Pancreatic β-cells are exquisitely organised to continually monitor and respond to dietary nutrients, under the modulation of additional neurohormonal signals, in order to secrete insulin to best meet the needs of the organism. β-cell nutrient sensing requires complex mechanisms of metabolic activation, resulting in production of stimulus-secretion coupling signals that promote insulin biosynthesis and release. The primary stimulus for insulin secretion is an elevation in blood glucose concentration and β-cells are particularly responsive to this important nutrient secretagogue via the tight regulation of glycolytic and mitochondrial pathways at steps such as glucokinase, pyruvate dehydrogenase, pyruvate carboxylase, glutamate dehydrogenase and mitochondrial redoxshuttles. With respect to development of type-2 diabetes (T2DM), it is important to consider individual effects of different classes of nutrient or other physiological or pharmacological agents on metabolism and insulin secretion and to also acknowledge and examine the interplay between glucose metabolism and that of the two other primary nutrient classes, amino acids (such as arginine and glutamine) and fatty acids. It is the mixed nutrient sensing and outputs of glucose, amino and fatty acid metabolism that generate the metabolic coupling factors (MCFs) essential for signalling for insulin exocytosis. Primary MCFs in the β-cell include ATP, NADPH, glutamate, long chain acyl coenzyme A and diacylglycerol. It is the failure to generate MCFs in a coordinated manner and at sufficient levels that underlies the failure of β-cell secretion during the pathogenesis of T2DM.