.04 and P = 0.04, respectively), and on LDL-C only in adjusted models (model 2 and 3, P = 0.03 and P = 0.029, respectively). Besides, Del-allele carriers with protein, SFA, MUFA and n-3PUFA of ≥ 14, 9, 12 and 0.6%, respectively, had a significant increase in their serum leptin than Ins/Ins homozygotes (P < 0.05). However, these associations were not significant between the two genetic groups in subjects with low intakes of protein, SFA, MUFA and n-3PUFA. Moreover, Del-allele carriers with low carbohydrate (< 54%) had significantly higher leptin and ghrelin than Ins/Ins homozygotes (P < 0.05), however, in high-carbohydrate group, leptin and ghrelin were not significantly lower. Conclusions: These findings indicate that the interaction between ApoB Ins/Del and dietary intake of MUFA, SFA, n-3PUFA, carbohydrate and protein could modulate the serum levels of TG, LDL-C, leptin and ghrelin in T2DM patients. [ABSTRACT FROM AUTHOR]

Vascular calcification is highly prevalent in patients with type 2 diabetes mellitus (T2DM), one of the most common chronic diseases with high morbidity and mortality. In recent years, microRNAs have been widely reported as potential biomarkers for the diagnosis and treatment of T2DM. We hypothesized that miR‐128‐3p is associated with cardiovascular calcification and insulin resistance (IR) in rats with T2DM by targeting ISL1 via the Wnt pathway. Microarray analysis was adopted to identify differentially expressed genes related to T2DM. T2DM models were induced in rats. Blood samples from normal and T2DM rats were used to detect islet β‐cell function, islet sensitivity, and calcium content. Next, islet tissues were obtained to identify the expression of miR‐128‐3p, ISL1, and the Wnt signaling pathway‐ and apoptosis‐related genes. Finally, apoptosis of islet β‐cells was determined by flow cytometry. Through microarray analysis of GSE27382 and GSE23343, ISL1 was found to be downregulated in T2DM. In blood samples from T2DM rats, basic biochemical indicators, IR, and calcium content were increased, and islet sensitivity and islet β‐cell function were decreased. Furthermore, upregulation of miR‐128‐3p and ISL1 gene silencing promoted the expression of Wnt‐1, β‐catenin, GSK‐3β, and Bax and the phosphorylation of β‐catenin and GSK‐3β, inhibited c‐fos, PDX‐1, and Bcl‐2 expression, and enhanced cell apoptosis. The key findings of our study demonstrate that miR‐128‐3p aggravates cardiovascular calcification and IR in T2DM rats by downregulating ISL1 through the activation of the Wnt pathway. Thus, miR‐128‐3p may serve as a potential target for the treatment of T2DM. [ABSTRACT FROM AUTHOR]

Abstract Aims ATP-binding cassette transporter 1 (ABCA1) gene polymorphism has been reported as one of the genetic risk factors for T2DM in various populations with conflicting results. The aim of this study is to investigate the association of ABCA1 C69T polymorphism and lipid profile with T2DM in Bangladeshi population. Materials and methods A total of 102 T2DM subjects and 98 healthy controls were recruited and their genotypes for ABCA1 gene polymorphisms were determined based on the PCR-RFLP technique. Serum lipid profiles (total cholesterol, HDL-C, LDL-C and TG) were also estimated by using standard methods. Results ABCA 1 (C69T) genotypes frequencies were estimated. The percentages of CC, CT and TT genotypes at 69 position of ABCA1 gene were 31.63%, 58.16% and 10.21% in control as well as 22.54%, 69.60% and 7.86% in diabetes group respectively. Significant association was not found between ABCA1 (C69T) genotypes and T2DM in Bangladeshi population (Odd Ratio: 1.67; 95% Confidence Interval: 0.88 to 3.19 for CT genotype and Odd Ratio: 1.07; Confidence Interval: 0.36 to 3.16 for TT genotype; p > 0.05). Serum lipid profiles were not associated with T2DM. Conclusion ABCA1 gene polymorphism might not be a genetic risk factor for T2DM subjects among Bangladeshis. We did not find a relationship between genotypes and lipid concentrations in our two groups. Study with a larger sample size will help us to understand the relationship of ABCA1 C69T genotype and lipid profile with T2DM. [ABSTRACT FROM AUTHOR]

