Egyptian Pediatric Association Gazette xxx (2017) xxx–xxx

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Egyptian Pediatric Association Gazette

journal homepage: www.elsevier.com/locate/epag

Long-term prognosis of type 1 diabetes in relation to the clinical

characteristics at the onset of diabetes
M.H. Elsamahy, Y.I. Elhenawy ⇑, N. Altayeb
Division of Pediatric Diabetes, Department of Pediatrics, Faculty of Medicine, Ain Shams University, Egypt

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

Article history: Introduction: It is known that age, the degree of glycemic deterioration and the immune status at the
Received 13 March 2017 time of the onset of type 1 diabetes (T1DM) are objective factors that can predict the residual B-cell func-
Accepted 21 April 2017 tion and the glycemic control 1 year after diagnosis. Objective: Evaluation of the long-term prognosis of
Available online xxxx
T1DM in relation to the clinical characteristics at the time of diabetes onset. Methods: An observational
retrospective study conducted on 200 patients including all the patients with newly diagnosed T1DM in
Keywords: the period from 2003 to 2013. Results: Fifty-three percent of the studied cohort presented initially by dia-
Diabetic ketoacidosis
betic ketoacidosis (DKA). The current studied cohort showed that younger patients required more insulin
Glycemic control
HbA1c
during follow-up. Female patients needed higher insulin doses at 8 and 10 years after diagnosis, yet no
Insulin requirements difference among both genders during early years of follow up. Patients presenting with DKA required
Type 1 diabetes higher insulin requirements over the first 2 years and poor glycemic control. C-peptide levels at diagnosis
correlated with insulin requirements during the first 2 years. Insulin dose at onset correlated positively
with the insulin dose over the entire follow up period. A positive correlation was found between HbA1c at
onset and 1, 2 and 4 year. Conclusion: Female gender, younger age, presence of DKA, lower C-peptide and
higher HbA1c at onset could predict a poor long-term outcome. Identification of factors related to a worse
outcome of T1DM at the onset of diabetes might help in selecting those patients who should be given
more intensive treatment.
Ó 2017 The Egyptian Pediatric Association. Production and hosting by Elsevier B.V. This is an open access
article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction However, there is relatively little information available in the

Type 1 diabetes (T1DM) is one of the most common endocrine
diseases in children. T1DM is an autoimmune disease deriving
from the interaction of genetic, environmental and immunological
factors. The traditional concept is that certain environmental fac-
tors could trigger an immune response against pancreatic B-cells
in genetically predisposed individuals.1 Glycemic control during
the long-term course of T1DM is known to be prone to the influ-
ence of emotional, psychological, behavioral and socio-economic
factors that affect the patient’s adherence to therapy.2
It is known that age, the degree of glycemic deterioration and
the immune status at the time of the onset of T1DM are objective
factors that can predict the residual B-cell function and the glyce-
mic control 1 year after diagnosis.3
Peer review under responsibility of Egyptian Pediatric Association Gazette.
⇑ Corresponding author at: Division of Pediatric Diabetes, Department of Pedi-
atrics, Faculty of Medicine, Ain Shams University, 26 Hassan Ibrahim Hassan Street,
Nasr City, Cairo, Egypt.
E-mail address: dr_yasmi@yahoo.com (Y.I. Elhenawy).
literature whether any of the clinical and analytical factors that
are present at diabetes onset might be predictors of future glyce-
mic control, independently of the patient’s compliance with
therapy.4
Thus the aim of the present observational study was to relate
the clinical and laboratory characteristic present at the time of
diagnosis of T1DM to the prognosis of the disease in terms of gly-
cemic control and insulin requirements.
Patients and methods
An observational retrospective study was performed, including
all the patients consecutively admitted to Diabetes Unit-Pediatrics
Hospital-Ain Shams University Hospitals-with newly diagnosed
T1DM from 2003 to 2013. The study was in agreement with the
guidelines of the ethics committee at our hospital and an informed
consent was obtained from all subjects. The studied cohort
included 200 patients with mean age of 11.69 ± 4.34 years and
the mean age at onset of the disease was 6.19 ± 3.64. Patients with

http://dx.doi.org/10.1016/j.epag.2017.04.004
1110-6638/Ó 2017 The Egyptian Pediatric Association. Production and hosting by Elsevier B.V.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: Elsamahy M.H., et al. Long-term prognosis of type 1 diabetes in relation to the clinical characteristics at the onset of
diabetes. Egypt Pediatr Assoc Gazette (2017), http://dx.doi.org/10.1016/j.epag.2017.04.004
2 M.H. Elsamahy et al. / Egyptian Pediatric Association Gazette xxx (2017) xxx–xxx

secondary diabetes and maturity onset diabetes of the young Table 1

(MODY) were excluded from the study. Clinical and laboratory characteristics of the studied diabetic cohort.

