Prevalence and risk factors of Taiwanese microalbuminuric type 2
diabetic mellitus with and without diabetic retinopathy
Min-Shien Chung*, Jong-Jer Lee**, Chien-Te Lee***, Feng-Chih Shen*, Hsi-Kung
Kuo**, Siang-Ting Huang*, Terry Ting-Yu Chiou***, Cheuk-Kwan Sun**** , Kuender D.
Yang*****, Rue-Tsuan Liu*
Division of Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan *
Department of Ophthalmology, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang
Gung University College of Medicine, Kaohsiung, Taiwan ** Division of Nephrology, Department of
Medicine, Chang-Gung Memorial Hospital, Kaohsiung Medical Center, Chang-Gung, University
College of Medicine, Kaohsiung, Taiwan*** Division of general surgery, Department of surgery,
Chang Gung Memorial Hospital - Kaohsiung Medical Center, Chang Gung University College of
Medicine, Kaohsiung, Taiwan **** Department of Medical Research, Chang Gung Memorial Hospital,
Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan *****
Running title: Retinopathy in microalbuminuric diabetes
Correspondence author: Dr. Rue-Tsuan Liu,
Division of Metabolism, Department of Internal Medicine, Chang Gung
Memorial
Hospital - Kaohsiung Medical Center, Kaohsiung,
Address: 123 Ta-Pei Road, Niao-Sung Hsiang, Kaohsiung Hsien 833,
Taiwan
Tel: 886-7-7317123 ext.8302
Fax: 886-7-7322402
Abstract
Background: Although microalbuminuria in diabetic patients is a
well-known manifestation of diabetic nephropathy, it does not necessarily
indicate the presence of other microvascular complication such as
diabetic retinopathy (DR). This study aims at determining the prevalence
and clinical characteristics of diabetic retinopathy in microalbuminuric
patients with type 2 diabetes.
Methods: A total of 417 microalbuminuric type 2 diabetic patients were
enrolled in this cross-sectional cohort study. Demographic characteristics
of patients, serum biochemistry [i.e. HbA1c, serum total cholesterol,
triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein
cholesterol, uric acid, albumin, creatinine, high sensitive C-reactive
protein (hsCRP)] and hematological parameters (i.e. complete blood
count, and differential white count) were recorded and analyzed. The
presence of retinopathy including background diabetic retinopathy,
non-proliferative retinopathy, or proliferative retinopathy, was
determined by an experienced ophthalmologist by fundus photography.
Logistic regression analysis was performed to identify the independent
risk factors of DR.
Results: The prevalence of DR was 46.2%. Independent risk factors
included the insulin use (OR: 3.437, P=0.001), presence of hypertension
(OR: 2.671, P=0.015), DM duration (OR: 1.063, P=0.013), age at DM
diagnosis (OR: 0.970, P=0.029), triglyceride (OR: 0.995, P=0.017),
hsCRP (OR: 0.773, P=0.006), hemoglobin (OR: 0.713, P=0.000).
Conclusions: Use of insulin, presence of hypertension, earlier age at DM
diagnosis, longer DM duration, lower serum level of triglyceride and high
sensitive C-reactive protein, and reduced hemoglobin are independently
associated with an increased prevalence of DR in type 2 diabetic patients
with microalbuminuria.
Key words: type 2 diabetes, microalbuminuria, diabetic retinopathy, risk
factor
Introduction
Microalbuminuria in type 2 diabetes may be an early clinical
manifestation of diabetic nephropathy, although it can also result from
other clinical situations such as hypertension or waist circumference.1 In
type 1 diabetes, microalbuminuria is closely associated with
microangiopathy, such as diabetic retinopathy (DR).2 Although this
association is also present in type 2 diabetes, some of these patients does
not appear to reflect generalized microvascular damage.3
Although the prevalence and risk factors for DR in type 2 diabetes
have been extensively investigated,4-7 few data exist addressing the issue
of clinical characteristics distinguishing microalbuminuric type 2 diabetic
patients with DR from those without. This cross-sectional cohort study
aims at determining the prevalence and characteristics of DR in patients
with type 2 diabetes who have microalbuminuria.