Introduction: Genetic polymorphisms in TCF7L2 are the strongest common risk variants for type 2 diabetes mellitus (T2D). We and others have shown that genetic variation in TCF7L2 and WFS1 affect incretin-stimulated insulin secretion. A recent genome-wide association study discovered genetic variants associated with incretin levels. We hypothesized that these SNPs (single nucleotide polymorphisms) interact with the well-known TCF7L2 variant rs7903146 on insulin secretion due to their incretin altering effect. Methods: In this retrospective analysis, we used data from the cross-sectional TUEF-cohort (n = 2929) and a hyperglycemic clamp study using additional GLP-1 infusion at the end of the clamp (n = 76). Insulin secretion was measured by evaluating OGTT-derived indexes of insulin secretion and insulin/C-peptide levels during clamp. We genotyped rs7903146 in TCF7L2 , rs10010131 in WFS1 , and six SNPs associated with GLP-1 and GIP levels. Results: One of the six incretin-associated SNPs, rs17681684 in GLP2R , exhibited significant SNP x SNP interactions with rs7903146 in TCF7L2 on insulin secretion (p = 0.0024) after correction for multiple testing. Three further SNP's showed nominally significant interactions (p < 0.05). In the hyperglycemic clamp study, rs7903146 in TCF7L2 also interacted with rs17681684 on AUC C-peptide during the GLP-1 stimulation phase, thereby replicating the above finding. Conclusion: The findings exemplify the role of SNP x SNP interactions in the genetics of type 2 diabetes mellitus and corroborate the existence of clinically relevant differences in incretin sensitivity. [ABSTRACT FROM AUTHOR]

Background: Maturity‐onset diabetes of the young (MODY) is caused by autosomal dominant mutations in one of 13 confirmed genes. Estimates of MODY prevalence vary widely, as genetic screening is usually restricted based on clinical features, even in population studies. We aimed to determine prevalence of MODY variants in a large and unselected pediatric diabetes cohort. Methods: MODY variants were assessed using massively parallel sequencing in the population‐based diabetes cohort (n = 1363) of the sole tertiary pediatric diabetes service for Western Australia (population 2.6 million). All individuals were screened, irrespective of clinical features. MODY variants were also assessed in a control cohort (n = 993). Results: DNA and signed consent were available for 821 children. Seventeen children had pathogenic/likely pathogenic variants in MODY genes, two diagnosed with type 2 diabetes, four diagnosed with antibody‐negative type 1 diabetes (T1DM), three diagnosed with antibody‐positive T1DM, and eight previously diagnosed with MODY. Prevalence of MODY variants in the sequenced cohort was 2.1%, compared to 0.3% of controls. Conclusions: This is the first comprehensive study of MODY variants in an unselected population‐based pediatric diabetes cohort. The observed prevalence, increasing access to rapid and affordable genetic screening, and significant clinical implications suggest that genetic screening for MODY could be considered for all children with diabetes, irrespective of other clinical features. [ABSTRACT FROM AUTHOR]

Objective: Innate immunity factors are associated with type 2 diabetes (T2DM) and its complications. Therefore, T2DM has been suggested to be an immune-dependent disease. Elevated fasting glucose level and higher concentrations of innate immunity soluble molecules are not only related with insulin resistance, but inflammation is also an important factor in beta cell dysfunction in T2DM. Toll-like receptor 2 (TLR-2), which has an important role in inducing innate immune cells, is thought to have suppressive roles on immune responses in T2DM. We therefore aimed to investigate the possible role of TLR-2 del -196-174 and Arg753Gln variants in T2DM pathogenesis. Materials and Methods: This study was designed as a case-control study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used to genotype the two variants in 100 T2DM patients and 98 agematched controls. Results: We found significantly higher frequencies of TLR-2 del -196-174 DD genotype (P=0.003), ID genotype (P=0.009) and D allele (P=0.001) in patients compared with controls. In addition, the II genotype (P=0.001) and the I allele (P=0.003) frequencies were elevated in healthy controls. We did not find any significant differences in frequency distribution for the Arg753Gln variant in study groups. Conclusion: We suggest that carrying the D allele of the TLR-2 del -196-174 variant may be related as a risk factor for T2DM. [ABSTRACT FROM AUTHOR]

