The objectives of this research program are: (1) To define the relative contributions of impaired tissue insensitivity to insulin and impaired beta cell sensitivity to glucose in the genesis of the carbohydrate intolerance in a) juvenile onset (insulin-dependent) diabetics, b) maturity onset (insulin-independent) diabetics with varying degrees of glucose intolerance, c) acute diabetic ketoacidosis before and after correction of the metabolic disturbance, d) obese diabetics before and after weight reduction, and e) subjects with chronic pancreatitis and glucose intolerance. (2) To define the contributions of a) decreased peripheral (muscle and adipose) uptake of glucose, b) decreased hepatic uptake of glucose, and c) failure of normal suppression of hepatic glucose production to the observed insulin resistance in the five diabetic groups outlined above. (3) To define the role of gastrointestinal factors on hepatic glucose uptake in normal and diabetic subjects. (4) To examine the separate effects of metabolic acidosis and ketosis on the tissue insensitivity to insulin observed in acute diabetic ketoacidosis. (5) To assess whether the impaired tissue sensitivity to insulin (with respect to glucose metabolism) in diabetic subjects also extends to other actions of insulin, specifically amino acid and potassium metabolism. (6) To examine insulin kinetics and hepatic extraction of insulin in normal and diabetic subjects.