Distinct Predictors and Comorbidities in Early Onset Type 2 Diabetes Mellitus Among Asian Indians

Abstract

Background:

The incidence of type 2 diabetes mellitus (T2DM) is increasing worldwide, and the age of disease onset is falling. Although there is rising prevalence of early onset T2DM in India, little is known about their clinical characteristics and cardiovascular risks profiles. The aim of this study was to address this knowledge gap by comparing the characteristics of early onset T2DM and usual onset T2DM patients from our clinic population in India.

Methods:

We studied the clinical and biochemical parameters of 98 consecutive early onset T2DM patients of age <45 and <5 years of disease duration and compared those parameters with 86 consecutive usual onset T2DM patients of age >50 years and similar disease duration.

Results:

There was a strong component of family history of T2DM in early onset T2DM patients; however, no difference was observed in body mass index or waist circumference between the groups. When compared with usual onset group, the early onset T2DM patients were more hypertriglycedemic, with higher total cholesterol, higher total cholesterol/high-density lipoprotein (HDL) ratio, higher low-density lipoprotein levels, and lower HDL cholesterol. Early onset T2DM patients showed significantly worse glycemic control and rapid decline in insulin secretion compared with usual onset T2DM patients.

Conclusions:

Our results demonstrate that early onset T2DM in Asian Indians appears to be a disease phenotype with adverse risk factors having poor glycemic control and longer disease duration demanding strategies for novel clinical management.

Introduction

Early onset type 2 diabetes mellitus (T2DM), where the onset of disease is below the age of 45 years, has increasingly become prevalent throughout the world. As the incidence of T2DM has been on the rise worldwide, the age of presentation is falling. There have been reports of early onset T2DM from many countries across the world.^1

–6 The number of people with diabetes in India has increased several fold in two decades from 19 million in 1995⁷ to 66.8 million in 2014.⁸ Rising prevalence of early onset T2DM has been reported in India as well,^9
–11 and this increase is largely due to the increasing number of T2DM.¹² It was already known that Asian Indians develop T2DM one or two decade earlier than their Caucasian counterparts.^13,14 Our own data, obtained (unpublished) from a total of 10,915 patients, who had attended our outpatient clinic during the last 10 years shows that about 48% of our patients could be categorized into early onset type 2 diabetes as their age of disease onset was between 20 and 45 years (Fig. 1). It is believed that a combination of several factors such as central obesity,^15,16 insulin resistance,¹⁷ genetic predisposition,¹⁸ and unfavorable intrauterine conditions¹⁹ have contributed toward the higher prevalence of T2DM among Asian Indians.

FIG. 1.

Percentage of type 2 diabetes patients categorized based on the age of onset of diabetes. The data are from 10,915 patients who attended our outpatient clinic in the last 10 years. Age of onset of disease starting from 20 years was categorized into two groups (1) between 20 and 45 years and (2) age of onset 50 years and above, and plotted against the percentage of patients in each group.

Early onset T2DM is considered as a distinct and more aggressive phenotype when compared with usual onset T2DM^20,21 and type 1 diabetes.^22
–24 It has been reported that patients with early onset T2DM not only have a more adverse cardiovascular risk profile^21,25 but also have a higher chance of getting microvascular and macrovascular complications compared with usual onset patients.^20,26 Irrespective of their young age, patients with early onset T2DM are extremely insulin resistant,²⁷ characterized by obesity as a major predisposing factor, where the age of onset has an inverse relationship with body mass index (BMI).²⁰ Clustering of multiple risk factors such as obesity, hypertension, and dyslipidemia is a common characteristic among patients with early onset T2DM.^28,29 In addition, a majority of these young patients have a family history of T2DM, and they lead a sedentary life style.³⁰ At present, it is unknown whether the findings from all these studies also apply to all the population in India. The objective of this study was to address this knowledge gap by comparing the characteristics of early onset T2DM and usual onset T2DM patients from our clinic population.

Subjects, Materials and Methods

All study participants gave their written and informed consent before their enrolment in this cross-sectional study and the study was approved by the Institutional Ethics Committee of Medical Trust Hospital, Kulanada. Study participants were T2DM patients categorized into two groups based upon the age at diagnosis: the early onset group (<45 years of age^20,29) and the usual onset group (≥50 years of age). The age of diabetes onset between 20 and 44 years was chosen for the early onset group. Those with type 1 diabetes and gestational diabetes were excluded from the study. Patients, whose age of disease onset was below 20 years, were excluded to avoid possible inclusion of type 1 diabetes. Consecutive patients, both men and women, having disease duration of 5 years or less attending our diabetes clinic were recruited. A total of 184 patients were enrolled for the study; 98 for the early onset and 86 for the usual onset group. The recruitment of study subjects was done over a period of 6 months.

