The TH01 microsatellite and INS VNTR are strongly associated with type 2 diabetes and fasting insulin secretion

A variable number of tandem repeats (VNTR) located in the insulin gene ( INS ) control region may be involved in the development of type 2 diabetes (T2D). The TH01 microsatellite is located close to INS and has previously been suggested to be involved its regulation. Therefore, this observational study investigated whether the TH01 microsatellite and INS VNTR, as assessed via the surrogate marker single nucleotide polymorphism (SNP) rs689, are associated with T2D in the Mexican population. Logistic regression models were used to calculate the risk conferred by TH01 and INS VNTR loci for T2D development. TH01 alleles 6, 8, 9 and 9.3 and allele A of rs689 were independently associated with T2D; differences were found between age at T2D diagnosis and sex. Larger alleles of TH01 (≥8 repeats) conferred an increased risk for T2D in males when compared with smaller alleles (≤7 repeats) (odds ratio, ≥1.46; 95% confidence interval, 1.1–1.95). In females, larger alleles conferred a 1.5-fold higher risk for T2D when diagnosed at ≥46 years whereas they conferred protection when diagnosed at ≤45 years. Both TH01 and SNP rs689 were associated with T2D in the same groups; the association remained significant for both loci in multivariate models. The median fasting plasma insulin concentration was significantly higher in patients with T2D versus controls, and in those diagnosed at ≤45 versus ≥46 years. TH01 larger alleles or the A allele of rs689 may potentiate insulin synthesis in males, but not females, without T2D, a process that is disabled in those with T2D. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by the Carlos Slim Foundation, the Laboratorio Huella Genica, and the Faculty of Medicine of the National Autonomous University of Mexico (UNAM). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The protocol for the main study was approved by the local ethics committee of each study site and the Federal Commission for the Protection Against Health Risks (COFEPRIS) (CAS/OR/CMN/113300410D0027-0577/2012). The clinical replica study was approved by the Ethics and Research Committees of the Comisión Nacional de Investigación Científica of the Instituto Mexicano del Seguro Social (IMSS R-2014-785-005), whilst the cross-sectional study was approved by the Ethics and Research Committees of the Hospital General de Puebla “Ignacio Romero Vargas” (68/ENS/INV/REV/2017). All three protocols complied with the Declaration of Helsinki and local ethical guidelines for clinical studies in Mexico. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.