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Younger-onset versus older-onset type 2 diabetes: Clinical profile and complications
Younger- onset versus older-onset type 2 diabetes: Clinical profile and complications Ranjit Unnikrishnan, Ranjit Mohan Anjana, Amutha Anandakumar, Ranjani Harish, Jebarani Saravanan, Mohammed K Ali, KM Venkat Narayan, Viswanathan Mohan PII: DOI: Reference:
S1056-8727(16)30934-5 doi: 10.1016/j.jdiacomp.2017.03.007 JDC 6988
To appear in:
Journal of Diabetes and Its Complications
Received date: Revised date: Accepted date:
29 November 2016 28 February 2017 18 March 2017
Please cite this article as: Unnikrishnan, R., Anjana, R.M., Anandakumar, A., Harish, R., Saravanan, J., Ali, M.K., Venkat Narayan, K.M. & Mohan, V., Younger- onset versus older-onset type 2 diabetes: Clinical profile and complications, Journal of Diabetes and Its Complications (2017), doi: 10.1016/j.jdiacomp.2017.03.007
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ACCEPTED MANUSCRIPT YOUNGER- ONSET VERSUS OLDER-ONSET TYPE 2 DIABETES: CLINICAL PROFILE AND COMPLICATIONS Ranjit Unnikrishnan*
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Amutha Anandakumar*
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Ranjit Mohan Anjana*
Ranjani Harish*
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Jebarani Saravanan* Mohammed K Ali **
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Venkat Narayan KM**
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Viswanathan Mohan*
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*Madras Diabetes Research Foundation &Dr.Mohan’s Diabetes Specialities Centre, WHO Collaborating Centre for Non-communicable Diseases Prevention and Control, ICMR Center for Advanced Research on Diabetes, Gopalapuram, Chennai, India **Emory Global Diabetes Research Center, Rollins School of Public Health, Emory University, Atlanta, USA
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Running title: Comparing younger and older onset diabetes Key words: T2DM, younger onset, older onset, risk factors, complications
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ADDRESS FOR CORRESPONDENCE:Dr. V. MOHAN,M.D., FRCP (London, Edinburgh, Glasgow, Ireland), Ph.D., D.Sc., FNASc, FASc, FNA, FACP, FACE,FTWAS, MACP CHAIRMAN & CHIEF DIABETOLOGIST, MADRAS DIABETES RESEARCH FOUNDATION & Dr. MOHAN’S DIABETES SPECIALITIES CENTRE, WHO COLLABORATING CENTRE FOR NON-COMMUNICABLE DISEASES PREVENTION AND CONTROL ICMR CENTER FOR ADVANCED RESEARCH ON DIABETES, 4, CONRAN SMITH ROAD, GOPALAPURAM, CHENNAI - 600 086.INDIA TELNO :( 9144) 4396 8888 FAX NO: (9144) 2835 0935 EMAIL: [email protected] Website: www.drmohansdiabetes.com, www.mdrf.in Words in text: 2882, No. of tables: 3, Figure: 1,No. of references: 30
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ACCEPTED MANUSCRIPT Abstract: Aims: To compare the clinical profile and complications between younger and older onset type 2 diabetes (T2DM) patients at a tertiary care diabetes centre in south
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India.
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Methods: We compared individuals with T2DM detected at ages ≤25 years (n=267) and at age ≥50 years (n=267), matched for gender and duration of diabetes. We
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reviewed electronic patient charts and extracted data on biochemical parameters (plasma glucose, serum lipids and glycated haemoglobin). We estimated
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prevalence of complications (retinopathy, nephropathy, neuropathy, and peripheral vascular disease). We examined odds of having each complication, after adjusting
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for clinical differences between younger- and older-onset T2DM. Results: Individuals with younger-onset T2DM had significantly greater glycated
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hemoglobin (8.7 vs. 7.5%), serum cholesterol (160 vs. 148mg/dl), serum triglycerides (147 vs. 128mg/dl), LDL cholesterol (92 vs. 82mg/dl) and lower HDL
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cholesterol levels (39 vs. 42mg/dl). However, waist circumference (90.4vs.92.6cm) and systolic blood pressure (125vs.133mmHg) were significantly higher in older
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onset T2DM.Prevalence of retinopathy (47.6vs. 31.0%) was higher in younger onset T2DM while neuropathy (41.8vs. 9.2%) and peripheral vascular disease (6.2 vs.
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1.2%) were higher in older onset T2DM.In multiple logistic regression analysis, after adjusting for glycated hemoglobin, hypertension, and hypercholesterolemia, younger onset T2DM had a higher odds of developing retinopathy [Odds Ratio: 2.19; Confidence Intervals: 1.42 –3.38] when compared to older onset T2DM. Conclusions: Younger onset T2DM participants have worse glycemic and lipid control, and higher prevalence of retinopathy compared to older onset T2DM patients. This underscores the need for more aggressive metabolic control in young-onset T2DM.
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ACCEPTED MANUSCRIPT 1.0 INTRODUCTION Type 2 diabetes mellitus (T2DM), conventionally considered a disease of middle and old age, is increasingly occurring in younger age groups. This transition in the
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epidemiology of T2DM has been noted in almost all ethnic groups and across
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different geographical locations [Alberti et al.,2004 & Brunton ,2008]. The earlier age at onset of T2DM is of great concern since it translates to a greater duration of exposure to hyperglycemia, and consequent development of chronic vascular
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complications of diabetes during the most productive years of an individual’s life
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[Alberti et al.,2004; D'Adamo & Caprio .,2011&Gregg , Sattar & Ali.,2016]. While type 1 diabetes (T1DM) is also associated with onset in childhood or youth,
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recent studies indicate that young-onset T2DM is associated with greater morbidity and mortality than T1DM possibly due to higher prevalence of cardiovascular risk factors like hypertension and hyperlipidemia among the former [Constantino et
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al.,2013]. There are relatively few data comparing the clinical profile and complications in T2DM with onset in youth compared to individuals with an older
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age at onset. The present paper attempts to fill this gap after matching participants for gender and duration of diabetes.
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2.0 METHODS
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2.1 Data Source
From the electronic medical records (EMR) of a large tertiary care diabetes centre in southern India, we extracted data for this study. Younger onset T2DM were defined as individuals with T2DM diagnosed at or below 25 years of age and older onset T2DM were individuals diagnosed at age 50 years or above. During the year 2010, we noted that 4354 older onset T2DM and 332 younger onset T2DM participants had come for follow up at our centre. Using random number tables (systematic random sampling) 25% (n=1121) of older onset T2DM were selected. From these 1121 individuals, 267 participants who were matched for gender and duration of diabetes with the younger onset T2DM group were included in the analysis.For all individuals, data regarding social, demographic, family history, and medical history were extracted. Participants underwent basic anthropometric 3
ACCEPTED MANUSCRIPT measurements, biochemical investigations, and had detailed clinical assessments of all diabetes complications. Data at a single time point during the year 2009-2010, when all the measurements and assessments for complications were done, were
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used for the present analysis.