Data collected included the age of onset of diabetes, gender, height, weight, family history of diabetes, systolic and diastolic blood pressures, and details of antidiabetic treatment. A positive family history of diabetes was defined as having at least one first-degree relative with diabetes. The presence of hypertension was defined as taking antihypertensive agents or a recorded systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg. BMI (kg/m²) was calculated with patient's weight (kg) divided by height squared (m²). Waist circumference (WC) cutoff was used 90 cm for males and 80 cm for females as specified for South Asians.⁸

Both fasting and 2 hr postprandial blood were drawn from each patient for various biochemical measurements. Plasma glucose was measured by enzymatic hexokinase procedure (AU480 Chemistry System; Beckman Coulter). Glycosylated hemoglobin (HbA1c) was measured by high performance liquid chromatography (D10, Bio-Rad Laboratories). Total cholesterol, triglycerides, and high-density lipoprotein were measured by enzymatic methods (AU480 Chemistry System; Beckman Coulter), and C-peptide was measured by a chemiluminescence immunoassay (Cobas E411 Immunoassay Analyzer; Roche).

Neuropathy was defined as an abnormal biothesiometry. Prevalence of hypertension was defined as history of hypertension (or received treatment for hypertension) or measured systolic blood pressure >130 mm Hg and/or diastolic blood pressure >90 mm Hg. A person was classified as having dyslipidemia if he/she had any of the following characteristics: total cholesterol >200 mg/dL, low-density lipoprotein cholesterol (LDL-C) >130 mg/dL, high-density lipoprotein cholesterol (HDL-C <40 (males) and <50 (female) 36 mg/dL, or triglycerides >150 mg/dL. Metabolic syndrome was recorded according to the International Diabetes Federation's definition.³¹ Peripheral vascular disease was considered present if the ankle–brachial index measured is 0.9 or less.

Statistical analyses

Data are represented as means ± standard error of the mean. The significance of the difference was tested by t-test for independent variables and a two-tailed model was used. Chi-squared test was used to compare categorical variables between two groups. A P-value <0.05 was considered significant.

Results

Clinical and biochemical profile of patients is summarized in Table 1. The mean age was 35.67 ± 0.58 and 59.49 ± 0.64 years for the early onset and the usual onset group, respectively. The mean age of disease onset was 34 years versus 57 years and the disease duration was 1.8 years versus 2.4 years (P < 0.05) for the early onset and the usual onset groups, respectively. The majority of the patients were male in the early onset (77.5%) as well as in the usual onset (53%) group.

Table 1.

Clinical and Biochemical Profiles of Study Participants

Parameters	EO-T2DM	UO-T2DM	P
Total no.	98	86
Female (%)	22.5	47.1	<0.05
Age (years)	35.67 ± 0.58	59.49 ± 0.64	<0.05
Age of onset (years)	33.92 ± 0.58	57.14 ± 0.62	<0.05
Duration of DM (years)	1.80 ± 0.16	2.40 ± 0.17	<0.05
Weight (kg)	68.26 ± 10.88	63.65 ± 11.48	<0.05
BMI (kg/m²)	24.50 ± 0.38	25.04 ± 0.48	NS
WC (cm)	89.58 ± 0.88	91.78 ± 1.00	NS
FBS (mg/dL)	206.30 ± 7.33	159.20 ± 6.75	<0.05
PPBS (mG/dL)	286.7 ± 11.30	239.78 ± 12.47	<0.05
HbA1c (%)	9.92 ± 0.29	8.94 ± 0.28	<0.05
T. CHOL (mg/dL)	206.56 ± 4.90	189.10 ± 4.92	<0.05
TGL (mg/dL)	149.33 ± 10.37	119.58 ± 5.83	<0.05
HDL (mg/dL)	39.46 ± 0.99	44.38 ± 1.43	<0.05
LDL (mg/dL)	136.94 ± 4.12	122.15 ± 4.87	<0.05
VLDL (mg/dL)	30.90 ± 2.71	24.29 ± 1.13	<0.05
C-peptide	2.85 ± 0.20	3.94 ± 0.27	<0.05
Serum creatinine	0.82 ± 0.01	1.00 ± 0.13	NS
Urine microalbumin	32.20 ± 9.86	30.34 ± 8.88	NS
Systolic BP (mm Hg)	124.43 ± 1.55	131.83 ± 2.08	<0.05
Diastolic BP (mm Hg)	82.78 ± 0.96	80.49 ± 0.95	NS

Values are presented as mean ± standard error of the mean; P < 0.05 is considered significant.

