International Journal of Diabetes Mellitus 2 (2010) 10–14

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International Journal of Diabetes Mellitus

journal homepage: ees.elsevier.com/locate/ijdm

Original Article

Fluctuations in glycosylated hemoglobin (HbA1C) as a predictor for the

development of diabetic nephropathy in type 1 diabetic patients
Jocelyn Eid Fares a, Mona Kanaan b, Monique Chaaya b, Sami T. Azar a,*
a
Department of Internal Medicine, Division of Endocrinology, American University of Beirut-Medical Center, 3 Dag Hammarskjold Plaza – 8th Floor, New York, NY 10017 2324, USA
b
Department of Epidemiology and Population Heath, American University of Beirut, USA

a r t i c l e i n f o a b s t r a c t

Article history: Objective: The incidence of diabetic nephropathy is higher in type 1 diabetic patients with associated risk
Received 28 October 2009 factors. The within individual fluctuations in HbA1C and its effect on the development of nephropathy
Accepted 20 December 2009 was not previously studied. The purpose of this study is to examine whether HbA1C fluctuations are a
predictor of the development of diabetic nephropathy independent of mean HbA1C and other risk factors.
Methods: One hundred and seventeen patients (64 females and 53 males) were recruited and followed up
Keywords: regularly at least every 3 months. The ‘‘fluctuations” in HbA1C over time was assessed. HbA1C fluctuation
Type 1 diabetes
was defined as an increase in HbA1C of more than 2% between two consecutive measurements, or an
Diabetic nephropathy
Glycosylated hemoglobin
increase of more than 1% at 2 points in time.
Albuminuria Results: Incipient nephropathy was present in 18 and absent in 99 patients. Mean HbA1C was signifi-
Microalbumin cantly higher in nephropathy than in non-nephropathy patients. The effect of fluctuations on nephropa-
thy appeared to be more significant in patients with poor metabolic control (HbA1C P 8%).
Conclusion: T1D patients who have a similar mean HbA1C may progressively behave differently in terms
of developing nephropathy, depending on the fluctuations in HbA1C. This effect seems to be more pro-
nounced among those who have higher values of HbA1C.
Ó 2010 International Journal of Diabetes Mellitus. Published by Elsevier Ltd.
Open access under CC BY-NC-ND license.

1. Introduction independently of previous control [4]. Other studies [5,6] showed

Diabetes mellitus is reported as the most common single cause
of end-stage renal disease (ESRD) in the US and Europe. Patients
(20–30%) with type 1 diabetes develop evidence of diabetic
nephropathy after a mean of 15 years [1,2]. Thus far, the earliest
clinical evidence of diabetic nephropathy is the appearance of
low but abnormal levels of albumin in the urine, referred to incip-
ient nephropathy (albuminuria P 30 mg/24 h or P20 lg/min).
These levels of microalbuminuria, when sustained, may lead to
overt nephropathy and consequently to ESRD [3].
The incidence of diabetic nephropathy is higher in type 1 dia-
betic patients with associated risk factors such as genetic factors,
presence of hypertension, and poor metabolic control. Essentially,
the metabolic control is a modifiable risk factor. The Diabetes Con-
trol and Complication Trial (DCCT) has shown that intensive diabe-
tes therapy defined as mean HbA1C of approximately 7% can
significantly reduce the risk of the development of microalbumin-
uria by 34%, as compared to those on conventional treatment
where HbA1C was 8.5%. It also showed that intervention to im-
prove metabolic control does reduce the risk of complications
* Corresponding author. Tel.: +1 961 3 234 250; fax: +1 961 1 365 189.
E-mail address: sazar@aub.edu.lb (S.T. Azar).
that a between-individual difference in HbA1C of 1–2% increased
the risk of developing microvascular complications by at least
25%. Until now, the within individual fluctuations in HbA1C and
their consequences on the development of nephropathy were not
studied. In fact, DCCT was an interventional study, where patients
on intensive treatment were followed up closely (insulin adjusted
daily and HbA1C checked monthly) and where HbA1C was sus-
tained close to 7%, unlike the conventional group, whose follow
up had been less frequently (every 3 months). In this setting, the
within individual ‘‘fluctuations” in HbA1C would be unexpected
in patients with good metabolic control and very probable in those
with poor control. Thus, the difference between the two groups in
the occurrence of diabetic nephropathy may be explained by the
differences of fluctuations within individuals. Although the effect
of fluctuations in HbA1C on the development of nephropathy could
be suspected indirectly from the findings of DCCT, a study directly
addressing this issue is needed.
The purpose of our study was to examine whether fluctuations
in HbA1C (as early as the diagnosis up till 5 years from diagnosis)
are a predictor of the development of diabetic nephropathy,
independent of mean HbA1C and of other risk factors such as age
at onset of diabetes, body mass index (BMI), the presence of hyper-
tension and the presence of family history of diabetes.

