OBESITY AND NIDDM - THE RETROGRADE REGULATION CONCEPT

The evolution from obesity to NIDDM represents a continuum that evolve s through successive phases, These phases can be clinically characteri zed as normal glucose tolerance, impaired glucose tolerance, hyperinsu linemic diabetes, and hypoinsulinemic diabetes, Longitudinal studies h ave shown the progressive impairment of glucose storage associated,vit h a rise in basal glycemia; weight loss studies, on the contrary, have demonstrated improvement of glucose storage associated,vith a drop in basal glycemia, In obese nondiabetic subjects, a decrease in glucose storage is seen during euglycemic clamp studies, but not during oral g lucose tolerance tests, where the rise in glycemia and in insulinemia stimulates glycogen synthase, Next to its anterograde stimulation by g lucose and insulin, glycogen synthase is simultaneously regulated by t he negative feedback of intracellular glycogen concentration, This ret rograde inhibition is a consequence of the decrease in glycogen mobili zation, itself resulting from the decrease in glucose utilization as a consequence of the preponderant increase in lipid oxidation in obesit y, In this review, a negative correlation between muscle glycogen conc entration and glycogen synthase activity is presented in a group of ob ese patients with different degrees of glucose tolerance. The retrogra de regulation plays an important role in the evolution of obesity towa rd diabetes through its progressive inhibition of glycogen synthase ac tivity, leading to inhibition of glucose storage and insulin resistanc e, Diabetes occurs when the inhibition of glucose storage can no longe r be counterbalanced by the anterograde stimulation, In conclusion, th e evolution of obesity to diabetes is dominated by its retrograde inhi bition in the glycogen cycle as a consequence of the permanent increas e in lipid oxidation.