Original Article
ANEMIA ASSOCIATED WITH NEW-ONSET DIABETES:
IMPROVEMENT WITH BLOOD GLUCOSE CONTROL
Antonio Piñero-Piloña, MD,1 Patrick Litonjua, MD,1 Sridevi Devaraj, PhD,2
Larissa Aviles-Santa, MD,1 and Philip Raskin, MD, FACE1
ABSTRACT
Objective: To evaluate the mild normochromic nor-
mocytic anemia associated with new-onset diabetes in
young, otherwise healthy patients.
Methods: We undertook a retrospective review of
medical records of patients with new-onset diabetes and
unexplained anemia. Anemia was defined as a hemoglo-
bin concentration of less than 12.5 g/dL in women and less
than 14 g/dL in men. Patients with obvious causes of ane-
mia, such as renal insufficiency, infection, pancreatitis,
deficiency of glucose-6-phosphate dehydrogenase, hemol-
ysis, or acute or chronic blood loss, were excluded from
the study.
Results: In 16 otherwise seemingly healthy patients
with new-onset diabetes, a normochromic normocytic
anemia (mean corpuscular volume, 86.4 ± 4 fL) was diag-
nosed at initial assessment. These 16 patients (8 men and
8 women) had a mean age of 33 ± 10 years. At diagnosis,
the mean glycated hemoglobin (HbA1c) was 15.5 ± 3.4%,
the mean hemoglobin concentration was 12.5 ± 0.6 g/dL,
and the mean hematocrit was 36.2 ± 2%. All patients were
treated with insulin. After a mean follow-up of 10.8 ± 17
months, insulin treatment resulted in a decline in HbA1c
to 7.7 ± 1.7% (P<0.001; confidence interval [CI], 5.7 to
9.8). The hemoglobin concentration increased to 14.3 ±
0.9 g/dL (P<0.001; CI, 1.22 to 2.38), and the hematocrit
increased to 42.1 ± 1.9% (P<0.001; CI, 3.59 to 7.04). All
patients had hemoglobin AA and normal levels of hemo-
globin A2. Men and women had equal improvement in
hematologic variables after improvement in glycemic
control.
Conclusion: Some patients with new-onset diabetes
have a mild normochromic normocytic anemia that is not
attributable to usual causes, such as infection, pancreatitis,
Submitted for publication March 29, 2001
Accepted for publication November 29, 2001
From the 1Department of Internal Medicine and 2Department of
Pathology, University of Texas Southwestern Medical School, and the
University Diabetes Treatment Center, Parkland Memorial Hospital,
Dallas, Texas.
Address correspondence and reprint requests to Dr. Philip Raskin,
Department of Internal Medicine, University of Texas Southwestern
Medical School, 5323 Harry Hines Boulevard, G5.238, Dallas, TX 75390-
8858.
© 2002 AACE.
276 ENDOCRINE PRACTICE Vol 8 No. 4 July/August 2002
or blood loss. Improvement in glycemic control tends to
be associated with normalization of hemoglobin levels.
The cause of such cases of anemia may be either direct
“glucose toxicity” to erythrocyte precursors in the bone
marrow or perhaps oxidative stress to mature erythrocytes.
(Endocr Pract. 2002;8:276-281)
Abbreviations:
CI = confidence interval; G6PD = glucose-6-phosphate
dehydrogenase; HbA1c = glycated hemoglobin; HMPS
= hexose-monophosphate shunt; NADPH = reduced
form of nicotinamide adenine dinucleotide phosphate
INTRODUCTION
New-onset type 1 or type 2 diabetes is often associat-
ed with severe volume depletion and oxidative stress. At
diagnosis, many patients have hemoconcentration due to
volume depletion related to osmotic diuresis, often com-
plicated by vomiting. In patients with hemoglobinopathies
and erythrocyte enzyme deficiencies, severe anemia can
develop in conjunction with new-onset diabetes—espe-
cially in the setting of ketoacidosis (1-8). This type of ane-
mia is hemolytic and has been reported in patients with
thalassemias, sickle cell disease, and glucose-6-phosphate
dehydrogenase (G6PD) deficiency. The patients with
G6PD deficiency (2,3,7) are particularly susceptible to the
oxidative stress brought on by hyperglycemia and ketoaci-
dosis due to reduction of antioxidants in cells. We have
noted that some young, otherwise healthy persons with
new-onset diabetes, despite their severe hemoconcentra-
tion, have a mild normochromic normocytic anemia. After
extensive workup, no clear cause for their anemia is
found, and the anemia seems most consistent with an
“anemia of inflammation,” formerly known as “anemia of
chronic disease” (9,10). This diagnosis seems inappropri-
ate because no known systemic inflammatory illness is
present to explain their anemia, and their diabetes is of
short duration—usually a few weeks to a few months. The
most interesting finding is that this anemia is corrected
with an improvement of glycemic control. This result sug-
gests that hyperglycemia and oxidative stress somehow
affect erythropoiesis and may be toxic to erythrocyte
precursors in the bone marrow or to mature erythrocytes in

