Normally islet β cells respond to insulin resistance by increased secretion through the processes of compensation. These include an expansion of β cell mass, increased insulin biosynthesis, and enhanced nutrient secretion coupling processes with increased sensitivity to glucose, FFAs, and GLP-1 stimuli. Enhanced glucose utilization, glucose oxidation, anaplerosis/cataplerosis, and TG/FFA cycling result in increased production of coupling signals necessary for insulin exocytosis. For expansion of β cell mass, roles are evident for increased activity of growth factor signaling pathways, postprandial glucose, and GLP-1 signaling that promote β cell proliferation and neogenesis and prevent apoptosis. Furthermore, signaling for growth may occur in response to FFAs, via the FFA receptors (FFAR) and via lipid signaling molecules derived from TG/FFA cycling. adr, adrenergic; ANS, autonomic nervous system; chol, cholinergic; CREB, cAMP response element–binding protein; DAG, diacylglycerol; GF, growth factor; GLP1R, GLP-1 receptor; GHR, growth hormone receptor; IGFR, insulin-like growth factor receptor; IR, insulin receptor, IRS-2, insulin receptor substrate 2; MCF, metabolic coupling factors; npt, neuropeptide; PKB, phosphokinase B; PL, phospholipids.