Pancreatic β cells secrete insulin in response to glucose, a process that is regulated at multiple levels, including a network of input signals from other organ systems. Impaired islet function contributes the pathogenesis of type 2 diabetes mellitus (T2DM) and targeting inter-organ communications, such as GLP-1 signalling, to enhance β cell function has been proven to be a successful therapeutic strategy in the last decade. In this review, we will discuss recent advances in inter-organ communication from the metabolic, immune, and neural system to pancreatic islets, their biological implication in normal pancreas endocrine function, as well as their role in the (mal)adaptive responses of islet to nutrition-induced stress.