INOSITOL, GLYCOGEN, INSULIN AND SIX NOBELISTS

My reflections cover my scientific work over a sixty-year period. At the University of Michigan, I was initially interested in embryology. In medical school in the army, I became entranced with biochemistry and DeWitt Stetten, who introduced me to Carl Cori. Carl along with Gerty Cori and Earl Sutherland became my scientific mentors. After medical school and a nine-month medical internship, I re-entered the army and was assigned to Edgewood Arsenal in Maryland, where I established the NAD requirement for brain pyruvate dehydrogenase to oxidize pyruvate and published my first Journal of Biological Chemistry (JBC) paper. At the University of Illinois, I obtained an M.S. degree in chemistry and was influenced by Will Rose and Herb Carter. At Washington University in St. Louis, I worked with Gerty and Carl Cori on glycogen metabolism and obtained my Ph.D. degree. I also worked with Bill Daughaday on the increased urinary excretion of myo-inositol in diabetic subjects and in rats preloaded with glucose. I was offered an instructor's appointment in biochemistry at Washington University, but I decided to accept an assistant professor's appointment in the Division of Biochemistry of the Chemistry Department at the University of Illinois. I spent four years at Illinois working on intestinal starch digestion with particular reference to glycosidases hydrolyzing the α1,6-branch point linkages. I was recruited by Earl Sutherland to join his Department of Pharmacology as an associate professor at Western Reserve University in Cleveland. Here, Carlos Villar-Palasi, my first postdoctoral fellow, and I began our insulin studies, which led to the discovery of two covalent forms of glycogen synthase controlled by insulin and epinephrine. These continued at the University of Minnesota, where I held an endowed chair in biochemistry. Here, with students and postdoctoral fellows, we further defined the two forms of glycogen synthase and worked on the possible role of cAMP in insulin action. Moving to the University of Virginia as Chair of Pharmacology, I recruited two future Nobelists, Al Gilman and Ferid (Fred) Murad, with Ted Rall, their past mentor for their Ph.D. degrees, as well as other faculty who would become departmental chairs. Our early studies on glycogen and inositol became united with studies on insulin action. We isolated a novel inositol glycan pseudo-disaccharide insulin second messenger containing a rare inositol, d-chiro-inositol (DCI). Its structure was determined as galactosamine β1,4-pinitol, where pinitol is the 3-O-methyl ether of DCI. It was chemically synthesized. We and others found that insulin resistance in several human diseases is related to an inositol imbalance consisting of a deficit of chiro-inositol and an excess of myo-inositol, an unfolding story now under way involving the myo-inositol to chiro-inositol epimerase. I am blessed to have had such superlative scientific mentors, a productive group of students and postdoctoral fellows, a loving wife of sixty-five years, three remarkable sons, and eight wonderful grandchildren. I am working full time on insulin, which has entranced me for a long time.