Journal of Diabetes and Its Complications 28 (2014) 291–297
Contents lists available at ScienceDirect
Journal of Diabetes and Its Complications journal homepage: WWW.JDCJOURNAL.COM
Prevalence and risk factors for diabetic retinopathy in Asian Indians with young onset Type 1 and Type 2 Diabetes Ramachandran Rajalakshmi a, Anandakumar Amutha a, Harish Ranjani a, Mohammed K. Ali b, Ranjit Unnikrishnan a, Ranjit Mohan Anjana a, K.M. Venkat Narayan b, Viswanathan Mohan a,⁎ a
Madras Diabetes Research Foundation & Dr. Mohan’s Diabetes Specialities Centre, WHO Collaborating Centre for Non-communicable Diseases Prevention and Control, IDF Centre for Education, Gopalapuram, Chennai, India b Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA
a r t i c l e
i n f o
Article history: Received 26 September 2013 Received in revised form 29 November 2013 Accepted 23 December 2013 Available online 6 January 2014 Keywords: Diabetic retinopathy T1DM-Y T2DM-Y Prevalence Risk factors Asian Indians
a b s t r a c t Aim: To assess the prevalence and risk factors for diabetic retinopathy (DR) in people with young onset type 1 (T1DM-Y) and type 2 diabetes (T2DM-Y). Methods: T1DM-Y(n = 150) and T2DM-Y(n = 150) participants, age between 10 and 25 years at diagnosis, had a complete clinical evaluation, biochemical assessment, and four field digital retinal colour photography. The Early Treatment Diabetic Retinopathy Study grading system was used to grade DR. Proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME) were considered as sight threatening DR. Results: The prevalence of any DR was 53.3% [95% CI 45.3–61.3] in T1DM-Y (duration of diabetes: 12.4 ± 7.4years) and 52.7% [44.7–60.7] in T2DM-Y (11.8 ± 8.3 years). The age and gender adjusted prevalence of DR, DME and PDR was 62.5%, 10% and 7.3% in T1DM-Y, whereas it was 65.8%,12.7% and 9.3% in T2DM-Y respectively. In multivariable logistic regression, diabetes duration [Odds ratio (OR) 1.99 per 5 years; CI 1.42–2.79], waist circumference [1.28 per 5 cm;1.05–1.56] and microalbuminuria [2.39 per 50 μg;1.07–5.31] were associated with DR in T1DM-Y, and diabetes duration [2.21 per 5 years; 1.61–3.02], diastolic blood pressure [1.54 per 5 mmHg;1.18–2.02], Glycated hemoglobin [1.37 per %;1.07–1.75] and lower stimulated C-peptide [1.54 per 0.5 pmol/ml;1.15–2.05;] were associated with DR in T2DM-Y. Conclusion: Over half of the people with young-onset diabetes, regardless of type, have retinopathy within 10–12 years of diabetes duration, emphasizing the need for regular eye screening and aggressive control of glucose and blood pressure to prevent DR. © 2014 Elsevier Inc. All rights reserved.
1. Introduction The growing burden of diabetes globally has been accompanied by a rise in numbers of young onset type 1diabetes (T1DM-Y) and particularly young onset type 2 diabetes (T2DM-Y) (American Diabetes Association, 2000; Amutha et al., 2011; International Diabetes Federation, 2011; McMahon et al., 2004; Mohan, Jaydip, & Deepa, 2007; Pinhas-Hamiel & Zeitler, 2005). Younger age of onset of diabetes results in a longer life time exposure to hyperglycemia and consequently a greater risk of developing complications during productive years of adulthood (Amutha, Datta, Unnikrishnan, Anjana, Conflict of interest: None declared. ⁎ Corresponding author at: Madras Diabetes Research Foundation & Dr. Mohan’s Diabetes Specialities Centre, WHO Collaborating Centre For Non-Communicable Diseases Prevention And Control &IDF Centre For Education, 4, Conran Smith Road, Gopalapuram, Chennai - 600 086. India. Tel.: + 91 44 4396 8888; fax: + 91 44 2835 0935. E-mail address: [email protected] (V. Mohan). URL: http://www.drmohansdiabetes.com, http://www.mdrf.in (V. Mohan). 1056-8727/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jdiacomp.2013.12.008
& Mohan, 2012; Amutha et al., 2011; Hillier & Pedula, 2003; PinhasHamiel & Zeitler, 2007). Diabetic retinopathy (DR) is a potentially sight-threatening microvascular complication of diabetes, and an important cause of preventable blindness. While disease duration and levels of glucose and blood pressure control strongly influence the risk of DR (Chaturvedi et al., 1998; Klein, Klein, Moss, Davis, & DeMets, 1984a; Raman et al., 2009; Rema et al., 2005; The DCCT Research Group, 1993), some data indicate that younger age of onset, especially for T2DM, may confer added susceptibility to DR (Eppens et al., 2006; Wong, Molyneaux, Constantino, Twigg, & Yue, 2008). In the multiethnic SEARCH study in the US, the prevalence of DR was 17% in T1DM and 42% in T2DM (Mayer-Davis et al., 2012). Although diabetes in the young (particularly T2DM) is becoming more frequent in India (Amutha et al., 2011; Mohan et al., 2007), epidemiological data on DR in India are largely limited to adult onset T2DM (Raman et al., 2009; Rema et al., 2005), and to a few studies in T1DM-Y (Rema, Mohan, & Ponnaiya, 1995; Rema, Mohan, Ramachandran, & Viswanathan, 1989). Data in people with T2DM-Y are scarce.
292
R. Rajalakshmi et al. / Journal of Diabetes and Its Complications 28 (2014) 291–297
We assessed the prevalence and risk factors for retinopathy in people with T1DM-Y and T2DM-Y, with onset of diabetes between ages 10 and 25 years, in a clinic population in India.
2. Research design and methods Data for this study were collected between January 2010 and June 2011 from individuals with T1DM-Y (n = 150) and T2DM-Y (n = 150), diagnosed between the ages of 10 and 25 years, with duration of diabetes over 2 years, registered at Dr. Mohan’s Diabetes Specialties Centre (DMDSC),a tertiary care network in Chennai (formerly Madras) in southern India. The Institutional Ethics Committee (IEC) approval was obtained prior to the start of the study. Written informed consent was obtained according to the local IEC guidelines and assent was obtained from the study subjects less than 18 years of age in addition to parental consent. Diabetes was defined as fasting plasma glucose (FPG) level ≥ 126 mg/dl (7.0 mmol/l) and/or 2-h post-load glucose level ≥ 200 mg/dl (11.1 mmol/l) (Alberti & Zimmet, 1998) or self-reported diabetes treated by a physician or on hypoglycemic medications or insulin. Diabetes was then classified as follows: T1DM-Y, if accompanied by abrupt onset of symptoms like polyuria, polydipsia, or unexplained weight loss, diabetic ketoacidosis (DKA), absent insulin reserve as shown by fasting and stimulated C-peptide (b0.3pmol/ml), and requirement of insulin from the time of diagnosis for control of hyperglycemia; and T2DM-Y, as absence of ketosis, good beta cell functional reserve as evidenced by stimulated C-peptide (≥ 0.6 pmol/ml), absence of pancreatic calculi (on X-ray abdomen), and good response to oral hypoglycemic agents for more than 2 years (Amutha et al., 2011). Anthropometric measurements included height, weight, and waist circumference (Deepa et al., 2003). Height was measured in centimetres using a stadiometer. Weight was measured with a traditional spring balance and recorded to the nearest 0.5 kg. Body mass index (BMI) was calculated using the formula: weight (kg)/height squared (in m 2). Waist circumference was measured using a non-stretchable measuring tape. The participants were asked to stand erect in a relaxed position with both feet together on a flat surface; one layer of clothing was accepted. Waist girth was measured as the smallest horizontal girth between the costal margins and the iliac crests at minimal respiration. Blood pressure was recorded in a rested sitting position in the right arm with a mercury sphygmomanometer and rounded off to the nearest 2 mmHg. Two readings were taken 5 min apart and the mean of the 2 readings was used. Fasting plasma glucose (hexokinase method) was measured on Hitachi 912 Autoanalyzer (Hitachi, Mannheim, Germany) using kits supplied by Roche Diagnostics (Mannheim, Germany); glycated haemoglobin (HbA1C) by high-pressure liquid chromatography using the Variant machine (Bio-Rad, Hercules, Calif., USA); serum total cholesterol (cholesterol oxidase-peroxidase-amidopyrine method), serum triglycerides (glycerol phosphate oxidase-peroxidase-amidopyrine method), and HDL cholesterol (direct method-polyethylene glycolpretreated enzymes) using Hitachi-912 Autoanalyser (Hitachi, Mannheim, Germany). Low-density lipoprotein (LDL) cholesterol was calculated using the Friedewald formula (Friedewald, Levy, & Fredrickson, 1972). Apo lipo-protein A and B were measured by immuno-turbidometric method (Olympus AU 2700 USA). Fasting and stimulated (post-breakfast) C-peptide was estimated by the electro-luminescence method on Elecsys2010 (Hitachi, Mannheim, Germany); glutamic acid decarboxylase (GAD) antibodies were measured on a Bio-Rad plate reader 680 (USA) using Elisa Euro Immun kit (Lubeck, Germany); and plasma concentration of hs-CRP by turbidometry method (Beckman Coulter AU 480 USA). The intraand inter-assay co-efficient of variation for the biochemical assays ranged between 3.1% and 7.6%.