BMI, body mass index; BP, blood pressure; DM, diabetes mellitus; EO, early onset; FBS, fasting blood sugar; HbA1c, glycosylated hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; NS, not significant; PPBS, postprandial blood sugar; T2DM, type 2 diabetes mellitus; TGL, triglycerides; VLDL, very low density lipoproteins; UO, usual onset; WC, waist circumference.

Family history of T2DM component, as determined by any first-degree relative with T2DM, was stronger in the early onset group (74.2%), when compared with the usual onset group (41.5%, P < 0.05). In the early onset group, more than 40% has a family history of either parent with diabetes (41.2% mother and 47.4% father), while 17% of them having a history of both parents with diabetes. There was no significant difference in the average BMI (24.50 kg/m² vs. 25.04 kg/m²) and the percentage of obese patients (44% vs. 44.2%) between the early onset and usual onset groups. Although the proportion of central obesity was higher in usual onset group (64%), 52.7% of early onset group had central obesity as measured by WC.

Co-morbidities

There was a significant difference for the plasma lipids between the early onset and usual onset groups (Table 1), showing higher values in the mean total cholesterol level (207 mG/dL vs. 189 mG/dL, P < 0.05), mean LDL level (137 mG/dL vs. 122 mG/dL, P < 0.05), and mean triglyceride level (149 mG/dL vs. 120 mG/dL, P < 0.05) for the early onset group. Similarly, mean HDLC level was significantly lower (39 mG/dL vs. 44 mG/dL, P < 0.05) for the early onset group when compared with the usual onset group. The total cholesterol-to-HDL-C ratio was much higher in the early onset T2DM group (5.4 vs. 4.5, P < 0.05). Among the early onset group, 55% had higher cholesterol, 30% had higher triglycerides, and 69% had lower HDL (Table 2). Moreover, among the early onset group, 91.8% of subjects had one of any dyslipidemia as opposed to 76.5% (P < 0.05) in the usual onset group (Table 2).

Table 2.

Proportion of Patients Having Different Lipid Abnormalities

Lipid abnormality	EO-T2DM	UO-T2DM	Difference	P
Total cholesterol >200	50	32.6	17.4	0.02
TGL >150	25.5	16.3	9.2	0.16
HDL <40 (male), <50 (female)	59.2	44.2	15	0.06
LDL >130	74.5	57	17.5	0.02
Any one dyslipidemia	91.8	76.5	15.3	0.005
All 4 lipid abnormalities	13.3	4.7	8.6	0.05
≥2 Lipid abnormalities	68.4	50.6	17.8	0.018

Chi-squared test was used to determine the difference (at 95% CI) and significance; P < 0.05 was considered significant.

CI, confidence interval.

The average level of C-peptide was significantly lower in early onset group (2.85 nG/mL vs. 3.94 nG/mL, P < 0.05) in comparison with the usual onset group (Table 1). The proportions of patients having various C-peptide levels are listed in Table 3. We also found that, in the early onset group, the C-peptide level decreases significantly as the disease duration increases (Table 3). While the prevalence of hypertension was higher with usual onset T2DM (56.6%), 41.8% of those with early onset T2DM group also had hypertension. However, diastolic hypertension was higher in those with early onset T2DM compared with usual onset T2DM (36% vs. 27%). A proportion of 46% of patients in the early onset T2DM group had three or more metabolic syndrome components as opposed to 55% of patients in the usual onset T2DM group.

Table 3.

C-Peptide Levels Versus Disease Duration

C-peptide (ng/mL)	EO-T2DM (%)	UO-T2DM (%)	Disease duration EO-T2DM (years)	Disease duration UO-T2DM (years)
≤1.0	9.0^a	1.3	3.7 ± 0.6^b	3
1.0 to 3.0	55.1^a	35.9	2.0 ± 0.2^b	2.7 ± 0.3
>3	32.6^a	61.5	1.1 ± 0.2^b	2.4 ± 0.2

Proportion of patients having various C-peptide levels and corresponding average duration of disease is tabulated for each study group.

Significant difference between EO and UO T2DM groups.

Significant difference between the C-peptide groups.