Summary: What is known and objective: Glibenclamide is a prescribed glucose‐lowering medication for diabetes, but there are interindividual variations in the therapeutic response. In this cross‐sectional study, the aim was to explore the association of genetic variants in CYP2C9, ABCC8, KCNJ11 and TCF7L2 with good glycaemic control in Mexican type 2 diabetes (T2D) treated with glibenclamide. Methods: Patients with T2D receiving treatment with glibenclamide or glibenclamide plus metformin were included. Patients with A1C ≤ 7% were considered to have good glycaemic control, whereas patients with A1C ≥ 8% were considered having poor glycaemic control. Genotyping was performed by real‐time PCR using TaqMan probes for the genetic variants. Association was performed by calculating OR with 95% confidence intervals (95% CI). For the multivariate analysis, a multiple logistic regression was performed including the confounding variables age, exercised, BMI, glibenclamide dose, time with T2D and concomitant metformin. Results and discussion: Four hundred and four patients were included in the study, median age of the participants was 50 years (IQR 11.0), the median time with disease was 6 years (IQR 8.0), 118 (29.2%) were men, and 243 (60.1%) received glibenclamide in combination with metformin. CYP2C9*3 variant was associated with good glycaemic control (OR = 2.747 [95% CI, 1.194‐6.324]), whereas the variants, CYP2C9*2, TCF7L2 rs7903146 and rs12255372, ABCC8 rs757110 and KCNJ11 rs5219, were not. In the multivariate analysis, the CYP2C9*3 variant maintained its association (OR = 2.779 [95% CI, 1.142‐6.763]). What is new and conclusion: The findings suggest that CYP2C9*3 genetic variant independently contributes to good glycaemic control of patients with type 2 diabetes treated with glibenclamide. The findings suggest that CYP2C9*3 genetic variant independently contributes to good glycemic control of patients with type 2 diabetes treated with glibenclamide. [ABSTRACT FROM AUTHOR]

To identify novel disease genes for type 2 diabetes (T2D) we generated two backcross populations of obese and diabetessusceptible New Zealand Obese (NZO/HI) mice with the two lean mouse strains 129P2/OlaHsd and C3HeB/FeJ. Subsequent wholegenome linkage scans revealed 30 novel quantitative trait loci (QTL) for T2D-associated traits. The strongest association with blood glucose [12 cM, logarithm of the odds (LOD) 13.3] and plasma insulin (17 cM, LOD 4.8) was detected on proximal chromosome 7 (designated Nbg7p, NZO blood glucose on proximal chromosome 7) exclusively in the NZOxC3H crossbreeding, suggesting that the causal gene is contributed by the C3H genome. Introgression of the critical C3H fragment into the genetic NZO background by generating recombinant congenic strains and metabolic phenotyping validated the phenotype. For the detection of candidate genes in the critical region (30-46 Mb), we used a combined approach of haplotype and gene expression analysis to search for C3H-specific gene variants in the pancreatic islets, which appeared to be the most likely target tissue for the QTL. Two genes, Atp4a and Pop4, fulfilled the criteria from our candidate gene approaches. The knockdown of both genes in MIN6 cells led to decreased glucosestimulated insulin secretion, indicating a regulatory role of both genes in insulin secretion, thereby possibly contributing to the phenotype linked to Nbg7p. In conclusion, our combined- and comparative-cross analysis approach has successfully led to the identification of two novel diabetes susceptibility candidate genes, and thus has been proven to be a valuable tool for the discovery of novel disease genes. [ABSTRACT FROM AUTHOR]