Urine samples were collected after an overnight fast. Microalbumin concentration was measured using an immunoturbidometric assay (Hitachi 902 autoanalyzer; Roche Diagnostics, Mannheim, Germany) (Varghese, Deepa, Rema, & Mohan, 2001). Microalbuminuria was defined as a urine albumin excretion of 30–299 mg/μg of creatinine (Pradeepa et al., 2010). Nephropathy was defined as macro-albuminuria i.e., a urine albumin excretion of ≥ 300 μg/mg of creatinine (Pradeepa et al., 2010). The DMDSC laboratory is certified by the College of American Pathologists and the Indian National Accreditation Board for Testing and Calibration of Laboratories. 2.1. Retinopathy Four-field digital retinal colour photography was taken by a trained photographer using a Carl-Zeiss Digital Fundus Camera. The 4 fields photographed were the macula, optic disc and nasal to the optic disc, and superior–temporal and inferior–temporal quadrants of each eye. The grading of retinopathy was done based on the modified Early Treatment Diabetic Retinopathy Study (ETDRS) grading system (Early Treatment Diabetic Retinopathy Study Research Group, 1991). Each eye was graded separately by an ophthalmologist trained in ETDRS grading, at DMDSC. The minimum criterion for diagnosis of DR was the presence of at least one definite microaneurysm in any field of the retina. Photographs were assessed and assigned a retinopathy level and the final diagnosis for each patient was determined from the level of DR of the worse eye using ETDRS final retinopathy scale (Early Treatment Diabetic Retinopathy Study Research Group, 1991; Rema et al., 2005). Briefly, level 10 represents no retinopathy, levels 20 to 50, non-proliferative diabetic retinopathy (NPDR) [Level 20: mild NPDR; levels 30 to 40: moderate NPDR; level 50: severe NPDR] and levels ≥ 60, proliferative diabetic retinopathy (PDR) (Early Treatment Diabetic Retinopathy Study Research Group, 1991). Diabetic macular edema (DME) was defined as retinal thickening at or within one disc diameter of the centre of the macula or the presence of definite hard exudates (Early Treatment Diabetic Retinopathy Study Research Group, 1985; Wilkinson et al., 2003). DME could be present in both NPDR and PDR stages, but, once PDR was diagnosed, the final severity scale was graded as PDR (Rema et al., 2005). Sight-threatening diabetic retinopathy (STDR) was defined as PDR or DME (clinically significant macular edema) in either or both eyes (Younis, Broadbent, Vora, & Harding, 2003). Where clinically indicated, optical coherence tomography (OCT) was done and appropriate treatment was offered to the subjects (Otani, Kishi, & Maruyama, 1999). 3. Statistical analysis All statistical analyses were done using SPSS statistical package version 15.0 (SPSS Inc., Chicago, IL, USA). Continuous data are expressed as mean ± standard deviation while categorical data are presented as proportions. Student’s t test was used to compare means of continuous variables between subjects with and without retinopathy in T1DM-Y and T2DM-Y groups. Chi square test was used to compare proportions. To assess independent risk factors for diabetic retinopathy and age adjusted prevalence, we used logistic regression models with DR as the dependent variable and reported odds ratios (OR) with 95% confidence intervals (CIs) and percentages. First, variables were independently tested with the outcomes using bivariable analysis and significant variables (p value b 0.05) were entered into a multivariable analysis. For all statistical tests, p value b 0.05 was considered significant. 4. Results Diabetic retinopathy was present in 80 (53.3% [95% CI 45.3–61.3]) people with T1DM-Y and 79 (52.7% [95% CI 44.7–60.7]) people with
R. Rajalakshmi et al. / Journal of Diabetes and Its Complications 28 (2014) 291–297
293
Fig. 1. Prevalence of diabetic retinopathy (DR) in young onset diabetes.
T2DM-Y (Fig. 1). The mean age of T1DM-Y and T2DM-Y with retinopathy was 31.8 ± 7.7 years and 38.1 ± 9.2 years (p b 0.001). The age and gender adjusted prevalence of retinopathy in T1DM-Y and T2DM-Y was 62.5% and 65.8% respectively. DME was present in 15 (10%) T1DM-Y and 19 (12.7%) T2DM-Y and PDR in 11(7.3%) T1DM-Y and 14 (9.3%) T2DM-Y participants. The prevalence of PDR and STDR was no different among T2DM-Y and T1DM-Y participants (Fig. 1). Fig. 2 shows the retinal colour photography of a T1DM-Y patient with PDR and Fig. 3 shows a T2DM-Y patient with DME. Fig. 4 shows the OCT of a T2DM-Y patient with severe sight threatening DME. Table 1 show the clinical and biochemical characteristics of the study participants with and without diabetic retinopathy (DR). In people with T1DM-Y, those with DR were significantly older, had longer duration of diabetes, had significantly higher BMI, waist circumference, higher systolic and diastolic blood pressures and a
greater proportion had microalbuminuria compared with those without DR. In T2DM-Y, in addition to the above, those with DR also had significantly higher fasting plasma glucose, glycated hemoglobin (HbA1C), and apolipoprotein A levels as well as significantly lower fasting and stimulated C-peptide levels when compared with those without DR. Prevalence of STDR was higher with longer duration of diabetes in both T1DM-Y and T2DM-Y, with the prevalence peaking in those with N 15 years of diabetes. Interestingly, none of the T1DM-Y with duration of diabetes b10 years had STDR but among T2DM-Y people, STDR was prevalent even in those with a known duration of diabetes of b 5 years (Fig. 5). The overall STDR prevalence was higher with longer duration of diabetes with 44.1% of the T1DM-Y and 52.5% of the T2DM-Y people with N 15 years of diabetes having STDR. The bivariable analysis for T1DM-Y participants showed age, duration of diabetes, waist circumference, systolic and diastolic blood
Fig. 2. Retinal colour photography of diabetic retinopathy in young onset type 1 diabetes.
Fig. 3. Retinal colour photography of diabetic retinopathy in young onset type 2 diabetes.
294
R. Rajalakshmi et al. / Journal of Diabetes and Its Complications 28 (2014) 291–297
Fig. 4. Optical coherence tomography (OCT) of a T2DM-Y patients with diabetic macular edema.
pressure and microalbuminuria to be associated with diabetic retinopathy. In addition to these factors, age of onset of diabetes, fasting plasma glucose, HbA1C and lower stimulated C-peptide were associated with DR in participants with T2DM-Y. For every 5 mm Hg higher systolic (SBP) and diastolic blood pressure (DBP), there were higher odds of DR in both T1DM-Y and T2DM-Y patients (T1DM-Y SBP: OR 1.3, 95% CI 1.09–1.48; DBP: OR 1.4, 95% CI 1.09–1.70; T2DM-Y SBP:OR 1.3, 95% CI 1.1–1.49, DBP:1.6, 95% CI 1.24–1.97 per 5 mm Hg). In T1DM-Y participants, the age of onset of diabetes was not associated with DR while in T2DM-Y, every 5-year increase in age of onset was associated with a 2.2 times odds of having DR. In multivariable regression analyses, significant independent predictors for DR in participants with T1DM-Y were duration of diabetes, waist circumference and microalbuminuria, whereas in T2DM-Y
participants, duration of diabetes, diastolic blood pressure, HbA1C and lower stimulated C-peptide values were associated (Table 2). 5. Discussion The prevalence of DR and STDR was high in both T1DM-Y and T2DM-Y from this clinic population studied in south India, with no significant difference in the age adjusted prevalence of diabetic retinopathy between T1DM-Y and T2DM-Y. This is in contrast to earlier epidemiological studies reporting that diabetic retinopathy in T1DM-Y has a different frequency, onset, and course than DR in T2DM (Klein, Klein, Moss, Davis, & DeMets, 1984b, Klein et al., 1984a,b). The high prevalence of DR among T2DM-Y in our study is similar to that reported from Japan in T2DM-Y subjects (diagnosed b 30years)
Table 1 Clinical and biochemical characteristics of T1DM-Y and T2DM-Y with and without diabetic retinopathy (DR). Variables
Age (years) Duration (years) Age at onset (years) Gender, male n (%)a Body mass index (kg/m2) Waist circumference(cm) Systolic Blood Pressure (mmHg) Diastolic Blood Pressure (mmHg) Fasting plasma glucose (mg/dl)b Glycated hemoglobin (%) Total Cholesterol (mg/dl) Serum Triglycerides (mg/dl)b HDL Cholesterol (mg/dl) LDL Cholesterol (mg/dl) Apo Lipoprotein A (mg/dl) Apo Lipoprotein B (mg/dl) Microalbuminuria (ug/mg) HS-CRP (mg/l)b C-Peptide Fasting (pmol/ml)b C-Peptide Stimulated (pmol/ml)b Smoking (n %)
T1DM-Y
T2DM-Y
No DR (n = 70)
With DR (n = 80)
p value
No DR (n = 71)
With DR (n = 79)
p value
24.6 ± 8.1 8.4 ± 6.5 16.6 ± 4.1 36(51.4) 21.1 ± 3.1 73.5 ± 10.6 116 ± 10 72 ± 7.0 163 (10) 9.0 ± 1.9 160 ± 32 69 (5) 48 ± 12 97 ± 27 126 ± 32 76 ± 18 11.9 ± 2.5 1.62 (0.37) 0.28 (0.01) 0.32 (0.01) 1(1.4)
31.8 ± 7.6 15.2 ± 6.7 17.0 ± 4.4 48(60.0) 23.0 ± 3.9 80.9 ± 10.4 124 ± 18 76 ± 9 163 (11) 8.5 ± 1.6 168 ± 41 81(6) 46 ± 11 102 ± 32 129 ± 31 82 ± 24 68.4 ± 13.2 1.92(0.37) 0.30 (0.03) 0.32 (0.04) 5(6.2)
b0.001 b0.001 0.571 0.291 0.001 b0.001 0.001 0.006 0.742 0.067 0.150 0.058 0.192 0.243 0.586 0.113 b0.001 0.398 0.227 0.182 0.133
28.0 ± 7.8 7.6 ± 5.9 20.8 ± 3.9 47(66.2) 26.5 ± 4.7 89.2 ± 11.6 123 ± 12 76 ± 8 141 (6) 8.1 ± 1.8 158 ± 35 120(10) 38 ± 9 93 ± 28 114 ± 34 84 ± 20 22.7 ± 6.36 2.46 (0.42) 0.87 (0.04) 1.89 (0.10) 5(7.0)
38.1 ± 9.1 15.6 ± 8.2 22.3 ± 2.9 45(57.0) 27.1 ± 4.2 92.6 ± 10.3 130 ± 14 81 ± 9 168 (8) 9.1 ± 2.0 155 ± 38 130(12) 40 ± 9 89 ± 29 126 ± 37 82 ± 19 55.0 ± 10.4 2.20 (0.39) 0.71(0.04) 1.30 (0.08) 5(6.3)
b0.001 b0.001 0.011 0.246 0.423 0.064 b0.001 b0.001 b0.001 0.020 0.537 0.362 0.338 0.403 0.048 0.417 0.009 0.467 0.017 b0.001 0.861
Data given as mean ± SD, p b 0.05 considered significant. Bold denotes statistical significance. a Chi square p value given. b Data given as Geometric mean (SE).