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2.2 Measurements
Anthropometric measurements including height, weight, and waist circumference
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were obtained using standardized techniques. Height was measured in centimetres using a stadiometer, with individuals requested to stand upright without shoes with
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their back against the wall, heels together and eyes directed forward. Weight was measured with a traditional spring balance kept on a firm horizontal surface, with
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individuals wearing light clothing and weight was rounded off to the nearest 0.5 kg. Body mass index (BMI) was calculated using the formula: weight (Kg) / (height in m)2. Waist circumference was measured by using a non-stretchable measuring
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tape. Individuals were asked to stand erect in a relaxed position with both feet together on a flat surface; one layer of clothing was accepted. Waist circumference
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was measured as the smallest horizontal girth between the costal margins and the
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iliac crests at minimal respiration. Blood pressure was recorded in the sitting position in the right arm with a mercury
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sphygmomanometer and rounded off to the nearest 2mmHg. Two readings were taken 5 minutes apart and the mean of the 2 readings was taken as the blood pressure.
Fasting plasma glucose (hexokinase method) was measured on Hitachi 912 Autoanalyzer (Hitachi, Mannheim, Germany) using kits supplied by Roche Diagnostics (Mannheim, Germany). Serum cholesterol (cholesterol oxidaseperoxidase-amidopyrine method), serum triglycerides (glycerol phosphate oxidaseperoxidase-amidopyrine method), and HDL cholesterol (direct method-polyethylene glycol-pretreated enzymes) were measured using Hitachi-912 Autoanalyser (Hitachi, Mannheim, Germany). Low-density lipoprotein (LDL) cholesterol was calculated using the Friedewald formula [Friedewald, Levy & Fredrickson., 1972]. Glycated
haemoglobin
(HbA1C)
was 4
estimated
by
high-pressure
liquid
ACCEPTED MANUSCRIPT chromatography using the Variant machine (Bio-Rad, Hercules, Calif., USA).Fasting and stimulated (post breakfast) C-peptide and Glutamic acid decarboxylase (GAD) antibodies were measured as mentioned in our earlier study [Amutha et al; 2017]. GAD-Ab values were categorized as <10 IU/ml, normal; 10 to 20 IU/ml, weakly
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positive; >20 IU/ml, strongly positive. Urinary albumin concentration was measured in a fasting urine sample using an immunoturbidometric assay (Hitachi 902 autoanalyser; Roche Diagnostics). The intra-assay and inter-assay coefficients of
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variation for the biochemical assays ranged between 3.1 and 7.6%. The study centre participates in external quality control programs and is certified by
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the College of American Pathologists (CAP) as well as the National Accreditation Board for Testing and Calibration of Laboratories (NABL) of the Government of
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India. Ethical approval was obtained from the Madras Diabetes Research Foundation Institutional Ethics Committee and written informed consent was
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obtained from all study participants to use their anonymized medical data.
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2.3 Definitions
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Diabetes was diagnosed based on the WHO Consulting Group Criteria [Alberti & Zimmet., 1998], i.e. fasting plasma glucose ≥126 mg/dl (≥7.0 mmol/l) and/or 2 h
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post-load plasma glucose (2 h PG) ≥200 mg/dl (≥11.1 mmol/l) or a self-reported history of diabetes on treatment by a physician or on drug treatment for diabetes (insulin or oral hypoglycemic agents).Type 2 diabetes [T2DM] was defined based on absence of ketosis, good beta cell reserve as shown by fasting C-peptide assay ≥0.6pmol/ml, absence of pancreatic calculi on abdomen X-ray, and good response to oral hypoglycemic agents for more than two years [Mohan V et al.,2013].T2DM subjects were then sub-classified as young onset T2DM (if the age at diagnosis of T2DM was at or below 25 years of age) and older onset T2DM (if the age at diagnosis of T2DM was equal to or greater than 50 years of age).Supplementary Table 1 provides the diagnostic and clinical criteria used for defining the two groups.
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ACCEPTED MANUSCRIPT GAD-Ab assays are done as a routine as part of the clinical assessment of all individuals with young onset diabetes seen at our centre except in the minority in whom it cannot be done due to financial constraints. Among the present group of patients with young onset type 2 diabetes, GAD-Ab values were available for 219
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subjects (82%) and only 4(1.8%) of them were weakly positive for GAD-Ab. These individuals were excluded from the analysis. Due to low cost-effectiveness, GAD-Ab estimation is not routinely done in older onset T2DM, unless Latent Autoimmune
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Diabetes of Adults (LADA) is suspected. None of the older onset T2DM included in
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this study belonged to the LADA group.
According to ADA recommendations [American Diabetes Association., 2016],
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HbA1c values of ≤7% reduces the risk of microvascular complications, hence individuals with A1c >7% were considered to be the “at risk” group in the regression
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analysis.
Generalized Obesity was diagnosed according to the WHO Asia Pacific guidelines,
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subjects with BMI < 18.5kg/m2 were considered as underweight, ≥18.5 to ≤ 22.9 kg/ m2 were considered as normal, BMI ≥23.0 kg/ m2 to 24.9 kg/ m2as overweight and
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BMI ≥ 25 kg/ m2 as obese [WHO/IASO/IOTF.,2000].
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Lipid abnormalities were diagnosed based on the NCEP (ATP III) guidelines [NCEP (ATP III).,2001], or if the individual was on drug treatment for dyslipidemia. Hypercholesterolemia was defined as total cholesterol levels ≥200mg/dl, high LDL cholesterol as LDL cholesterol levels ≥100mg/dl, hypertriglyceridemia as triglyceride levels ≥150mg/dl and low HDL cholesterol as HDL cholesterol levels<40mg/dl in males and<50mg/dl in females. Hypertension was defined as blood pressure ≥140/90 mmHg or self-reported hypertension, on drug treatment [Chobanian et al., 2003]. Retinopathy was defined based on both direct and indirect ophthalmoscopy assessments done by a retinal specialist after full mydriasis and confirmed by fundus photography. The latter was done using four-field stereo color retinal photography. An Early Treatment Diabetic Retinopathy Study (ETDRS) grading 6
ACCEPTED MANUSCRIPT system that has been modified and standardized in our earlier population-based studies was used for the diagnosis of retinopathy. The minimum requirement for diagnosis of diabetic retinopathy was the presence of at least one microaneurysm in any field in either eye [Early Treatment of Diabetic Retinopathy Study Research
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Group.,1991 &Rema et.al., 2005].
Nephropathy was defined by the presence of urinary albumin excretion rates. Microalbuminuria was defined as urinary albumin excretion of 30-299µg/mg of
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creatinine, while macroalbuminuria was defined as urinary albumin excretion ≥300 μg/mg of creatinine [Unnikrishnan et al.,2007].
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Neuropathy was assessed using a biothesiometer. Vibratory perception threshold (VPT) of the great toes was measured in a standardized fashion by a single
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observer. Neuropathy was diagnosed if the mean VPT was ≥20V [Deepa et al., 2003].
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Peripheral vascular disease was diagnosed if the ankle-brachial index (ABI) on peripheral Doppler was less than 0.9 [Premalatha, Shanthirani, Deepa , Markovitz &
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Mohan, 2000].
