- Email: [email protected]
Prevalence of double diabetes in youth onset diabetes patients from east Delhi and neighboring NCR region
G Model DSX 862 No. of Pages 4
Diabetes & Metabolic Syndrome: Clinical Research & Reviews xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Diabetes & Metabolic Syndrome: Clinical Research & Reviews journal homepage: www.elsevier.com/locate/dsx
Original Article
Prevalence of double diabetes in youth onset diabetes patients from east Delhi and neighboring NCR region B.K. Mishra, P. Shukla, M. Aslam, A.A. Siddiqui, S.V. Madhu* Department of Endocrinology, Centre for Diabetes Endocrinology & Metabolism, University College of Medical Sciences & Guru Teg Bahadur Hospital, Delhi, India
A R T I C L E I N F O
A B S T R A C T
Article history: Available online xxx
Background: It is being increasingly reported that some of the youth onset diabetes patients cannot be classified clearly as type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) based on usual criteria and the term double diabetes (DD) coined for these cases. Aim: The objective of the study was to find out the prevalence of DD in youth onset diabetes patients from east Delhi and neighboring NCR region. Methods: A total of 200 patients with youth onset diabetes below 25 years of age were recruited from a tertiary care hospital in East Delhi. Clinical history, family history of diabetes and anthropometry of patients were recorded. Fasting serum C-peptide, Anti-IA2-antibody and Anti-GAD-antibody were measured in all patients. Patients positive for Anti-GAD-antibody (>1.05 U/ml) and C-peptide level >0.3 nmol/l were characterized as DD patients. Patients negative for Anti-GAD-antibody and C-peptide >0.3 nmol/l were kept under the category of T2DM. Patients with low C-peptide level along with one of the following, positive Anti-GAD-antibody, positive Anti-IA2-antibody and diabetic ketoacidosis (DKA) were considered as T1DM. Remaining patients were kept under the unknown category. Results: Mean age of study subjects was 18.2 7.1 years. Seven percent (7%) of the subjects were classified as DD, 51% as T1DM, 13% as T2DM and 29% were kept under the unknown category. Mean age of subjects with 22.2 9.7, 16.9 6.7, 20.6 7.7 and 19.4 7.4 years in DD, T1DM, T2DM and unknown category respectively. Mean BMI of subjects with DD, T1DM, T2DM and unknown category was 19.8 5.7, 16.6 3.7, 19.3 4.1 and 18.0 4.6 kg/m2 respectively. Conclusion: Double diabetes is an important occurrence among youth onset diabetes subjects. Only half of the subjects with youth onset of diabetes had T1DM. © 2017 Diabetes India. Published by Elsevier Ltd. All rights reserved.
Keywords: Anti GAD antibody Anti IA2 antibody C-peptide Double diabetes
1. Introduction Double diabetes, is a condition in which subjects have characteristics of both type 1 and type 2 diabetes. It can develop in individuals who are already having type 1 or type 2 diabetes mellitus [1–4]. If an individual has type 1 diabetes and during a certain period of time he starts gaining excess weight and becomes obese then insulin resistance can develop as obesity is a major risk factor for development of insulin resistance and T2DM [5–8]. Similarly if an individual already has T2DM then it is believed that due to the long standing glucotoxicity and lipotoxicity metabolic
Abbreviations: DD, double diabetes; DOY, diabetes of young; DKA, diabetic ketoacidosis; NCR, national capital region. * Corresponding author at: Department of Endocrinology, Centre for Diabetes Endocrinology & Metabolism, University College of Medical Sciences & Guru Teg Bahadur Hospital, Delhi 110095, India. E-mail address: [email protected] (S.V. Madhu).