R. Rajalakshmi et al. / Journal of Diabetes and Its Complications 28 (2014) 291–297
295
Fig. 5. Frequency of diabetic retinopathy (DR) and sight threatening diabetic retinopathy (STDR) based upon the duration of diabetes.
(Okudaira, Yokoyama, Otani, Uchigata, & Iwamoto, 2000) and also in another study by Wong et al., (2008), which showed that younger T2DM had more severe grades of DR than the older T2DM patients. Krakoff et al. (2003) reported that the incidence of retinopathy was lower in the youth-onset group (b20 years at onset of diabetes) than in either adult group (onset of diabetes at 20 to 39 and 40 to 59 years of age) in all categories of diabetes duration. Interestingly, we noted that the age of onset of diabetes did not play a role in T1DM-Y, while age of onset of diabetes between 21 and 25 years increased the risk for DR in T2DM-Y patients. A younger onset of diabetes with an increasing life span implies longer duration of diabetes (Klein et al., 1984a; Namperumalsamy et al., 2009; Okudaira et al., 2000), hence a large number of people are at risk of developing DR. In the Wisconsin Epidemiological Study of Diabetic Retinopathy (WESDR), the prevalence of DR in young people with diabetes for N15 years was 98% (Klein et al., 1984a). In our study, in those with diabetes for N 15 years, the prevalence of DR was 82.9% and 90.7% in T1DM-Y and T2DM-Y respectively. The higher prevalence of DR and STDR in T2DM-Y in those with more than 15 years of diabetes, points to the aggressive nature of the disease. However, it is
Table 2 Multivariable logistic regression—Factors associated with diabetic retinopathy in T1DM-Y and T2DM-Y. Variablesa
Increment/value
OR(95% CI)
p value
T1DM-Y Duration of diabetes (years) Waist circumference (cm) Microalbuminuria (μg/mg)
5 years 5 cm 50 μg/mg
Variablesa
Increment/value
1.99 (1.42–2.79) 1.28 (1.05–1.56) 2.39 (1.07–5.31)
b0.001 0.014 0.033
OR(95% CI)
p value
T2DM-Y Duration of diabetes (years) Diastolic blood pressure(mmHg) Glycated hemoglobin (%) C-peptide stimulated (pmol/ml)
5 years 5 mmHg
2.21 (1.61–3.02) 1.54 (1.18–2.02)
b0.001 0.002
1% 0.5 pmol/ml decrease
1.37 (1.07–1.75) 1.54(1.15–2.05)
0.011 0.003
For T1DM-Y subjects, along with the above predictors age (per 5 yrs), systolic and diastolic blood pressures (per 5 mmHg) were included in the analysis and for T2DM-Y subjects, age (per 5 years), age onset of diabetes (per 5 years), waist circumference (per 5 cm), systolic blood pressure (per 5 mmHg), fasting plasma glucose (per 50 mg) and microalbuminuria (per 50ug/mg) were included. a Only significant independent predictors are given, p b 0.05 considered significant.
uncertain whether this may be reflecting a longer period of asymptomatic undiagnosed diabetes in T2DM-Y. To our knowledge, there have been only a few studies, comparing the prevalence of retinopathy in T1DM-Y versus T2DM-Y. In the pilot study on DR in the SEARCH study for diabetes in youth, the prevalence of DR was higher in T2DM-Y (42%) than T1DM-Y (17%). However, this difference was largely attributed to the ethnic variation, with DR in T2DM-Y being more common in the non-Caucasian populations (e.g., native American, Hispanic, non-Hispanic Black) (Mayer-Davis et al., 2012). In our study, we recruited equal numbers of patients with T1DM-Y and T2DM-Y that were of the same race/ethnicity and with similar mean duration of diabetes. Eppens et al. reported that DR was more prevalent in adolescents with T1DM-Y than T2DM-Y (20% vs. 4%) (Eppens et al., 2006). However in their study, the duration of diabetes was very different between the two groups (T1DM-Y = 6.8 years, T2DM-Y = 1.3 years) making comparisons difficult. We found that increased systolic and diastolic blood pressure, regardless of the type of young onset diabetes, increased the risk for retinopathy. Diastolic blood pressure was also an independent predictor for DR in T2DM-Y patients. The United Kingdom Prospective Diabetes Study (UKPDS) study showed a continuous relationship between the risk of DR and systolic blood pressure (UK Prospective Diabetes Study Group, 1998b) and lowering blood pressure to a mean of 144/82 mm Hg reduced microvascular complications and visual loss (UK Prospective Diabetes Study Group, 1998a). In the WESDR, diastolic blood pressure was seen as a significant predictor of progression of diabetic retinopathy (Klein et al., 1984a). We also found that in T2DM-Y, increased HbA1C was associated with prevalent DR as seen in other studies (Early Treatment Diabetic Retinopathy Study Research Group, 1991; Namperumalsamy et al., 2009). However, there was no association seen between present glycemic status and development of DR in T1DM-Y subjects. This could probably be attributed to the hyperglycemic memory influencing the development of DR in T1DM-Y patients (Zhang, Chen, & Tang, 2012). We found that lower stimulated C-peptide levels were associated with increased risk for retinopathy in T2DM-Y. Klein, Moss, Klein, Davis, and Demets (1990) have shown that diabetes patients using insulin, with undetectable or very low plasma C-peptide (b0.3 pmol/ ml), are more likely to have DR and also more severe DR than older onset individuals who have higher levels of C-peptide (N0.3 pmol/ ml). The Diabetes Control and Complications Trial (DCCT) showed that higher and sustained levels of stimulated C-peptide were associated with reduced incidence of retinopathy (Steffes, Sibley,
296
R. Rajalakshmi et al. / Journal of Diabetes and Its Complications 28 (2014) 291–297
Jackson, & Thomas, 2003). This highlights the possible benefit of sustaining pancreatic β cell function in order to reduce the development and progression of microvascular complications like retinopathy (Yoon et al., 2012). Another risk factor associated with DR in both T1DM-Y and T2DM-Y was the presence of microalbuminuria. Associations between retinopathy and microalbuminuria have also been demonstrated in many studies (Collins et al., 1995; Farah, Wals, Friedman, Pisacano, & DiMartino-Nardi, 2006; Gall et al., 1991; Matyka, 2008). T1DM-Y people with increased waist circumference also had greater risk for DR. Dirani et al. (2011) have shown that in persons with diabetes, higher BMI and larger waist circumference confer a higher risk of DR and are also associated with severity of DR. Our study has certain limitations. It is cross-sectional, and thus causal inferences cannot be drawn. Our population was recruited at a tertiary care clinic, and therefore these findings may not apply to the population of T2DM-Y and T1DM-Y at large. Moreover they cannot be extrapolated to the country as a whole as referral bias could have affected the results. However our study has certain strengths as well. This is the first study from a developing country to compare the prevalence and risk factors of diabetic retinopathy in T1DM-Y versus T2DM-Y with objective measurement of diabetic retinopathy using state-of-the-art digital retinal colour photography. Overall, half the people with youth-onset diabetes of N10 years duration have retinopathy. Our findings emphasise the need for regular and periodic screening for diabetic retinopathy and especially in patients with pre-existing DR, a shorter interval of ≤ 1 year may be needed (Echouffo-Tcheugui, Ali, Roglic, Hayward, & Venkat Narayan, 2013). Tight control of glucose and blood pressure from the time of diagnosis is important in order to reduce morbidity and disability due to diabetic eye disease in young onset diabetes. Acknowledgments We acknowledge the help of all the optometrists at DMDSC for performing the digital retinal colour photography. We acknowledge the support of the study team members. Most importantly, we wish to thank the subjects who participated in the study. We acknowledge the financial support from the Emory Global Health Institute through the Global Diabetes Research Center (GDRC) — collaboration between Madras Diabetes Research Foundation, Chennai and Emory University, Atlanta, USA. This is the 11th paper from this collaboration (GDRC-11). References Alberti, K. G., & Zimmet, P. Z. (1998). Definition diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus, provisional report of a WHO Consultation. Diabetic Medicine, 15, 539–553. American Diabetes Association (2000). Type 2 diabetes in children and adolescents (consensus statement). Diabetes Care, 23, 381–389. Amutha, A., Datta, M., Unnikrishnan, R., Anjana, R. M., & Mohan, V. (2012). Clinical profile and complications of childhood and adolescent onset type 2 diabetes seen at a diabetes centre in South India. Diabetes Technology & Therapeutics, 14, 497–504. Amutha, A., Datta, M., Unnikrishnan, I. R., Anjana, R. M., Rema, M., Venkat Narayan, K. M., et al. (2011). Clinical profile of diabetes in the young seen between 1992 and 2009 at a specialist diabetescentre in south India. Primary Care Diabetes, 5, 223–229. Chaturvedi, N., Sjolie, A. K., Stephenson, J. M., Abrahamian, H., Keipes, M., Castellarin, A., et al. (1998). Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus. Lancet, 35, 28–31. Collins, V. R., Dowse, G. K., Plehwe, W. E., Imo, T. T., Toelupe, P. M., & Taylor, H. R. (1995). High prevalence of diabetic retinopathy and nephropathy in Polynesians of Western Samoa. Diabetes Care, 18, 1140–1149. Deepa, M., Pradeepa, R., Rema, M., Mohan, A., Deepa, R., Shanthirani, S., et al. (2003). The Chennai Urban Rural Epidemiology Study (CURES): study design and methodology (urban component) (CURES-1). Journal of the Association of Physicians of India, 51, 863–870. Dirani, M., Xie, J., Fenwick, E., Benarous, R., Rees, G., Wong, T. Y., et al. (2011). Are obesity and anthropometry risk factors for diabetic retinopathy? The