Objectives. AQP7 and AQP9 represent glycerol channel in adipose tissue and liver and have been associated with metabolic diseases. We aimed to investigate the associations between genetic variants in AQP7 and AQP9 genes and the risk of type 2 diabetes (T2DM) in Chinese population. Methods. Blood samples were drawn from 400 T2DM patients and 400 age- and gender-matched controls. Genomic DNA was extracted by proteinase K digestion and phenol–chloroform extraction. Genotyping of 5 single nucleotide polymorphisms (SNPs) in AQP7 (rs2989924, rs3758269, and rs62542743) and AQP9 (rs57139208, rs16939881) was performed by the polymerase chain reaction assay with TaqMan probes. Results. The subjects with rs2989924 GA+AA genotypes had 1.47-fold increased risk of T2DM (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.06-2.04), compared to those with GG genotype, and this association remained significant after adjustment for covariates (OR 1.66, 95% CI 1.07-2.57). When compared with rs3758269 CC genotype, the subjects with CT+TT genotypes had 45% decreased T2DM risk after multivariate adjustment (OR 0.55, 95% CI 0.35-0.85). The associations were evident in elder and overweight subjects and those with central obesity. No association was observed between AQP9 SNPs and T2DM risk. Conclusions. AQP7 SNP rs2989924 and rs3758269 were associated with T2DM risk in Chinese Han population. [ABSTRACT FROM AUTHOR]

Background: Causative mutations cannot be identified in the majority of Asian patients with suspected maturity‐onset diabetes of the young (MODY). Objectives: To elucidate the genetic basis of Japanese patients with MODY‐like diabetes and gain insight into the etiology of patients without mutations in the major MODY genes. Subjects A total of 263 Japanese patients with early‐onset, non‐obese, MODY‐like diabetes mellitus referred to Osaka City General Hospital for diagnosis. Methods: Mutational analysis of the four major MODY genes (GCK, HNF1A, HNF4A, HNF1B) by Sanger sequencing. Mutation‐positive and mutation‐negative patients were further analyzed for clinical features. Results: Mutations were identified in 103 (39.2%) patients; 57 mutations in GCK; 29, HNF1A; 7, HNF4A; and 10, HNF1B. Contrary to conventional diagnostic criteria, 18.4% of mutation‐positive patients did not have affected parents and 8.2% were in the overweight range (body mass index [BMI] >85th percentile). HOMA‐IR at diagnosis was elevated (>2) in 15 of 66 (22.7%) mutation‐positive patients. Compared with mutation‐positive patients, mutation‐negative patients were significantly older (P = 0.003), and had higher BMI percentile at diagnosis (P = 0.0006). Interestingly, maternal inheritance of diabetes was significantly more common in mutation‐negative patients (P = 0.0332) and these patients had significantly higher BMI percentile as compared with mutation‐negative patients with paternal inheritance (P = 0.0106). Conclusions: Contrary to the conventional diagnostic criteria, de novo diabetes, overweight, and insulin‐resistance are common in Japanese patients with mutation‐positive MODY. A significant fraction of mutation‐negative patients had features of early‐onset type 2 diabetes common in Japanese, and non‐Mendelian inheritance needs to be considered for these patients. [ABSTRACT FROM AUTHOR]

Abstract Purpose Long-noncoding RNAs (lncRNAs) have been reported to regulate glucose homeostasis and insulin synthesis and secretion. However, the association of genetic variants of lncRNAs and type 2 diabetes (T2D) has not been evaluated. Therefore, in the present study we investigated the association between H19 rs217727 and H19 rs3741219 variants and MEG3 rs7158663 polymorphism with T2D susceptibility. Materials and methods The study population consists of 969 subjects including 496 T2D patients and 473 non-diabetic age and sex-matched controls. The H19 and MEG3 variants genotyping were performed by PCR-RFLP method. Results Our results revealed that the T allele of rs217727 was more frequent in T2D group compared with controls ( P = 0.007, OR = 1.1, 95% CI: 1.02–1.18). Moreover, the rs217727-TT genotype was significantly associated with T2D after adjustment for age, BMI and lipid levels ( P = 0.041, OR = 1.53, 95% CI: 1.01–2.32). However, no significant difference was detected for allele or genotype frequencies of H19 rs3741219 between T2D and controls ( P = 0.71). Furthermore, the findings showed that the AA genotype of MEG3 rs7158663 was associated with significantly increased risks of T2D compared with the GG genotype ( P = 0.026, OR = 1.79, 95% CI: 1.07–2.99). The results remained significance after analysis by logistic regression ( P = 0.033, Adjusted OR = 1.72, 95% CI: 1.04–2.84). Finally, bioinformatics analysis showed that these SNPs could alter local RNA folding structure and also the miRNA-lncRNA interactions. Conclusions Our findings provided the evidence of significant association between H19 rs217727-TT and MEG3 rs7158663-AA genotypes with T2D susceptibility. Highlights • The H19 rs217727-TT and MEG3 rs7158663-AA genotypes were significantly associated with T2D susceptibility • No significant difference was detected for allele or genotype frequencies of H19 rs3741219 between T2D patients and controls • These SNPs could alter local RNA folding structure and also the miRNA-lncRNA interactions [ABSTRACT FROM AUTHOR]

