During total fasting, insulin regulates plasma glucose concentrations primarily by controlling hepatic glucose production rather than by influencing peripheral tissue glucose utilization. Administration of ethanol to individuals deprived of food lowers plasma glucose principally by suppressing hepatic gluconeogenesis. With these two observations in mind, an indirect study was made of insulin deficiency and disturbed hepatic carbohydrate metabolism with persistent hyperglycemia during total fasting in six severely diabetic obese women, matched in age and weight with six nondiabetic and six moderately diabetic, obese female subjects. The degree of abnormal hyperglycemia that distinguished the two diabetic groups from each other and from control patients during a seven day total fast were related to the degree of hypoinsulinemia. Plasma glucogenic amino acids, including alanine were significantly depressed in the severely diabetic patients throughout the fasting interval. Four hour intravenous infusions of ethanol after fasting lowered plasma glucose to the greatest extent in patients with severe diabetes and least in the nondiabetic obese. In all instances, ethanol infusion decreased plasma glucogenic amino acids. Differential sensitivities of plasma glucose responses to fasting and to ethanol administration in these patients suggest that hepatic glucose production is inappropriate in severely diabetic, obese subjects. The defect correlates with subnormal plasma glucogenic substrate concentrations, suggesting increased hepatic extraction and conversion to glucose. Hypoglycemic effects of ethanol may be induced, in part, by altered availability of plasma amino acid precursors.