Diabetes Management Project. Investigative Ophthalmology & Visual Science, 52, 4416–4421. Early Treatment Diabetic Retinopathy Study Research Group (1985). Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study Report Number 1. Archives of Ophthalmology, 103, 1796–1806. Early Treatment Diabetic Retinopathy Study Research Group (1991). Grading diabetic retinopathy from stereoscopic colour fundus photographs: An extension of the modified Airlie House classification. Early Treatment Diabetic Retinopathy Study Report Number 10. Ophthalmology, 98, 786–806. Echouffo-Tcheugui, J. B., Ali, M. K., Roglic, G., Hayward, R. A., & Venkat Narayan, K. M. (2013). Screening intervals for diabetic retinopathy and incidence of visual loss: A systematic review. Jul 2. Diabetic Medicine, http://dx.doi.org/10.1111/dme.12274 [Epub ahead of print]. Eppens, M. C., Craig, M. E., Cusumano, J., Hing, S., Chan, A. K. F., Howard, N. J., et al. (2006). Prevalence of diabetes complications in adolescents with type 2 compared with type 1 diabetes. Diabetes Care, 29, 1300–1306. Farah, S. E., Wals, K. T., Friedman, I. B., Pisacano, M. A., & DiMartino-Nardi, J. (2006). Prevalence of retinopathy and microalbuminuria in pediatric type 2 diabetes mellitus. Journal of Pediatric Endocrinology & Metabolism, 19, 937–942. Friedewald, W. T., Levy, R. I., & Fredrickson, D. S. (1972). Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clinical Chemistry, 18, 499–502. Gall, M. A., Rossing, P., Skott, P., Damsbo, P., Vaag, A., & Bech, K. (1991). Prevalence of micro- and macroalbuminuria, arterial hypertension, retinopathy, and large vessel disease in European type 2 (non-insulin dependent) diabetic patients. Diabetologia, 34, 655–661. Hillier, T. A., & Pedula, K. (2003). Complications in young adults with early-onset type 2 diabetes: Losing the relative protection of youth. Diabetes Care, 26, 2999–3005. International Diabetes Federation. (2011). Diabetes atlas (Fifth ed.)Brussels, Belgium: International Diabetes Federation. Klein, R., Klein, B. E., Moss, S. E., Davis, M. D., & DeMets, D. L. (1984a). The Wisconsin Epidemiologic Study of Diabetic Retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Archives of Ophthalmology, 102, 520–526. Klein, R., Klein, B. E., Moss, S. E., Davis, M. D., & DeMets, M. L. (1984b). The Wisconsin Epidemiologic Study of Diabetic Retinopathy. III Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Archives of Ophthalmology, 102, 527–532. Klein, R., Moss, S. E., Klein, B. E. K., Davis, M. D., & Demets, D. L. (1990). Wisconsin Epidemiologic Study of Diabetic Retinopathy: XII. Relationship of C-peptide and diabetic retinopathy. Diabetes, 39, 1445–1450. Krakoff, J., Lindsay, R. S., Looker, H. C., Nelson, R. G., Hanson, R. L., & Knowler, C. (2003). Incidence of retinopathy and nephropathy in youth-onset compared with adultonset type 2 diabetes. Diabetes Care, 26, 76–81. Matyka, K. A. (2008). Type 2 diabetes in childhood: Epidemiological and clinical aspects. British Medical Bulletin, 86, 59–75. Mayer-Davis, E. J., Davis, C., Saadine, J., D'Agostino, R. B., Jr., Dabelea, D., Dolan, L., et al. (2012). SEARCH for Diabetes in Youth Study Group. Diabetic retinopathy in the SEARCH for Diabetes in Youth cohort: A pilot study. Diabetic Medicine, 29, 1148–1152. McMahon, S. K., Haynes, A., Ratnam, N., Grant, M. T., Carne, C. L., Jones, T. W., et al. (2004). Increase in type 2 diabetes in children and adolescents in Western Australia. Medical Journal of Australia, 180, 459–461. Mohan, V., Jaydip, R., & Deepa, R. (2007). Type 2 diabetes in Asian Indian youth. Pediatric diabetes, 9, 28–34. Namperumalsamy, P., Kim, R., Vignesh, T. P., Nithya, N., Royes, J., Gijo, T., et al. (2009). Prevalence and risk factors for diabetic retinopathy: A population-based assessment from Theni District, south India. British Journal of Ophthalmology, 93, 429–434. Okudaira, M., Yokoyama, H., Otani, T., Uchigata, Y., & Iwamoto, Y. (2000). Slightly elevated blood pressure as well as poor metabolic control are risk factors for the progression of retinopathy in early-onset Japanese type 2 diabetes. Journal of Diabetes and its Complications, 14, 281–287. Otani, T., Kishi, S., & Maruyama, Y. (1999). Patterns of diabetic macular edema in optical coherence tomography. American Journal of Ophthalmology, 127, 688–693. Pinhas-Hamiel, O., & Zeitler, P. (2005). The global spread of type 2 diabetes mellitus in children and adolescents. Journal of Pediatrics, 146, 693–700. Pinhas-Hamiel, O., & Zeitler, P. (2007). Acute and chronic complications of type 2 diabetes mellitus in children and adolescents. Lancet, 369, 1823–1831. Pradeepa, R., Anjana, R. M., Unnikrishnan, R., Ganesan, A., & Mohan, V.,& Rema, M. (2010). Risk factors for microvascular complications of diabetes among South Indian subjects with type 2 diabetes: The Chennai Urban Rural Epidemiology Study (CURES) Eye Study-5. Diabetes Technology & Therapeutics, 12, 755–761. Raman, R., Padmaja, K. R., Reddi, S., Gnanamoorthy, R. P., Uthra, S., Kumaramanickavel, G., et al. (2009). Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular Genetics Study report. Prevalence of diabetic retinopathy in India. Ophthalmology, 116, 311–318. Rema, M., Mohan, V., & Ponnaiya, M. (1995). Natural history of retinopathy in FCPD. MODY and IDDM: A follow-up study. International Journal of Diabetes in Developing Countries, 15, 45–48. Rema, M., Mohan, V., Ramachandran, A., & Viswanathan, M. (1989). Retinopathy in insulin dependent diabetes mellitus (IDDM) in south India. Journal of the Association of Physicians of India, 37, 370–373. Rema, M., Premkumar, S., Anitha, B., Deepa, R., Pradeepa, R., & Mohan, V. (2005). Prevalence of diabetic retinopathy in urban India: The Chennai Urban Rural Epidemiology Study (CURES) Eye Study-1. Investigative Ophthalmology & Visual Science, 46, 2328–2333.
R. Rajalakshmi et al. / Journal of Diabetes and Its Complications 28 (2014) 291–297 Steffes, M. W., Sibley, S., Jackson, M., & Thomas, W. (2003). Beta-cell function and the development of diabetes-related complications in the Diabetes Control and Complications Trial, 26. (pp. 832–836), 832–836. The DCCT Research Group (1993). The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. New England Journal of Medicine, 329, 977–986. UK Prospective Diabetes Study Group (1998a). Efficacy of atenolol and captopril in reducing risk of both macrovascular and microvascular complications in type 2 diabetes (UKPDS 39). BMJ, 317, 713–720. UK Prospective Diabetes Study Group (1998b). Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 38). BMJ, 317, 703–713. Varghese, A., Deepa, R., Rema, M., & Mohan, V. (2001). Prevalence of microalbuminuria in type 2 diabetes mellitus at a diabetes centre in Southern India. Postgraduate Medical Journal, 77, 399–402.
297
Wilkinson, C. P., Ferris, F. L., 3rd, Klein, R. E., Lee, P. P., Agardh, C. D., Davis, M., et al. (2003). Global Diabetic Retinopathy Project Group. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology, 110, 1677–1682. Wong, J., Molyneaux, L., Constantino, M., Twigg, S., & Yue, D. (2008). Age of onset influences long-term retinopathy risk in type 2 diabetes, independent of traditional risk factors. Diabetes Care, 31, 1985–1990. Yoon, H. J., Cho, Y. Z., Kim, J. Y., Kim, B. J., Park, K. Y., Koh, G. P., et al. (2012). Correlations between glucagon stimulated C-peptide levels and microvascular complications in type 2 diabetes patients. Diabetes & Metabolism Journal, 36, 379–387. Younis, N., Broadbent, D. M., Vora, J. P., & Harding, S. P. (2003). Incidence of sightthreatening retinopathy in patients with type 2 diabetes in the Liverpool Diabetic Eye Study: A cohort study. Lancet, 361, 195–200. Zhang, L., Chen, B., & Tang, L. (2012). Metabolic memory: Mechanisms and implications for diabetic retinopathy. Diabetes research and clinical practice, 96, 286–293.