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2.4 Statistical Analysis
Statistical analysis was performed using SPSS for Windows version 15.0 software
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(SPSS Inc., Chicago, IL). Values were expressed as means ± S.D. Student’s t-test was used to compare continuous variables, and the chi-square test was used to compare proportions between individuals with younger-and older-onset T2DM. Multiple logistic regression analysis was done to assess what risk factors might be associated with retinopathy, nephropathy, neuropathy and PVD (dependent variable) in younger onset T2DM using older onset T2DM as the reference. 3.0 RESULTS The clinical and biochemical characteristics of participants are presented in Table 1. The mean age of individuals with younger and older onset T2DM were 31.6 ± 7.9and 69.9 ± 7.0 years, respectively, with minimal overlap between the groups (Figure 1). The mean age at onset of diabetes in the two groups was 21.3 ± 3.6 vs. 7
ACCEPTED MANUSCRIPT 57.2 ± 5.7years, respectively (p<0.001). Individuals with younger-onset T2DM had significantly greater glycated hemoglobin (8.7 ± 2.1 vs. 7.5 ± 1.5%), total cholesterol (160 ± 43 vs.148 ± 32mg/dl), serum triglycerides (147 ± 123 vs. 128 ± 58mg/dl), and LDL cholesterol (92 ± 31 vs. 82 ± 27mg/dl), and lower HDL cholesterol levels
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(39 ± 9 vs. 42 ± 10mg/dl). However, waist circumference (p=0.031) and systolic blood pressure (p<0.001) were significantly higher in older onset participants.
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There was no significant difference in the mean BMI between the groups, or in the proportion of individuals in each group classified as normal weight, overweight and obese (Supplementary Figure 1). A significantly higher number of individuals with
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young onset T2DM were on insulin compared to those with older onset T2DM (p=0.001).Equal numbers of subjects were on lipid lowering medications in both the
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groups, whereas a much higher proportion of individuals with older onset T2DM were taking medications for hypertension. Almost 90% of individuals with young
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onset T2DM had a parental history of diabetes (often in both parents) compared to around 40% of those with older onset T2DM (p<0.001).
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A higher proportion of those with older onset T2DM had hypertension (76.0% vs 46.8%; p<0.001) (Table 2).It is of interest that a higher proportion of young onset
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T2DM (33.7 vs. 24.3%) had high LDL cholesterol levels i.e. greater than 100mg/dl (p=0.019). A significantly higher prevalence of retinopathy was seen among those
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with young onset T2DM (p<0.001), whereas a significantly higher proportion of older onset T2DM patients had neuropathy (p<0.001) and PVD (p=0.004). In multiple logistic regression models, adjusted for glycated hemoglobin, hypertension, hypercholesterolemia and insulin treatment (Table 3) individuals with young onset T2DM had a higher risk of developing retinopathy [Odds Ratio – OR: 2.06; Confidence interval – CI: 1.32 – 3.22; p=0.002] but not nephropathy (1.07 (0.66 – 1.73); p=0.781). Older onset T2DM individuals had higher odds (6.49;3.72 – 11.31; p<0.001) of neuropathy and PVD (4.41;1.19 – 16.36; p=0.027).The above results did not change even when HbA1c, serum cholesterol and systolic and diastolic blood pressure were added as continuous variables in the models.
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ACCEPTED MANUSCRIPT 4.0 DISCUSSION Our results suggest that compared to individuals who develop T2DM after the age of 50 years, those who develop it at or below the age of 25 years have poorer
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glucose and lipid control and also an increased odds of developing diabetic
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retinopathy. While duration of diabetes and severity of hyperglycemia have been recognised as the main risk factors for developing microvascular disease, the
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increased risk of retinopathy in early onset T2DM persisted even after adjusting for glycated haemoglobin, hypertension, and hypercholesterolemia. This finding has
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major clinical implications which are further discussed below. Our findings regarding poorer metabolic control in young onset T2DM compared to
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those developing diabetes at older ages agrees with other literature. In the TODAY study of young individuals with diabetes from the U.S., only half of the study participants were able to achieve good glycemic control [Narasimhan &
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Weinstock.,2014]. Earlier studies from Europe, Singapore, and Hong Kong have also consistently shown that individuals with young onset T2DM had worse
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glycemic control than those developing diabetes at later ages [Hatunic, Burns, Finucane, Mannion & Nolan.,2005; Quah , Liu , Luo, How & Tay.,2013 &Chan et
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al.,2014]. More recently, the Joint Asia Diabetes Evaluation (JADE) programme conducted in 9 Asian countries has shown that patients with young-onset T2DM
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had higher HbA1c and LDL cholesterol than those with older onset disease [Yeung et al., 2014], and that they were less likely to be receiving cardio-protective drugs such as statins.
There could be several explanations for these findings. It can be postulated that younger individuals with diabetes have competing priorities such as building a career and taking care of family and hence they are unable to make health a priority in this phase of their life. This further prevents them from devoting full attention to the management of an asymptomatic condition like diabetes [Yeung et al., 2014]. Physicians are also less likely to aggressively treat metabolic risk factors in young individuals, under the mistaken impression that their younger age will protect them from the development of vascular complications.
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ACCEPTED MANUSCRIPT The higher frequency of retinopathy in the younger-onset T2DM plus nephropathy rates being equivalent to older-onset T2DM (despite lower blood pressure rates) raises the possibility that early-onset T2DM is an inherently more aggressive phenotype of the disease, conferring a higher risk of complications than could be
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explained by hyperglycemia alone. Similar findings have been reported in studies from Australia [Wong, Molyneaux, Constantino, Twigg & Yue.,2008 &Constantino et al.,2013] and among Pima Indians [Pavkov et al., 2006], although in the latter study,
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the increased risk was explained by the longer duration of diabetes. It has been postulated that the age at which tissues are exposed to hyperglycemia is an
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important determinant of outcomes. It has been shown that hyperglycemia stimulates the production of angiogenic factors such as VEGF and IGF-I, more
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avidly in younger compared to older individuals [Wong, Molyneaux, Constantino, Twigg & Yue.,2008]. This might render individuals with younger-onset T2DM more prone to developing diabetic retinopathy as compared to older individuals with
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hyperglycemia of comparable duration and severity. As mentioned above, individuals with young-onset T2DM are also less likely to be treated effectively for
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co-morbidities such as hypertension and dyslipidemia, further increasing their risk of
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vascular complications.
Our findings are of great significance as Asian Indians are known to develop T2DM
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at younger ages than white Caucasians [Qiao et al.,2003; Nakagami et al., 2003 &Anjana et al.,2011].These young individuals who develop diabetes in their twenties and thirties will be at risk of developing vascular complications by their fifties and sixties decades, with adverse impact on quality of life and thus productivity. Our findings also underscore the importance of diagnosing individuals with youth-onset T2DM earlier. Individuals with a family history of diabetes or with other risk factors such as obesity need to be screened for diabetes and the use of validated risk scores may be useful in this regard [Mohan, Deepa, Deepa, Somannavar & Datta]. The higher prevalence of neuropathy and peripheral vascular disease in older onset T2DM could be explained by age, as aging itself is a risk factor for these two complications. Though the prevalence of neuropathy and PVD are lower among 10
ACCEPTED MANUSCRIPT young-onset T2DM, it is worrisome that these complications are present at all in these young individuals [Chiang.,2015].It may be logical to expect that, as individuals with young onset T2DM grow older, the prevalence of these two
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complications will likely rise exponentially.