immuno-suppression occurs which further changes the T cell immunity and can lead to autoimmunity. If a patient with type 2 diabetes stops producing insulin due to islet cell destruction, insulin dependence supervenes resulting in the entity that charecterizes double diabetes [9–13]. Double diabetes subjects have symptoms of both types of diabetes and while treating these subjects one needs to take care of insulin requirements as well as measures to treat obesity [1–4]. There are very few studies reporting the prevalence of double diabetes in youth onset diabetes subjects [1,10]. Therefore present study was planned to study the antibody profile, glycemic profiles and C-peptide in young diabetes subjects with young age at onset i.e. below 25 years belonging to East Delhi and neighboring NCR region to assess the prevalence rate of double diabetes among them.
http://dx.doi.org/10.1016/j.dsx.2017.08.016 1871-4021/© 2017 Diabetes India. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: B.K. Mishra, et al., Prevalence of double diabetes in youth onset diabetes patients from east Delhi and neighboring NCR region, Diab Met Syndr: Clin Res Rev (2017), http://dx.doi.org/10.1016/j.dsx.2017.08.016
G Model DSX 862 No. of Pages 4
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B.K. Mishra et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews xxx (2017) xxx–xxx
Table 1 Demographic and glycemic profile of study subjects. Variables
T1DM (n = 102)
T2DM (n = 26)
Unknown (n = 58)
Double diabetes (n = 14)
P-value
Age (years) Male/female (%) Duration of diabetes (years)
16.9 6.7 62.5/37.4 3.0 3.9 (0–16)
20.6 7.7 43.5/56.5 2.65 3.7 (0–15)
19.4 7.4 62.1/37.9 5.4 4.5 (0–19)
22.2 9.7 42.8/57.2 1.8 2.1 (0–7)
BMI (kg/m2) Positive family history of diabetes (%) Fasting plasma glucose (mg/dl) Postprandial plasma glucose (mg/ dl) Fasting serum insulin (m IU/ml)
16.6 3.7 15.0
19.3 4.1 19.3
18.0 4.6 24.1
19.8 5.7 28.7
a,b,d,e,f = > 0.05, c = 0.05 – a,c,e = > 0.05, b = < 0.001, d, f = < 0.05 a,b,d,e,f = > 0.05, c = 0.05 –
249.8 106.6 292.2 104.6
231.5 95.6 273.7 122.6
262.1 130.4 299.8 125.3
217.1 127.7 253.6 83.2
a,b,c,d,e,f = > 0.05 a,b,c,d,e,f = > 0.05
12.2 10.1 (1.63– 52.0) 10.4 2.7
16.2 28.2 (1.84– 123.0) 9.3 3.4
12.7 12.2 (1.58– 61.4) 10.3 2.4
5.0 5.1 (1.99–18.1)
a,b,c,d,e,f = > 0.05
10.9 4.1
a,b,c,d,e,f = > 0.05
HbA1c (%)
a = T1DM vs T2DM, b = T1DM vs Unknown, c = T1DM vs DD, d = T2DM vs Unknown, e = T2DM vs DD, f = Unknown vs DD.
2. Methods
3. Results
Study was approved by Institutional ethics committee-Human research, University college of medical sciences, Delhi. Written consent was obtained from all study participants. 200 diabetes subjects with young age at onset i.e. below 25 years of age from east Delhi and neighboring NCR region were recruited from those enrolled under the project “Registry of people with diabetes with young age at onset” of Indian Council of Medical Research, New Delhi India. A structured questionnaire was filled to obtain data on socio-economic parameters and behavioural aspects. Anthropometric measurements were carried out. Family history was obtained to assess the role of genetic factors. Glycaemic measures i.e., fasting plasma glucose, postprandial plasma glucose (glucose oxidase peroxidase method) and HbA1c (HPLC method, BioRad Kit) were also done in all the study subjects. Serum C-peptide, insulin, Anti-IA2-antibody and Anti-GAD-antibody were measured in fasting samples. Serum