Contents lists available at ScienceDirect
Journal of Diabetes and Its Complications journal homepage: WWW.JDCJOURNAL.COM
Prevalence and risk factors for diabetic retinopathy in Asian Indians with young onset Type 1 and Type 2 Diabetes Ramachandran Rajalakshmi a, Anandakumar Amutha a, Harish Ranjani a, Mohammed K. Ali b, Ranjit Unnikrishnan a, Ranjit Mohan Anjana a, K.M. Venkat Narayan b, Viswanathan Mohan a,⁎ a
Madras Diabetes Research Foundation & Dr. Mohan’s Diabetes Specialities Centre, WHO Collaborating Centre for Non-communicable Diseases Prevention and Control, IDF Centre for Education, Gopalapuram, Chennai, India b Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA
a r t i c l e
i n f o
Article history: Received 26 September 2013 Received in revised form 29 November 2013 Accepted 23 December 2013 Available online 6 January 2014 Keywords: Diabetic retinopathy T1DM-Y T2DM-Y Prevalence Risk factors Asian Indians
a b s t r a c t Aim: To assess the prevalence and risk factors for diabetic retinopathy (DR) in people with young onset type 1 (T1DM-Y) and type 2 diabetes (T2DM-Y). Methods: T1DM-Y(n = 150) and T2DM-Y(n = 150) participants, age between 10 and 25 years at diagnosis, had a complete clinical evaluation, biochemical assessment, and four field digital retinal colour photography. The Early Treatment Diabetic Retinopathy Study grading system was used to grade DR. Proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME) were considered as sight threatening DR. Results: The prevalence of any DR was 53.3% [95% CI 45.3–61.3] in T1DM-Y (duration of diabetes: 12.4 ± 7.4years) and 52.7% [44.7–60.7] in T2DM-Y (11.8 ± 8.3 years). The age and gender adjusted prevalence of DR, DME and PDR was 62.5%, 10% and 7.3% in T1DM-Y, whereas it was 65.8%,12.7% and 9.3% in T2DM-Y respectively. In multivariable logistic regression, diabetes duration [Odds ratio (OR) 1.99 per 5 years; CI 1.42–2.79], waist circumference [1.28 per 5 cm;1.05–1.56] and microalbuminuria [2.39 per 50 μg;1.07–5.31] were associated with DR in T1DM-Y, and diabetes duration [2.21 per 5 years; 1.61–3.02], diastolic blood pressure [1.54 per 5 mmHg;1.18–2.02], Glycated hemoglobin [1.37 per %;1.07–1.75] and lower stimulated C-peptide [1.54 per 0.5 pmol/ml;1.15–2.05;] were associated with DR in T2DM-Y. Conclusion: Over half of the people with young-onset diabetes, regardless of type, have retinopathy within 10–12 years of diabetes duration, emphasizing the need for regular eye screening and aggressive control of glucose and blood pressure to prevent DR. © 2014 Elsevier Inc. All rights reserved.
1. Introduction The growing burden of diabetes globally has been accompanied by a rise in numbers of young onset type 1diabetes (T1DM-Y) and particularly young onset type 2 diabetes (T2DM-Y) (American Diabetes Association, 2000; Amutha et al., 2011; International Diabetes Federation, 2011; McMahon et al., 2004; Mohan, Jaydip, & Deepa, 2007; Pinhas-Hamiel & Zeitler, 2005). Younger age of onset of diabetes results in a longer life time exposure to hyperglycemia and consequently a greater risk of developing complications during productive years of adulthood (Amutha, Datta, Unnikrishnan, Anjana, Conflict of interest: None declared. ⁎ Corresponding author at: Madras Diabetes Research Foundation & Dr. Mohan’s Diabetes Specialities Centre, WHO Collaborating Centre For Non-Communicable Diseases Prevention And Control &IDF Centre For Education, 4, Conran Smith Road, Gopalapuram, Chennai - 600 086. India. Tel.: + 91 44 4396 8888; fax: + 91 44 2835 0935. E-mail address: [email protected] (V. Mohan). URL: http://www.drmohansdiabetes.com, http://www.mdrf.in (V. Mohan). 1056-8727/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jdiacomp.2013.12.008
& Mohan, 2012; Amutha et al., 2011; Hillier & Pedula, 2003; PinhasHamiel & Zeitler, 2007). Diabetic retinopathy (DR) is a potentially sight-threatening microvascular complication of diabetes, and an important cause of preventable blindness. While disease duration and levels of glucose and blood pressure control strongly influence the risk of DR (Chaturvedi et al., 1998; Klein, Klein, Moss, Davis, & DeMets, 1984a; Raman et al., 2009; Rema et al., 2005; The DCCT Research Group, 1993), some data indicate that younger age of onset, especially for T2DM, may confer added susceptibility to DR (Eppens et al., 2006; Wong, Molyneaux, Constantino, Twigg, & Yue, 2008). In the multiethnic SEARCH study in the US, the prevalence of DR was 17% in T1DM and 42% in T2DM (Mayer-Davis et al., 2012). Although diabetes in the young (particularly T2DM) is becoming more frequent in India (Amutha et al., 2011; Mohan et al., 2007), epidemiological data on DR in India are largely limited to adult onset T2DM (Raman et al., 2009; Rema et al., 2005), and to a few studies in T1DM-Y (Rema, Mohan, & Ponnaiya, 1995; Rema, Mohan, Ramachandran, & Viswanathan, 1989). Data in people with T2DM-Y are scarce.
292
R. Rajalakshmi et al. / Journal of Diabetes and Its Complications 28 (2014) 291–297
We assessed the prevalence and risk factors for retinopathy in people with T1DM-Y and T2DM-Y, with onset of diabetes between ages 10 and 25 years, in a clinic population in India.
2. Research design and methods Data for this study were collected between January 2010 and June 2011 from individuals with T1DM-Y (n = 150) and T2DM-Y (n = 150), diagnosed between the ages of 10 and 25 years, with duration of diabetes over 2 years, registered at Dr. Mohan’s Diabetes Specialties Centre (DMDSC),a tertiary care network in Chennai (formerly Madras) in southern India. The Institutional Ethics Committee (IEC) approval was obtained prior to the start of the study. Written informed consent was obtained according to the local IEC guidelines and assent was obtained from the study subjects less than 18 years of age in addition to parental consent. Diabetes was defined as fasting plasma glucose (FPG) level ≥ 126 mg/dl (7.0 mmol/l) and/or 2-h post-load glucose level ≥ 200 mg/dl (11.1 mmol/l) (Alberti & Zimmet, 1998) or self-reported diabetes treated by a physician or on hypoglycemic medications or insulin. Diabetes was then classified as follows: T1DM-Y, if accompanied by abrupt onset of symptoms like polyuria, polydipsia, or unexplained weight loss, diabetic ketoacidosis (DKA), absent insulin reserve as shown by fasting and stimulated C-peptide (b0.3pmol/ml), and requirement of insulin from the time of diagnosis for control of hyperglycemia; and T2DM-Y, as absence of ketosis, good beta cell functional reserve as evidenced by stimulated C-peptide (≥ 0.6 pmol/ml), absence of pancreatic calculi (on X-ray abdomen), and good response to oral hypoglycemic agents for more than 2 years (Amutha et al., 2011). Anthropometric measurements included height, weight, and waist circumference (Deepa et al., 2003). Height was measured in centimetres using a stadiometer. Weight was measured with a traditional spring balance and recorded to the nearest 0.5 kg. Body mass index (BMI) was calculated using the formula: weight (kg)/height squared (in m 2). Waist circumference was measured using a non-stretchable measuring tape. The participants were asked to stand erect in a relaxed position with both feet together on a flat surface; one layer of clothing was accepted. Waist girth was measured as the smallest horizontal girth between the costal margins and the iliac crests at minimal respiration. Blood pressure was recorded in a rested sitting position in the right arm with a mercury sphygmomanometer and rounded off to the nearest 2 mmHg. Two readings were taken 5 min apart and the mean of the 2 readings was used. Fasting plasma glucose (hexokinase method) was measured on Hitachi 912 Autoanalyzer (Hitachi, Mannheim, Germany) using kits supplied by Roche Diagnostics (Mannheim, Germany); glycated haemoglobin (HbA1C) by high-pressure liquid chromatography using the Variant machine (Bio-Rad, Hercules, Calif., USA); serum total cholesterol (cholesterol oxidase-peroxidase-amidopyrine method), serum triglycerides (glycerol phosphate oxidase-peroxidase-amidopyrine method), and HDL cholesterol (direct method-polyethylene glycolpretreated enzymes) using Hitachi-912 Autoanalyser (Hitachi, Mannheim, Germany). Low-density lipoprotein (LDL) cholesterol was calculated using the Friedewald formula (Friedewald, Levy, & Fredrickson, 1972). Apo lipo-protein A and B were measured by immuno-turbidometric method (Olympus AU 2700 USA). Fasting and stimulated (post-breakfast) C-peptide was estimated by the electro-luminescence method on Elecsys2010 (Hitachi, Mannheim, Germany); glutamic acid decarboxylase (GAD) antibodies were measured on a Bio-Rad plate reader 680 (USA) using Elisa Euro Immun kit (Lubeck, Germany); and plasma concentration of hs-CRP by turbidometry method (Beckman Coulter AU 480 USA). The intraand inter-assay co-efficient of variation for the biochemical assays ranged between 3.1% and 7.6%.