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The strength of our study is that we have included a fairly large cohort of wellmatched individuals with early- and older-onset T2DM. Specifically, we matched for
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duration of diabetes to understand what other factors might be related to progression of disease. To our knowledge, this is the first such data in a nonEuropean population. Use of distinct age cut-offs (≤25 years and ≥50 years) for the
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two groups has enabled us to achieve clear differentiation of risk factors and complications between them. The main limitation of the study is that the patient
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population is drawn cross-sectionally from a single tertiary care centre and could thus be subject to referral bias. Also, assessment of glycemic control was based on
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a single HbA1c value at the time of the index visit, which does not provide sufficient information of the trajectory of glycemic control over the patient’s lifetime with
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diabetes. In addition, since this study is done in Asian Indians, the results need to be interpreted with caution among non Asians. Finally, the diagnosis of Maturity
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Onset Diabetes of Young (MODY) requires genetic analysis, which could not be performed in the younger onset T2DM due to financial constraints. However, based
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on our earlier studies, it is very unlikely that MODY would have been diagnosed in a significant number of these individuals with the typical clinical presentation of T2DM.
In conclusion, individuals with young-onset T2DM have poorer control of metabolic risk factors and are at higher risk of developing retinopathy compared to their counterparts with onset of diabetes at older age. Thus individuals with young-onset T2DM need to be identified early and treated aggressively, so as to prevent or delay complications of diabetes.
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ACCEPTED MANUSCRIPT Acknowledgments We thank the staff of Dr. Mohan’s Diabetes Specialities Centre and the Madras Diabetes Research Foundation, Chennai, India, for their help with this study. We
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also acknowledge the Emory Global Health Institute for their support to this study.
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Conflict of interest: The authors have not declared any conflicts of interest. Author contributions: V.M, R.U, and R.M.A conceived the study. R.U wrote the
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first draft of the article and A.A carried out the corrections in consecutive drafts. A.A and J.S coordinated and checked the data integrity. R.M.A and R.U provided input for statistical analysis of the data. R.M.A, R.U, R.H, KMV and MKA gave valuable
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suggestions and helped in revising the manuscript.
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ACCEPTED MANUSCRIPT Wong J, Molyneaux L, Constantino M, Twigg SM, Yue DK. Timing is everything: age of onset influences long-term retinopathy risk in type 2 diabetes, independent of traditional risk factors. Diabetes Care 2008;31:1985-1990.doi: 10.2337/dc08-
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Yeung RO, Zhang Y, LukA et al. Metabolic profiles and treatment gaps in youngonset type 2 diabetes in Asia (the JADE programme): a cross-sectional study of a cohort.
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Endocrinol2014;2:935-943.doi:
ACCEPTED MANUSCRIPT Table 1: Clinical and biochemical profile of younger-onsetT2DM (age onset less than equal to 25 years) and older-onsetT2DM (age onset 50 years and above) Older T2DM
(n=263)
(n=267)
155 (58.1)
Age (years)
p value
155 (58.1)
0.284
31.6 ± 7.9 31(14-59)* 21.3 ± 3.6
69.9± 7.0 69(56-93)* 57.2± 5.7
<0.001
9.5 ± 6.1
9.7 ± 5.8
0.647
26.9 ± 4.8
26.6 ± 4.7
0.445
90.4 ± 11.4
92.6 ± 10.8
0.031
125 ± 14
133 ± 15
<0.001
78 ± 8
78± 7
0.566
165 ± 61
132 ± 50
<0.001
8.7 ± 2.1
7.5 ± 1.5
<0.001
Total serum cholesterol (mg/dl)
160 ± 43
148 ± 32
0.001
147 ± 123
128 ± 58
0.025
39 ± 9
42 ± 10
0.009
92 ± 31
82 ±27
<0.001
12(4.5) 141(52.8) 114(42.7) 139(52.1) 111(41.6) 220(89.4)
5(1.9) 174(65.2) 82(30.7) 6(2.2) 146(54.7) 179(67.0) 106(39.7)
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Male n (%)
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Younger T2DM
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Variables
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Age at diagnosis (years) Duration of diabetes (years)
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Body mass index ( kg/m2)
Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg)
Glycated hemoglobin (%)
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Fasting plasma glucose (mg/dl)
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Waist circumference(cm)
Serum triglycerides(mg/dl)
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HDL cholesterol(mg/dl) LDL cholesterol(mg/dl)
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Treatment n (%) Insulin Oral hypoglycemic agents(OHA) Insulin and OHA Diet and Exercise Lipid lowering medications n (%) Blood pressure medications n(%) Parental history of diabetes n(%)
Data given as Mean ± S.D. * Data shown as median (range)
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<0.001
0.001
0.544 <0.001 <0.001
ACCEPTED MANUSCRIPT Table 2: Prevalence rates of risk factors and complications in younger and older onset T2DM Younger T2DM n (%) 125/267(46.8)
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Hypertension
Older T2DM n (%) 203/267(76.0)
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Variables
p value <0.001
148/263(56.3)
152/267(56.9)
0.879
High LDL Cholesterol
84/249(33.7)
64/263(24.3)
0.019
Hypertriglyceridemia
84/254(33.1)
72/265(27.2)
0.143
Low HDL Cholesterol
176/254(69.3)
168/265(63.4)
0.156
Retinopathy
107/225 (47.6)
75/242(31.0)
<0.001
55/267 (20.6)
54/258 (20.9)
0.926
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Nephropathy (Micro and Macroalbuminuria) Neuropathy
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Hypercholesterolemia
3/244(1.2)
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Peripheral vascular disease
22/240 (9.2)
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107/256(41.8) 16/258(6.2)
<0.001 0.004
ACCEPTED MANUSCRIPT Table 3: Multiple logistic regression using complications as dependent variable and younger and older onset T2DM as independent variables adjusted for risk factors
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0.98 (0.64 – 1.49) 0.926 1.07 (0.66 – 1.73) 0.781
0.14 (0.08 – 0.23) <0.001 0.15 (0.09 – 0.27) <0.001 0.18(0.05 – 0.65) 0.009 0.23(0.06 – 0.84) 0.027
for hypertension, HbA1c, hypercholesterolemia and insulin treatment [hypertension (<140/90mmHg=0 and ≥140/90mmHg =1); glycated hemoglobin (≤7.0%=0 and >7.0%=1 poor glycemic control); hypercholesterolemia (<200mg/dl=0 and ≥200mg/dl=1, insulin treatment (individuals on OHA= 0 and individuals on Insulin, Insulin & OHA =1).
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*Adjusted
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Unadjusted Adjusted * Neuropathy Unadjusted Adjusted * Peripheral Vascular Disease Unadjusted Adjusted *
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Younger-onset T2DM (older-onset T2DM taken as OR (95% CI) p value reference) Retinopathy Unadjusted 2.02 (1.38 – 2.95) <0.001 Adjusted * 2.06 (1.32 – 3.22) 0.002 Nephropathy
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Figure 1: Age distribution of younger and older onset type 2 diabetes
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ACCEPTED MANUSCRIPT Highlights
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1. Younger-onset T2DM has worse glycemic and lipid control compared to
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older-onset T2DM.
