ZRANB3 is an African-specific type 2 diabetes locus associated with beta-cell mass and insulin response.
Ontology highlight
ABSTRACT:
SUBMITTER: Adeyemo AA
PROVIDER: S-EPMC6642147 | biostudies-literature | 2019 Jul
REPOSITORIES: biostudies-literature
Publications
ZRANB3 is an African-specific type 2 diabetes locus associated with beta-cell mass and insulin response.
Adeyemo Adebowale A AA Zaghloul Norann A NA Chen Guanjie G Doumatey Ayo P AP Leitch Carmen C CC Hostelley Timothy L TL Nesmith Jessica E JE Zhou Jie J Bentley Amy R AR Shriner Daniel D Fasanmade Olufemi O Okafor Godfrey G Eghan Benjamin B Agyenim-Boateng Kofi K Chandrasekharappa Settara S Adeleye Jokotade J Balogun William W Owusu Samuel S Amoah Albert A Acheampong Joseph J Johnson Thomas T Oli Johnnie J Adebamowo Clement C Collins Francis F Dunston Georgia G Rotimi Charles N CN
Nature communications 20190719 1
Genome analysis of diverse human populations has contributed to the identification of novel genomic loci for diseases of major clinical and public health impact. Here, we report a genome-wide analysis of type 2 diabetes (T2D) in sub-Saharan Africans, an understudied ancestral group. We analyze ~18 million autosomal SNPs in 5,231 individuals from Nigeria, Ghana and Kenya. We identify a previously-unreported genome-wide significant locus: ZRANB3 (Zinc Finger RANBP2-Type Containing 3, lead SNP p = ...[more]
Similar Datasets
Project description:Although type 2 diabetes (T2D) results from metabolic defects in insulin secretion and insulin sensitivity, most of the genetic risk loci identified to date relates to insulin secretion. We reported that T2D loci influencing insulin sensitivity may be identified through interactions with insulin secretion loci, thereby leading to T2D. Here, we hypothesize that joint testing of variant main effects and interaction effects with an insulin secretion locus increases power to identify genetic interactions leading to T2D. We tested this hypothesis with an intronic MTNR1B SNP, rs10830963, which is associated with acute insulin response to glucose, a dynamic measure of insulin secretion. rs10830963 was tested for interaction and joint (main + interaction) effects with genome-wide data in African Americans (2,452 cases and 3,772 controls) from five cohorts. Genome-wide genotype data (Affymetrix Human Genome 6.0 array) was imputed to a 1000 Genomes Project reference panel. T2D risk was modeled using logistic regression with rs10830963 dosage, age, sex, and principal component as predictors. Joint effects were captured using the Kraft two degrees of freedom test. Genome-wide significant (P < 5 × 10-8 ) interaction with MTNR1B and joint effects were detected for CMIP intronic SNP rs17197883 (Pinteraction = 1.43 × 10-8 ; Pjoint = 4.70 × 10-8 ). CMIP variants have been nominally associated with T2D, fasting glucose, and adiponectin in individuals of East Asian ancestry, with high-density lipoprotein, and with waist-to-hip ratio adjusted for body mass index in Europeans. These data support the hypothesis that additional genetic factors contributing to T2D risk, including insulin sensitivity loci, can be identified through interactions with insulin secretion loci.