Urine samples were collected after an overnight fast. Microalbumin concentration was measured using an immunoturbidometric assay (Hitachi 902 autoanalyzer; Roche Diagnostics, Mannheim, Germany) (Varghese, Deepa, Rema, & Mohan, 2001). Microalbuminuria was defined as a urine albumin excretion of 30–299 mg/μg of creatinine (Pradeepa et al., 2010). Nephropathy was defined as macro-albuminuria i.e., a urine albumin excretion of ≥ 300 μg/mg of creatinine (Pradeepa et al., 2010). The DMDSC laboratory is certified by the College of American Pathologists and the Indian National Accreditation Board for Testing and Calibration of Laboratories. 2.1. Retinopathy Four-field digital retinal colour photography was taken by a trained photographer using a Carl-Zeiss Digital Fundus Camera. The 4 fields photographed were the macula, optic disc and nasal to the optic disc, and superior–temporal and inferior–temporal quadrants of each eye. The grading of retinopathy was done based on the modified Early Treatment Diabetic Retinopathy Study (ETDRS) grading system (Early Treatment Diabetic Retinopathy Study Research Group, 1991). Each eye was graded separately by an ophthalmologist trained in ETDRS grading, at DMDSC. The minimum criterion for diagnosis of DR was the presence of at least one definite microaneurysm in any field of the retina. Photographs were assessed and assigned a retinopathy level and the final diagnosis for each patient was determined from the level of DR of the worse eye using ETDRS final retinopathy scale (Early Treatment Diabetic Retinopathy Study Research Group, 1991; Rema et al., 2005). Briefly, level 10 represents no retinopathy, levels 20 to 50, non-proliferative diabetic retinopathy (NPDR) [Level 20: mild NPDR; levels 30 to 40: moderate NPDR; level 50: severe NPDR] and levels ≥ 60, proliferative diabetic retinopathy (PDR) (Early Treatment Diabetic Retinopathy Study Research Group, 1991). Diabetic macular edema (DME) was defined as retinal thickening at or within one disc diameter of the centre of the macula or the presence of definite hard exudates (Early Treatment Diabetic Retinopathy Study Research Group, 1985; Wilkinson et al., 2003). DME could be present in both NPDR and PDR stages, but, once PDR was diagnosed, the final severity scale was graded as PDR (Rema et al., 2005). Sight-threatening diabetic retinopathy (STDR) was defined as PDR or DME (clinically significant macular edema) in either or both eyes (Younis, Broadbent, Vora, & Harding, 2003). Where clinically indicated, optical coherence tomography (OCT) was done and appropriate treatment was offered to the subjects (Otani, Kishi, & Maruyama, 1999). 3. Statistical analysis All statistical analyses were done using SPSS statistical package version 15.0 (SPSS Inc., Chicago, IL, USA). Continuous data are expressed as mean ± standard deviation while categorical data are presented as proportions. Student’s t test was used to compare means of continuous variables between subjects with and without retinopathy in T1DM-Y and T2DM-Y groups. Chi square test was used to compare proportions. To assess independent risk factors for diabetic retinopathy and age adjusted prevalence, we used logistic regression models with DR as the dependent variable and reported odds ratios (OR) with 95% confidence intervals (CIs) and percentages. First, variables were independently tested with the outcomes using bivariable analysis and significant variables (p value b 0.05) were entered into a multivariable analysis. For all statistical tests, p value b 0.05 was considered significant. 4. Results Diabetic retinopathy was present in 80 (53.3% [95% CI 45.3–61.3]) people with T1DM-Y and 79 (52.7% [95% CI 44.7–60.7]) people with
R. Rajalakshmi et al. / Journal of Diabetes and Its Complications 28 (2014) 291–297
293
Fig. 1. Prevalence of diabetic retinopathy (DR) in young onset diabetes.
T2DM-Y (Fig. 1). The mean age of T1DM-Y and T2DM-Y with retinopathy was 31.8 ± 7.7 years and 38.1 ± 9.2 years (p b 0.001). The age and gender adjusted prevalence of retinopathy in T1DM-Y and T2DM-Y was 62.5% and 65.8% respectively. DME was present in 15 (10%) T1DM-Y and 19 (12.7%) T2DM-Y and PDR in 11(7.3%) T1DM-Y and 14 (9.3%) T2DM-Y participants. The prevalence of PDR and STDR was no different among T2DM-Y and T1DM-Y participants (Fig. 1). Fig. 2 shows the retinal colour photography of a T1DM-Y patient with PDR and Fig. 3 shows a T2DM-Y patient with DME. Fig. 4 shows the OCT of a T2DM-Y patient with severe sight threatening DME. Table 1 show the clinical and biochemical characteristics of the study participants with and without diabetic retinopathy (DR). In people with T1DM-Y, those with DR were significantly older, had longer duration of diabetes, had significantly higher BMI, waist circumference, higher systolic and diastolic blood pressures and a
greater proportion had microalbuminuria compared with those without DR. In T2DM-Y, in addition to the above, those with DR also had significantly higher fasting plasma glucose, glycated hemoglobin (HbA1C), and apolipoprotein A levels as well as significantly lower fasting and stimulated C-peptide levels when compared with those without DR. Prevalence of STDR was higher with longer duration of diabetes in both T1DM-Y and T2DM-Y, with the prevalence peaking in those with N 15 years of diabetes. Interestingly, none of the T1DM-Y with duration of diabetes b10 years had STDR but among T2DM-Y people, STDR was prevalent even in those with a known duration of diabetes of b 5 years (Fig. 5). The overall STDR prevalence was higher with longer duration of diabetes with 44.1% of the T1DM-Y and 52.5% of the T2DM-Y people with N 15 years of diabetes having STDR. The bivariable analysis for T1DM-Y participants showed age, duration of diabetes, waist circumference, systolic and diastolic blood
Fig. 2. Retinal colour photography of diabetic retinopathy in young onset type 1 diabetes.
Fig. 3. Retinal colour photography of diabetic retinopathy in young onset type 2 diabetes.
294
R. Rajalakshmi et al. / Journal of Diabetes and Its Complications 28 (2014) 291–297
Fig. 4. Optical coherence tomography (OCT) of a T2DM-Y patients with diabetic macular edema.
pressure and microalbuminuria to be associated with diabetic retinopathy. In addition to these factors, age of onset of diabetes, fasting plasma glucose, HbA1C and lower stimulated C-peptide were associated with DR in participants with T2DM-Y. For every 5 mm Hg higher systolic (SBP) and diastolic blood pressure (DBP), there were higher odds of DR in both T1DM-Y and T2DM-Y patients (T1DM-Y SBP: OR 1.3, 95% CI 1.09–1.48; DBP: OR 1.4, 95% CI 1.09–1.70; T2DM-Y SBP:OR 1.3, 95% CI 1.1–1.49, DBP:1.6, 95% CI 1.24–1.97 per 5 mm Hg). In T1DM-Y participants, the age of onset of diabetes was not associated with DR while in T2DM-Y, every 5-year increase in age of onset was associated with a 2.2 times odds of having DR. In multivariable regression analyses, significant independent predictors for DR in participants with T1DM-Y were duration of diabetes, waist circumference and microalbuminuria, whereas in T2DM-Y
participants, duration of diabetes, diastolic blood pressure, HbA1C and lower stimulated C-peptide values were associated (Table 2). 5. Discussion The prevalence of DR and STDR was high in both T1DM-Y and T2DM-Y from this clinic population studied in south India, with no significant difference in the age adjusted prevalence of diabetic retinopathy between T1DM-Y and T2DM-Y. This is in contrast to earlier epidemiological studies reporting that diabetic retinopathy in T1DM-Y has a different frequency, onset, and course than DR in T2DM (Klein, Klein, Moss, Davis, & DeMets, 1984b, Klein et al., 1984a,b). The high prevalence of DR among T2DM-Y in our study is similar to that reported from Japan in T2DM-Y subjects (diagnosed b 30years)
Table 1 Clinical and biochemical characteristics of T1DM-Y and T2DM-Y with and without diabetic retinopathy (DR). Variables
Age (years) Duration (years) Age at onset (years) Gender, male n (%)a Body mass index (kg/m2) Waist circumference(cm) Systolic Blood Pressure (mmHg) Diastolic Blood Pressure (mmHg) Fasting plasma glucose (mg/dl)b Glycated hemoglobin (%) Total Cholesterol (mg/dl) Serum Triglycerides (mg/dl)b HDL Cholesterol (mg/dl) LDL Cholesterol (mg/dl) Apo Lipoprotein A (mg/dl) Apo Lipoprotein B (mg/dl) Microalbuminuria (ug/mg) HS-CRP (mg/l)b C-Peptide Fasting (pmol/ml)b C-Peptide Stimulated (pmol/ml)b Smoking (n %)
T1DM-Y
T2DM-Y
No DR (n = 70)
With DR (n = 80)
p value
No DR (n = 71)
With DR (n = 79)
p value
24.6 ± 8.1 8.4 ± 6.5 16.6 ± 4.1 36(51.4) 21.1 ± 3.1 73.5 ± 10.6 116 ± 10 72 ± 7.0 163 (10) 9.0 ± 1.9 160 ± 32 69 (5) 48 ± 12 97 ± 27 126 ± 32 76 ± 18 11.9 ± 2.5 1.62 (0.37) 0.28 (0.01) 0.32 (0.01) 1(1.4)
31.8 ± 7.6 15.2 ± 6.7 17.0 ± 4.4 48(60.0) 23.0 ± 3.9 80.9 ± 10.4 124 ± 18 76 ± 9 163 (11) 8.5 ± 1.6 168 ± 41 81(6) 46 ± 11 102 ± 32 129 ± 31 82 ± 24 68.4 ± 13.2 1.92(0.37) 0.30 (0.03) 0.32 (0.04) 5(6.2)
b0.001 b0.001 0.571 0.291 0.001 b0.001 0.001 0.006 0.742 0.067 0.150 0.058 0.192 0.243 0.586 0.113 b0.001 0.398 0.227 0.182 0.133
28.0 ± 7.8 7.6 ± 5.9 20.8 ± 3.9 47(66.2) 26.5 ± 4.7 89.2 ± 11.6 123 ± 12 76 ± 8 141 (6) 8.1 ± 1.8 158 ± 35 120(10) 38 ± 9 93 ± 28 114 ± 34 84 ± 20 22.7 ± 6.36 2.46 (0.42) 0.87 (0.04) 1.89 (0.10) 5(7.0)
38.1 ± 9.1 15.6 ± 8.2 22.3 ± 2.9 45(57.0) 27.1 ± 4.2 92.6 ± 10.3 130 ± 14 81 ± 9 168 (8) 9.1 ± 2.0 155 ± 38 130(12) 40 ± 9 89 ± 29 126 ± 37 82 ± 19 55.0 ± 10.4 2.20 (0.39) 0.71(0.04) 1.30 (0.08) 5(6.3)
b0.001 b0.001 0.011 0.246 0.423 0.064 b0.001 b0.001 b0.001 0.020 0.537 0.362 0.338 0.403 0.048 0.417 0.009 0.467 0.017 b0.001 0.861
Data given as mean ± SD, p b 0.05 considered significant. Bold denotes statistical significance. a Chi square p value given. b Data given as Geometric mean (SE).
