For perfect glycemic control in diabetics, therapeutic modalities which enhance impaired hepatic glucose uptake seen in diabetics should be utilized. In animal experiments, we demonstrated that factors promoting hepatic glucose uptake are the glucose gradient between the central nervous system and the hepato-portal system, portal hyperinsulinemia and normal premeal glycemia. Therefore, we investigated both the effects of intensified insulin therapy and a single bout of exercise on hepatic glucose uptake by euglycemic hyperinsulinemic clamp combined with oral glucose loading. In 56 out of 77 patients, perfect glycemic normalization was established with mean regular insulin doses of 10, 7, 7 U at breakfast, lunch and dinner, respectively. The ratio of splanchnic glucose disposal to the amount of ingested glucose increased significantly from 19.0 to 42.1%. A single bout of exercise enhanced hepatic glucose uptake from 23.4 to 50.5%. Both strict glycemic regulation and exercise enhance hepatic glucose uptake significantly in non-obese diabetic patients.