Glucose effectiveness is a critical pathogenic factor leading to glucose intolerance and type 2 diabetes: An ignored hypothesis

Background: Although the ability of glucose to mediate its own in vivo metabolism is long documented, the quantitative measurement of whole body glucose-mediated glucose disposal at basal insulin levels (glucose effectiveness [GE]), followed the introduction of the Minimal Model intravenous glucose tolerance test technique. Methods: A literature review, combined with our own studies, of the role of GE in glucose metabolism in normal and at risk individuals, was undertaken to determine GE's contribution to glucose homeostasis. Results: GE accounts for similar to 45% to 65% of glucose disposal in man. A negative association between GE and insulin meditated glucose disposal (Si), is present in normal subjects without a family history of type 2 diabetes mellitus but is absent in normoglycaemic at risk relatives with a positive family history of diabetes mellitus. Intracellular GE disposal is mediated by mass action of glucose through the skeletal muscle membrane via facilitated Glut 4 transporters. However, GE is frequently forgotten as a significant contributor to the development of glucose intolerance in at risk individuals. Only limited studies have examined the role of a lower GE in such normoglycemic subjects with preexisting mild insulin resistance and -cell dysfunction. These studies demonstrate that in at risk individuals, an initial low GE is a key contributor and predictor of future glucose intolerance, whereas an initial raised GE is protective against future glucose intolerance. ConclusionIn at risk individuals, a low GE and genetically determined vulnerable-cell function are more critical determinants of future glucose intolerance than their preexisting insulin-resistant state.