the peripheral blood. Because this clinical association has
not been reported before, the mechanism involved in this
phenomenon is unknown. In light of these observations,
we were interested in evaluating the incidence of anemia
in young, otherwise healthy persons with newly diagnosed
diabetes and in ascertaining the mechanism of its
development.
PATIENTS AND METHODS
The data for this report were compiled from a review
of medical records of patients with new-onset diabetes and
unexplained anemia admitted during the 10-year period
from 1989 to 1999 to the University Diabetes Treatment
Center at Parkland Memorial Hospital in Dallas, Texas.
The patients were identified by the presence of anemia, as
defined by a hemoglobin concentration of less than 12.5
g/dL in women and less than 14 g/dL in men, at the time
of admission to the hospital before intravenous adminis-
tration of any fluids. Patients with a prior history of dia-
betes or an obvious cause of anemia, such as renal insuffi-
ciency (serum creatinine level in excess of 1.5 mg/dL),
infection, pancreatitis, chronic hepatitis, alcohol abuse,
hemolysis, or acute or chronic blood loss, were excluded
from this study. Patients who received intravenously
administered fluids before any laboratory measurements
were excluded from analysis to avoid confusion with dilu-
tion anemia. Hematologic studies and workup for the ane-
mia were done at the time of diagnosis. Although the com-
ponents of the evaluation were variable, all study patients
underwent sufficient assessment to rule out the presence
of hemoglobinopathy, blood loss, acute hemolysis, or iron
deficiency. The calculations of the corrected reticulocyte
count were done by using the reticulocyte production
index. This index corrects the reticulocyte count on the
basis of the patient’s hematocrit and also the maturation
index, which accounts for the early release of immature
reticulocytes (“shift reticulocytes”) from the bone marrow
depending on the degree of anemia. A reticulocyte pro-
duction index of less than 2 was considered reflective of a
hypoproliferative marrow. None of the patients had ane-
mia that was sufficiently severe to warrant bone marrow
aspiration. For statistical analysis of all variables,
Student’s t test for nominal values was used (Glantz’s
Statistical Software, version 3.02, McGraw-Hill, 1992).
The values are reported as the mean ± standard deviation;
most results were not normally distributed.
RESULTS
We reviewed the medical records of more than 1,500
patients who were admitted to the University Diabetes
Treatment Center at Parkland Memorial Hospital in
Dallas, Texas, between 1989 and 1999 for management of
new-onset diabetes. Of these patients, 83 were found to
fulfill the initial criteria for anemia. Thus, the incidence of
anemia in patients with new-onset diabetes was 5.5%. The
workup of patients with anemia usually included a reticu-
locyte count, corrected reticulocyte count, serum iron,
Diabetes and Anemia, Endocr Pract. 2002;8(No. 4) 277
ferritin, total iron-binding capacity, hemoglobin elec-
trophoresis, hemoglobin A2 quantification, haptoglobin,
G6PD, folate, vitamin B12, thyroid function tests, and ser-
ial complete blood cell counts. On the basis of these stud-
ies, 45 of the 83 patients were found to have a readily iden-
tifiable cause of their anemia, including 13 patients with
iron deficiency anemia, 13 with β-thalassemia minor, 7
with G6PD deficiency, 6 with hemoglobin AS, 2 with
hemoglobin AC, and 2 with hemoglobin SC. One patient
had both hemoglobin AS and G6PD deficiency. One
patient from Thailand had hemoglobin EE, which is com-
mon in Asia. In addition, 10 patients with mild anemia did
not undergo hematologic evaluation at diagnosis and thus
were not included in the statistical analysis. Two of these
patients were diagnosed years later with prostate and
endometrial cancer, respectively.
Thus, our study population included 28 patients with
new-onset diabetes who had an unexplained nor-
mochromic normocytic anemia at the time of diagnosis.
Of these 28 patients, 12 had no follow-up laboratory stud-
ies and could not be included in the statistical analysis.
The other 16 patients had an initial workup and had a fol-
low-up evaluation including blood cell counts and glycat-
ed hemoglobin (HbA1c). Therefore, our report consists of
data from 16 otherwise seemingly healthy patients with
new-onset diabetes who had a normochromic normocytic
anemia at the time of diagnosis. The 16 patients (8 men
and 8 women) had a mean age of 33 ± 10 years. They had
no other acute or chronic systemic illness or history of
cancer to explain their anemia. Eight patients were African
American, six were Hispanic, one was Asian Indian, and
one was non-Hispanic white. At the time of initial diagno-
sis, eight patients with type 1 diabetes had diabetic
ketoacidosis, and eight patients had hyperglycemia with-
out ketoacidosis. The clinical characteristics at the time of
diagnosis are summarized in Table 1.
At the time of diagnosis of diabetes in the 16 study
patients, the mean HbA1c was 15.5 ± 3.4%, the mean
hemoglobin level was 12.5 ± 0.6 g/dL, and the mean
hematocrit was 36.2 ± 2% (mean corpuscular volume,
86.4 ± 4 fL; range, 81 to 91.2). The corrected mean retic-
ulocyte production index of all patients at diagnosis was
0.89 ± 0.3 (median, 0.86; range, 0.38 to 1.47). No statisti-
cally significant difference was found between men (0.92
± 0.32) and women (0.85 ± 0.3) (difference of 0.07; P =
0.66). All patients were treated with insulin in the hospital
and after dismissal. At dismissal from the hospital, the
mean hemoglobin concentration was 12.4 ± 1.4 g/dL, and
the mean hematocrit was 36.1 ± 3.9%.
After a mean follow-up of 10.8 ± 17 months (median,
6; range, 2 to 48), insulin treatment resulted in a decline in
HbA1c to 7.7 ± 1.7% (P<0.001; confidence interval [CI],
5.7 to 9.8). The mean hemoglobin level increased to 14.3
± 0.9 g/dL (P<0.001 versus baseline; CI, 1.22 to 2.38), and
the mean hematocrit increased to 42.1 ± 1.9% (P<0.001
versus baseline; CI, 3.59 to 7.04) (Fig. 1). Men and
women had equal improvement in hematologic variables
after improvement in glycemic control. In women, the
mean hemoglobin concentration was 12.1 ± 0.37 g/dL at
278 Diabetes and Anemia, Endocr Pract. 2002;8(No. 4)