2. Prevalence of retinopathy was higher in younger-onset than in gender and duration matched older-onset T2DM.
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3. Aggressive metabolic control is urgently needed among younger-onset
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T2DM.
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S1056-8727(16)30934-5 doi: 10.1016/j.jdiacomp.2017.03.007 JDC 6988
To appear in:
Journal of Diabetes and Its Complications
Received date: Revised date: Accepted date:
29 November 2016 28 February 2017 18 March 2017
Please cite this article as: Unnikrishnan, R., Anjana, R.M., Anandakumar, A., Harish, R., Saravanan, J., Ali, M.K., Venkat Narayan, K.M. & Mohan, V., Younger- onset versus older-onset type 2 diabetes: Clinical profile and complications, Journal of Diabetes and Its Complications (2017), doi: 10.1016/j.jdiacomp.2017.03.007
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ACCEPTED MANUSCRIPT YOUNGER- ONSET VERSUS OLDER-ONSET TYPE 2 DIABETES: CLINICAL PROFILE AND COMPLICATIONS Ranjit Unnikrishnan*
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Amutha Anandakumar*
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Ranjit Mohan Anjana*
Ranjani Harish*
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Jebarani Saravanan* Mohammed K Ali **
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Venkat Narayan KM**
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Viswanathan Mohan*
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*Madras Diabetes Research Foundation &Dr.Mohan’s Diabetes Specialities Centre, WHO Collaborating Centre for Non-communicable Diseases Prevention and Control, ICMR Center for Advanced Research on Diabetes, Gopalapuram, Chennai, India **Emory Global Diabetes Research Center, Rollins School of Public Health, Emory University, Atlanta, USA
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Running title: Comparing younger and older onset diabetes Key words: T2DM, younger onset, older onset, risk factors, complications
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ADDRESS FOR CORRESPONDENCE:Dr. V. MOHAN,M.D., FRCP (London, Edinburgh, Glasgow, Ireland), Ph.D., D.Sc., FNASc, FASc, FNA, FACP, FACE,FTWAS, MACP CHAIRMAN & CHIEF DIABETOLOGIST, MADRAS DIABETES RESEARCH FOUNDATION & Dr. MOHAN’S DIABETES SPECIALITIES CENTRE, WHO COLLABORATING CENTRE FOR NON-COMMUNICABLE DISEASES PREVENTION AND CONTROL ICMR CENTER FOR ADVANCED RESEARCH ON DIABETES, 4, CONRAN SMITH ROAD, GOPALAPURAM, CHENNAI - 600 086.INDIA TELNO :( 9144) 4396 8888 FAX NO: (9144) 2835 0935 EMAIL: [email protected] Website: www.drmohansdiabetes.com, www.mdrf.in Words in text: 2882, No. of tables: 3, Figure: 1,No. of references: 30
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ACCEPTED MANUSCRIPT Abstract: Aims: To compare the clinical profile and complications between younger and older onset type 2 diabetes (T2DM) patients at a tertiary care diabetes centre in south
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India.
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Methods: We compared individuals with T2DM detected at ages ≤25 years (n=267) and at age ≥50 years (n=267), matched for gender and duration of diabetes. We
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reviewed electronic patient charts and extracted data on biochemical parameters (plasma glucose, serum lipids and glycated haemoglobin). We estimated
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prevalence of complications (retinopathy, nephropathy, neuropathy, and peripheral vascular disease). We examined odds of having each complication, after adjusting
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for clinical differences between younger- and older-onset T2DM. Results: Individuals with younger-onset T2DM had significantly greater glycated
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hemoglobin (8.7 vs. 7.5%), serum cholesterol (160 vs. 148mg/dl), serum triglycerides (147 vs. 128mg/dl), LDL cholesterol (92 vs. 82mg/dl) and lower HDL
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cholesterol levels (39 vs. 42mg/dl). However, waist circumference (90.4vs.92.6cm) and systolic blood pressure (125vs.133mmHg) were significantly higher in older
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onset T2DM.Prevalence of retinopathy (47.6vs. 31.0%) was higher in younger onset T2DM while neuropathy (41.8vs. 9.2%) and peripheral vascular disease (6.2 vs.
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1.2%) were higher in older onset T2DM.In multiple logistic regression analysis, after adjusting for glycated hemoglobin, hypertension, and hypercholesterolemia, younger onset T2DM had a higher odds of developing retinopathy [Odds Ratio: 2.19; Confidence Intervals: 1.42 –3.38] when compared to older onset T2DM. Conclusions: Younger onset T2DM participants have worse glycemic and lipid control, and higher prevalence of retinopathy compared to older onset T2DM patients. This underscores the need for more aggressive metabolic control in young-onset T2DM.
Word count: 247
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ACCEPTED MANUSCRIPT 1.0 INTRODUCTION Type 2 diabetes mellitus (T2DM), conventionally considered a disease of middle and old age, is increasingly occurring in younger age groups. This transition in the
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epidemiology of T2DM has been noted in almost all ethnic groups and across
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different geographical locations [Alberti et al.,2004 & Brunton ,2008]. The earlier age at onset of T2DM is of great concern since it translates to a greater duration of exposure to hyperglycemia, and consequent development of chronic vascular
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complications of diabetes during the most productive years of an individual’s life
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[Alberti et al.,2004; D'Adamo & Caprio .,2011&Gregg , Sattar & Ali.,2016]. While type 1 diabetes (T1DM) is also associated with onset in childhood or youth,
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recent studies indicate that young-onset T2DM is associated with greater morbidity and mortality than T1DM possibly due to higher prevalence of cardiovascular risk factors like hypertension and hyperlipidemia among the former [Constantino et
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al.,2013]. There are relatively few data comparing the clinical profile and complications in T2DM with onset in youth compared to individuals with an older
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age at onset. The present paper attempts to fill this gap after matching participants for gender and duration of diabetes.
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2.0 METHODS
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2.1 Data Source
From the electronic medical records (EMR) of a large tertiary care diabetes centre in southern India, we extracted data for this study. Younger onset T2DM were defined as individuals with T2DM diagnosed at or below 25 years of age and older onset T2DM were individuals diagnosed at age 50 years or above. During the year 2010, we noted that 4354 older onset T2DM and 332 younger onset T2DM participants had come for follow up at our centre. Using random number tables (systematic random sampling) 25% (n=1121) of older onset T2DM were selected. From these 1121 individuals, 267 participants who were matched for gender and duration of diabetes with the younger onset T2DM group were included in the analysis.For all individuals, data regarding social, demographic, family history, and medical history were extracted. Participants underwent basic anthropometric 3
ACCEPTED MANUSCRIPT measurements, biochemical investigations, and had detailed clinical assessments of all diabetes complications. Data at a single time point during the year 2009-2010, when all the measurements and assessments for complications were done, were
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used for the present analysis.