Materials and methods
Study setting, inclusion and exclusion criteria
A cross-sectional study was performed in 1,715 diabetic patients
attending a single outpatient diabetic clinic managed by one diabetologist
(Rue-Tsuan Liu) for more than one year at Chang Gung Memorial
Hospital- Kaohsiung medical center between April 2008 and November
2008. Of all patients, 46 were diagnosed as type 1 diabetes and excluded
from this study. Fourteen patients with prolonged indwelling Foley
catheter, repeated urinary tract infection, chronic glomerulonephritis, or
receiving chemotherapy for malignant diseases were also excluded.
Study parameters and definitions
Urinary albumin concentration was measured by random daytime
urine samples. Albumin excretion rate (AER) was defined entirely by
calculation of albumin-to-creatinine ratio (ACR) in urine specimen. The
definitions of normoalbuminuria (NA), microalbuminuria (MA), and
macroalbuminuria (MAA) were an ACR <0.03 mg/mg once, 0.03 – 0.3
mg/mg, and >0.3 mg/mg in two urine samples collected, respectively.
Retinopathy was determined through fundus photography by an
experienced ophthalmologist blinded to the study. DR was defined as
background diabetic retinopathy (BDR), non-proliferative retinopathy
(NPDR), or proliferative retinopathy (PDR). Finally, a total of 417
microalbuminuric patients with (n=193) or without (n=224) retinopathy
were recruited in the study. Prevalence of DR in different DM duration
groups (<5 years, 5-10 years, 11-15 years, and >15 years) was also
analyzed.
Each patient participated in a detailed interview regarding his or her
personal disease, smoking and drinking history by two trained
interviewers. The data compiled for this study included age, age at DM
diagnosis, gender, duration of diabetes, body height and weight (for the
calculation of BMI), drinking and smoking (defined as current smoker
and ex-smoker who had quitted smoking irrespective of the duration).
Neuropathy was defined as abnormal vibration perception of the tuning
fork.8
Coronary heart disease (CHD) was defined as acute myocardial
infarction, coronary artery disease confirmed by coronary angiography,
and presentations of typical angina pectoris. Blood pressure was obtained
from the upper limbs with the patients in supine position, using an
automated device which simultaneously measured bilateral brachial and
ankle blood pressure using the modified oscillometric pressure sensor
method (BP-203RPE; Colin, Komaki, Japan). Hypertension was defined
as a systolic blood pressure of >140 mmHg and/or a diastolic blood
pressure >90 mmHg, or if the patients were receiving antihypertensive
treatment. Insulin use was defined as any insulin treatment alone or in
combination with oral antidiabetic agents.
Metabolic syndrome was defined as the fulfillment of at least three of
the following criteria: (1) Waist circumference >90 cm for men and >80
cm for women, (2) Serum triglyceride >150mg/dL, (3) Serum
high-density lipoprotein (HDL) level <40 mg/dL, (4) Elevated blood
pressure (systolic blood pressure >130 mmHg and/or diastolic blood
pressure >85 mmHg, or previous diagnosis of hypertension) and (5)
Increased fasting plasma glucose (>100 mg/dL) or previous diagnosis of
DM.
Venous blood samples were collected for measurements of total
cholesterol, triglycerides, HDL cholesterol, low-density lipoprotein (LDL)
cholesterol, uric acid, albumin after 12 hours fasting, serum creatinine,
HbA1c, hsCRP, complete blood count, and differential count. Two blood
samples were obtained for serum hsCRP analysis. Data were discarded
when a hsCRP level >10 mg/l. The average hsCRP level was chosen for
each patient. HsCRP was measured with the cardiophase high-sensitivity
nephelometric method (Dade Behring, Marburg, Germany) via a Behring
Nephelometer II Analyzer. The lowest detection limit was <0.15 mg/l.
Mean intra-assay coefficients of variance were less than 3.5% in our
laboratory. Creatinine concentrations in plasma and urine were
determined with a Wako Creatinine-Test kit by the Jaffe method (Wako
Pure Chemicals, Osaka, Japan). Albumin concentrations were determined
by immunonephelometry (Dade-Behring, Marburg, Germany).
The absolute count of a leukocyte subtype was calculated as the
product of the percentage of each subtype and the total leukocyte count.
Patients with WBC >10 x 1012/l or WBC <4 x 1012/l and/or those with
hemoglobin of MCV >100 fl or MCV <80 fl were excluded. Patients with
platelet <150 x 1012/l or >400 x 1012/l were also excluded. Hemoglobin
level was compared among the three different DR groups (Non-DR, BDR
+ NPDR, and PDR).