Criteria for the diagnosis of diabetes:5,6 Variable Mean ± SD (range)

Gender (M/F) (%) 120/80 (60%/40%)
i. Fasting plasma glucose level
7.0 mmol/L (126 mg/dL). Age(years) 11.69 ± 4.34 (2–18)
Fasting is defined as no caloric intake for at least 8 h. Age at onset of diabetes(years) 6.19 ± 3.64 (1–15)
ii. Symptoms of hyperglycemia and casual plasma glu- Clinical presentation at onset
DKA (N-%) 106–53%
cose
11.1 mmol/L (200 mg/dL). Casual is defined as any Hyperglycemia without ketosis (N-%) 20–10%
time of day without regard to time since last meal. The clas- Accidental discovery (N-%) 74–37%
sic symptoms of hyperglycemia include polyurea, polydip- Prescribed basal insulin at onset
sia, and unexplained weight loss. Insulin Glargine (N-%) 75–37.5%
NPH (N-%) 125–62.5%
iii. Plasma glucose
11.1 mmol/L (200 mg/dL) two hours after
Insulin dose at onset (u/kg/day) 0.90 ± 0.40 (0.4–1.2)
a 75 g oral glucose load as in a glucose tolerance test. The HbA1c% at onset 7.3 ± 1.12(5.0–9.1)
test should be performed as described by the World Health HbA1c (mmol/mol) 56 ± 8
Organization, using a glucose load containing the equivalent C-peptide at onset (ng/ml) 0.20 ± 0.09 (0–0.5)
of 75 g anhydrous glucose dissolved in water.
iv. Glycated hemoglobin (Hb A1c)
6.5%.

0.20 ± 0.09 ng /ml and mean HbA1c was 7.3 ± 1.12 %

Baseline variables at the time of the patient arrival at the hospi-
tal before initiation of insulin treatment were reported from files
and medical charts. The following variables were reported from
medical charts: gender, age at presentation, presence of concomi-
tant infection, presence of clinically significant associated medical
comorbidities, metabolic status (blood glucose, pH, standard bicar-
bonate, and urinary ketones), presentation with DKA (Diabetic
ketoacidosis), fasting serum C-peptide and HbA1C.
DKA was defined as blood glucose > 11 mmol/L, venous pH < 7.3
or bicarbonate < 15 mmol/L, and ketonaemia and ketonuria.7
The prognosis of T1DM after diagnosis was evaluated by
reviewing the clinical files. For evaluation of prognosis, HbA1c
and the mean dosage of insulin was extracted from the follow-up
outpatient visits performed 1, 2, 4, 6, 8 and 10 years after diagnosis.
Blood sampling
Fasting serum C-peptide was performed after fasting for at least
8 h. Serum C-peptide was analyzed by a fluoroimmunometric
assay (AutoDELFIATM C-peptide, PerkinElmer Life and Analytical
Sciences Inc., Turku, Finland).
HbA1c analysis was performed by automatic high-pressure liq-
uid chromatography.
Statistical methodology
Statistical analyses were carried out using SPSS 17.0 software
package program. The comparison between two groups with qual-
itative data was done using Chi-square test or Fisher exact test.
Independent t-test or Mann-Whitney test were used for two inde-
pendent groups with quantitative data. Paired t-test or Wilcoxon
Rank test for two paired groups with quantitative data. One Way
ANOVA or Kruskall-Wallis for more than two groups with quanti-
tative data. Pearson correlation test was used to determine the cor-
relation between the parameters.
(56 ± 8 mmol/mol).
The studied cohort showed a significant negative correlation
between age and insulin requirement at onset (r = 0.268,
P < 0.001) as well as entire follow-up period (Table 2). Additionally,
C-peptide levels at the time of diabetes onset were found to be
inversely correlated with both insulin requirements (r = 0.051,
P = 0.05) and HbA1c at onset(r = 0.027, P = 0.029) (Tables 3 and 4).
Regarding patients’ gender, studied patients with T1DM did not
show significant difference at onset of disease and early years of
follow up (P > 0.05) but a significant higher insulin dosage was
required in female at year 8 and year 10 (P < 0.05) to achieve ade-
quate glycemic control (Supplemental Fig. 1).
Data from our study observed that insulin dose at onset
correlated positively with the insulin dose 1, 2, 4,6,8 and 10 years
after diagnosis (r = 0.964, P < 0.001; r = 0.871, P < 0.001; r = 0.811,
P < 0.001; r = 0.738, P < 0.001; r = 0.673, P < 0.001; r = 0.603,
P = 0.013 respectively) (Table 3).
Diabetic cohort presenting with DKA were significantly younger
than those not presenting with DKA with a mean of age
5.96 ± 2.39 years compared to 7.09 ± 1.54 years respectively
(P < 0.05) (Fig. 1A). Additionally, those presenting with DKA
required higher insulin dosage at onset with a mean 1.07 ± 0.39
(U/kg/day) compared to 0.9 ± 0.51 (U/kg/day) respectively
(P < 0.05). Insulin dosage at 1 year in patients presenting with
DKA was 1.15 ± 0.60 (U/kg/day) compared to 1.01 ± 0.30 (U/kg/-
day) respectively (P < 0.05) (Fig. 1B).Furthermore, these patients
had higher HbA1c at onset and early years of follow up (P < 0.05)
(Fig. 1C).
When evaluating the relation between HbA1c at onset of diag-
nosis and disease prognosis, a significant positive correlation was
found between HbA1c at onset and 1 year after diagnosis
(r = 0.579, P < 0.001), HbA1c at 2 years(r = 0.343, P = 0.005) and
4 years (r = 0.282, P = 0.046) (Table 4).

