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.

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.

The rs225017 polymorphism in the 3'UTR of the human DIO2 gene is associated with increased insulin resistance.

The Thr92Ala (rs225014) polymorphism in the type 2 deiodinase (DIO2) 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 DIO2 expression. Thus, we aimed to investigate whether other DIO2 polymorphisms, individually or in combination with the Thr92Ala, may contribute to IR. The entire coding-region of DIO2 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. DIO2 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; r2 = 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.

D2 Thr92Ala and PPARγ2 Pro12Ala polymorphisms interact in the modulation of insulin resistance in type 2 diabetic patients.

Type 2 deiodinase (D2) converts T4 into its active metabolite T3, an essential step in thyroid metabolism. A Thr92Ala polymorphism in the gene encoding D2 has been inconsistently associated with insulin resistance (IR). Recently, it was reported that the D2 Thr92Ala (rs225014) and the peroxisome proliferator-activated receptor (PPAR) γ2 Pro12Ala (rs1801282) polymorphisms interact in the modulation of metabolic syndrome in nondiabetic subjects. Here, we investigated the effect of both polymorphisms, isolated or in combination, on IR in patients with type 2 diabetes mellitus (DM2). The D2 Thr92Ala and PPARγ2 Pro12Ala polymorphisms were genotyped in 721 DM2 patients. IR was evaluated using the homeostasis model assessment-IR (HOMA(IR)) index in a subgroup of 246 DM2 subjects. The frequencies of D2 Ala92 and PPARγ2 Ala12 variants were 0.390 and 0.074, respectively. Patients carrying D2 Ala/Ala genotype had a higher fasting plasma insulin and HOMA(IR) index as compared to patients carrying Thr/Ala or Thr/Thr genotypes (P = 0.022 and P = 0.001, respectively). A significant synergistic effect was observed between D2 Thr92Ala and PPARγ2 Pro12Ala polymorphisms on HOMA(IR) index, with carriers of both D2 Ala/Ala genotype and PPARγ2 Ala12 allele showing the highest HOMA(IR) values, after adjusting for age, gender, BMI, and use of medication for DM2 (P = 0.010). In conclusion, DM2 patients harboring both D2 Ala/Ala genotype and PPARγ2 Ala12 allele seem to present more severe IR than those with other D2/PPARγ2 genotype combinations. These findings suggest that these polymorphisms interact in the IR modulation, which may constitute a potential therapeutic target.

Prevalence of 15 mitochondrial DNA mutations among type 2 diabetic patients with or without clinical characteristics of maternally inherited diabetes and deafness / Prevalência de 15 mutações no DNA mitocondrial entre pacientes diabéticos tipo 2 com ou sem características clínicas de diabetes e surdez herdados maternalmente

The aim of the present study is to investigate the prevalence of ten described mitochondrial DNA (mtDNA) mutations in patients with type 2 diabetes, and search for new mutations in four mtDNA genes in a subgroup of patients with characteristics of maternally inherited diabetes and deafness (MIDD). These mutations were investigated in 407 type 2 diabetic patients without characteristics of mitochondrial diabetes ("classical" type 2 diabetes group) and in 38 type 2 diabetic patients with characteristics suggestive of MIDD. Through sequencing of four mtDNA genes in MIDD patients, we selected five others potentially pathogenic mutations that were also screened in the remaining patients. Overall, the frequency of the fifteen analyzed mutations was 36.84 percent in the MIDD group and 2.45 percent in the "classical" type 2 diabetes group (p < 0.001). In conclusion, our study reinforces the importance of mtDNA mutations in the pathogenesis of MIDD.

Os objetivos deste estudo foram investigar a prevalência de dez mutações conhecidas no DNA mitocondrial (mtDNA) em pacientes com diabetes tipo 2, e procurar por novas mutações em quatro genes mitocondriais em um subgrupo de pacientes com características de MIDD (Maternally Inherited Diabetes and Deafness). Estas mutações foram investigadas em 407 pacientes diabéticos tipo 2 sem características de diabetes mitocondrial (grupo de diabetes tipo 2 clássico) e em 38 pacientes com diabetes tipo 2 e com características sugestivas de MIDD. Através do seqüenciamento de quatro genes mitocondriais nos pacientes com MIDD, selecionou-se cinco outras mutações potencialmente patogênicas que também foram investigadas no restante dos pacientes. De uma forma geral, a freqüência total das 15 mutações analisadas foi de 36,8 por cento no grupo de pacientes com MIDD e de 2,4 por cento no grupo de diabetes tipo 2 clássico (p < 0,001). Em conclusão, nosso estudo reforça a importância de mutações mitocondriais na patogênese do MIDD.

Prevalence of 15 mitochondrial DNA mutations among type 2 diabetic patients with or without clinical characteristics of maternally inherited diabetes and deafness.

The aim of the present study is to investigate the prevalence of ten described mitochondrial DNA (mtDNA) mutations in patients with type 2 diabetes, and search for new mutations in four mtDNA genes in a subgroup of patients with characteristics of maternally inherited diabetes and deafness (MIDD). These mutations were investigated in 407 type 2 diabetic patients without characteristics of mitochondrial diabetes ('classical' type 2 diabetes group) and in 38 type 2 diabetic patients with characteristics suggestive of MIDD. Through sequencing of four mtDNA genes in MIDD patients, we selected five others potentially pathogenic mutations that were also screened in the remaining patients. Overall, the frequency of the fifteen analyzed mutations was 36.84% in the MIDD group and 2.45% in the 'classical' type 2 diabetes group (p < 0.001). In conclusion, our study reinforces the importance of mtDNA mutations in the pathogenesis of MIDD.