Estimated glomerular filtration rate (eGFR) was calculated by the
modified Diet and Renal Disease (MDRD) equation. The Human
Research Ethics Committee of our hospital approved this study and
informed consent was obtained from each patient.
Statistical analysis
Data are shown as means ± SD or percentage. The Statistical Package
for Social Science program (SPSS for Windows, version 13.0; SPSS) was
used to perform the statistical analysis. The independent t-test or
ANOVA were used for comparisons between different groups for
continuous variables and the Chi-square test was used for categorical
variables. All parameters significantly different between groups with or
without retinopathy were enrolled in logistic regression analysis the
results of which were shown as odds ratio (OR) and 95% confidence
interval (CI). P-value less than 0.05 is considered statistically significant.
Results
A total of 417 type 2 diabetic patients were included in this
cross-sectional study. The mean age of the study subjects was 64.9 ± 10.8
years (range, 25-94), and the mean duration of diabetes was 11.4 ± 6.5
years (range, 1-39). The prevalence of background diabetic nephropathy,
non-proliferative retinopathy or proliferative retinopathy was 29.0%,
5.0%, and 12.2%, respectively (Table 1).
The patients’ demographic characteristics and relevant laboratory
parameters between groups with or without retinopathy are shown in
Table 2. Retinopathy in microalbuminuric type 2 diabetic patients was
found to be positively associated with female gender, habit of drinking,
use of insulin, age at DM diagnosis, DM duration, presence of
hypertension, neuropathy, and stroke. Negative correlation was noted in
the level of total cholesterol, triglyceride, HDL-cholesterol, total
cholesterol to HDL-cholesterol ratio, albumin and hemoglobin.
Independent risk factors included the use of insulin (OR: 3.437, 95%
CI: 1.629 – 7.653, P=0.001), presence of hypertension (OR: 2.671, 95%
CI: 1.206 – 5.917, P=0.015), DM duration (OR: 1.06 3, 95% CI: 1.013 –
1.115, P=0.013), age at DM diagnosis (OR: 0.970, 95% CI: 0.944 – 0.997,
P=0.029), triglyceride (OR: 0.995, 95% CI: 0.992 – 0.999, P=0.017),
hsCRP (OR: 0.773, 95% CI: 0.644 – 0.930, P=0.006), hemoglobin (OR:
0.713, 95% CI: 0.603 – 0.843, P=0.000) (Table 3).
Hemoglobin concentration of the three DR groups (i.e. Non-DR,
BDR + NPDR, and PDR) was 13.5 ± 1.7, 12.8 ± 1.9, 12.3 ± 1.7
mg/dL, respectively, and significantly different among the three DR
groups (P =0.000, followed by LSD test to compare group means) (Figure
1). DR prevalence was 21.6, 29.8, 58.7 and 74.0% in the four DM
duration groups (i.e. <5 years, 5-10 years, 11-15 years, and >15 years) (P
=0.000) (Figure 2).
Discussion
In this hospital-based cross-sectional study, DR was noted in 46.2%
of type 2 diabetic patients with microalbuminuria. The prevalence of
diabetic retinopathy in the present study was similar to that found in two
previous cross-sectional hospital-based studies with figures of 43.4 and
40.3 %, respectively.4,9 Thus, our results and those of other studies
suggest that longer duration of DM may be required for the development
of DR in comparison to the development of diabetic nephropathy in type
2 diabetic patients. Alternatively, these results confirm the heterogeneity
of microalbuminuria in type 2 diabetes. In this study, use of insulin,
hypertension, earlier age at DM diagnosis, longer DM duration, lower
serum level of triglyceride and hsCRP and reduced hemoglobin were all
independently associated with the occurrence of DR in type 2 diabetic
patients with microalbuminuria.
Of the risk factors identified in our cohort, hypertension and longer
DM duration have been the most consistently reported in other studies. In
the United Kingdom Prospective Diabetes Study (UKPDS), longer
duration of diabetes and hypertension have been shown to contribute to
the development of DR in type 2 diabetes.10 In this cross-sectional study,
we demonstrated that longer duration of diabetes was significantly
associated with DR in type 2 diabetes with microalbuminuria (Table 3)
with the odds ratio of 1.063. It must be noted, however, that the
prevalence of DR was reported to be rapidly increasing when DM
duration was longer than 10 year.4,9,11 Similar findings were observed in
this study (Figure 2), in agreement with a comparable series described
previously in Korean type 2 diabetes with microalbuminuria.9
Our study and those of other investigators12,13 found that the use of
insulin was independently associated with DR in type 2 diabetes. In line
with our previous studies of peripheral arterial disease and diabetic
nephropathy in type 2 diabetes,14,15 we consistently demonstrated that
insulin use was an independent risk factor for diabetic chronic
complications. Use of insulin for glycemic control has been
recommended in type 2 diabetic patients with varying degree of loss ofβ
cell function.16 In the clinical practice of the author (R-T Liu) and perhaps
in most diabetologists in Taiwan, insulin treatment begins when type 2
diabetic patients experience oral antidiabtic drug failure. At this point,
most of patients might already have developed microvascular
complications. Therefore, it would not be surprising that use of insulin
was an independent factor for DR.
