The in vitro effects of glucose and analogs of glucose on insulin secretion have been reinvestigated with rat and mouse islets. Curves relating rates of insulin secretion to glucose concentration were sigmoid with a Km of 6–8 mM and tending to Vmax at approximately 20 mM glucose. Mannose and glucosamine were the only analogs of glucose which stimulated secretion in the absence of glucose. Fructose, N-acetyl glucosamine and galactose (rat only) potentiated secretion at 2.5 or 5 mM glucose but not at 20mM glucose. Other analogs of glucose were inactive. Mannoheptulose inhibited glucose effects at all concentrations of glucose; glucosamine was inhibitory at 5 mM and 20 mM glucose. It is concluded that there may be quantitatively or qualitatively two distinct types of receptor mechanism in islets: (1) an initiator unit sensitive to effects of glucose, mannose, glucosamine, mannoheptulose and leucine and (2) a potentiator unit sensitive to effects of fructose, N-acetyl glucosamine and galactose (and also glucose and mannose?). Rates of glucose utilization measured in islets with [5·3H] glucose were linearly related to rates of insulin secretion with varying glucose concentrations, with mannoheptulose and with glucosamine. It is concluded that evidence currently available does not determine whether initiation of insulin secretion by glucose, mannose or glucosamine involves a direct effect of the sugar or of a metabolite.