Abstract
Study background: Insulin resistance plays an important role in the pathogenesis of type2 diabetes and the metabolic syndrome. Many of the genes and pathways involved have been identified but some remain to be defined. Metallothioneins (Mts) are a family of anti-oxidant proteins and metallothionein 2a (Mt2a) polymorphims have been recently associated with type 2 diabetes and related complications. Our objective was to determine Mt2a gene expression levels in adipose tissues from diabetic patients and determine the effect of Mt treatment on adipocyte insulin sensitivity. Methods: Samples of subcutaneous and visceral adipose tissues from lean, type 2 diabetic and non-diabetic obese patients were analysed using RT-qPCR for Mt2a mRNA abundance. The regulation of Mt2a expression was further studied in 3T3-L1 adipocytes treated or not with TNFα (10 ng/ml, 72oh) to induce insulin resistance. The effects of Mt on glucose uptake were investigated in cultured adipocytes treated with recombinant Mt protein. Results: We found that Mt2a gene expression was significantly higher in adipose tissue of type 2 diabetic patients in comparison to lean (p=0.003) subjects. In 3T3-L1 adipocytes, insulin resistance induced by TNFα increased Mt2a mRNA levels (p=3×10-4) and insulin-stimulated glucose uptake was significantly inhibited by 53% (p=8×10-4) compared to vehicle, when 3T3-L1 adipocytes were treated with Mt protein. Conclusions: These data suggest that Mt2a might be involved in insulin resistance through the up-regulation of Mt gene expression, which may lead to the modulation of insulin action in fat cells. These results suggest the concept of considering Mt proteins as markers and potential targets in type 2 diabetes.
Highlights
Insulin resistance, defined as a diminished response to insulin in one or more peripheral tissues such as adipose tissue, skeletal muscle and the liver, plays an important role in the pathogenesis of type 2 diabetes and the metabolic syndrome
We found that metallothionein 2a (Mt2a) gene expression was significantly higher in adipose tissue of type 2 diabetic patients in comparison to lean (p=0.003) subjects
In 3T3-L1 adipocytes, insulin resistance induced by TNFα increased Mt2a mRNA levels (p=3×10-4) and insulin-stimulated glucose uptake was significantly inhibited by 53% (p=8×10-4) compared to vehicle, when 3T3-L1 adipocytes were treated with Mt protein
Summary
Insulin resistance, defined as a diminished response to insulin in one or more peripheral tissues such as adipose tissue, skeletal muscle and the liver, plays an important role in the pathogenesis of type 2 diabetes and the metabolic syndrome. It can be caused by a wide range of physiological disturbances including hyperglycaemia, hyperlipidemia, elevated levels of pro-inflammatory cytokines and oxidative stress [1]. We hypothesized a potential association of Mt2 with insulin resistance and type 2 diabetes by analysing Mt2 gene expression in subcutaneous and visceral adipose tissue of obese subjects with or without diabetes. We used 3T3-L1 adipocytes to analyse the effects of Mt on insulin-stimulated glucose uptake
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