Abstract With the advent of recent advances in molecular techniques and whole genome sequencing, we have come to know that the non-coding landscape (including non-coding RNAs, tRNAs and even telomeres) plays a major role in the regulation of cellular processes. Furthermore, the deregulation of this landscape has been found to contribute to and even bring about the pathogenesis of a large number of diseases. One of such diseases is diabetes mellitus (type 2 specifically) whose incidence rate and global burden is constantly increasing. Nutrition has been proven to be a key player in the development, onset and control of type 2 diabetes mellitus. Additionally, non-coding DNA based molecular markers are emerging as biomarkers of T2D, susceptibility, and perhaps dietary supplements can modulate non-coding DNA based markers expression and function in T2D management. In this review, we provide a brief overview of the developmental origins and genetics of type 2 diabetes mellitus, how each component of the non-coding landscape contributes to the development and progression of the disease and finally we discuss how dietary interventions modulate the non-coding landscape in T2D. Highlights • The non-coding landscape plays a major role in the regulation of cellular processes • Preliminary evidence suggests that the non-coding landscape is heavily implicated in pathogenesis of T2D • Nutrition has been proven to be a key player in the development, onset and control of type 2 diabetes mellitus • Changes in the expression patterns of the non-coding landscape have been reported due to dietary interventions in T2D [ABSTRACT FROM AUTHOR]

Abstract In the current study, a sample population of Northern Iranians was selected to investigate the association of K121Q, rs1799774, rs7754561, and rs997509 ENPP1 gene variants and their haplotypes with T2DM. Genomic DNAs of 978 samples were extracted by Salting Out standard technique and then genotyped by the TaqMan assay. The results show significant differences between study groups for K121Q ( p = 0.0004) under a Dominant and rs7754561 ( p = 0.002) under a co-dominant hereditary model. Based on allele frequency, there was a significant difference between two study groups at K121Q and rs7754561 variants ( p = 0.010 and p = 0.01, respectively). There was no evidence for an association between ENPP1 haplotypes and overall risk of T2DM. Genotype-phenotype sub-analyses showed no significant relationship of four studied polymorphisms with age, gender, FBS, and systolic and diastolic blood pressures. Homology modeling and molecular docking of ENPP1 in K173 and Q173 models with ATP, AMP, and 2′3′-cGAMP as ligands revealed that all ligands had a more binding affinity to Lys173 protein model, and 2′3′-cGAMP had a higher affinity to both ENPP1 protein models compared to ATP and AMP. These findings suggest that ENPP1 gene variants may have a potential impact on the occurrence of T2DM in Northern Iranians. Highlights • Genotyping of K121Q might have key roles in the association of ENPP1 gene with type 2 diabetes mellitus among Iranians. • Investigation of rs7754561 showed association with T2DM among Iranians. • Genotyping of K121Q could have potential impacts on drug designing and administration of T2DM as a complementary test. [ABSTRACT FROM AUTHOR]