1877-5934 Ó 2010 International Journal of Diabetes Mellitus. Published by Elsevier Ltd. Open access under CC BY-NC-ND license.
doi:10.1016/j.ijdm.2009.12.012
 J.E. Fares et al. / International Journal of Diabetes Mellitus 2 (2010) 10–14
2. Patients and methods
Type 1 diabetic patients were recruited from a type 1 diabetes
center in the Lebanon: the Chronic Care Center for children and
young adults with type 1 diabetes mellitus. Type 1 diabetic pa-
tients are followed up regularly at least every 3 months. At each
visit, HbA1C is measured; body weight and the average dose of to-
tal insulin required per day are measured. Height is documented
once a year. Blood pressure is systematically measured at diagno-
sis, and recorded at least once a year. Eye examination, for the
presence of diabetic retinopathy, is done by an ophthalmologist
at the first visit to the center then followed up a yearly basis.
Microalbuminuria is tested in each patient 5 years after the diag-
nosis of type 1 diabetes, as recommended by ADA [7], and then
yearly.
Patients with type 1 diabetes, as defined by ADA [8], admitted
to the chronic care center were studied. The institutional review
board (IRB) in the chronic care center approved the protocol. Only
patients admitted to the chronic care center within 18 months of
diagnosis of type 1 diabetes mellitus were included, since struc-
tural renal abnormalities due to diabetes usually occurs afterward
[9]. Patients were excluded from the study if the duration of diabe-
tes was less than 5 years, since diabetic nephropathy is known to
occur after at least 5 years of the disease [7]. Patients were also ex-
cluded from the study if they suffered from wolfram syndrome, or
had thalassemia or other hemoglobinopathy. Two hundred and
four patients met the inclusion criteria, and 87 patients were ex-
cluded. The final sample size was 117 patients.
The following information was obtained: age, gender, date of
birth, date of onset of diabetes, date of admission to the center,
family history for diabetes, results of microalbuminuria after
5 years of diagnosis, the dates and the results of HbA1C at each vis-
it, BMI at baseline and blood pressure. Patients (microalbuminurea
vs non-microalbuminurea) were selected based on a cut off point
of 24 h urine microalbumin of >30 mg/24 h on more than two
occasions.
2.1. Definition of ‘‘fluctuations in HbA1C”
The main predictor ‘‘fluctuations in HbA1C” was defined as an
increase in HbA1C of more than 2% between two consecutive mea-
surements (3 months interval ± 2 weeks) or an increase in HbA1C
of more than 1% at 2 points in time. Our decision was based on pre-
vious evidence that a between-individual difference in HbA1C of
more than 2% more than doubled the risk of developing microvas-
cular complications [5]. HbA1C was measured by Bayer’s DCA
2000, an assay method that is certified as traceable to the DCCT ref-
erence. The normal range for this method, based on 103 healthy
individuals, is 4.2–6.5%. The precision of this method in measuring
HbA1C has been proven (variability between-run is negligible)
(Manufacture’s instructions).
2.2. Diagnosis of nephropathy
The outcome was incipient nephropathy, defined as a rate of
albumin excretion between 20 and 200 lg/min (or between 30
and 300 mg/24 h). It was coded as 0 and 1 for the absence and
presence of nephropathy, respectively.
2.3. Other clinical characteristics
The following is a list of covariates that were included in the
analyses: age, age at onset, BMI, mean HbA1C per individual, gen-
der, hypertension (defined as systolic blood pressure and diastolic
11
blood pressure above the 95th percentile for age) and presence of
family history for diabetes mellitus.
2.4. Acceptable vs poor metabolic control
Acceptable metabolic control was defined as having a mean
HbA1C <8% and a poor metabolic control denoted a mean HbA1C
P8%. Although the definition of poor vs acceptable metabolic con-
trol is not standardized, our definition was based on our assay
methodology.
3. Statistical analysis
The outcome of insidious nephropathy was treated as a dichot-
omous variable. Bivariate analyses were performed between covar-
iates and the outcome, using v2 or t-test according to whether the
variable was continuous or categorical. Correlation of repeated
measures (for the differences of two consecutive HbA1C) was ex-
plored and showed no evidence of correlation between the two
measures. The pattern of missing data was investigated, as recom-
mended by Twisk [10], and was found to be ignorable (neither
dependent on the outcome nor on other predictors). Further anal-
yses were performed on a dataset where missing data on HbA1C
were inputted using linear interpolation.
The association between HbA1C and the outcome was explored
by performing bivariate analysis first between mean HbA1C and
nephropathy, and then between ‘‘fluctuations” in HbA1C and the
outcome.
Furthermore, we studied the association between fluctuations
and nephropathy, adjusting for all covariates using logistic regres-
sion analysis. Models were compared using Bayesian information
criterion (BIC) as a measure of fit, for more details refer to Appen-
dix A, Raftery [11,12] and Long [13].
To study whether the effect of fluctuations in HbA1C on
nephropathy differs with the level of metabolic control, we divided
the sample into two groups: those with acceptable metabolic con-
trol and those with poor metabolic control. Afterwards, we studied
the association between fluctuations in HbA1C and the develop-
ment of nephropathy separately in each group, using bivariate
analysis. Results were considered significant at the 5% critical level
(p < 0.05). All the calculations were performed using STATA (ver-
sion 7.0) statistical soft-ware package.
4. Ethics
The protocol was approved by the institutional review board
(IRB) at the Chronic Care Center, Lebanon. All the procedures fol-
lowed were in accordance with the ethical standards of the respon-
sible committee on human experimentation (institutional or
regional) and with the Helsinki Declaration of 1975, as revised in
1983.
5. Results
The sample analyzed consisted of 117 type 1 diabetic patients,
64 females and 53 males, aged 9–33 years at the time of enroll-
ment. Eighteen among 117 (15.38%) developed nephropathy after
5 years of onset of diabetes.
As shown in Table 1, there was no association between gender
and the development of diabetic nephropathy (p = 0.94). There
were no significant group differences in the ‘‘age at onset of diabe-
tes” or ‘‘time period from the onset of diabetes till admission to the
chronic care center” (p = 0.47 and p = 0.80, respectively). BMI at
first visit for those who developed nephropathy was not signifi-
cantly different from the BMI at first visit for those who did not
12 J.E. Fares et al. / International Journal of Diabetes Mellitus 2 (2010) 10–14