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2.2 Measurements
Anthropometric measurements including height, weight, and waist circumference
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were obtained using standardized techniques. Height was measured in centimetres using a stadiometer, with individuals requested to stand upright without shoes with
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their back against the wall, heels together and eyes directed forward. Weight was measured with a traditional spring balance kept on a firm horizontal surface, with
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individuals wearing light clothing and weight was rounded off to the nearest 0.5 kg. Body mass index (BMI) was calculated using the formula: weight (Kg) / (height in m)2. Waist circumference was measured by using a non-stretchable measuring
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tape. Individuals were asked to stand erect in a relaxed position with both feet together on a flat surface; one layer of clothing was accepted. Waist circumference
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was measured as the smallest horizontal girth between the costal margins and the
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iliac crests at minimal respiration. Blood pressure was recorded in the sitting position in the right arm with a mercury
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sphygmomanometer and rounded off to the nearest 2mmHg. Two readings were taken 5 minutes apart and the mean of the 2 readings was taken as the blood pressure.
Fasting plasma glucose (hexokinase method) was measured on Hitachi 912 Autoanalyzer (Hitachi, Mannheim, Germany) using kits supplied by Roche Diagnostics (Mannheim, Germany). Serum cholesterol (cholesterol oxidaseperoxidase-amidopyrine method), serum triglycerides (glycerol phosphate oxidaseperoxidase-amidopyrine method), and HDL cholesterol (direct method-polyethylene glycol-pretreated enzymes) were measured using Hitachi-912 Autoanalyser (Hitachi, Mannheim, Germany). Low-density lipoprotein (LDL) cholesterol was calculated using the Friedewald formula [Friedewald, Levy & Fredrickson., 1972]. Glycated
haemoglobin
(HbA1C)
was 4
estimated
by
high-pressure
liquid
ACCEPTED MANUSCRIPT chromatography using the Variant machine (Bio-Rad, Hercules, Calif., USA).Fasting and stimulated (post breakfast) C-peptide and Glutamic acid decarboxylase (GAD) antibodies were measured as mentioned in our earlier study [Amutha et al; 2017]. GAD-Ab values were categorized as <10 IU/ml, normal; 10 to 20 IU/ml, weakly
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positive; >20 IU/ml, strongly positive. Urinary albumin concentration was measured in a fasting urine sample using an immunoturbidometric assay (Hitachi 902 autoanalyser; Roche Diagnostics). The intra-assay and inter-assay coefficients of
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variation for the biochemical assays ranged between 3.1 and 7.6%. The study centre participates in external quality control programs and is certified by
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the College of American Pathologists (CAP) as well as the National Accreditation Board for Testing and Calibration of Laboratories (NABL) of the Government of
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India. Ethical approval was obtained from the Madras Diabetes Research Foundation Institutional Ethics Committee and written informed consent was
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obtained from all study participants to use their anonymized medical data.
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2.3 Definitions
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Diabetes was diagnosed based on the WHO Consulting Group Criteria [Alberti & Zimmet., 1998], i.e. fasting plasma glucose ≥126 mg/dl (≥7.0 mmol/l) and/or 2 h
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post-load plasma glucose (2 h PG) ≥200 mg/dl (≥11.1 mmol/l) or a self-reported history of diabetes on treatment by a physician or on drug treatment for diabetes (insulin or oral hypoglycemic agents).Type 2 diabetes [T2DM] was defined based on absence of ketosis, good beta cell reserve as shown by fasting C-peptide assay ≥0.6pmol/ml, absence of pancreatic calculi on abdomen X-ray, and good response to oral hypoglycemic agents for more than two years [Mohan V et al.,2013].T2DM subjects were then sub-classified as young onset T2DM (if the age at diagnosis of T2DM was at or below 25 years of age) and older onset T2DM (if the age at diagnosis of T2DM was equal to or greater than 50 years of age).Supplementary Table 1 provides the diagnostic and clinical criteria used for defining the two groups.
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ACCEPTED MANUSCRIPT GAD-Ab assays are done as a routine as part of the clinical assessment of all individuals with young onset diabetes seen at our centre except in the minority in whom it cannot be done due to financial constraints. Among the present group of patients with young onset type 2 diabetes, GAD-Ab values were available for 219
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subjects (82%) and only 4(1.8%) of them were weakly positive for GAD-Ab. These individuals were excluded from the analysis. Due to low cost-effectiveness, GAD-Ab estimation is not routinely done in older onset T2DM, unless Latent Autoimmune
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Diabetes of Adults (LADA) is suspected. None of the older onset T2DM included in
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this study belonged to the LADA group.
According to ADA recommendations [American Diabetes Association., 2016],
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HbA1c values of ≤7% reduces the risk of microvascular complications, hence individuals with A1c >7% were considered to be the “at risk” group in the regression
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analysis.
Generalized Obesity was diagnosed according to the WHO Asia Pacific guidelines,
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subjects with BMI < 18.5kg/m2 were considered as underweight, ≥18.5 to ≤ 22.9 kg/ m2 were considered as normal, BMI ≥23.0 kg/ m2 to 24.9 kg/ m2as overweight and
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BMI ≥ 25 kg/ m2 as obese [WHO/IASO/IOTF.,2000].
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Lipid abnormalities were diagnosed based on the NCEP (ATP III) guidelines [NCEP (ATP III).,2001], or if the individual was on drug treatment for dyslipidemia. Hypercholesterolemia was defined as total cholesterol levels ≥200mg/dl, high LDL cholesterol as LDL cholesterol levels ≥100mg/dl, hypertriglyceridemia as triglyceride levels ≥150mg/dl and low HDL cholesterol as HDL cholesterol levels<40mg/dl in males and<50mg/dl in females. Hypertension was defined as blood pressure ≥140/90 mmHg or self-reported hypertension, on drug treatment [Chobanian et al., 2003]. Retinopathy was defined based on both direct and indirect ophthalmoscopy assessments done by a retinal specialist after full mydriasis and confirmed by fundus photography. The latter was done using four-field stereo color retinal photography. An Early Treatment Diabetic Retinopathy Study (ETDRS) grading 6
ACCEPTED MANUSCRIPT system that has been modified and standardized in our earlier population-based studies was used for the diagnosis of retinopathy. The minimum requirement for diagnosis of diabetic retinopathy was the presence of at least one microaneurysm in any field in either eye [Early Treatment of Diabetic Retinopathy Study Research
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Group.,1991 &Rema et.al., 2005].
Nephropathy was defined by the presence of urinary albumin excretion rates. Microalbuminuria was defined as urinary albumin excretion of 30-299µg/mg of
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creatinine, while macroalbuminuria was defined as urinary albumin excretion ≥300 μg/mg of creatinine [Unnikrishnan et al.,2007].
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Neuropathy was assessed using a biothesiometer. Vibratory perception threshold (VPT) of the great toes was measured in a standardized fashion by a single
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observer. Neuropathy was diagnosed if the mean VPT was ≥20V [Deepa et al., 2003].
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Peripheral vascular disease was diagnosed if the ankle-brachial index (ABI) on peripheral Doppler was less than 0.9 [Premalatha, Shanthirani, Deepa , Markovitz &
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Mohan, 2000].
