This research perspective allows me to summarize some of my work completed over 50 years, and it is organized in seven sections. 1) The treatment of diabetes concentrates on the liver and/or the periphery. We quantified hormonal and metabolic interactions involved in physiology and the pathogenesis of diabetes by developing tracer methods to separate the effects of diabetes on both. We collaborated in the first tracer clinical studies on insulin resistance, hypertriglyceridemia, and the Cori cycle. 2) Diabetes reflects insulin deficiency and glucagon abundance. Extrapancreatic glucagon changed the prevailing dogma and permitted precise exploration of the roles of insulin and glucagon in physiology and diabetes. 3) We established the critical role of glucagon-insulin interaction and the control of glucose metabolism during moderate exercise and of catecholamines during strenuous exercise. Deficiencies of the release and effects of these hormones were quantified in diabetes. We also revealed how acute and chronic hyperglycemia affects the expression of GLUT2 gene and protein in diabetes. 4) We outlined molecular and physiological mechanisms whereby exercise training and repetitive neurogenic stress can prevent diabetes in ZDF rats. 5) We and others established that the indirect effect of insulin plays an important role in the regulation of glucose production in dogs. We confirmed this effect in humans and demonstrated that in type 2 diabetes it is mainly the indirect effect. 6) We indicated that the muscle and the liver protected against glucose changes. 7) We described molecular mechanisms responsible for increased HPA axis in diabetes and for the diminished responses of HPA axis, catecholamines, and glucagon to hypoglycemia. We proposed a new approach to decrease the threat of hypoglycemia.