R. Rajalakshmi et al. / Journal of Diabetes and Its Complications 28 (2014) 291–297
295
Fig. 5. Frequency of diabetic retinopathy (DR) and sight threatening diabetic retinopathy (STDR) based upon the duration of diabetes.
(Okudaira, Yokoyama, Otani, Uchigata, & Iwamoto, 2000) and also in another study by Wong et al., (2008), which showed that younger T2DM had more severe grades of DR than the older T2DM patients. Krakoff et al. (2003) reported that the incidence of retinopathy was lower in the youth-onset group (b20 years at onset of diabetes) than in either adult group (onset of diabetes at 20 to 39 and 40 to 59 years of age) in all categories of diabetes duration. Interestingly, we noted that the age of onset of diabetes did not play a role in T1DM-Y, while age of onset of diabetes between 21 and 25 years increased the risk for DR in T2DM-Y patients. A younger onset of diabetes with an increasing life span implies longer duration of diabetes (Klein et al., 1984a; Namperumalsamy et al., 2009; Okudaira et al., 2000), hence a large number of people are at risk of developing DR. In the Wisconsin Epidemiological Study of Diabetic Retinopathy (WESDR), the prevalence of DR in young people with diabetes for N15 years was 98% (Klein et al., 1984a). In our study, in those with diabetes for N 15 years, the prevalence of DR was 82.9% and 90.7% in T1DM-Y and T2DM-Y respectively. The higher prevalence of DR and STDR in T2DM-Y in those with more than 15 years of diabetes, points to the aggressive nature of the disease. However, it is
Table 2 Multivariable logistic regression—Factors associated with diabetic retinopathy in T1DM-Y and T2DM-Y. Variablesa
Increment/value
OR(95% CI)
p value
T1DM-Y Duration of diabetes (years) Waist circumference (cm) Microalbuminuria (μg/mg)
5 years 5 cm 50 μg/mg
Variablesa
Increment/value
1.99 (1.42–2.79) 1.28 (1.05–1.56) 2.39 (1.07–5.31)
b0.001 0.014 0.033
OR(95% CI)
p value
T2DM-Y Duration of diabetes (years) Diastolic blood pressure(mmHg) Glycated hemoglobin (%) C-peptide stimulated (pmol/ml)
5 years 5 mmHg
2.21 (1.61–3.02) 1.54 (1.18–2.02)
b0.001 0.002
1% 0.5 pmol/ml decrease
1.37 (1.07–1.75) 1.54(1.15–2.05)
0.011 0.003
For T1DM-Y subjects, along with the above predictors age (per 5 yrs), systolic and diastolic blood pressures (per 5 mmHg) were included in the analysis and for T2DM-Y subjects, age (per 5 years), age onset of diabetes (per 5 years), waist circumference (per 5 cm), systolic blood pressure (per 5 mmHg), fasting plasma glucose (per 50 mg) and microalbuminuria (per 50ug/mg) were included. a Only significant independent predictors are given, p b 0.05 considered significant.
uncertain whether this may be reflecting a longer period of asymptomatic undiagnosed diabetes in T2DM-Y. To our knowledge, there have been only a few studies, comparing the prevalence of retinopathy in T1DM-Y versus T2DM-Y. In the pilot study on DR in the SEARCH study for diabetes in youth, the prevalence of DR was higher in T2DM-Y (42%) than T1DM-Y (17%). However, this difference was largely attributed to the ethnic variation, with DR in T2DM-Y being more common in the non-Caucasian populations (e.g., native American, Hispanic, non-Hispanic Black) (Mayer-Davis et al., 2012). In our study, we recruited equal numbers of patients with T1DM-Y and T2DM-Y that were of the same race/ethnicity and with similar mean duration of diabetes. Eppens et al. reported that DR was more prevalent in adolescents with T1DM-Y than T2DM-Y (20% vs. 4%) (Eppens et al., 2006). However in their study, the duration of diabetes was very different between the two groups (T1DM-Y = 6.8 years, T2DM-Y = 1.3 years) making comparisons difficult. We found that increased systolic and diastolic blood pressure, regardless of the type of young onset diabetes, increased the risk for retinopathy. Diastolic blood pressure was also an independent predictor for DR in T2DM-Y patients. The United Kingdom Prospective Diabetes Study (UKPDS) study showed a continuous relationship between the risk of DR and systolic blood pressure (UK Prospective Diabetes Study Group, 1998b) and lowering blood pressure to a mean of 144/82 mm Hg reduced microvascular complications and visual loss (UK Prospective Diabetes Study Group, 1998a). In the WESDR, diastolic blood pressure was seen as a significant predictor of progression of diabetic retinopathy (Klein et al., 1984a). We also found that in T2DM-Y, increased HbA1C was associated with prevalent DR as seen in other studies (Early Treatment Diabetic Retinopathy Study Research Group, 1991; Namperumalsamy et al., 2009). However, there was no association seen between present glycemic status and development of DR in T1DM-Y subjects. This could probably be attributed to the hyperglycemic memory influencing the development of DR in T1DM-Y patients (Zhang, Chen, & Tang, 2012). We found that lower stimulated C-peptide levels were associated with increased risk for retinopathy in T2DM-Y. Klein, Moss, Klein, Davis, and Demets (1990) have shown that diabetes patients using insulin, with undetectable or very low plasma C-peptide (b0.3 pmol/ ml), are more likely to have DR and also more severe DR than older onset individuals who have higher levels of C-peptide (N0.3 pmol/ ml). The Diabetes Control and Complications Trial (DCCT) showed that higher and sustained levels of stimulated C-peptide were associated with reduced incidence of retinopathy (Steffes, Sibley,
296
R. Rajalakshmi et al. / Journal of Diabetes and Its Complications 28 (2014) 291–297
Jackson, & Thomas, 2003). This highlights the possible benefit of sustaining pancreatic β cell function in order to reduce the development and progression of microvascular complications like retinopathy (Yoon et al., 2012). Another risk factor associated with DR in both T1DM-Y and T2DM-Y was the presence of microalbuminuria. Associations between retinopathy and microalbuminuria have also been demonstrated in many studies (Collins et al., 1995; Farah, Wals, Friedman, Pisacano, & DiMartino-Nardi, 2006; Gall et al., 1991; Matyka, 2008). T1DM-Y people with increased waist circumference also had greater risk for DR. Dirani et al. (2011) have shown that in persons with diabetes, higher BMI and larger waist circumference confer a higher risk of DR and are also associated with severity of DR. Our study has certain limitations. It is cross-sectional, and thus causal inferences cannot be drawn. Our population was recruited at a tertiary care clinic, and therefore these findings may not apply to the population of T2DM-Y and T1DM-Y at large. Moreover they cannot be extrapolated to the country as a whole as referral bias could have affected the results. However our study has certain strengths as well. This is the first study from a developing country to compare the prevalence and risk factors of diabetic retinopathy in T1DM-Y versus T2DM-Y with objective measurement of diabetic retinopathy using state-of-the-art digital retinal colour photography. Overall, half the people with youth-onset diabetes of N10 years duration have retinopathy. Our findings emphasise the need for regular and periodic screening for diabetic retinopathy and especially in patients with pre-existing DR, a shorter interval of ≤ 1 year may be needed (Echouffo-Tcheugui, Ali, Roglic, Hayward, & Venkat Narayan, 2013). Tight control of glucose and blood pressure from the time of diagnosis is important in order to reduce morbidity and disability due to diabetic eye disease in young onset diabetes. Acknowledgments We acknowledge the help of all the optometrists at DMDSC for performing the digital retinal colour photography. We acknowledge the support of the study team members. Most importantly, we wish to thank the subjects who participated in the study. We acknowledge the financial support from the Emory Global Health Institute through the Global Diabetes Research Center (GDRC) — collaboration between Madras Diabetes Research Foundation, Chennai and Emory University, Atlanta, USA. This is the 11th paper from this collaboration (GDRC-11). References Alberti, K. G., & Zimmet, P. Z. (1998). Definition diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus, provisional report of a WHO Consultation. Diabetic Medicine, 15, 539–553. American Diabetes Association (2000). Type 2 diabetes in children and adolescents (consensus statement). Diabetes Care, 23, 381–389. Amutha, A., Datta, M., Unnikrishnan, R., Anjana, R. M., & Mohan, V. (2012). Clinical profile and complications of childhood and adolescent onset type 2 diabetes seen at a diabetes centre in South India. Diabetes Technology & Therapeutics, 14, 497–504. Amutha, A., Datta, M., Unnikrishnan, I. R., Anjana, R. M., Rema, M., Venkat Narayan, K. M., et al. (2011). Clinical profile of diabetes in the young seen between 1992 and 2009 at a specialist diabetescentre in south India. Primary Care Diabetes, 5, 223–229. Chaturvedi, N., Sjolie, A. K., Stephenson, J. M., Abrahamian, H., Keipes, M., Castellarin, A., et al. (1998). Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus. Lancet, 35, 28–31. Collins, V. R., Dowse, G. K., Plehwe, W. E., Imo, T. T., Toelupe, P. M., & Taylor, H. R. (1995). High prevalence of diabetic retinopathy and nephropathy in Polynesians of Western Samoa. Diabetes Care, 18, 1140–1149. Deepa, M., Pradeepa, R., Rema, M., Mohan, A., Deepa, R., Shanthirani, S., et al. (2003). The Chennai Urban Rural Epidemiology Study (CURES): study design and methodology (urban component) (CURES-1). Journal of the Association of Physicians of India, 51, 863–870. Dirani, M., Xie, J., Fenwick, E., Benarous, R., Rees, G., Wong, T. Y., et al. (2011). Are obesity and anthropometry risk factors for diabetic retinopathy? The