Table 1
Clinical Characteristics of Patients With
Anemia Associated With New-Onset Diabetes*†

Factor Normal range At diagnosis

Age (yr) … 33 ± 10
Weight (kg) … 78.7 ± 29
Glucose (mg/dL) 70-110 498 ± 98
HbA1c (%) 3.8-5.6 15.5 ± 3.4
RBC (×106/µL) 3.8-5.5 4.29 ± 0.33
Hemoglobin (g/dL) 12.5-14 12.5 ± 0.6
Hematocrit (%) 37-46 36.2 ± 2
MCV (fL) 80-101 86.4 ± 4
MCHC (g/dL) 31-35 34.5 ± 0.77
RDW (%) 11.5-14 12.6 ± 0.95
Iron (µg/dL) 48-180 71.6 ± 25
Ferritin (ng/mL) 7-282 248 ± 150
TIBC (µg/dL) 262-474 287 ± 61
Reticulocyte count (%) 0.8-2.5 1.61 ± 0.57
Hemoglobin A2 (%) 0.0-3.5 2.7 ± 0.5
Creatinine (mg/dL) 0.6-1.2 0.8 ± 0.3
MCH (pg) 27-33 29.5 ± 1.74

*HbA1c = glycated hemoglobin; MCH = mean corpuscular

hemoglobin; MCHC = mean corpuscular hemoglobin concentration;
MCV = mean corpuscular volume; RBC = red blood cells
(erythrocytes); RDW = red blood cell distribution width; TIBC =
total iron-binding capacity.
†Data are shown as mean ± standard deviation; values were not
normally distributed. All patients had hemoglobin AA.