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2.4 Statistical Analysis
Statistical analysis was performed using SPSS for Windows version 15.0 software
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(SPSS Inc., Chicago, IL). Values were expressed as means ± S.D. Student’s t-test was used to compare continuous variables, and the chi-square test was used to compare proportions between individuals with younger-and older-onset T2DM. Multiple logistic regression analysis was done to assess what risk factors might be associated with retinopathy, nephropathy, neuropathy and PVD (dependent variable) in younger onset T2DM using older onset T2DM as the reference. 3.0 RESULTS The clinical and biochemical characteristics of participants are presented in Table 1. The mean age of individuals with younger and older onset T2DM were 31.6 ± 7.9and 69.9 ± 7.0 years, respectively, with minimal overlap between the groups (Figure 1). The mean age at onset of diabetes in the two groups was 21.3 ± 3.6 vs. 7
ACCEPTED MANUSCRIPT 57.2 ± 5.7years, respectively (p<0.001). Individuals with younger-onset T2DM had significantly greater glycated hemoglobin (8.7 ± 2.1 vs. 7.5 ± 1.5%), total cholesterol (160 ± 43 vs.148 ± 32mg/dl), serum triglycerides (147 ± 123 vs. 128 ± 58mg/dl), and LDL cholesterol (92 ± 31 vs. 82 ± 27mg/dl), and lower HDL cholesterol levels
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(39 ± 9 vs. 42 ± 10mg/dl). However, waist circumference (p=0.031) and systolic blood pressure (p<0.001) were significantly higher in older onset participants.
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There was no significant difference in the mean BMI between the groups, or in the proportion of individuals in each group classified as normal weight, overweight and obese (Supplementary Figure 1). A significantly higher number of individuals with
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young onset T2DM were on insulin compared to those with older onset T2DM (p=0.001).Equal numbers of subjects were on lipid lowering medications in both the
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groups, whereas a much higher proportion of individuals with older onset T2DM were taking medications for hypertension. Almost 90% of individuals with young
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onset T2DM had a parental history of diabetes (often in both parents) compared to around 40% of those with older onset T2DM (p<0.001).
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A higher proportion of those with older onset T2DM had hypertension (76.0% vs 46.8%; p<0.001) (Table 2).It is of interest that a higher proportion of young onset
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T2DM (33.7 vs. 24.3%) had high LDL cholesterol levels i.e. greater than 100mg/dl (p=0.019). A significantly higher prevalence of retinopathy was seen among those
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with young onset T2DM (p<0.001), whereas a significantly higher proportion of older onset T2DM patients had neuropathy (p<0.001) and PVD (p=0.004). In multiple logistic regression models, adjusted for glycated hemoglobin, hypertension, hypercholesterolemia and insulin treatment (Table 3) individuals with young onset T2DM had a higher risk of developing retinopathy [Odds Ratio – OR: 2.06; Confidence interval – CI: 1.32 – 3.22; p=0.002] but not nephropathy (1.07 (0.66 – 1.73); p=0.781). Older onset T2DM individuals had higher odds (6.49;3.72 – 11.31; p<0.001) of neuropathy and PVD (4.41;1.19 – 16.36; p=0.027).The above results did not change even when HbA1c, serum cholesterol and systolic and diastolic blood pressure were added as continuous variables in the models.
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ACCEPTED MANUSCRIPT 4.0 DISCUSSION Our results suggest that compared to individuals who develop T2DM after the age of 50 years, those who develop it at or below the age of 25 years have poorer
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glucose and lipid control and also an increased odds of developing diabetic
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retinopathy. While duration of diabetes and severity of hyperglycemia have been recognised as the main risk factors for developing microvascular disease, the
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increased risk of retinopathy in early onset T2DM persisted even after adjusting for glycated haemoglobin, hypertension, and hypercholesterolemia. This finding has
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major clinical implications which are further discussed below. Our findings regarding poorer metabolic control in young onset T2DM compared to
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those developing diabetes at older ages agrees with other literature. In the TODAY study of young individuals with diabetes from the U.S., only half of the study participants were able to achieve good glycemic control [Narasimhan &
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Weinstock.,2014]. Earlier studies from Europe, Singapore, and Hong Kong have also consistently shown that individuals with young onset T2DM had worse
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glycemic control than those developing diabetes at later ages [Hatunic, Burns, Finucane, Mannion & Nolan.,2005; Quah , Liu , Luo, How & Tay.,2013 &Chan et
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al.,2014]. More recently, the Joint Asia Diabetes Evaluation (JADE) programme conducted in 9 Asian countries has shown that patients with young-onset T2DM
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had higher HbA1c and LDL cholesterol than those with older onset disease [Yeung et al., 2014], and that they were less likely to be receiving cardio-protective drugs such as statins.
There could be several explanations for these findings. It can be postulated that younger individuals with diabetes have competing priorities such as building a career and taking care of family and hence they are unable to make health a priority in this phase of their life. This further prevents them from devoting full attention to the management of an asymptomatic condition like diabetes [Yeung et al., 2014]. Physicians are also less likely to aggressively treat metabolic risk factors in young individuals, under the mistaken impression that their younger age will protect them from the development of vascular complications.
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ACCEPTED MANUSCRIPT The higher frequency of retinopathy in the younger-onset T2DM plus nephropathy rates being equivalent to older-onset T2DM (despite lower blood pressure rates) raises the possibility that early-onset T2DM is an inherently more aggressive phenotype of the disease, conferring a higher risk of complications than could be
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explained by hyperglycemia alone. Similar findings have been reported in studies from Australia [Wong, Molyneaux, Constantino, Twigg & Yue.,2008 &Constantino et al.,2013] and among Pima Indians [Pavkov et al., 2006], although in the latter study,
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the increased risk was explained by the longer duration of diabetes. It has been postulated that the age at which tissues are exposed to hyperglycemia is an
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important determinant of outcomes. It has been shown that hyperglycemia stimulates the production of angiogenic factors such as VEGF and IGF-I, more
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avidly in younger compared to older individuals [Wong, Molyneaux, Constantino, Twigg & Yue.,2008]. This might render individuals with younger-onset T2DM more prone to developing diabetic retinopathy as compared to older individuals with
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hyperglycemia of comparable duration and severity. As mentioned above, individuals with young-onset T2DM are also less likely to be treated effectively for
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co-morbidities such as hypertension and dyslipidemia, further increasing their risk of
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vascular complications.
Our findings are of great significance as Asian Indians are known to develop T2DM
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at younger ages than white Caucasians [Qiao et al.,2003; Nakagami et al., 2003 &Anjana et al.,2011].These young individuals who develop diabetes in their twenties and thirties will be at risk of developing vascular complications by their fifties and sixties decades, with adverse impact on quality of life and thus productivity. Our findings also underscore the importance of diagnosing individuals with youth-onset T2DM earlier. Individuals with a family history of diabetes or with other risk factors such as obesity need to be screened for diabetes and the use of validated risk scores may be useful in this regard [Mohan, Deepa, Deepa, Somannavar & Datta]. The higher prevalence of neuropathy and peripheral vascular disease in older onset T2DM could be explained by age, as aging itself is a risk factor for these two complications. Though the prevalence of neuropathy and PVD are lower among 10
ACCEPTED MANUSCRIPT young-onset T2DM, it is worrisome that these complications are present at all in these young individuals [Chiang.,2015].It may be logical to expect that, as individuals with young onset T2DM grow older, the prevalence of these two
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complications will likely rise exponentially.