Many studies report an independent association between either higher
HbA1c or higher systolic blood pressure and DR in type 2 diabetic
patients upon multivariate analysis.4,5,7 In this cross-sectional cohort
analysis, we observed a tendency for higher HbA1c and higher systolic
blood pressure among those with retinopathy compared to those without,
albeit short of significance. Failure to replicate the results of previous
studies could be due to the intensification of glycemic and blood pressure
control in our patients.
The impact of age at diagnosis of type 2 diabetes on the risk of
developing retinopathy is unclear. In this cross-sectional analysis, earlier
age at DM diagnosis is an independent risk factor for DR. This
observation is compatible with a previous finding of an association
between earlier age at DM diagnosis and DR in Non-Chinese
population.17 Interestingly, this relationship was observed not only in
diabetic retinopathy, but also in other chronic complications we studied
(unpublished data).
Anemia is associated with an increased risk of the vascular
complications of diabetes including nephropathy18-20 and retinopathy.21-23
Here, we show that the degree of anemia was proportional to the severity
of DR in type 2 diabetic patients with microalbuminuria (Figure 1). Our
results confirm previous observation of the relationship between reduced
hemoglobin level and DR.24 These findings lend support to the hypothesis
that anemia may modulate the activity of pathways that lead to
progressive end-organ damage in diabetes.23
Recent developments indicate that the classical pathophysiological
determinants of diabetic microangiopathy, namely hyperglycemia, and
hypertension are accompanied by heightened inflammatory activity,
endothelial dysfunction, and disturbed coagulation, and these processes
may constitute final common pathways to the vascular complications of
diabetes.25 It is noteworthy that both serum levels of triglyceride and
hsCRP were negatively and independently associated with DR in this
study. These findings were not limited to the microalbuminuric subgroup
of type 2 diabetes we studied. In analysis of our type 2 diabetes cohort
regardless of their albuminuria status, same results for hsCRP were
observed (unpublished data). Elevated triglyceride levels have been
shown to independently increase the likelihood of albuminuria in type 2
diabetes in several studies including ours.1,15,26,27 Recent reports and our
study (unpublished data) also demonstrated an independent association of
higher hsCRP levels with albuminuria in subjects with type 2
diabetes.27,28 The significant association of hsCRP with albuminuria
supports the role of inflammation in diabetic nephropathy. However, the
relationship between triglyceride, or hsCRP with DR was controversial.5-7,
21, 22, 29-33
Most, but not all, studies did not find a significant association
between higher triglyceride or higher hsCRP levels and DR in type 2
diabetic subjects. These results suggest different pathogenesis between
DN and DR in type 2 diabetes.
The results presented for the current study need to be interpreted in the
context of the study’s limitations. First, the cross-sectional nature of the
present study limits assessment of the causal relationship between the
independent risk factors we identified and occurrence of diabetic
retinopathy in type 2 diabetic patients with microalbuminuria. A
prospective study should be undertaken to confirm its causality. Second,
since our study cohort was hospital-based and from one diabetologist,
selection bias was a potential confounding factor. Thus, the
generalizability of our study findings to the general diabetic population
requires further investigation. Despite these limitations, there are several
strengths involved in the current study. This study involved a well
characterized and sufficient sample size, a cohort design and a
comprehensive risk factor analysis. Furthermore, all patients were treated
by a single physician, which minimized potential bias during treatment
and follow-up.
In conclusion, use of insulin, presence of hypertension, earlier age at
DM diagnosis, longer DM duration, lower serum level of triglyceride and
hsCRP, and reduced hemoglobin are independently associated with an
increased prevalence of diabetic retinopathy in type 2 diabetes with
microalbuminuria. Further studies are required to confirm the
reproducibility of these results and its causal relationship.
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