Table 1 was the only significant predictive factor; all other variables were
Main characteristics of the study population in relation to the development of not significant. Since our hypothesis is to test whether the pres-
diabetic nephropathy.
ence of fluctuations in HbA1C predicts the development of
Variable Nephropathy No p- nephropathy adjusting for the mean HbA1C, we further studied
N = 18 nephropathy value three other models one including the two covariates the mean
N = 99
and the ‘‘fluctuations” in HbA1C (referred to Model 2), another
Gender [n (%)]a model including only mean HbA1C as a covariate (referred to as
Male 8 (44) 45 (45) 0.94
Female 10 (56) 54 (54)
Model 3) and the last model including the fluctuations in HbA1C
Age at onset (years) 10.94 ± 4.5 10.12 ± 3.9 0.47 (Model 4). The Model 2 leads to a smaller BIC than Model 3 (BIC
Time period from onset of diabetes to 3.96 ± 4.2 3.72 ± 4.2 0.80 dropped from 101.4 to 104.7), indicating positive evidence for
admission to CCC (years) a better fit. We also noticed that the odds ratio of the mean HbA1C
BMI at baseline (kg/m2) 19.84 ± 5.2 19.04 ± 3.4 0.40
decreases from 1.75 to 1.50 when the covariate ‘‘fluctuations” is
Family history of diabetes [n (%)]b
Positive 8 (47) 58 (59) added to the model and becomes closer to 1. Considering Model
Negative 9 (53) 40 (41) 0.35 4, the odds ratio of the fluctuations in HbA1C is 4.17; however
Mean HbA1C (%) 9.4 ± 1.6 8.5 ± 1.1 0.003 when adjusting for the mean HbA1C (Model 2), the odds ratio
Fluctuations in HbA1C [n (%)] dropped to 2.34 and the fluctuations in HbA1c was no more a sig-
Present 15 (83) 54 (54)
nificant predictor factor.
Absent 3 (17) 45 (45) 0.04
Next, we investigated whether the level of metabolic control af-
Data are means ± SD unless otherwise specified. fects the association between ‘‘fluctuations” in HbA1c and the odds
a
[n (%)] indicates the number in each category and (percentage).
b of nephropathy. Forty patients had acceptable metabolic control
Totals do not add up to 117 due to missing data.
and 77 had poor metabolic control. Among those with poor control,
the incidence of nephropathy was 26.3% for those with fluctua-
tions. This is higher than the 5% incidence for those who did not
have evidence of nephropathy (p = 0.40). There was no significant have ‘‘fluctuations” (p = 0.056) (Table 3). However, the effect of
difference in the outcome between those with and without family ‘‘fluctuations” did not appear among those with acceptable meta-
history of diabetes. Hypertension was omitted, because of no var- bolic control (data not shown).
iability, as patients were not hypertensive.