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The strength of our study is that we have included a fairly large cohort of wellmatched individuals with early- and older-onset T2DM. Specifically, we matched for
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duration of diabetes to understand what other factors might be related to progression of disease. To our knowledge, this is the first such data in a nonEuropean population. Use of distinct age cut-offs (≤25 years and ≥50 years) for the
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two groups has enabled us to achieve clear differentiation of risk factors and complications between them. The main limitation of the study is that the patient
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population is drawn cross-sectionally from a single tertiary care centre and could thus be subject to referral bias. Also, assessment of glycemic control was based on
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a single HbA1c value at the time of the index visit, which does not provide sufficient information of the trajectory of glycemic control over the patient’s lifetime with
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diabetes. In addition, since this study is done in Asian Indians, the results need to be interpreted with caution among non Asians. Finally, the diagnosis of Maturity
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Onset Diabetes of Young (MODY) requires genetic analysis, which could not be performed in the younger onset T2DM due to financial constraints. However, based
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on our earlier studies, it is very unlikely that MODY would have been diagnosed in a significant number of these individuals with the typical clinical presentation of T2DM.
In conclusion, individuals with young-onset T2DM have poorer control of metabolic risk factors and are at higher risk of developing retinopathy compared to their counterparts with onset of diabetes at older age. Thus individuals with young-onset T2DM need to be identified early and treated aggressively, so as to prevent or delay complications of diabetes.
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ACCEPTED MANUSCRIPT Acknowledgments We thank the staff of Dr. Mohan’s Diabetes Specialities Centre and the Madras Diabetes Research Foundation, Chennai, India, for their help with this study. We
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also acknowledge the Emory Global Health Institute for their support to this study.
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Conflict of interest: The authors have not declared any conflicts of interest. Author contributions: V.M, R.U, and R.M.A conceived the study. R.U wrote the
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first draft of the article and A.A carried out the corrections in consecutive drafts. A.A and J.S coordinated and checked the data integrity. R.M.A and R.U provided input for statistical analysis of the data. R.M.A, R.U, R.H, KMV and MKA gave valuable
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suggestions and helped in revising the manuscript.
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ACCEPTED MANUSCRIPT Table 1: Clinical and biochemical profile of younger-onsetT2DM (age onset less than equal to 25 years) and older-onsetT2DM (age onset 50 years and above) Older T2DM
(n=263)
(n=267)
155 (58.1)
Age (years)
p value
155 (58.1)
0.284
31.6 ± 7.9 31(14-59)* 21.3 ± 3.6
69.9± 7.0 69(56-93)* 57.2± 5.7
<0.001
9.5 ± 6.1
9.7 ± 5.8
0.647
26.9 ± 4.8
26.6 ± 4.7
0.445
90.4 ± 11.4
92.6 ± 10.8
0.031
125 ± 14
133 ± 15
<0.001
78 ± 8
78± 7
0.566
165 ± 61
132 ± 50
<0.001
8.7 ± 2.1
7.5 ± 1.5
<0.001
Total serum cholesterol (mg/dl)
160 ± 43
148 ± 32
0.001
147 ± 123
128 ± 58
0.025
39 ± 9
42 ± 10
0.009
92 ± 31
82 ±27
<0.001
12(4.5) 141(52.8) 114(42.7) 139(52.1) 111(41.6) 220(89.4)
5(1.9) 174(65.2) 82(30.7) 6(2.2) 146(54.7) 179(67.0) 106(39.7)
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Male n (%)
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Younger T2DM
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Variables
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Age at diagnosis (years) Duration of diabetes (years)
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Body mass index ( kg/m2)
Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg)
Glycated hemoglobin (%)
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Fasting plasma glucose (mg/dl)
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Waist circumference(cm)
Serum triglycerides(mg/dl)
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HDL cholesterol(mg/dl) LDL cholesterol(mg/dl)
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Treatment n (%) Insulin Oral hypoglycemic agents(OHA) Insulin and OHA Diet and Exercise Lipid lowering medications n (%) Blood pressure medications n(%) Parental history of diabetes n(%)
Data given as Mean ± S.D. * Data shown as median (range)
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<0.001
0.001
0.544 <0.001 <0.001
ACCEPTED MANUSCRIPT Table 2: Prevalence rates of risk factors and complications in younger and older onset T2DM Younger T2DM n (%) 125/267(46.8)
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Hypertension
Older T2DM n (%) 203/267(76.0)
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p value <0.001
148/263(56.3)
152/267(56.9)
0.879
High LDL Cholesterol
84/249(33.7)
64/263(24.3)
0.019
Hypertriglyceridemia
84/254(33.1)
72/265(27.2)
0.143
Low HDL Cholesterol
176/254(69.3)
168/265(63.4)
0.156
Retinopathy
107/225 (47.6)
75/242(31.0)
<0.001
55/267 (20.6)
54/258 (20.9)
0.926
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Nephropathy (Micro and Macroalbuminuria) Neuropathy
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Hypercholesterolemia
3/244(1.2)
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Peripheral vascular disease
22/240 (9.2)
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107/256(41.8) 16/258(6.2)
<0.001 0.004
ACCEPTED MANUSCRIPT Table 3: Multiple logistic regression using complications as dependent variable and younger and older onset T2DM as independent variables adjusted for risk factors
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0.98 (0.64 – 1.49) 0.926 1.07 (0.66 – 1.73) 0.781
0.14 (0.08 – 0.23) <0.001 0.15 (0.09 – 0.27) <0.001 0.18(0.05 – 0.65) 0.009 0.23(0.06 – 0.84) 0.027
for hypertension, HbA1c, hypercholesterolemia and insulin treatment [hypertension (<140/90mmHg=0 and ≥140/90mmHg =1); glycated hemoglobin (≤7.0%=0 and >7.0%=1 poor glycemic control); hypercholesterolemia (<200mg/dl=0 and ≥200mg/dl=1, insulin treatment (individuals on OHA= 0 and individuals on Insulin, Insulin & OHA =1).
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*Adjusted
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Unadjusted Adjusted * Neuropathy Unadjusted Adjusted * Peripheral Vascular Disease Unadjusted Adjusted *
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Younger-onset T2DM (older-onset T2DM taken as OR (95% CI) p value reference) Retinopathy Unadjusted 2.02 (1.38 – 2.95) <0.001 Adjusted * 2.06 (1.32 – 3.22) 0.002 Nephropathy
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Figure 1: Age distribution of younger and older onset type 2 diabetes
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ACCEPTED MANUSCRIPT Highlights
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1. Younger-onset T2DM has worse glycemic and lipid control compared to
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older-onset T2DM.
2. Prevalence of retinopathy was higher in younger-onset than in gender and duration matched older-onset T2DM.
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3. Aggressive metabolic control is urgently needed among younger-onset
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T2DM.
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