C-peptide, insulin, Anti-IA2-antibody were measured using radioimmunoassay kits (Beckman Coulter, USA) and Anti-GAD-antibody were measured using ELISA kit (DRG, USA). Specificity, sensitivity, inter assay and intra assay precision of C-peptide kit was 97%, 0.011 ng/ml, <5.2% and <3.1%, insulin kit was 100%, 0.5 m IU/ml, <3.4% and <4.3%, Anti-IA2-antibody kit was 100%, 0.16 U/ml, <5.3% and <2.8% and Anti-GAD-antibody kit was 87.1%, 85.0%, <5.4% and <4.6% respectively. Youth onset diabetes subjects recruited in the study were initially classified on the basis of pre defined WHO criteria [14]. The study subjects were re-categorized as T1DM, T2DM and double diabetes based on their antibodies and C peptide concentrations (Anti-GAD-antibody, Anti-IA2-antibody, DKA and C-peptide levels). Subjects positive for Anti-GAD(>1.05 U/ml) and C-peptide levels more than 0.3 nmol/l were characterized as double diabetes subjects; subjects negative for Anti-GAD and C-peptide >0.3 nmol/ l were kept under the category of T2DM and subjects with Cpeptide <0.3 nmol/l and have any one of the following i.e. positive Anti-GAD-antibody, positive Anti-IA2-antibody or DKA were kept under the category of T1DM. Subjects who had low level of Cpeptide but were negative for Anti-GAD-antibody, Anti-IA2antibody or DKA were kept under the unknown category. Statistical analysis: One way ANOVA followed by Tukey’s test was used to compare age, duration of diabetes, BMI, fasting insulin, fasting and postprandial plasma glucose and HbA1c between the groups using SPSS 20.0. Data was considered significantly different if P-value was <0.05.
The demographic details and glycemic profile of study subjects under various categories has been presented in Table 1. Mean age of study subjects was 18.2 7.1 years. Seven percent (7%, n = 14) of the subjects were classified as DD, 51% (n = 102) as T1DM, 13% (n = 26) as T2DM and 29% (n = 58) were kept under the unknown category as per our study criteria defined on the basis of Anti-GAD, Anti IA2, DKA and C-peptide (Fig. 1). Three out of 14 subjects with DD were characterized as T2DM clinically and 11 were characterized as type 1 diabetes mellitus clinically. Twenty nine percent (29%, n = 58) of the subjects with low C-peptide level were found negative for all antibodies and were also negative for DKA. These cases were kept under the unknown category. Anti GAD was the most prominent (29.5%) type of antibody followed by Anti IA2 (13%) found in the present study. C-peptide was found to be high in 20% of the subjects. Data of family history shows that 28.7% of subjects with DD had a positive family history of diabetes (first degree relative). Antibody positivity rates in DOY (diabetes of young) subjects with increasing duration of diabetes has been shown in Table 2. There was a progressive decline in Anti-GAD and Anti-IA2 antibodies concentrations with increase in duration of diabetes. Fifty percent (50%, n = 7) of the subjects with DD, 30.3% subjects with T2DM, 29.8% subjects of unknown category and 17.52% subjects with T1DM had diabetes related complications. Ten (10) out of 14 subjects were on insulin, 3 on oral antidiabetic agents (OADs) and 1 on insulin plus OADs in the DD group. Ninty three (93) out of 102 subjects with T1DM were on insulin and 9 on OADs.
Fig. 1. Various categories of youth onset diabetes subjects. n = 200. T1DM; type 1 diabetes mellitus, T2DM; type 2 diabetes mellitus, DD; double diabetes.
