Metformin treatment affects adipocytokine secretion and lipid composition in adipose tissues of diet-induced insulin-resistant rats.

OBJECTIVES: Adipose tissue plays a central role in the pathogenesis of insulin resistance (IR) and type 2 diabetes. However, the molecular changes that promote these diseases are not completely understood. Several studies demonstrated that ceramide (Cer) and diacylglycerol (DAG) accumulation in muscle is associated with IR. The aim of this study was to explain whether a high-fat diet (HFD) leads to bioactive lipid accumulation in adipose tissue and how metformin affects the lipid content in adipocytes and the concentration of plasma adipocytokines. METHODS: The experiments were conducted on male Wistar rats divided into three groups: control, HFD-fed, and HFD-fed and treated with metformin. Cer and DAGs were analyzed by liquid chromatography tandem mass spectrometry. Phosphorylation of hormone-sensitive lipase (HSL) was analyzed by Western blot. Oral glucose tolerance and insulin tolerance tests were also performed. Plasma adiponectin and tumor necrosis factor (TNF)-α concentration were measured by enzyme-linked immunosorbent assay. RESULTS: HFD induced IR and elevated DAGs and Cer content in subcutaneous and visceral adipose tissues, which was accompanied by an increased phosphorylation of HSL. Metformin improved insulin sensitivity, decreased Cer and DAG levels, and attenuated the phosphorylation of HSL in both fat depots. Furthermore, we observed a strong correlation between adiponectin (negative) and TNF-α (positive) and bioactive lipids in both fat tissues. CONCLUSIONS: These results indicated that bioactive lipids accumulation in adipose tissue influences the induction of IR and, at least in part, answered the question of what the insulin-sensitizing effect of metformin at the level of adipose tissue is.

The role of adipose tissue and excess of fatty acids in the induction of insulin resistance in skeletal muscle.

Skeletal muscle is the main tissue responsible for insulin-stimulated glucose uptake. Consumption of a high-fat diet rich in saturated fats (HFD) and obesity are associated with accumulation of intramuscular lipids that leads to several disorders, e.g. insulin resistance (IRes) and type 2 diabetes (T2D). The mechanism underlying the induction of IRes is still unknown. It was speculated that accumulation of intramuscular triacylglycerols (TAG) is linked to induction of IRes. Now, research focuses on bioactive lipids: long-chain acyl-CoA (LCACoA), diacylglycerols (DAG) and ceramides (Cer). It has been demonstrated that accumulation of each of the above-mentioned lipid classes negatively affects the insulin signaling pathway. It is not clear which of those lipids play the most important role in HFD-induced skeletal muscle IRes. The aim of the present work is to present the current knowledge of the role of adipose tissue and excess of fatty acids in the induction of insulin resistance.

Antidiabetic drugs and risk of cancer.

Antidiabetic drugs are an important group of medications used worldwide. They differ from each other in the mechanisms of lowering blood glucose as well as in adverse effects that may affect the course of the treatment and its efficacy. In recent years, new drugs have been discovered in order to improve the maintenance of proper blood glucose level and to reduce unwanted effects of these drugs. Their growing administration is related to the increasing incidence of diabetes observed in all countries in the world. Epidemiological data indicate that diabetes increases the risk of cancer, as well as the risk of death linked with neoplasms. It is still unknown whether this is an effect of antidiabetic drugs or just the effect of diabetes itself. In recent years there have been numerous investigations and meta-analyzes, based on both comparative and cohort studies trying to establish the relationship between antidiabetic pharmacotherapy and the incidence and mortality due to cancer. According to their findings, most of antidiabetic drugs increase the risk of cancer while only few of them show antitumor properties. Different mechanisms of action of glucose-lowering drugs may be responsible for these effects. However, most of the published studies concerning the influence of these drugs on cancer incidence were designed with some limitations and differed from each other in the approach. In this review, we discuss the association between antidiabetic drugs used in monotherapy or polytherapy and cancer risk, and consider potential mechanisms responsible for the observed effects.