diagnosis and increased to 14.1 ± 0.74 g/dL at follow-up DISCUSSION

(P<0.0001; CI, 1.16 to 2.8 g/dL). In men, the mean hemo-
globin concentration was 12.9 ± 0.48 g/dL and increased
to 14.8 ± 0.95 g/dL at follow-up. At follow-up, one man
had improvement in his hemoglobin level after correction
of the acute hyperglycemia; however, mild anemia per-
sisted in association with relatively poor glycemic control.
This patient (a Hispanic man) had a follow-up hemoglobin
level of 13.7 g/dL and HbA1c value of 8.5% at 12 months
after diagnosis. Only one patient (an African American
man) had worse glycemic control at follow-up in compar-
ison with at diagnosis. His hemoglobin concentration was
slightly lower at 4-year follow-up (13.4 g/dL) than it was
at diagnosis (13.7 g/dL). This patient also had HbA1c val-
ues of 10.6% at diagnosis and of 11.5% at 48 months after
diagnosis. Both of these patients continue to receive
insulin therapy. A correlation was noted between improve-
ment in glycemic control and improvement in hemoglobin
concentration, but it did not reach statistical significance
(P = 0.08) (Fig. 2).
New-onset diabetes is associated with oxidative stress
and hemoconcentration due to volume depletion, acidosis,
and osmotic diuresis. Some patients with hemoglo-
binopathies and erythrocyte enzyme deficiencies are sus-
ceptible to development of severe anemia with new-onset
diabetes, especially in the setting of ketoacidosis and
oxidative stress. This anemia is hemolytic, attributable to
accelerated erythrocyte destruction.
In this report, we have described, for the first time, a
small number of patients with new-onset diabetes who
have anemia even in the presence of volume depletion and
osmotic diuresis. This anemia is not usually severe, cannot
be explained by any known factors that influence erythro-
cyte survival or production, and seems to be hypoprolifer-
ative, as reflected by a low corrected reticulocyte index.
The anemia is also normocytic and normochromic, with
normal erythrocyte indices and erythrocyte morphologic
features. Our patients were young and had no systemic

Fig. 1. Effects of insulin treatment on hemoglobin concentration
and glycated hemoglobin (HbA1c) values in patients with
anemia associated with new-onset diabetes.
chronic illness to explain their anemia. None had evidence
of hemolysis. After workup of the anemia, the findings
were consistent with so-called anemia of inflammation
(formerly known as anemia of chronic disease) (9,10),
even though these patients were otherwise apparently
healthy. The most interesting aspect of this anemia seems
to be the notable improvement in the hemoglobin and
hematocrit levels once glycemic control is improved. This
result suggests that hyperglycemia has a key role in the
pathogenesis of this phenomenon. This association has not
been described before, and there is limited literature avail-
able to explain this phenomenon. We propose that hyper-
glycemia has an important pathophysiologic role in the
development of this anemia.
Possible explanations for our findings are the key role
that hyperglycemia and oxidative stress have in the
destruction of mature erythrocytes or the decrease in pro-
duction of erythrocytes by bone marrow precursors (or
both). Hyperglycemia causes oxidative stress by different
mechanisms, including the increased flux of glucose
through the polyol pathway (Fig. 3). The polyol pathway
is believed to be the major contributor of oxidative stress
in patients with diabetes (11). Increased flux of glucose
through the polyol pathway causes greater consumption of
the reduced form of nicotinamide adenine dinucleotide
phosphate (NADPH) due to increased production of sor-
bitol. This augmented utilization of NADPH can cause a
deficiency of this cofactor for other enzymes that use
NADPH. One important enzyme that uses NADPH as a
cofactor is glutathione reductase. Glutathione reductase is
responsible for the reduction of oxidized glutathione,
which is one of the major antioxidants in cells, including
erythrocytes. Reduced glutathione is a scavenger for free
oxygen radicals and peroxides that can damage cell mem-
brane lipids. The decreased production of glutathione
causes an increase in free oxygen radicals that damage cell
membrane lipids in erythrocytes, an action that causes
erythrocytes to be fragile and prone to lysis. Erythrocytes
of patients with diabetes have been shown to have high
Diabetes and Anemia, Endocr Pract. 2002;8(No. 4) 279
Fig. 2. Correlation between changes in glycated hemoglobin
(HbA1c) values and hemoglobin concentration at follow-up of
patients with new-onset diabetes and unexplained anemia.
levels of oxidized glutathione (12,13), a shorter half-life
(14), a decreased NADPH/NADP ratio (15), and an
increased cellular fragility (16). Oxidative stress has also
been shown to cause mitochondrial DNA damage to skele-
tal myocytes in patients with diabetes (17). This DNA
damage causes apoptosis involving various cell lines
including neurons (18) and perhaps bone marrow precur-
sors, leading to decreased production of erythrocytes or
decreased synthesis of hemoglobin.
The NADPH in erythrocytes originates from the reac-
tions derived from the hexose-monophosphate shunt
(HMPS). Hyperglycemia will theoretically increase the
flux of glucose through this pathway and should protect
erythrocytes from oxidative stress. Why then did hyper-
glycemia not protect erythrocytes or its precursors from
oxidative damage in these patients? Why do not all
patients with diabetes have anemia?
The administration of glucose has been shown to
increase markers of oxidative stress in erythrocyte mem-
branes in patients with diabetes (19) and those without dia-
betes (20). High glucose levels have also been shown to
inhibit G6PD in vitro (21) and in experimental diabetes
(22). The inhibition of production of G6PD will reduce the
flux of glucose through the HMPS and can result in
decreased production of NADPH. Therefore, it is possible
that glucose is being used preferentially in the polyol and
glycolytic pathway rather than through the HMPS. The
preferential shunting of glucose through the polyol
pathway will make erythrocytes prone to oxidative
damage and fragility because of peroxidation of cell mem-
brane lipids. Another theoretical mechanism to explain
this phenomenon is that this group of patients may have a
gene polymorphism that causes some of the enzymes in
the HMPS or G6PD to be less effective in producing
NADPH.
Therefore, we believe that severe persistent hyper-
glycemia is sufficient to cause abnormalities in the
production of mature erythrocytes and the fragility of
mature erythrocytes. Once the metabolic derangements
280 Diabetes and Anemia, Endocr Pract. 2002;8(No. 4)