5.1. Association between mean HbA1C and diabetic nephropathy 6. Discussion

The mean HbA1C per individual was 8.64 ± 1.2 in the whole
sample. As shown in Table 1, mean HbA1C was 9.4 ± 1.6% among
those who developed nephropathy compared to a mean of
8.5 ± 1.1% for those who did not develop nephropathy, and was sta-
tistically significant between the two groups (p = 0.003).
5.2. Association between fluctuations in HbA1C and diabetic
nephropathy
The association between fluctuations in HbA1C and diabetic
nephropathy is shown in Table 1. Among those who developed
nephropathy, 15 of 18 (83%) had fluctuations in HbA1C; compared
to those who do not develop nephropathy 54 of 99 (54%) had fluc-
tuations in HbA1C (p = 0.04).
In order to identify the predictors for diabetic nephropathy, we
performed a multivariate analysis, by entering all risk covariates
into a multiple logistic regression analysis (Table 2). Results from
the full model (referred to as Model 1) revealed that mean HbA1C
The incidence of insidious nephropathy after 5 years of onset of
type 1 diabetes, based on our data, was 15.1% similar to the previ-
ous findings by others [14–16]. Lower incidences were reported in
the US [17] and Europe [18]. A discrepancy between the different
reports may be related to ethnic variability; however it resulted
mostly from the use of a different methodology. One main differ-
ence is the duration of diabetes, well known as an independent risk
factor for the development of microvascular complications [8,5].
However, in our study, the duration of diabetes was set to 5 years
after diagnosis. Our finding that the age at onset of diabetes is not
associated with the development of diabetic nephropathy is com-
mensurate with recent data [19]; however, as in their study, we
did not account for pubertal staging [20].
The results of our study, like many other reports, did not show
an association between gender and the development of diabetic
nephropathy. This contrasts with a previous finding by Holl et al.,
showing an impact of female gender on the development of insid-
ious nephropathy [18]. Any association between gender and

Table 2
Multivariate analysis for the prediction of diabetic nephropathy (Model 1 includes all covariates, Model 2 includes 2 covariates: the average mean of HbA1C and fluctuations in
HbA1C and Model 3 includes only the average mean of HbA1C).

Variable Odds ratio (95%CI)

Model 1 Model 2 Model 3 Model 4
* *
Average mean of HbA1C 1.66 (1.03; 2.68) 1.55 (1.01; 2.38) 1.75 (1.18; 2.59)
Fluctuations in HbA1C 1.89 (0.42; 8.41) 2.34 (0.56; 9.77) 4.17 (1.13; 15.31)*
Gender 0.85 (0.27; 2.63)
Family history 1.32 (0.42; 4.13)
Age at onset 1.06 (0.88; 1.26)
Time between onset of diabetes till admission to CCC 0.93 (0.80; 1.08)
Baseline BMI 0.93 (0.75; 1.14)
BIC 123.40 104.71 101.40 104.22

CI denotes the confidence interval.