Microtubule actin cross-linking factor 1 (MACF1) gene variant rs2296172 has recently been associated with type 2 diabetes (T2D). However, this variant has never been evaluated as such in Indian populations. In the present replication study, we genotyped variant rs2296172 by Taqman allele discrimination assay in 432 individuals belonging to the Bania caste group from Punjab, India. The single-nucleotide polymorphism (SNP) was evaluated for association with T2D, in a population based candidate gene case-control association study design, by estimating odds ratio with 95% confidence interval. The SNP rs2296172 of MACF1 was found to be significantly associated with T2D (p = 0.02) and odds ratio (OR) = 1.59 (1.06-2.38) at 95% CI. We further emphasize that the Indian population as such is a conglomeration of various endogamous population groups. It is critical that such replication studies be carried out in various populations to find association of variants to T2D susceptibility and understand genetic heterogeneity. However, it is important to avoid pooling of samples to address the concern of population stratification. [ABSTRACT FROM AUTHOR]

Background: TCF7L2 gene encodes a transcription factor that plays an important role in the Wnt signaling pathway. In this pathway TCF7L2 protein induces transcription of genes involved in glucose homeostasis, such as intestinal proglucagon. The aim of present study was to investigate the association of rs12255372, and rs290487 polymorphisms of TCF7L2 with T2DM in Arab ethnic of Khuzestan province in Iran. Methods: 100 patients with T2D and 97 normoglycemic subjects were included in this study. The PCR-RFLP and TETRA ARMS- PCR technique, subsequently validated by direct sequencing, was used for genotyping. Results: A significant difference in TT genotype was observed between two groups patient and control (OR=4.12, 95%CI=1.55-10.55, P=0.005). Also T allele frequencies of rs12255372 was different in the groups (0R=1.69, 95%CI=1.12-2.53, p=0.02). No allelic or genotypic association with T2D was detected for rs290487. Conclusion: Our finding suggest that TT genotypes rs12255372 confers an increased risk of developing T2D. The rs290487 is unlikely an influential variant with type 2 diabetes in this population. [ABSTRACT FROM AUTHOR]

Background Apolipoprotein B (APOB), and hepatic lipase (LIPC) genes have been shown to play a key role in lipid metabolism in type 2 diabetes (T2D). This study aimed to investigate the association of the three polymorphisms (rs679899 in APOB and rs6078 and rs6083 in LIPC) with T2D and related clinical quantitative traits. Methods We conducted a case-control study in Chinese Han population, with a total of 929 T2D patients and 1044 healthy subjects in Chinese Han population. Polymorphisms were genotyped by MassARRAY Genotyping System. Results The risk allele G of the polymorphism rs679899 was related to T2D (odds ratio (OR): 1.207, 95% confidence interval (CL): 1.006–1.448, P  = 0.043) and the polymorphism rs679899 was associated with glutamyl transpeptidase (GGT) levels ( P  = 0.001). We also showed that the polymorphism rs6083 was associated with cholesterol (CHOL) levels ( P  = 0.012), triglyceride (TG) levels ( P  = 0.040), and low-density lipoprotein cholesterol (LDL) levels ( P  = 0.033). No significant difference in genotypic frequencies of rs6078 and rs6083 was observed between T2D patients and controls. Conclusion This study suggests that the APOB polymorphism rs679899 is associated with type 2 diabetes and GGT levels, while the LIPC polymorphism rs6083 may influence CHOL, TG, and LDL levels in Chinese Han population. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes (T2D) susceptibility is influenced by genetic and lifestyle factors. To date, the majority of genetic studies of T2D have been in populations of European and Asian descent. The focus of this study is on genetic variations underlying T2D in Qataris, a population with one of the highest incidences of T2D worldwide. Results: Illumina HiSeq exome sequencing was performed on 864 Qatari subjects (574 T2D cases, 290 controls). Sequence kernel association test (SKAT) gene-based analysis identified an association for low frequency potentially deleterious variants in 6 genes. However, these findings were not replicated by SKAT analysis in an independent cohort of 12,699 exomes, primarly due to the absence of low frequency potentially deleterious variants in 5 of the 6 genes. Interestingly one of the genes identified, catenin beta 1 (CTNNB1, β-catenin), is the key effector of the Wnt pathway and interacts with the nuclear receptor transcription factor 7-like 2 (TCF7L2), variants which are the most strongly associated with risk of developing T2D worldwide. Single variant analysis did not identify any associated variants, suggesting the SKAT association signal was not driven by individual variants. None of the 6 associated genes were among 634 previously described T2D genes. Conclusions: The observation that genes not previously linked to T2D in prior studies of European and Asian populations are associated with T2D in Qatar provides new insights into the complexity of T2D pathogenesis and emphasizes the importance of understudied populations when assessing genetic variation in the pathogenesis of common disorders. [ABSTRACT FROM AUTHOR]

