Abstract: The appropriate regulation of intracellular bioenergy and nutrient metabolism is a basic requirement for proper function and survival of pancreatic beta cells, where mitochondria-endoplasmic reticulum (ER)-associations play crucial roles. Mitochondria are changed dynamically according to intracellular energy and nutrients, which provides material foundation for energy homeostasis; while ER regulates metabolic enzymes and protein synthesis in different pathways. This review sheds light upon the development of mitochondria-ER associations and its role in the regulation of insulin secretion in pancreatic beta cell. The impact on beta cell viability is discussed. Interruption of calcium and redox oxidative species results in reduction of glucose-stimulated insulin secretion, while intracellular calcium levels could be partial altered by depleting calcium from the ER. Given the tight link between ER and mitochondria, the association are crucial to the homeostasis and are an indicator of overall beta cell status, with a potential as a novel drug target for treatment of type 2 diabetes mellitus.