Table 2
Results
Correlation between patients’ age at onset of diabetes and insulin requirements
during follow-up period.
Demographic data of the studied cohort is illustrated in Table 1,
Age at onset
60% of patients were male and 40% were female. The mean age was
(r, P-value)
10.69 ± 4.34 years and the mean age at onset of diabetes was
7.19 ± 3.64 years. Regarding patients’ initial presentation, 53% pre- Insulin dose at onset (r = 0.268, P < 0.001)
Insulin dose at 1 year (r = 0.211, P = 0.003)
sented with DKA, 37% were accidentally discovered and the rest Insulin dose at 2 year (r = 0.327, P < 0.001)
presented with hyperglycemia without ketosis. The mean insulin Insulin dose at 4 year (r = 0.307, P < 0.001)
dosage at onset was 0.90 ± 0.40. 37.5% were given insulin glargine Insulin dose at 6 year (r = 0.420, P < 0.001)
(lantus) as their basal insulin at onset of diagnosis, whereas 62.5% Insulin dose at 8 year (r = 0.432, P < 0.001)
Insulin dose at 10 year (r = 0.498, P < 0.001)
were given NPH. The mean C-peptide level at onset was

Please cite this article in press as: Elsamahy M.H., et al. Long-term prognosis of type 1 diabetes in relation to the clinical characteristics at the onset of
diabetes. Egypt Pediatr Assoc Gazette (2017), http://dx.doi.org/10.1016/j.epag.2017.04.004
 M.H. Elsamahy et al. / Egyptian Pediatric Association Gazette xxx (2017) xxx–xxx 3

Table 3
Correlation between insulin dosages during follow-up period.

Insulin dose at onset Insulin At 1 year Insulin At 2 year Insulin At4 year Insulin At 6 year Insulin At 8 year
Insulin at1 year (r = 0.964, P < 0.001) NA NA NA NA NA
Insulin at 2 year (r = 0.871, P < 0.001) (r = 0.849, P < 0.001) NA NA NA NA
Insulin at 4 year (r = 0.811, P < 0.001) (r = 0.82, P < 0.001) (r = 0.906, P < 0.001) NA NA NA
Insulin at 6 year (r = 0.738, P < 0.001) (r = 0.747, P < 0.001) (r = 0.795, P < 0.001) (r = 0.908, P < 0.001) NA NA
Insulin at 8 years (r = 0.673, P < 0.001) (r = 0.701, P < 0.001) (r = 0.678, P < 0.001) (r = 0.751, P < 0.001) (r = 0.736, P < 0.001) NA
Insulin at 10 year (r = 0.603, P = 0.013) (r = 0.603, P = 0.013) (r = 0.57, P = 0.021) (r = 0.583, P = 0.018) (r = 0.65, P = 0.006) (r = 0.603, P = 0.013)
c-peptide at onset* (r = 0.051, P = 0.05)

NA = non-applicable.
*
Correlation between C-peptide at onset of disease and insulin dosage at onset.