| S-EPMC6160319 | biostudies-literature
Project description:As a transcription factor, Ets1 (E26 transformation-specific-1 transcription factor) plays an important role in cell growth, development, differentiation, etc. Our research found that it plays an crucial role in β cell dysfunction induced by metabolic stress such as high glucose. In order to further clarify the downstream target molecules of Ets1 in β cells and the potential mechanism of regulating the mRNA level of target molecules, we transfected Min6(Mouse insulinoma cells) with control virus (Ad-GFP) and Ets-1 overexpression adenovirus (Ad-Ets-1) respectively. Through immunoprecipitation of Ets1 antibody, the DNA fragment specifically bound to Ets1 was obtained and used in high-throughput sequencing. By comparing the enriched DNA fragment with mouse genome (mm10) DNA, the downstream genes that Ets1 can bind to under physiological conditions and the differential peak related genes after overexpression of Ets1 were obtained. Through GO analysis and KFGG analysis of the above related genes, it was confirmed that there was an obvious regulatory relationship between Ets1 and β cell function related genes. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for E26 transformation-specific-1 transcription factor (Ets-1) in Min6 cells transfected Control virus (Ad-GFP) and Ets-1 overexpression adenovirus (Ad-Ets-1)
2022-10-09 | GSE214924 | GEO
Project description:ObjectiveThis study evaluates insulin sensitivity, pancreatic beta-cell function (BCF), and the balance between the two in youth with type 2 diabetes and assesses the relationship of diabetes duration and HbA(1c) to insulin sensitivity and BCF.Research design and methodsThe subjects were 14 adolescents with type 2 diabetes and 20 obese control subjects of comparable age, BMI, body composition, and puberty. Insulin sensitivity was evaluated with a 3-h hyperinsulinemic (80 mU . m(-2) . min(-1)) euglycemic clamp. First-phase insulin secretion (FPIS) and second-phase insulin secretion (SPIS) were evaluated with a 2-h hyperglycemic (12.5 mmol/l) clamp. Fasting glucose rate of appearance was determined with the use of [6,6-(2)H(2)]glucose.ResultsFasting glucose rate of appearance was higher in type 2 diabetic patients than in obese control subjects (16.5 +/- 1.1 vs. 12.3 +/- 0.5 micromol . kg(-1) . min(-1); P = 0.002). Insulin sensitivity was lower in type 2 diabetic patients than in obese control subjects (1.0 +/- 0.1 vs. 2.0 +/- 0.2 micromol . kg(-1) . min(-1) per pmol/l; P = 0.001). Fasting insulin was higher in type 2 diabetic patients than in obese control subjects (289.8 +/- 24.6 vs. 220.2 +/- 18.0 pmol/l; P = 0.007), and FPIS and SPIS were lower (FPIS: 357.6 +/- 42.0 vs. 1,365.0 +/- 111.0 pmol/l; SPIS: 652.2 +/- 88.8 vs. 1,376.4 +/- 88.8 pmol/l; P < 0.001 for both). The glucose disposition index (GDI = insulin sensitivity x FPIS) was approximately 86% lower in type 2 diabetic patients than in obese control subjects. HbA(1c) correlated with FPIS (r = -0.61, P = 0.025) with no relationship to insulin sensitivity.ConclusionsDespite the impairment in both insulin sensitivity and BCF in youth with type 2 diabetes, the magnitude of the derangement is greater in BCF than insulin sensitivity when compared with that in obese control subjects. The inverse relationship between BCF and HbA(1c) may either reflect the impact of deteriorating BCF on glycemic control or be a manifestation of a glucotoxic phenomenon on BCF. Future studies in youth type 2 diabetes should target the natural course of beta-cell failure and means of retarding and/or preventing it.
| S-EPMC3428068 | biostudies-literature
Project description:ObjectiveTo determine the pharmacokinetic and pharmacodynamic dose-response effects of insulin glargine administered subcutaneously in individuals with type 2 diabetes.Research design and methodsTwenty obese type 2 diabetic individuals (10 male and 10 female, aged 50 +/- 3 years, with BMI 36 +/- 2 kg/m(2) and A1C 8.3 +/- 0.6%) were studied in this single-center, placebo-controlled, randomized, double-blind study. Five subcutaneous doses of insulin glargine (0, 0.5, 1.0, 1.5, and 2.0 units/kg) were investigated on separate occasions using the 24-h euglycemic clamp technique. RESULTS Glargine duration of action to reduce glucose, nonessential fatty acid (NEFA), and beta-hydroxybutyrate levels was close to or >24 h for all four doses. Increases in glucose flux revealed no discernible peak and were modest with maximal glucose infusion rates of 9.4, 6.6, 5.5, and 2.8 mumol/kg/min for the 2.0, 1.5, 1.0, and 0.5 units/kg doses, respectively. Glargine exhibited a relatively hepatospecific action with greater suppression (P < 0.05) of endogenous glucose production (EGP) compared with little or no increases in glucose disposal.ConclusionA single subcutaneous injection of glargine at a dose of >or=0.5 units/kg can acutely reduce glucose, NEFA, and ketone body levels for 24 h in obese insulin-resistant type 2 diabetic individuals. Glargine lowers blood glucose by mainly inhibiting EGP with limited effects on stimulating glucose disposal. Large doses of glargine have minimal effects on glucose flux and retain a relatively hepatospecific action in type 2 diabetes.
