Glucose Effectiveness Is a Critical Pathogenic Factor Leading to Glucose Intolerance and Type 2 Diabetes: An Ignored Hypothesis

Diabetes Metab Res Rev. 2018 May;34(4):e2989. doi: 10.1002/dmrr.2989. Epub 2018 Mar 24.


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 ~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 β-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.

Conclusion: In "at risk" individuals, a low GE and genetically determined vulnerable β-cell function are more critical determinants of future glucose intolerance than their preexisting insulin-resistant state.

Keywords: beta cell function; glucose effectiveness; glucose intolerance; type 2 diabetes.

MeSH terms

  • Australia / epidemiology
  • Blood Glucose / metabolism*
  • Diabetes Mellitus, Type 2 / epidemiology*
  • Diabetes Mellitus, Type 2 / metabolism
  • Glucose Intolerance / epidemiology*
  • Glucose Intolerance / metabolism
  • Glucose Tolerance Test
  • Humans
  • Insulin Resistance
  • Prediabetic State / epidemiology*
  • Prediabetic State / metabolism


  • Blood Glucose