Diabetes Management Project. Investigative Ophthalmology & Visual Science, 52, 4416–4421. Early Treatment Diabetic Retinopathy Study Research Group (1985). Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study Report Number 1. Archives of Ophthalmology, 103, 1796–1806. Early Treatment Diabetic Retinopathy Study Research Group (1991). Grading diabetic retinopathy from stereoscopic colour fundus photographs: An extension of the modified Airlie House classification. Early Treatment Diabetic Retinopathy Study Report Number 10. Ophthalmology, 98, 786–806. Echouffo-Tcheugui, J. B., Ali, M. K., Roglic, G., Hayward, R. A., & Venkat Narayan, K. M. (2013). Screening intervals for diabetic retinopathy and incidence of visual loss: A systematic review. Jul 2. Diabetic Medicine, http://dx.doi.org/10.1111/dme.12274 [Epub ahead of print]. Eppens, M. C., Craig, M. E., Cusumano, J., Hing, S., Chan, A. K. F., Howard, N. J., et al. (2006). Prevalence of diabetes complications in adolescents with type 2 compared with type 1 diabetes. Diabetes Care, 29, 1300–1306. Farah, S. E., Wals, K. T., Friedman, I. B., Pisacano, M. A., & DiMartino-Nardi, J. (2006). Prevalence of retinopathy and microalbuminuria in pediatric type 2 diabetes mellitus. Journal of Pediatric Endocrinology & Metabolism, 19, 937–942. Friedewald, W. T., Levy, R. I., & Fredrickson, D. S. (1972). Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clinical Chemistry, 18, 499–502. Gall, M. A., Rossing, P., Skott, P., Damsbo, P., Vaag, A., & Bech, K. (1991). Prevalence of micro- and macroalbuminuria, arterial hypertension, retinopathy, and large vessel disease in European type 2 (non-insulin dependent) diabetic patients. Diabetologia, 34, 655–661. Hillier, T. A., & Pedula, K. (2003). Complications in young adults with early-onset type 2 diabetes: Losing the relative protection of youth. Diabetes Care, 26, 2999–3005. International Diabetes Federation. (2011). Diabetes atlas (Fifth ed.)Brussels, Belgium: International Diabetes Federation. Klein, R., Klein, B. E., Moss, S. E., Davis, M. D., & DeMets, D. L. (1984a). The Wisconsin Epidemiologic Study of Diabetic Retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Archives of Ophthalmology, 102, 520–526. Klein, R., Klein, B. E., Moss, S. E., Davis, M. D., & DeMets, M. L. (1984b). The Wisconsin Epidemiologic Study of Diabetic Retinopathy. III Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Archives of Ophthalmology, 102, 527–532. Klein, R., Moss, S. E., Klein, B. E. K., Davis, M. D., & Demets, D. L. (1990). Wisconsin Epidemiologic Study of Diabetic Retinopathy: XII. Relationship of C-peptide and diabetic retinopathy. Diabetes, 39, 1445–1450. Krakoff, J., Lindsay, R. S., Looker, H. C., Nelson, R. G., Hanson, R. L., & Knowler, C. (2003). Incidence of retinopathy and nephropathy in youth-onset compared with adultonset type 2 diabetes. Diabetes Care, 26, 76–81. Matyka, K. A. (2008). Type 2 diabetes in childhood: Epidemiological and clinical aspects. British Medical Bulletin, 86, 59–75. Mayer-Davis, E. J., Davis, C., Saadine, J., D'Agostino, R. B., Jr., Dabelea, D., Dolan, L., et al. (2012). SEARCH for Diabetes in Youth Study Group. Diabetic retinopathy in the SEARCH for Diabetes in Youth cohort: A pilot study. Diabetic Medicine, 29, 1148–1152. McMahon, S. K., Haynes, A., Ratnam, N., Grant, M. T., Carne, C. L., Jones, T. W., et al. (2004). Increase in type 2 diabetes in children and adolescents in Western Australia. Medical Journal of Australia, 180, 459–461. Mohan, V., Jaydip, R., & Deepa, R. (2007). Type 2 diabetes in Asian Indian youth. Pediatric diabetes, 9, 28–34. Namperumalsamy, P., Kim, R., Vignesh, T. P., Nithya, N., Royes, J., Gijo, T., et al. (2009). Prevalence and risk factors for diabetic retinopathy: A population-based assessment from Theni District, south India. British Journal of Ophthalmology, 93, 429–434. Okudaira, M., Yokoyama, H., Otani, T., Uchigata, Y., & Iwamoto, Y. (2000). Slightly elevated blood pressure as well as poor metabolic control are risk factors for the progression of retinopathy in early-onset Japanese type 2 diabetes. Journal of Diabetes and its Complications, 14, 281–287. Otani, T., Kishi, S., & Maruyama, Y. (1999). Patterns of diabetic macular edema in optical coherence tomography. American Journal of Ophthalmology, 127, 688–693. Pinhas-Hamiel, O., & Zeitler, P. (2005). The global spread of type 2 diabetes mellitus in children and adolescents. Journal of Pediatrics, 146, 693–700. Pinhas-Hamiel, O., & Zeitler, P. (2007). Acute and chronic complications of type 2 diabetes mellitus in children and adolescents. Lancet, 369, 1823–1831. Pradeepa, R., Anjana, R. M., Unnikrishnan, R., Ganesan, A., & Mohan, V.,& Rema, M. (2010). Risk factors for microvascular complications of diabetes among South Indian subjects with type 2 diabetes: The Chennai Urban Rural Epidemiology Study (CURES) Eye Study-5. Diabetes Technology & Therapeutics, 12, 755–761. Raman, R., Padmaja, K. R., Reddi, S., Gnanamoorthy, R. P., Uthra, S., Kumaramanickavel, G., et al. (2009). Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular Genetics Study report. Prevalence of diabetic retinopathy in India. Ophthalmology, 116, 311–318. Rema, M., Mohan, V., & Ponnaiya, M. (1995). Natural history of retinopathy in FCPD. MODY and IDDM: A follow-up study. International Journal of Diabetes in Developing Countries, 15, 45–48. Rema, M., Mohan, V., Ramachandran, A., & Viswanathan, M. (1989). Retinopathy in insulin dependent diabetes mellitus (IDDM) in south India. Journal of the Association of Physicians of India, 37, 370–373. Rema, M., Premkumar, S., Anitha, B., Deepa, R., Pradeepa, R., & Mohan, V. (2005). Prevalence of diabetic retinopathy in urban India: The Chennai Urban Rural Epidemiology Study (CURES) Eye Study-1. Investigative Ophthalmology & Visual Science, 46, 2328–2333.
R. Rajalakshmi et al. / Journal of Diabetes and Its Complications 28 (2014) 291–297 Steffes, M. W., Sibley, S., Jackson, M., & Thomas, W. (2003). Beta-cell function and the development of diabetes-related complications in the Diabetes Control and Complications Trial, 26. (pp. 832–836), 832–836. The DCCT Research Group (1993). The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. New England Journal of Medicine, 329, 977–986. UK Prospective Diabetes Study Group (1998a). Efficacy of atenolol and captopril in reducing risk of both macrovascular and microvascular complications in type 2 diabetes (UKPDS 39). BMJ, 317, 713–720. UK Prospective Diabetes Study Group (1998b). Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 38). BMJ, 317, 703–713. Varghese, A., Deepa, R., Rema, M., & Mohan, V. (2001). Prevalence of microalbuminuria in type 2 diabetes mellitus at a diabetes centre in Southern India. Postgraduate Medical Journal, 77, 399–402.
297
Wilkinson, C. P., Ferris, F. L., 3rd, Klein, R. E., Lee, P. P., Agardh, C. D., Davis, M., et al. (2003). Global Diabetic Retinopathy Project Group. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology, 110, 1677–1682. Wong, J., Molyneaux, L., Constantino, M., Twigg, S., & Yue, D. (2008). Age of onset influences long-term retinopathy risk in type 2 diabetes, independent of traditional risk factors. Diabetes Care, 31, 1985–1990. Yoon, H. J., Cho, Y. Z., Kim, J. Y., Kim, B. J., Park, K. Y., Koh, G. P., et al. (2012). Correlations between glucagon stimulated C-peptide levels and microvascular complications in type 2 diabetes patients. Diabetes & Metabolism Journal, 36, 379–387. Younis, N., Broadbent, D. M., Vora, J. P., & Harding, S. P. (2003). Incidence of sightthreatening retinopathy in patients with type 2 diabetes in the Liverpool Diabetic Eye Study: A cohort study. Lancet, 361, 195–200. Zhang, L., Chen, B., & Tang, L. (2012). Metabolic memory: Mechanisms and implications for diabetic retinopathy. Diabetes research and clinical practice, 96, 286–293.