| S-EPMC2890358 | biostudies-literature
Project description:Type 1 diabetes (T1D) is characterized by impairment in beta-cell mass and insulin levels, resulting in hyperglycemia and diabetic complications. Since diagnosis, appropriate control of glycaemia in T1D requires insulin administration, which can result in side effects, such as hypoglycemia. In this sense, some bile acids have emerged as new therapeutic targets to treat T1D and T2D, as well as metabolic diseases. The taurine conjugated bile acid, tauroursodeoxycholic (TUDCA) reduces the incidence of T1D development and improves glucose homeostasis in obese and T2D mice. However, its effects in early-stage of T1D have not been well explored. Therefore, we have assessed the effects of TUDCA on the glycemic control of mice with early-stage T1D. To achieve this, C57BL/6 mice received intraperitoneal administration of streptozotocin (STZ, 40 mg/kg) for 5 days. Once diabetes was confirmed in the STZ mice, they received TUDCA treatment (300 mg/kg) or phosphate buffered saline (PBS) for 24 days. After 15 days of treatment, the STZ+TUDCA mice showed a 43% reduction in blood glucose, compared with the STZ group. This reduction was likely due to an increase in insulinemia. This increase in insulinemia may be explained, at least in part, by a reduction in hepatic IDE activity and, consequently, reduction on insulin clearance, as well as an increase in beta-cell mass and a higher beta-cell number per islet. Also, the groups did not present any alterations in insulin sensitivity. All together, these effects contributed to the improvement of glucose metabolism in T1D mice, pointing TUDCA as a potential therapeutic agent for the glycemic control in early-stage of T1D.
| S-EPMC6529580 | biostudies-literature
Project description:Defective insulin secretion is a key defect in the pathogenesis of type 2 diabetes (T2DM). The beta-cell specific transcription factor, insulin promoter factor 1 gene (IPF1), is essential to pancreatic development and the maintenance of beta-cell mass. We hypothesized that regulatory or coding variants in IPF1 contribute to defective insulin secretion and thus T2DM.We screened 71 Caucasian and 69 African American individuals for genetic variants in the promoter region, three highly conserved upstream regulatory sequences (PH1, PH2 and PH3), the human beta-cell specific enhancer, and the two exons with adjacent introns. We tested for an association of each variant with T2DM Caucasians (192 cases and 192 controls) and African Americans (341 cases and 186 controls).We identified 8 variants in the two populations, including a 3 bp insertion in exon 2 (InsCCG243) in African Americans that resulted in an in-frame proline insertion in the transactivation domain. No variant was associated with T2DM in Caucasians, but polymorphisms at -3766 in the human beta-cell enhancer, at -2877 bp in the PH1 domain, and at -108 bp in the promoter region were associated with T2DM in African American subjects (p < 0.01), both individually and as haplotypes (p = 0.01 correcting by permutation test). No SNP altered a binding site for the expected beta-cell transcription factors. The rare alleles of InsCCG243 in exon 2 showed a trend to over-representation among African American diabetic subjects (p < 0.1), but this trend was not significant on permutation test.The common alleles of regulatory variants in the 5' enhancer and promoter regions of the IPF1 gene increase susceptibility to type 2 diabetes among African American individuals, likely as a result of gene-gene or gene-environment interactions. In contrast, IPF1 is not a cause of type 2 diabetes in Caucasians. A previously described InsCCG243 variant may contribute to diabetes susceptibility in African American individuals, but is of low penetrance.
