Serum glucose and gastric inhibitory polypeptide (GIP) responses during mixed test meals and primed continuous infusion of insulin using the insulin clamp technique were studied in nine patients with noninsulin-dependent diabetes mellitus (NIDDM) before and after vigorous insulin treatment. Fasting serum glucose concentrations fell an average of 167 mg/dl (P less than 0.001), and there was a 67% reduction (P less than 0.001) in the postprandial glucose response. Mean hemoglobin A1c declined and paralleled the fall in serum glucose concentrations (9.2 +/- 0.5% to 5.9% +/- 0.3%; P less than 0.01). This improvement in glycemic control, however, was not associated with any appreciable change in GIP secretion. Basal and meal-stimulated serum GIP levels were not reduced after intense insulin therapy. Furthermore, hyperinsulinemia at physiological (100 microU/ml) and superphysiological (1000 microU/ml) levels failed to reduce GIP secretion before and after insulin therapy. Before insulin therapy, seven patients had elevated basal GIP levels and five had increased GIP levels after meals compared to values in nondiabetic subjects. Insulin administration did not alter these elevated GIP levels. These findings suggest that the increased meal-stimulated GIP secretion in some patients with NIDDM is not due to a failure of insulin feedback on GIP secretion.