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 MemorialHospital - Kaohsiung Medical Center, Kaohsiung, Address: 123 Ta-Pei Road, Niao-Sung Hsiang, Kaohsiung Hsien 833, TaiwanTel: 886-7-7317123 ext.8302Fax: 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

ofβcell 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.

Reference

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