Abstract: Aims/Introduction: Emerging evidence has suggested that the genetic background of gestational diabetes mellitus (GDM) was analogous to type 2 diabetes mellitus. In contrast to type 2 diabetes mellitus, the genetic studies for GDM were limited. Accordingly, the aim of the present study was to extensively explore the influence of micro‐ribonucleic acid‐binding single‐nucleotide polymorphisms (SNPs) in type 2 diabetes mellitus candidate loci on GDM susceptibility in Chinese. Materials and Methods: A total of 839 GDM patients and 900 controls were enrolled. Six micro‐ribonucleic acid‐binding SNPs were selected from 30 type 2 diabetes mellitus susceptibility loci and genotyped using TaqMan allelic discrimination assays. Results: The minor allele of three SNPs, PAX4 rs712699 (OR 1.366, 95% confidence interval 1.021–1.828, P = 0.036), KCNB1 rs1051295 (OR 1.579, 95% confidence interval 1.172–2.128, P = 0.003) and MFN2 rs1042842 (OR 1.398, 95% confidence interval 1.050–1.862, P = 0.022) were identified to significantly confer higher a risk of GDM in the additive model. The association between rs1051295 and increased fasting plasma glucose (b = 0.006, P = 0.008), 3‐h oral glucose tolerance test plasma glucose (b = 0.058, P = 0.025) and homeostatic model assessment of insulin resistance (b = 0.065, P = 0.017) was also shown. Rs1042842 was correlated with higher 3‐h oral glucose tolerance test plasma glucose (b = 0.056, P = 0.028). However, no significant correlation between the other included SNPs (LPIN1 rs1050800, VPS26A rs1802295 and NLRP3 rs10802502) and GDM susceptibility were observed. Conclusions: The present findings showed that micro‐ribonucleic acid‐binding SNPs in type 2 diabetes mellitus candidate loci were also associated with GDM susceptibility, which further highlighted the similar genetic basis underlying GDM and type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

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 reported to be associated with type 2 diabetes and various metabolic derangements. We investigated the associations between specific calpain- 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 characteristics 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 significantly 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. [ABSTRACT FROM AUTHOR]

Manipulation of the gut microbiota presents a new opportunity to combat chronic diseases. Randomized controlled trials of probiotics suggest some associations with adiposity, lipids, and insulin resistance, but to our knowledge no trials with “hard” outcomes have been conducted. We used separate-sample Mendelian randomization to obtain estimates of the associations of 27 genera of gut microbiota with ischemic heart disease, type 2 diabetes mellitus, adiposity, lipid levels, and insulin resistance, based on summary data from CARDIoGRAAMplusC4D and other consortia. Among the 27 genera, a 1-allele increase in single nucleotide polymorphisms related to greater abundance of Bifidobacterium was associated with lower risk of ischemic heart disease (odds ratio = 0.985, 95% confidence interval (CI): 0.971, 1.000; P = 0.04), a 0.011–standard-deviation lower body mass index (95% CI: −0.017, −0.005), and a 0.026–standard-deviation higher low-density lipoprotein cholesterol level (95% CI: 0.019, 0.033), but the findings were not robust to exclusion of potential pleiotropy. We also identified Acidaminococcus, Aggregatibacter, Anaerostipes, Blautia, Desulfovibrio, Dorea, and Faecalibacterium as being nominally associated with type 2 diabetes mellitus or other risk factors. Results from our study indicate that these 8 genera of gut microbiota should be given priority in future research relating the gut microbiome to ischemic heart disease and its risk factors. [ABSTRACT FROM AUTHOR]