"The alternative hypothesisis that iron excess or even sufficiency
might worsen glucose tolerance"

Diabetes Care. 1998 Dec;21(12):2190.Links
Effect of phlebotomy on plasma glucose and insulin concentrations.
Facchini FS.
PMID: 9839115 [PubMed - indexed for MEDLINE]

OBSERVATIONS
Effect of Phlebotomy on Plasma Glucose
and Insulin Concentrations
Two recent reports in Diabetes Care
(1,2) showed that iron stores, as
assessed by serum ferritin concentration
(3), are associated with plasma glucose
and insulin concentrations, i.e., the
greater the serum ferritin concentration, the
greater the plasma glucose and insulin concentrations.
Greater plasma glucose and
insulin concentrations indicate a more
severe degree of insulin resistance (4).
Complementaryfindings were described
by Moirand et al. (5), who detected a high
prevalence of insulin-resistant states such
as obesity, glucose intolerance, and type 2
diabetes in individuals with normal to high
iron stores but without the genetic traits of
hemochromatosis.
In this context, it is possible
that insulin-resistant individuals
might have a tendency to synthesize more
ferritin and/or to accumulate more iron .
However, this hypothesis is not supported
by studies in polytransfused thalassemic
children, who eventually become severely
insulin resistant (6), or by findings in
Sprague-Dawley rats, in which progressive
iron depletion enhances, in a dose-dependent
fashion, insulin-mediated glucose
uptake (7,8).
Thus, the alternative hypothesis
is that iron excess or even sufficiency
might worsen glucose tolerance, where a s
iron deficiency or lowering should induce
the opposite phenomenon.
To test such a hypothesis, phlebotomy
was used to lower iron stores in 10 healthy
blood donors (mean age ± SEM, 42 ± 4
years), and the consequent effects on glucose-
stimulated insulin levels are here i n
reported. Four weeks after phlebotomy,
serum ferritin concentration halved (75 ±
18 to 38 ± 10 μg/l; P 0.001); compare d
with baseline, the 2-h plasma insulin and
glucose concentrations after a 75-g oral
glucose load were reduced by 37 ± 9%
(665 ± 158 to 418 ± 93 pmol/l; P 0 . 0 2 )
and 19 ± 3% (7.4 ± 1.2 to 6.0 ± 0.8
mmol/l; P 0.05), respectively.
Thus, 1 month after a 500-ml phleb
o t o m y, improved glucose tolerance was
o b s e rved. Such effect correlated with the
reduction of serum ferritin concentration
(r = 0.53; P 0.03) but not with that of
hematocrit (Hct). Because all the part i c ipating
individuals had baseline ferritin
concentrations within normal limits, the
current finding seems to support the
notion that a reduction of body iron stores
enhances insulin sensitivity, even in “iron -
sufficient” individuals.
Mechanisms other than iron depletion
are worthy of consideration. For instance,
after phlebotomy, blood volume is re s t o re d
to normal within 24–48 h by hemodilution,
whereas Hct returns to baseline values
at a slower rate (9). One can postulate that
the reduction in Hct and blood viscosity
could increase muscle perfusion and,
therefore, glucose uptake (10). This effect might
result in improved glucose tolerance. There
a re inconsistencies, however, that argue
against this hypothesis. First, 4 weeks after
phlebotomy, Hct was only 1% lower than at
baseline (43.9 ± 0.9 vs. 44.5 ± 1.0%; NS);
this variation appears too small to explain a
persistent change in glucose tolerance of
40%. In addition, the reduction of Hct
was insignificantly correlated to such
change. Therefore, it seems unlikely that
the variation in Hct, per se, determined the
change in glucose tolerance.
In summary, after a 500-ml phlebotomy,
enhanced oral glucose tolerance is
demonstrated in 10 healthy individuals.
Such results help clarify the nature of the
recently reported association between
insulinemia, insulin resistance, and serum
ferritin concentration (1,2).
FR A N C E S C O S. FA C C H I N I, M D
From the Department of Medicine, St. Mary ’s Hospital
and Medical Center, San Francisco, California .
Address correspondence to F.S. Facchini, MD,
UC Renal Center at San Francisco General Hospital,
Box 1341 UCSF, San Francisco, CA 94080-1341.
Email:francesco.facchini@ncal.kaiperm . o rg .
R e f e re n c e s
1 . Tuomainen T- P, Nyyssönen K, Salonen R,
Te rvahauta A, Korpela H, Lakka T, Kaplan
GA, Salonen JT: Body iron stores are associated
with serum insulin and blood glucose
concentrations: population study in
1,013 eastern Finnish men. Diabetes Care
20:426–428, 1997
2 . F e rnández-Real J-M, Ricart-Engel W,
A rroyo E, Balançá R, Casamitjana-Abella
R, Cabre ro D, Fernández-Castañer M,
Soler J: Serum ferritin as a component of
the insulin resistance syndrome. Diabetes
C a re 21:62–68, 1998
3 . Cook JD, Lipschitz DA, Miles LEM, Finch
CA: Serum ferritin as a measure of iron
stores in normal subjects. Am J Clin Nutr
27:681–687, 1974
4 . Hollenbeck CB, Chen N, Chen Y-DI, Reaven
GM: Relationship between the plasma
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glucose utilization in norm a l
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5 . Moirand R, Mortaji AM, Loreal O, Paillard
F, Brissot P, Deugnier Y: A new syndro m e
of liver iron overload with normal transferrin
saturation. Lancet 349:95–97, 1997
6 . Merkel PA, Simonson D, Amiel S, Plewe G,
S h e rwin RS, Pearson HA, Ta m b o r l a n e
W V: Insulin resistance and hyperinsulinemia
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318:809–814, 1988
7 . Henderson S, Dallman PR, Brooks GE:
Glucose turnover and oxidation are
increased in the iron deficient rat. Am J
P h y s i o l250:E414–E421, 1986
8 . B o rel MJ, Beard JL, Farrell PA: Hepatic glucose
production and insulin sensitivity and
responsiveness in iron - deficient anemic
rats. Am J Physiol264:E380–E390, 1993
9 . E b e rt RV, Stead EA, Gibson JG: Response
of normal subjects to acute blood loss.
A rch Intern Med68:578–590, 1941
1 0 . B a ron AD, Laakso M, Brechtel G, Hoitt C,
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