Diabetes control

Glycemic control of the patients was assessed by their blood sugar and HbA1c values. The mean fasting blood sugar values (Table 1) were significantly higher among early onset T2DM group than the usual onset T2DM group (206 mg/dL vs. 159 mg/dL, P ≤ 0.05). Similarly, postprandial blood sugar values were significantly higher among early onset T2DM group than the usual onset T2DM groups (287 mg/dL vs. 240 mg/dL, P ≤ 0.05). Majority of the patients in the early onset T2DM group was having poor glycemic control as 65% (Table 4) of them had their fasting blood sugar more than 150 mg/dL and 63% had postprandial blood sugar more than 250 mg/dL compared with 36%, and 31%, respectively, for the usual onset T2DM group (Table 4). Likewise, the mean HbA1c value was significantly higher among early onset T2DM group than the usual onset T2DM group (9.92 vs. 8.94%, P ≤ 0.05, Table 1) and additionally, 73.3% had their HbA1c value >8 in the early onset T2DM group, which is only 50% for the usual onset T2DM group (Table 4).

Table 4.

Proportion of Patients Having Poor Glycemic Control

Parameter	EO-T2DM (%)	UO-T2DM (%)	Difference (%)	Significance level (P)
FBS (>150 mg/dL)	65	36	39.40	<0.0001
PPBS (>250 mg/dL)	63.44	31.25	15.70	0.0327
HbA1c (>8%)	73.3	50	32.10	0.0001

Chi-squared test was used to determine the difference (at 95% CI) and significance; P < 0.05 was considered significant.

Complications

Neuropathy (mild to severe) was found significantly higher in the usual onset T2DM group (71%) in comparison with the early onset T2DM group, which was 35%. Only one patient was found suffering from diabetic retinopathy in the usual onset T2DM group, but none from the early onset T2DM group. The disease duration of the study participants were 5 years or less and that may be the reason for the absence of retinopathy in early onset group and the presence of only one patient with retinopathy in the usual onset group. Although the number of patients with peripheral vascular disease was higher in usual onset T2DM (8.4%), 3.8% of patients with early onset T2DM also had peripheral vascular disease.

Treatment

The proportion of the patients requiring insulin treatment was almost similar in the early onset T2DM group (10.4%) as in the usual onset T2DM group (11.8%). The rest of the patients (except 4%) in the early onset T2DM group were on oral hypoglycemic agents, either on sulphonylurea alone (3.1% vs. 8.1%), or biguanides alone (33.3% vs. 43%), or in combination of both (48.9% vs. 38.4%) in comparison with usual onset T2DM group. None of the study participants was under lipid-lowering therapy.

Discussion

The current study performed on consecutive T2DM patients demonstrate that early onset T2DM is a phenotype having significant future risks for microvascular and cardiovascular complications at a younger age than later onset cohort. The relative protection generally granted for being young adult is severely compromised with the ever increasing occurrence of early onset T2DM. Exposure to adverse diabetic milieu at young age and the longer exposure of the same due to increasing life expectancy are important contributing factors to this phenomenon. Early onset group in the current study presented with a worse level of poor glycemic control both in terms of average blood sugar values (Table 1) and proportion of patients with poor glycemic control, (Table 4) despite undergoing antihyperglycemic treatments similar to that of the usual onset group. Hyperglycemia is an established independent predictor of cardiovascular disease in T2DM.^32,33 It is also known that as the disease duration prolongs, the metabolic control of the patient generally deteriorates regardless of the mode of treatment.^34,35 The current study signifies the long-term risk of complications in the early onset T2DM. It is also alarming that equal percentage of patients in the early onset group (10.4%) have progressed into insulin therapy similar to usual onset group (11.8%), and despite having the insulin therapy, their average fasting blood sugar continued to be at a significantly higher level (226.67 ± 22.48 mg/dL) than the usual onset group (135.73 ± 13.17 mg/dL). The higher levels of hyperglycemia in younger group compared with the older patients could be because of their increased working hours and decreased physical activity and of their confidence in being young.^4,36 It can be assumed that the knowledge and attitude toward the disease and its management are severely lacking in the young population. Similar trend was reported in other studies done on early onset T2DM as well.^4,21,29

Although the early onset group is significantly heavier than the usual onset group (Table 1), the BMI is similar in both the groups. The average BMI values of both the study groups are higher than the normal cutoff values for Indians.³⁷ This observation of similar BMI for both early onset and usual onset T2DM patients corroborates other studies done on Asians^4,38 and is in contrary to what is observed in studies done on Caucasians, where the early onset T2DM group had significantly higher BMI when compared with the usual onset group.^20,21,29 Obesity based on WC is considered as a better predictor for diabetes in Asian Indians than based on BMI.^39,40 The mean WC is similar for men in both early onset T2DM (90.53 cm) and usual onset (91.4 cm) group, and the average values are at the cutoff values recommended for Asian Indians. However, women showed not only a higher level of abdominal obesity but also a significant difference in WC between early onset T2DM (89.6 cm) and usual onset (92.2 cm). The inverse relationship between obesity and age of diagnosis of T2DM²⁹ was not observed in our study, and obesity as measured by BMI or WC has found no correlation with early onset T2DM in the current study.

