The rs225017 Polymorphism in the 3′UTR of the Human <i>DIO2</i> Gene Is Associated with Increased Insulin Resistance

<div><p>The Thr92Ala (rs225014) polymorphism in the type 2 deiodinase (<i>DIO2</i>) gene has been associated with insulin resistance (IR) and decreased enzyme activity in human tissues but kinetic studies failed to detect changes in the mutant enzyme, suggesting that this variant might be a marker of abnormal <i>DIO2</i> expression. Thus, we aimed to investigate whether other <i>DIO2</i> polymorphisms, individually or in combination with the Thr92Ala, may contribute to IR. The entire coding-region of <i>DIO2</i> gene was sequenced in 12 patients with type 2 diabetes mellitus (T2DM). Potentially informative variants were evaluated in 1077 T2DM patients and 516 nondiabetic subjects. IR was evaluated using the homeostasis model assessment (HOMA-IR) index. <i>DIO2</i> gene sequencing revealed no new mutation but 5 previously described single nucleotide polymorphisms (SNPs). We observed that all T2DM patients displaying high HOMA-IR index (n = 6) were homozygous for the rs225017 (T/A) polymorphism. Further analysis showed that the median fasting plasma insulin and HOMA-IR of T2DM patients carrying the T/T genotype were higher than in patients carrying the A allele (P = 0.013 and P = 0.002, respectively). These associations were magnified in the presence of the Ala92Ala genotype of the Thr92Ala polymorphism. Moreover, the rs225017 and the Thr92Ala polymorphisms were in partial linkage disequilibrium (|D′| = 0.811; <i>r</i>² = 0.365). In conclusion, the rs225017 polymorphism is associated with greater IR in T2DM and it seems to interact with the Thr92Ala polymorphism in the modulation of IR.</p></div

Clinical and laboratory characteristics of patients with T2DM broken down according to <i>DIO2</i> rs225017 (T/A) polymorphism.

<p>Data are mean ± SD, median (minimum - maximum values) or %. A1C, glycated haemoglobin; BMI, body mass index; HOMA-IR, homeostasis model assessment - insulin resistance; Met, metformin; SU, sulfonylureas; WHR, waist-to-hip ratio; P values were estimated by χ² or ANOVA, as appropriate.</p>a<p>Variables which were logarithmically transformed before analyses.</p>b<p>For comparisons of fasting insulin levels and HOMA-IR index among rs225017 genotypes, we analyzed only 227 individuals (162 individuals harboring the A/A or A/T genotypes and 65 individuals harboring the T/T genotype).</p

Candidate polymorphisms identified by sequencing of the <i>DIO2</i> gene.

<p><b>A.</b> The vertical arrows show the five candidate variants in human <i>DIO2</i> gene identified through sequencing. Black boxes are coding regions. *polymorphisms associated with T2DM/IR/fasting insulin. ESECIS, Selenocysteine Insertion Sequence Element; 3′UTR = 3′-untranslated region. <b>B.</b> The characteristics of the 12 patients with T2DM selected for the screening of the <i>DIO2</i> gene. These patients had extreme HOMA-IR indexes and were selected from two subgroups according low or high HOMA-IR values.</p

Human pancreatic islet transplantation: an update and description of the establishment of a pancreatic islet isolation laboratory

Type 1 diabetes mellitus (T1DM) is associated with chronic complications that lead to high morbidity and mortality rates in young adults of productive age. Intensive insulin therapy has been able to reduce the likelihood of the development of chronic diabetes complications. However, this treatment is still associated with an increased incidence of hypoglycemia. In patients with “brittle T1DM”, who have severe hypoglycemia without adrenergic symptoms (hypoglycemia unawareness), islet transplantation may be a therapeutic option to restore both insulin secretion and hypoglycemic perception. The Edmonton group demonstrated that most patients who received islet infusions from more than one donor and were treated with steroid-free immunosuppressive drugs displayed a considerable decline in the initial insulin independence rates at eight years following the transplantation, but showed permanent C-peptide secretion, which facilitated glycemic control and protected patients against hypoglycemic episodes. Recently, data published by the Collaborative Islet Transplant Registry (CITR) has revealed that approximately 50% of the patients who undergo islet transplantation are insulin independent after a 3-year follow-up. Therefore, islet transplantation is able to successfully decrease plasma glucose and HbA1c levels, the occurrence of severe hypoglycemia, and improve patient quality of life. The goal of this paper was to review the human islet isolation and transplantation processes, and to describe the establishment of a human islet isolation laboratory at the Endocrine Division of the Hospital de Clínicas de Porto Alegre – Rio Grande do Sul, Brazil