BIC refers to Bayesian information criterion.
*
p-value <0.05.
 J.E. Fares et al. / International Journal of Diabetes Mellitus 2 (2010) 10–14
Table 3
The effect of fluctuations on the incidence of nephropathy among the 77 patients who
had a poor metabolic control (HbA1C P 8%); data are presented as n (%) the number in
each category of fluctuation and (percentage).
Fluctuation present Fluctuation absent
Nephropathy present 15 (26%) 1 (5%)
Nephropathy absent 42 (74%) 19 (95%)
Fisher test: p = 0.056.
nephropathy should take into consideration the pubertal stage
since the hormonal effects could be at the base of this difference.
Data on the association between BMI, an index of metabolic
state, and the development of diabetic nephropathy, is scarce
[18]. In our study, BMI was measured at the first visit to the center,
when most of the patients had poor metabolic control (reflected by
the elevated mean HbA1C at that visit) that might have negatively
affected the weight. Although the baseline BMI was found to be
associated with the development of microvascular complications
[5], the impact of BMI was apparent only at higher values. Follow-
ing BMI longitudinally and accounting for pubertal changes would
help in establishing the associations between BMI and diabetic
nephropathy.
Metabolic control was the only established and consistent pre-
dictor for the development of diabetic nephropathy. In reviewing
the literature, different measures have been used in order to study
the association between metabolic control and diabetic nephropa-
thy. The mean HbA1C is repeatedly used [4,20]; the median has
also been used as a summary measure [14]. Based on the results
of our study, the mean HbA1C remains the only significant predic-
tor for the development of diabetic nephropathy in type 1 diabetic
patients, even after adjusting for ‘‘fluctuations”. However, the mag-
nitude of this association decreases when accounting for ‘‘fluctua-
tions”. While the odds of developing nephropathy increased by at
least 18%, with an increase in mean HbA1C of 1%, accounting for
the ‘‘fluctuations” in HbA1C showed that the odds ratio of develop-
ing nephropathy, at least, did not change when the mean HbA1C
increased by 1%.
The use of ‘‘fluctuations” in HbA1C as a longitudinal measure for
the change in the metabolic state is original. It may better reflect
the changes in ambient glycemia within one individual. This latter
was found to be the culprit in the development of diabetic
nephropathy through activation of the proteinase C [21], upregu-
lating the heparanase expression [22], enhancing sensitivity to
TGF beta 1 [23] and increasing VEGF (vascular endothelial growth
factor) expression [24]. Our data showed that ‘‘fluctuations” in
HbA1C predicted the incidence of nephropathy, based on the posi-
tive evidence that the model including fluctuations fits the data
better. In addition, an increase of greater than 2% between two
consecutive measurements seems to increase the risk of develop-
ing nephropathy by 21% among those with poor metabolic control.
This may have many implications: first, these findings may help to
achieve a better understanding of the pathophysiology of diabetic
nephropathy, since they suggest that, although this latter is accel-
erated by the chronic hyperglycemia (manifested as mean HbA1C),
it is much worse during acute increases in glycemia which is re-
flected by fluctuations in HbA1C. Second, our data highlight the is-
sue that a single jump in HbA1C have a durable effect, this agrees
with the hypothesis of ‘‘long time- glycemic memory” and sup-
ported by findings from DCCT on microvascular complications.
Third, as diabetic nephropathy has an insidious onset, one large
increment in HbA1C during the first 5 years, would be an indicator
of a development of nephropathy well before the appearance of
microalbuminuria.
Nevertheless, our data were unable to establish the association
between fluctuations in HbA1C and the development of nephropa-
13
thy in diabetics with acceptable control. The sample size was small
to permit the comparison between the different groups; this was
well seen by the wide confidence intervals. Interestingly, taking
the whole model, the mean HbA1C explains 10% the prediction
for the development of diabetic nephropathy. Other factors, such
as genetic predisposition, have been known to be associated with
the development of nephropathy. Family history of hypertension
[25], kidney disease and other cardiovascular risk factors [26],
were used as a measure for genetic predisposition. However, our
study lacks this information. Puberty data were not obtained; this
is a limitation for our results. since puberty onset and its related
physiologic changes had been known as risk factor for the develop-
ment of diabetic nephropathy [27].
Our data should be interpreted with caution, since the measure
used to define ‘‘fluctuations”, which is at the cornerstone of the re-
sults, had been based on our assumptions. This measure is not yet
validated as a measure for ‘‘fluctuations”, and needs to be repli-
cated in order to add more confidence to the results.
Finally, we conclude that type 1 diabetic patients who have a
similar mean HbA1C, in the long run, may behave differently in
terms of developing nephropathy, depending on the fluctuations
in HbA1C and more precisely, depending on the frequency of the
acute ‘‘jumps” in the HbA1C. However, this effect seems to be more
pronounced among those who have higher values of HbA1C con-
sidered as poorly controlled.
Declaration of competing interests
None to declare.
Appendix A. Appendix
A.1. Bayesian information criterion (BIC)
BIC has been proposed by Raftery [11,12] as a measure of over-
all fit and a means of comparing nested and non-nested models.
BIC is defined as LM + log(N)  p, Where LM = 2 (log likelihood)
of the fitted model, N is the sample size and p the number of
parameters in the model. The smaller the BIC, the better the fit.
The difference in the BICs associated with two models indicates
which model is more likely to have generated the observed data.
A difference of 0–2 implies weak evidence, a difference of 2–6 im-
plies positive evidence, a difference of 6–10 implies strong evi-
dence and a difference >10 implies very strong evidence.
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