Type 2 diabetes mellitus (T2DM) is one of the common clinical endocrine disorders, insulin resistance and insulin deficiency are the two most characteristic pathological features of T2DM. The pathogenesis of T2DM are complex. Endoplasmic reticulum stress (ERS), mitochondrial oxidative stress, apoptosis and other mechanisms were closely related to the pathogenesis of T2DM, whereas the specifically pathogenesis is unclear. The endoplasmic reticulum-mitochondrial structure coupling also known as mitochondria-associated ER membranes (MAM), has a direct or indirect regulation on intracellular calcium (Ca2+) distribution, and the distribution of Ca2+ has great significance to the stability of the intracellular environment. Persistent ERS results in structure damage to MAM, reducing the ability of MAM for regulating the endoplasmic reticulum and mitochondrial to release and uptake Ca2+. Excessive accumulation of Ca2+ in mitochondria activates oxidative stress, exacerbates ERS, and then initiates the apoptotic process of islet β cell. ERS in peripheral tissues can lead to insulin resisitance. The above causes eventually lead to the occurrence and development of T2DM. This article describes the regulatory role of the MAM structure in ERS and its association with the pathogenesis of insulin resistance, and provides the basis to explore the clinical treatment and pathogenesis of T2DM.