Hyperinsulinemia may boost both hematocrit and iron absorption by up-regulating activity of hypoxia-inducible factor-1alpha

Med Hypotheses. Nov-Dec 2003;61(5-6):567-73. doi: 10.1016/s0306-9877(03)00231-7.


There is growing evidence that increases in both hematocrit and body iron stores are components of the insulin resistance syndrome. The ability of insulin and of IGF-I - whose effective activity is increased in the context of insulin resistance - to boost activity of the transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha), may be at least partially responsible for this association. HIF-1alpha, which functions physiologically as a detector of both hypoxia and iron-deficiency, promotes synthesis of erythropoietin, and may also mediate the up-regulatory impact of hypoxia on intestinal iron absorption. Insulin/IGF-I may also influence erythropoiesis more directly, as they are growth factors for developing reticulocytes. Conversely, the activation of HIF-1alpha associated with iron deficiency may be responsible for the increased glucose tolerance noted in iron-deficient animals; HIF-1alpha promotes efficient glucose uptake and glycolysis - a sensible adaptation to hypoxia - by inducing increased synthesis of glucose transporters and glycolytic enzymes. Recent reports that phlebotomy can increase the efficiency of muscle glucose uptake in lean healthy omnivores are intriguing and require further confirmation. Whether increased iron stores contribute to the elevated vascular risk associated with insulin resistance is doubtful, inasmuch as most prospective studies fail to correlate serum ferritin or transferrin saturation with subsequent vascular events. However, current data are reasonably consistent with the possibility that moderately elevated iron stores are associated with increased overall risk for cancer - and for colorectal cancer in particular; free iron may play a catalytic role in 'spontaneous' mutagenesis. Thus, iron excess may mediate at least some of the increased cancer risk associated with insulin resistance and heme-rich diets. People who are insulin resistant can minimize any health risk associated with iron overload by avoiding heme-rich flesh foods and donating blood regularly.

MeSH terms

  • Erythropoiesis
  • Glucose / metabolism
  • Hematocrit*
  • Humans
  • Hyperinsulinism*
  • Hypoxia
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Insulin / metabolism
  • Insulin Resistance
  • Iron / metabolism
  • Iron / pharmacokinetics*
  • Models, Theoretical
  • Muscles / metabolism
  • Prospective Studies
  • Reticulocytes / metabolism
  • Transcription Factors / biosynthesis*
  • Up-Regulation*


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Insulin
  • Transcription Factors
  • Iron
  • Glucose