Type 2 diabetes (T2D) and insulin resistance have attracted ever-increasing attention from biomedical researchers because of astonishing increase in its prevalence. Decreased capacity of oxidative metabolism and mitochondrial dysfunction are a major contributor to the development of T2D. Recent studies indicate that alteration of Ca2+ level and downstream Ca2+-dependent signaling pathways can modulate the insulin signaling cascade, resulting in insulin resistance of  cells and adipocytes. Mitochondria and ER play an important role in the maintenance of intracellular Ca2+ homeostasis and their defects may be an etiology factor of insulin resistance and T2D. It is established that mitochondria-associated ER membranes (MAMs) are essential for efficient communication between the ER and mitochondria. Thus, the abnormalities in the structure and function of MAMs in affected tissue cells in T2D and other metabolic disorders are an important subject of study. Recently, we have demonstrated that deficiency of Cisd2, an iron-sulfur protein localized to the ER and mitochondrial outer membranes, could lead to mitochondrial dysfunction and disturbance of intracellular Ca2+ homeostasis. Moreover, we first elucidated that defects in the function of MAMs in Ca2+ uptake resulted in insulin insensitivity of adipocytes, and this scenario plays an important role in the pathogenesis of diabetes in Cisd2 knockout mice. Based on these observations we suggest that to improve the bioenergetic function of mitochondria and the function of MAMs in the maintenance of Ca2+ homeostasis is a novel strategy for the development of new therapeutics for the prevention and treatment of insulin resistance and T2D.