Table 4 of DKA, lower pancreatic reserve as evidenced by C-peptide and

Correlation coefficients between HbA1c at onset of diabetes, c-peptide and HbA1C 1, 2 higher HbA1c levels at onset could predict a poor long-term clini-
and 4 years after diagnosis.
cal outcome of T1DM in terms of insulin requirements and glyce-
Hb A1c at onset mic control.
(r, P-value) Similarly, Klingensmith et al. concluded that the incidence of
C-peptide (r = 0.027, P = 0.029) DKA in children at the onset of T1D remains high, with approxi-
Hb A1c 1 year (r = 0.58, P < 0.001) mately one-third presenting with DKA and one-sixth with moder-
Hb A1c 2 year (r = 0.34, P = 0.005)
ate or severe DKA.8
Hb A1c 4 year (r = 0.28, P = 0.046)
Furthermore, Dabelea et al. in their multicenter Youth study
reported that the prevalence of DKA was high and stable over time.
Higher prevalence was associated with younger age at diagnosis.9
The longer term clinical course of T1DM also seems to be influ-
Discussion
enced by DKA; children with diabetic ketoacidosis at diagnosis
have poorer glycemic control, less residual b cell function up to
Results from the current observational study, regarding progno-
two years after diagnosis, and a lower frequency of remission.10–12
sis of disease, concluded that female gender, younger age, presence

Fig. 1. Age, insulin requirements and HbA1C in patients with diabetes presenting with DKA. Diabetic cohort presenting with DKA were significantly younger (P < 0.05) (A).
They required higher insulin dosage at onset, 1 year and 2 years after diagnosis (P < 0.05) (B). HbA1c was higher at onset and at 1, 2 year after diagnosis (P < 0.05) (C).