Please cite this article in press as: B.K. Mishra, et al., Prevalence of double diabetes in youth onset diabetes patients from east Delhi and neighboring NCR region, Diab Met Syndr: Clin Res Rev (2017), http://dx.doi.org/10.1016/j.dsx.2017.08.016
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Table 2 Autoantibody positivity according to duration of youth onset diabetes. Duration of diabetes (years)
Antibody positive (Anti-GAD and Anti-IA2 antibody)
0–2.5 2.5–5 5–7.5 >7.5
60/118 (50.84%) 14/31 (45.16%) 4/18(22.22%) 6/33(18.18%)
Eighteen (18) out of 26 subjects were on OADs and 8 on insulin plus OADs in T2DM group. In unknown group, 54 out of 58 were on insulin and 4 on OADs. 4. Discussion Present study in subjects of diabetes with young age at onset in the age group 03-32 years found 7% of subjects who had the characteristics of both type 1 and type2 diabetes and were labelled as double diabetes. This is the first study from India to report on the prevalence of double diabetes in the subjects with young age at onset. It would help to better characterize diabetes in younger subjects particularly those who have phenotypes of both T1DM and T2DM. Prevalence of double diabetes was found to be 32% in Caucasian populations [10] and 4.61% in the study conducted in continental Italy [1] as compared to 7% in our study indicating the role of geographic variance and genetic factors. However Reinehr et al. who reported a higher prevalence of double diabetes (32%) have not mentioned the duration of diabetes in their study. It is unclear whether shorter duration of diabetes in these subjects resulted in a higher rate of antibody positivity [15,16], which might be an important factor underlying the difference in prevalence of double diabetes from our study. When the subjects in our study were analyzed considering the duration of diabetes we found highest antibody positive with shorter duration of diabetes mellitus. This could also explain the absence of Anti GAD antibodies in a significant number of clinically diagnosed T1DM in our study as many (29%) of those subjects had diabetes for more than 5 years. Antibody profiling done in the initial stage after the onset of diabetes to obtain the actual autoimmune status could characterize diabetes subjects more accurately. Double diabetes subjects were older, more obese and had a stronger family history of diabetes as compared with T1DM subjects. They also had a higher proportion of females and a relatively shorter duration of diabetes at diagnosis. 11 out of 14 DD subjects were clinically T1DM it may be possible that these subjects may have susceptible genes for T2DM also. Obesity in double diabetes could be the result of weight gain in T1DM subjects [5–8] or as a result of development of autoimmunity in primarily obese T2DM subjects [9–13]. In T1DM, insulin can be considered as a factor associated with weight gain and obesity which further results in Insulin resistance, a characteristic of T2DM [6]. Obesity is also seen to be associated autoimmunity as fat cells attracts the macrophages which carries cytokines and reduces the sensitivity of insulin receptors causing insulin resistance a typical characteristic of T2DM and increases the chance of conversion of T1DM to DD10. As per the accelerator hypothesis both type 1 as well as type 2 diabetes mellitus depends upon insulin resistance and beta cell destruction, the only difference is rate of occurrence [11]. Similarly in T2DM subjects chronic inflammation raises due to the obesity which is associated with insulin resistance. T cell mediated immunity and circulating inflammatory proteins like IL-6 and IL1b leads to the functional and structural destruction of beta cells. Cytokine-associated reaction in the form of innate immune response has also been shown to be associated with T2DM [9–13]. Lifestyle modifications, including diet and exercise, which are relevant for the prevention of type 2 diabetes, may be important