Fig. 3. Schematic diagram of the intermediary metabolism of erythrocytes and

proposed pathways involved in oxidative stress in patients with diabetes. In
experimental diabetes, there is evidence of reduced glucose-6-phosphate dehy-
drogenase (G6PD) activity, a decreased ratio of the reduced form (NADPH) to
the oxidized form (NADP+) of nicotinamide adenine dinucleotide phosphate,
and high levels of oxidized glutathione, all favoring oxidation of important
components of erythrocytes including membrane lipids. AGE = advanced gly-
cosylation end products.

and severe hyperglycemia have been corrected, the pro-
duction of mature and new erythrocytes improves with an
increase in hemoglobin and hematocrit. Peterson et al (23)
reported improvements in erythrocyte half-life in patients
with a long history of diabetes with achievement of inten-
sive glycemic control. There was no mention of improve-
ments in hemoglobin concentration with improved
glycemic control.
Another potential explanation is that all these patients
had α-thalassemia with only one α-chain locus affected
and that hyperglycemia somehow affected the synthesis of
the other α-chains. This possibility seems unlikely
because all the patients had improvements in their hemo-
globin concentration after insulin treatment, although most
patients were not euglycemic at follow-up. Published
reports have described resistance to the action of erythro-
poietin in erythrocyte precursors in the bone marrow
(24,25) or low production of erythropoietin (26) in
patients with long-standing diabetes. There are no such
reports in patients with new-onset diabetes. Because these
patients had normal renal function, plasma erythropoietin
was not measured. Perhaps acute hyperglycemia as is seen
in new-onset diabetes can inhibit the production of eryth-
ropoietin; such a process would explain the low corrected
reticulocyte index.
Certain limitations that are common to retrospective
studies warrant mention. In this retrospective study, con-
siderable variation existed from the time of initial sam-
pling to the time of follow-up. Moreover, 12 patients with
unexplained anemia were untraceable at follow-up, and
their inclusion might have altered the statistical analysis.
Even though we observed a tendency toward a correlation
between glycemic control and improvement in hemoglo-
bin level, this correlation did not reach statistical signifi-
cance because of the small sample size. Finally, other
factors that could influence erythrocyte production were
not directly measured. Because most of the patients had
normal reticulocyte counts, peripheral smears, and serum
creatinine levels, erythropoietin levels, haptoglobin levels,
and bone marrow aspiration were not done. Perhaps these
studies should be done in future investigations in an effort
to understand this phenomenon better.
CONCLUSION
New-onset diabetes can be associated with a mild nor-
mochromic normocytic anemia. The anemia is not
explainable by usual causes, such as infection, pancreati-
tis, or blood loss, and the hemoglobin concentration nor-
malizes with improvement in glycemic control. The cause
of anemia may be direct “glucose toxicity” to erythrocyte
precursors in the bone marrow or to mature erythrocytes,
perhaps because of oxidative stress. Further studies are
needed to evaluate these findings.
ACKNOWLEDGMENT
We thank the staff of the University Diabetes
Treatment Center and the Medical Records Department at
Parkland Memorial Hospital for helping with data collec-
tion. We also thank Beverly Adams-Huet, the General
Clinical Research Unit biostatistician, for assistance with
statistical analyses and Dan Chan for collection of data
and review of medical records. Drs. Piñero-Piloña and
Litonjua were supported in part by NIDDK Training Grant
T-32-DK070307-22. Beverly Adams-Huet was supported
in part by the General Clinical Research Unit Grant
M01RR00633.

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