Please cite this article in press as: Elsamahy M.H., et al. Long-term prognosis of type 1 diabetes in relation to the clinical characteristics at the onset of
diabetes. Egypt Pediatr Assoc Gazette (2017), http://dx.doi.org/10.1016/j.epag.2017.04.004
4 M.H. Elsamahy et al. / Egyptian Pediatric Association Gazette xxx (2017) xxx–xxx
It is unclear why some children present in diabetic ketoacidosis
whereas others do not and whether the development of DKA is a
consequence of delayed diagnosis and treatment or whether it
reflects a particularly aggressive form of diabetes.13
Younger age was consistently associated with an increased risk
of DKA at diagnosis. This increased risk was most noticeable in
children less than 2 years old and was still present at 5 years, but
by age 10 there was no significant difference. The reasons for this
are probably multifactorial.14
Beato-Vı0 bora and Tormo-Garcı, in their study evaluating prog-
nosis of T1DM in relation to clinical characteristics at the time of
diabetes, similarly found that younger patients at time of diagnosis
required greater insulin dose during the entire follow-up period.4
Additionally Mortensen et al. reported in their studied cohort
that younger patients had higher blood glucose levels and thus
higher insulin requirements.3
Several studies have reported an association between greater
loss of beta-cell function and younger age and more severe ketoaci-
dosis at onset.3,7
Moreover, b cell destruction may be more aggressive in young
children: serum levels of proinsulin C peptide are lower in children
under 2 years old at diagnosis of diabetes, and they continue to
lose their endogenous insulin secretory capacity faster than older
children after diagnosis.14,15
Studied patients did not show significant difference at onset of
disease and early years of follow up yet a significant higher insulin
dosage was required in female at year 8 and year 10.
Wiegand et al. in their observational study reported that insulin
dosage in significantly different in boys and girls (0.92 IU/kg in
male versus 0.94 IU/kg in female; P < 0.001).16
Allard et al. attributed these changes to different growth pattern
and pubertal development in boys and girls. Furthermore, child-
hood and adolescence cover phases of growth and pubertal devel-
opment with substantial changes of metabolic condition.17
Potential underlying causes are related to the physiology of
puberty but furthermore, insulin resistance might aggravate
pathophysiology of autoimmune b-cell destruction and accelerate
progression to overt type 1 diabetes.18
Insulin resistance is physiological during puberty to some
extent, to reduce the protein consumption and parallel shift this
amount into anabolic effect and growth.19 Furthermore, there is
some evidence for menstrual cycle effects on insulin sensitivity.20
Unfortunately, in our study, Tanner staging of cohort was not
documented.
Several studies evaluated the relation between initial insulin
dosage at hospital discharge and subsequent insulin dosage.
Beato-Vı0 bora and Tormo-Garcı, in their studied Spanish cohort
also found a significant positive correlation between insulin dosage
at hospital discharge and yearly follow up of mean insulin dosage.4
Several studies reported that patients who had received more
vigorous treatment immediately at disease onset had both a higher
incidence of post-initial remission and better diabetes control.
Results suggest that rapid glycemic normalization after diagnosis
of diabetes increases the possibility of preserving some endoge-
nous insulin production.2,21
C-peptide levels at the time of diabetes onset were found to be
inversely correlated with insulin requirements at hospital dis-
charge. This is attributed to lose and/or low endogenous insulin
secretory capacity as evidenced by c-peptide.14 One of our study
limitations is absence of C-peptide assessment after 1, 6, and
12 months and stimulated C-peptide during a challenge to assess
residual-cell function especially in the partial remission phase.
Clinically, newly diagnosed T1DM is characterized by a tran-
sient partial remission period (‘‘honeymoon”), starting shortly after
insulin treatment is initiated and during which the patient’s need
for exogenous insulin treatment declines and in some cases even
Please cite this article in press as: Elsamahy M.H., et al. Long-term prognosis of type 1 diabetes in relation to the clinical characteristics at the onset of
diabetes. Egypt Pediatr Assoc Gazette (2017), http://dx.doi.org/10.1016/j.epag.2017.04.004
totally disappears, and metabolic control is near optimal.22 The
pathogenesis of this has been the subject of discussion but is likely
to be a combination of factors such as an amelioration of glucose
toxicity, a reduction in the immune inflammatory conditions in
the islets (insulitis), improvement of peripheral insulin sensitivity,
or even a still regenerating beta-cell mass.23,24 The duration of the
remission period depends at least partly on the recovery of the
beta-cell function, which may be assessed by measurement of
stimulated C-peptide secretion.25
Additionally, patients who had DKA at the time of the admission
to hospital required a greater insulin dose over the first 2 years of
follow-up. In previous reports, the occurrence of DKA has also been
associated with greater insulin requirements over the first years of
the course of the illness.4 The presence of diabetic ketoacidosis
(DKA) at the moment of diagnosis can influence prognosis, proba-
bly because it reflects more advanced B-cell destruction with
poorer recovery of B-cell function and a poorer glycemic control
after initiating insulin treatment.26
Of increasing interest is the correlation between HbA1c at onset
of diagnosis and disease prognosis. The correlation between HbA1c
at onset, 1, 2 and 4 year after diagnosis is similar to the findings
reported by other author.2,4,27 The phenomenon recently described
as ‘‘HbA1c tracking’’ refers to the long term good glycemic control
found in patients who achieved a good control soon after
diagnosis.2,4,27
There are several assumptions for its occurrence, such as resid-
ual insulin production and individual biological variation in insulin
sensitivity that may facilitate achievement of better glycemic con-
trol for a longer period, as well as diabetes-management-related
factors, such as familial social, behavioral, psychological, and emo-
tional factors, which can persist over time.2
Glycated hemoglobin is the important clinical outcome mea-
sured during the remission phase. Some studies have found a sig-
nificant inverse relationship between C-peptide and HbA1c at
onset, and at 6 and 12 months. We observed a similar relationship,
whereas other studies have failed to find such an association.28
Therefore, the strong association we found between achieving
the target HbA1c during follow-up and the HbA1c levels in the first
year of diabetes emphasizes the importance of attaining the target
as early as possible, which may facilitate diabetes control also
beyond the remission. It may also reflect that establishment of
good habits early may predict long-term compliance and adher-
ence with therapy, especially in young patients, when parents
are usually the principal caregivers.2
The main limitation of the present study is its retrospective
design which means that missing data could have influenced the
results in various ways. Another limitation of our study is absence
of assessment of both autoantibodies and HLA genotype which
may predispose to the onset of the disease as well as the partial
recovery of the injured beta-cell.
Conclusion
Identification from the moment of diagnosis of factors related to
a worse outcome of T1DM might help in selecting those patients
who should be given more intensive treatment. Rapid glycemic
normalization after diagnosis of diabetes increases the possibility
of preserving some endogenous insulin production.
Ethical statement
The study was conducted according to Good Clinical Practices,
applicable regulatory requirements, and the Declaration of Hel-
sinki. Ethical approval was obtained from the participating center’s
ethics committee with written or oral witnessed informed consent.
 M.H. Elsamahy et al. / Egyptian Pediatric Association Gazette xxx (2017) xxx–xxx
Conflict of interest
Nothing to declare.
Funding sources
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.epag.2017.04.004.
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