Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 16 No. 3 • March 2013

Understanding the Mechanism: Why Bleeding Might Be Beneficial in Obesity or Diabetes

Going back even a couple hundred years, bleeding was a popular therapy for a wide variety of disorders, but the mechanism(s) was (were) not understood so that the likelihood of doing harm (recall the case of George Washington, for example) was probably in most cases greater than the likelihood of benefit. As reported in a paper in the latest issue of The Journal of Clinical Investigation,1 “phlebotomy [bleeding] of humans with impaired glucose tolerance and ferritin values in the highest quartile of normal increased adiponectin and improved glucose tolerance. These findings demonstrate a causal role for iron as a risk factor for metabolic syndrome and a role of adipocytes in modulating metabolism through adiponectin in response to iron stores.”

Ferritin is the commonly used marker for total body iron stores. Phlebotomy improves blood glucose levels and aspects of the “metabolic syndrome” associated with obesity and diabetes (e.g., insulin resistance). The latter suggests that excess iron, which can be decreased by bleeding, may be a causal factor in these disorders.1 The authors note that recent studies have found a negative correlation between serum ferritin and the insulin-sensitizing adipokine, adiponectin. Moreover, obesity and diabetes are associated with lower levels of adiponectin, with the latter being causally related to insulin resistance. “Studies in cell culture, mouse models, and humans demonstrate that iron plays a direct and causal role in determining adiponectin levels and diabetes risk.”1

One of the findings of this paper was that mice on a high-iron diet had a significant decrease in their maximal glucose disposal rate per gram of lean tissue, indicating impaired glucose tolerance.

The researchers found that when ferroportin, an iron channel and exporter in adipocytes, was deleted (knocked out) in mice, they had increased adipocyte iron levels, decreased serum adiponectin, and increased insulin resistance. In the ferroportin knockout mice, there was an increased level of adipocyte iron accompanied with a 58% decrease in adipocyte adiponectin RNA, which was reflected in decreased serum adiponectin. The researchers also studied human subjects with impaired glucose tolerance that had serum ferritin levels in the highest quartile of the normal range. By about six months after phlebotomy, there was a fall in serum ferritin to the lowest quartile of normal, with the average blood donation being 3.7 units.

These findings suggest that frequent blood donations could help reduce the risk of diabetes and could even be therapeutic for those who already had the disease, although we do not know whether blood from diabetics taking drugs for their medical condition would be suitable for transfusion to normal subjects.

Another 2012 paper2 reports finding similar results in an epidemiological study of 27,548 people (16,644 women mainly aged 35–65 years and 10,904 men mainly aged 40–65 years) as part of the multicentre European Prospective Investigation into Cancer and Nutrition (EPIC). High ferritin levels were associated with higher risk of type 2 diabetes independently of established diabetic risk factors and a range of diabetes biomarkers. The authors conclude that “[t]hese results support the hypothesis that higher iron stores below the level of haemochromatosis [iron overload disorder] are associated with risk of type 2 diabetes.” In order to reduce the possibility of including individuals with undiagnosed haemochromatosis, the researchers excluded subjects in whom serum ferritin was elevated beyond three times the SD (standard deviation) from the mean (25 women with ferritin over 37.3 mg/l, 21 men with ferritin over 100.0 mg/l).2

A third 2012 paper3 also reported an association between iron metabolism and adipocyte insulin resistance and plasma adiponectin, suggesting (per the authors) that “factors related to iron and iron metabolism may contribute to adipocyte IR [insulin resistance] early in the pathogenesis of T2DM [type 2 diabetes mellitus].”


  1. Gabrielsen et al. Adipocyte iron regulates adiponectin and insulin sensitivity. Jnbsp;Clin Invest. 122(10):3529-40 (2012). doi:10.1172/JCI144421.
  2. Montonen et al. Body iron stores and risk of type 2 diabetes: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study. Diabetologia. 55:2613-21 (2012).
  3. Wlazio et al. Iron metabolism is associated with adipocyte insulin resistance and plasma adiponectin: the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study. Diabetes Care. 36(2):309-15 (2013 Feb).

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