Early onset T2DM patients in the current study not only have high levels of lipid abnormalities but also the levels are worse than the levels in the usual onset T2DM group. Dyslipidemia is considered as a major contributing factor for the cardiovascular risk profile and cardiovascular complications in the early onset T2DM.^21,26,41 Higher levels of triglycerides, lower HDL-C levels, and higher ratio of total cholesterol to HDL-C or triglycerides to HDL-C are features of dyslipidemia in T2DM⁴² and predictors of cardiovascular disease.^43,44 The various components of the dyslipidemia in T2DM are not individual abnormalities but closely linked to each other metabolically,⁴² making dyslipidemia the major risk factor for atherosclerosis and coronary artery disease. Based on the above studies and observations, the early onset T2DM patients in the current study are at a significantly higher long-term risk for CVD complications than the usual onset T2DM patients.

The current study observed a significantly higher proportion of early onset T2DM patients having positive family history of diabetes. It could be explained that the high prevalence of family history of diabetes in our population is part of the reason for the high incidence rates of T2DM in our population even at a younger age.⁴⁵ A study done in the United Kingdom on the incidence of T2DM in children report that 71% of patients had a family history of diabetes.³⁰ Similarly, a positive family history of diabetes was found in all patients in a study done on Asian Indian urban children with T2DM.⁴⁶ Another Indian study indicates that a positive family history of diabetes would be a signal for the onset of diabetes at a younger age.⁴⁷ Moreover, early onset T2DM patients of South Asian origin were reported to have more frequent positive family history of T2DM than their European counterparts.⁴⁸ Our results mirror these findings and identify family history of T2DM as a strong predictor for the development of early onset T2DM. The risk for developing T2DM is higher in those who are having positive family history of diabetes not only because of genetic predisposition but also because families often share similar environment.

The C-peptide levels in the early onset group in the present study show their clinical heterogeneity (Table 3). Just 33% of early onset T2DM patients had a C-peptide level >3 ng/mL, which can be a measure of their insulin resistance, leaving the majority (55%) of them within the normal C-peptide levels, whereas, 62% of the usual onset T2DM patients had a C-peptide level of >3 mg/mL (Table 3). Insulin resistance places an increased demand on the beta cells to hypersecrete insulin and that influences the progressive beta cell failure in T2DM.⁴⁹ It can be assumed that the patients who have normal C-peptide levels in this group may be at a stage of declining insulin secretion and beginning of beta cell destruction. This assumption is based on the observation that the C-peptide levels in the early onset T2DM groups showed an inverse relationship with the disease duration (Table 3). The average disease duration was 3.9 years for those patients whose C-peptide levels are <1 ng/mL, 2 years for C-peptide between 1 and 3 ng/mL, and 1.1 years for C-peptide >3 ng/mL and the differences were significant (P < 0.05). Whereas, for the usual onset group the disease duration was 3, 2.7 and 2.4 years, respectively, for the patients of C-peptide levels <1, 1–3, and >3 ng/mL and the differences were not significant. Our results are consistent with the hypothesis that disease progression in the early onset T2DM is more rapid and characterized by severe insulin resistance followed by defect in beta cell insulin secretion.^50

–53

T2DM with metabolic syndrome will have a higher risk for cardiovascular disease than those with T2DM or metabolic syndrome alone,⁵⁴ and it is believed that such risk is much higher in early onset T2DM with metabolic syndrome.⁵⁵ Although the prevalence of microvascular complications was lower for early onset T2DM patients in the current study, they nevertheless have a much higher complication rate than usual onset group at similar chronological age due to their longer disease duration and poor glycemic control.²⁶ There are evidences already to propose that early onset T2DM is associated with an increased risk for complications compared with usual onset diabetes^20,56 and that the development and progression of complications might be more rapid in early onset T2DM.^26,57

In summary, our results indicate that patients with early onset T2DM have worse glycemic control and dyslipidemia than the usual onset T2DM patients from the same clinic. Family history of diabetes emerged as the single most important predictor for the early onset type 2 diabetes in our population. Above all, early onset T2DM is a disease phenotype with adverse risk factors having poor glycemic control and longer disease duration. This phenomenon sets a new and grave challenge for proper diabetes management.

Footnotes

Acknowledgments

We thank the patients for their participation and the research staff of Medical Trust Hospital and Diabetes Care Centre for their assistance.

Author Disclosure Statement

No conflicting financial interests exist.

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