| S-EPMC1274317 | biostudies-literature
Project description:Identifying patients with new-onset type 2 diabetes who have insulin deficiency can aid in timely insulin replacement therapy. In this study, we measured fasting C-peptide concentration to assess endogenous insulin secretion and determine the prevalence and characteristics of patients with insulin deficiency in adult Ugandan patients with confirmed type 2 diabetes at presentation.MethodsAdult patients with new-onset diabetes were recruited from seven tertiary hospitals in Uganda. Participants who were positive for the three islet autoantibodies were excluded. Fasting C-peptide concentrations were measured in 494 adult patients, and insulin deficiency was defined as a fasting C-peptide concentration <0.76 ng/ml. The socio-demographic, clinical, and metabolic characteristics of participants with and without insulin deficiency were compared. Multivariate analysis was performed to identify independent predictors of insulin deficiency.ResultsThe median (IQR) age, glycated haemoglobin (HbA1c), and fasting C-peptide of the participants was 48 (39-58) years,10.4 (7.7-12.5) % or 90 (61-113) mmol/mol, and 1.4 (0.8-2.1) ng/ml, respectively. Insulin deficiency was present in 108 (21.9%) participants. Participants with confirmed insulin deficiency were more likely to be male (53.7% vs 40.4%, p=0.01), and had a lower body mass index or BMI [p<0.001], were less likely to be hypertensive [p=0.03], had reduced levels of triglycerides, uric acid, and leptin concentrations [p<0.001]), but higher HbA1c concentration (p=0.004). On multivariate analysis, BMI (AOR 0.89, 95% CI 0.85-0.94, p<0.001), non-HDLC (AOR 0.77, 95% CI 0.61-0.97, p=0.026), and HbA1c concentrations (AOR 1.08, 95% CI 1.00-1.17, p=0.049) were independent predictors of insulin deficiency.ConclusionInsulin deficiency was prevalent in this population, occurring in about 1 in every 5 patients. Participants with insulin deficiency were more likely to have high HbA1c and fewer markers of adiposity and metabolic syndrome. These features should increase suspicion of insulin deficiency and guide targeted testing and insulin replacement therapy.
| S-EPMC10012075 | biostudies-literature
Project description:AIMS/HYPOTHESIS:Genetic studies show coupling of genes affecting beta cell function to type 1 diabetes, but hitherto no studies on whether beta cell dysfunction could precede insulitis and clinical onset of type 1 diabetes are available. METHODS:We used 40-day-old BioBreeding (BB) DRLyp/Lyp rats (a model of spontaneous autoimmune type 1 diabetes) and diabetes-resistant DRLyp/+ and DR+/+ littermates (controls) to investigate beta cell function in vivo, and insulin and glucagon secretion in vitro. Beta cell mass was assessed by optical projection tomography (OPT) and morphometry. Additionally, measurements of intra-islet blood flow were performed using microsphere injections. We also assessed immune cell infiltration, cytokine expression in islets (by immunohistochemistry and qPCR), as well as islet Glut2 expression and ATP/ADP ratio to determine effects on glucose uptake and metabolism in beta cells. RESULTS:DRLyp/Lyp rats were normoglycaemic and without traces of immune cell infiltrates. However, IVGTTs revealed a significant decrease in the acute insulin response to glucose compared with control rats (1685.3 ± 121.3 vs 633.3 ± 148.7; p < 0.0001). In agreement, insulin secretion was severely perturbed in isolated islets, and both first- and second-phase insulin release were lowered compared with control rats, while glucagon secretion was similar in both groups. Interestingly, after 5-7 days of culture of islets from DRLyp/Lyp rats in normal media, glucose-stimulated insulin secretion (GSIS) was improved; although, a significant decrease in GSIS was still evident compared with islets from control rats at this time (7393.9 ± 1593.7 vs 4416.8 ± 1230.5 pg islet-1 h-1; p < 0.0001). Compared with controls, OPT of whole pancreas from DRLyp/Lyp rats revealed significant reductions in medium (4.1 × 109 ± 9.5 × 107 vs 3.8 × 109 ± 5.8 × 107 μm3; p = 0.044) and small sized islets (1.6 × 109 ± 5.1 × 107 vs 1.4 × 109 ± 4.5 × 107 μm3; p = 0.035). Finally, we found lower intra-islet blood perfusion in vivo (113.1 ± 16.8 vs 76.9 ± 11.8 μl min-1 [g pancreas]-1; p = 0.023) and alterations in the beta cell ATP/ADP ratio in DRLyp/Lyp rats vs control rats. CONCLUSIONS/INTERPRETATION:The present study identifies a deterioration of beta cell function and mass, and intra-islet blood flow that precedes insulitis and diabetes development in animals prone to autoimmune type 1 diabetes. These underlying changes in islet function may be previously unrecognised factors of importance in type 1 diabetes development.