modifiable environmental factors also for type 1 diabetes prevention in subjects with double diabetes1.In double diabetes subjects the risk of complication of both types of diabetes increases and consequently these subjects will be more prone to microvascular, macrovascular and metabolic complication which will further worsen the condition [17]. A precise treatment including a combination of life style measures and adequate insulin is required to be made for this class of subjects for improving their glycemic control and prevent diabetes related complications. In conclusion, double diabetes is an important occurrence among youth onset diabetes subjects. A strong positive family history and higher BMI can be clinical indicators to identify such cases among those with apparent TIDM. Funding Financial grant for this research work was provided by Indian Council of Medical Research (ICMR), New Delhi, India. Grant ID: 55/ 3/5/Registry/2012-NCD-II Conflict of interest All authors declare no conflict of interest. References [1] Pozzilli P, Chiara G, Sonia C, Buzzetti R, et al. Obesity, autoimmunity, and double diabetes in youth. Diab Care 2011;34(Supplement 2):S166–70. [2] Pozzilli P, Buzzetti R. A new expression of diabetes: double diabetes. Trends Endocrinol Metab 2007;18(2):52–7. [3] Pozzilli P, Chiara G, Ekaterina P, Elena P. Double or hybrid diabetes associated with an increase in type 1 and type 2 diabetes in children and youths. Pediatr Diab 2007;8(s9):88–95. [4] Pozzilli P, Guglielmi C. Double diabetes: a mixture of type 1 and type 2 diabetes in youth. Karger 2009;14:151–66. [5] Cleland J, Fisher BM, Colhoun HM, Sattar N, Petrie JR. Insulin resistance in type 1 diabetes: what is ‘double diabetes’ and what are the risks? Diabetologia 2013;56(7):1462–70. [6] Kilpatrick ES, Rigby AS, Atkin SL. Insulin resistance, the metabolic syndrome, and complication risk in type 1 diabetes double diabetes in the diabetes control and complications trial. Diab Care 2007;30(3):707–12. [7] Conway B, Miller R, Costacou T, Fried L, Kelsey S, Evans RW. Temporal patterns in overweight and obesity in type 1 diabetes. Diabet Med 2010;27(4):398–404. [8] Kahn Barbara B, Flier Jeffrey S. Obesity and insulin resistance. J Clin Invest 2000;106(4):473–81. [9] Man'kovs' kyı B, Urbanovych A. The blood leptin and the activity of the system inflammatory response in patients with diabetes mellitus type 2 with different body weight and disease duration. Fiziolohichnyizhurnal (Kiev, Ukraine: 1994) 2013;60(4):56–60. [10] Reinehr T, Schober E, Wiegand S, Thon A, Holl R. b-Cell autoantibodies in children with type 2 diabetes mellitus: subgroup or misclassification? Arch Dis Child 2006;91(6):473–7. [11] Wilkin T. The accelerator hypothesis: a review of the evidence for insulin resistance as the basis for type I as well as type II diabetes. Int J Obes 2009;33 (7):716–26. [12] Brooks-Worrell B, Palmer P. Immunology in the clinic review series; focus on metabolic diseases: development of islet autoimmune disease in type 2 diabetes patients: potential sequelae of chronic inflammation. J Transl Immunol 2011;167:40–6. [13] Pietropaolo M, Barinas-Mitchell E, Pietropaolo S, Kuller HL, Trucco M. Evidence of islet cell autoimmunity in elderly patients with type 2 diabetes. Diabetes 2000;49:32–6. [14] Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: report of a WHO/IDF consultation. Geneva: World Health Organization; 2006.
Please cite this article in press as: B.K. Mishra, et al., Prevalence of double diabetes in youth onset diabetes patients from east Delhi and neighboring NCR region, Diab Met Syndr: Clin Res Rev (2017), http://dx.doi.org/10.1016/j.dsx.2017.08.016
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[15] Ohta M, Ohta K, Hiroshi O, Naoto N, Hirofumi S, Koji N, et al. Clinical evaluation of a radioimmunoprecipitation assay for IA-2 antibody and comparison of GAD antibody in type 1 diabetes mellitus. Autoimmunity 2000;32(2):79–88. [16] Tuomilehto J, Vidgren G, Toivanen L, Tuomilehto E, Kohtamaki K, Stengard J, et al. Antibodies to glutamic acid decarboxylase as predictors of insulin-
dependent diabetes mellitus before clinical onset of disease. Lancet 1994;343 (8910):1383–5. [17] Nwosu BU, Double diabetes: the evolving treatment paradigm in children and adolescents. 2013; 2(1):1–3.