| S-EPMC6448977 | biostudies-literature
Project description:BackgroundVery recently, a novel type 2 diabetes risk gene, i.e., MTNR1B, was identified and reported to affect fasting glycemia. Using our thoroughly phenotyped cohort of subjects at an increased risk for type 2 diabetes, we assessed the association of common genetic variation within the MTNR1B locus with obesity and prediabetes traits, namely impaired insulin secretion and insulin resistance.Methodology/principal findingsWe genotyped 1,578 non-diabetic subjects, metabolically characterized by oral glucose tolerance test, for five tagging single nucleotide polymorphisms (SNPs) covering 100% of common genetic variation (minor allele frequency > 0.05) within the MTNR1B locus (rs10830962, rs4753426, rs12804291, rs10830963, rs3781638). In a subgroup (N = 513), insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and in a further subgroup (N = 301), glucose-stimulated insulin secretion was determined by intravenous glucose tolerance test. After appropriate adjustment for confounding variables and Bonferroni correction for multiple comparisons, none of the tagging SNPs was reliably associated with measures of adiposity. SNPs rs10830962, rs4753426, and rs10830963 were significantly associated with higher fasting plasma glucose concentrations (p < 0.0001) and reduced OGTT- and IVGTT-induced insulin release (p < or = 0.0007 and p < or = 0.01, respectively). By contrast, SNP rs3781638 displayed significant association with lower fasting plasma glucose levels and increased OGTT-induced insulin release (p<0.0001 and p < or = 0.0002, respectively). Moreover, SNP rs3781638 revealed significant association with elevated fasting- and OGTT-derived insulin sensitivity (p < or = 0.0021). None of the MTNR1B tagging SNPs altered proinsulin-to-insulin conversion.Conclusions/significanceIn conclusion, common genetic variation within MTNR1B determines glucose-stimulated insulin secretion and plasma glucose concentrations. Their impact on beta-cell function might represent the prevailing pathomechanism how MTNR1B variants increase the type 2 diabetes risk.
| S-EPMC2597741 | biostudies-literature
Project description:There is a paucity of literature describing metabolic and histological data in adult-onset autoimmune diabetes. This subgroup of diabetes mellitus affects at least 5% of clinically diagnosed type 2 diabetic patients (T2DM) and it is termed Latent Autoimmune Diabetes in Adults (LADA). We evaluated indexes of insulin secretion, metabolic assessment, and pancreatic pathology in clinically diagnosed T2DM patients with and without the presence of humoral islet autoimmunity (Ab). A total of 18 patients with at least 5-year duration of clinically diagnosed T2DM were evaluated in this study. In those subjects we assessed acute insulin responses to arginine, a glucose clamp study, whole-body fat mass and fat-free mass. We have also analyzed the pancreatic pathology of 15 T2DM and 43 control cadaveric donors, using pancreatic tissue obtained from all the T2DM organ donors available from the nPOD network through December 31, 2013. The presence of islet Ab correlated with severely impaired β-cell function as demonstrated by remarkably low acute insulin response to arginine (AIR) when compared to that of the Ab negative group. Glucose clamp studies indicated that both Ab positive and Ab negative patients exhibited peripheral insulin resistance in a similar fashion. Pathology data from T2DM donors with Ab or the autoimmune diabetes associated DR3/DR4 allelic class II combination showed reduction in beta cell mass as well as presence of autoimmune-associated pattern A pathology in subjects with either islet autoantibodies or the DR3/DR4 genotype. In conclusion, we provide compelling evidence indicating that islet Ab positive long-term T2DM patients exhibit profound impairment of insulin secretion as well as reduced beta cell mass seemingly determined by an immune-mediated injury of pancreatic β-cells. Deciphering the mechanisms underlying beta cell destruction in this subset of diabetic patients may lead to the development of novel immunologic therapies aimed at halting the disease progression in its early stage.
| S-EPMC4165581 | biostudies-literature