Please cite this article in press as: B.K. Mishra, et al., Prevalence of double diabetes in youth onset diabetes patients from east Delhi and neighboring NCR region, Diab Met Syndr: Clin Res Rev (2017), http://dx.doi.org/10.1016/j.dsx.2017.08.016
Diabetes & Metabolic Syndrome: Clinical Research & Reviews xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Diabetes & Metabolic Syndrome: Clinical Research & Reviews journal homepage: www.elsevier.com/locate/dsx
Original Article
Prevalence of double diabetes in youth onset diabetes patients from east Delhi and neighboring NCR region B.K. Mishra, P. Shukla, M. Aslam, A.A. Siddiqui, S.V. Madhu* Department of Endocrinology, Centre for Diabetes Endocrinology & Metabolism, University College of Medical Sciences & Guru Teg Bahadur Hospital, Delhi, India
A R T I C L E I N F O
A B S T R A C T
Article history: Available online xxx
Background: It is being increasingly reported that some of the youth onset diabetes patients cannot be classified clearly as type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) based on usual criteria and the term double diabetes (DD) coined for these cases. Aim: The objective of the study was to find out the prevalence of DD in youth onset diabetes patients from east Delhi and neighboring NCR region. Methods: A total of 200 patients with youth onset diabetes below 25 years of age were recruited from a tertiary care hospital in East Delhi. Clinical history, family history of diabetes and anthropometry of patients were recorded. Fasting serum C-peptide, Anti-IA2-antibody and Anti-GAD-antibody were measured in all patients. Patients positive for Anti-GAD-antibody (>1.05 U/ml) and C-peptide level >0.3 nmol/l were characterized as DD patients. Patients negative for Anti-GAD-antibody and C-peptide >0.3 nmol/l were kept under the category of T2DM. Patients with low C-peptide level along with one of the following, positive Anti-GAD-antibody, positive Anti-IA2-antibody and diabetic ketoacidosis (DKA) were considered as T1DM. Remaining patients were kept under the unknown category. Results: Mean age of study subjects was 18.2 7.1 years. Seven percent (7%) of the subjects were classified as DD, 51% as T1DM, 13% as T2DM and 29% were kept under the unknown category. Mean age of subjects with 22.2 9.7, 16.9 6.7, 20.6 7.7 and 19.4 7.4 years in DD, T1DM, T2DM and unknown category respectively. Mean BMI of subjects with DD, T1DM, T2DM and unknown category was 19.8 5.7, 16.6 3.7, 19.3 4.1 and 18.0 4.6 kg/m2 respectively. Conclusion: Double diabetes is an important occurrence among youth onset diabetes subjects. Only half of the subjects with youth onset of diabetes had T1DM. © 2017 Diabetes India. Published by Elsevier Ltd. All rights reserved.
Keywords: Anti GAD antibody Anti IA2 antibody C-peptide Double diabetes
1. Introduction Double diabetes, is a condition in which subjects have characteristics of both type 1 and type 2 diabetes. It can develop in individuals who are already having type 1 or type 2 diabetes mellitus [1–4]. If an individual has type 1 diabetes and during a certain period of time he starts gaining excess weight and becomes obese then insulin resistance can develop as obesity is a major risk factor for development of insulin resistance and T2DM [5–8]. Similarly if an individual already has T2DM then it is believed that due to the long standing glucotoxicity and lipotoxicity metabolic
Abbreviations: DD, double diabetes; DOY, diabetes of young; DKA, diabetic ketoacidosis; NCR, national capital region. * Corresponding author at: Department of Endocrinology, Centre for Diabetes Endocrinology & Metabolism, University College of Medical Sciences & Guru Teg Bahadur Hospital, Delhi 110095, India. E-mail address: [email protected] (S.V. Madhu).
immuno-suppression occurs which further changes the T cell immunity and can lead to autoimmunity. If a patient with type 2 diabetes stops producing insulin due to islet cell destruction, insulin dependence supervenes resulting in the entity that charecterizes double diabetes [9–13]. Double diabetes subjects have symptoms of both types of diabetes and while treating these subjects one needs to take care of insulin requirements as well as measures to treat obesity [1–4]. There are very few studies reporting the prevalence of double diabetes in youth onset diabetes subjects [1,10]. Therefore present study was planned to study the antibody profile, glycemic profiles and C-peptide in young diabetes subjects with young age at onset i.e. below 25 years belonging to East Delhi and neighboring NCR region to assess the prevalence rate of double diabetes among them.
http://dx.doi.org/10.1016/j.dsx.2017.08.016 1871-4021/© 2017 Diabetes India. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: B.K. Mishra, et al., Prevalence of double diabetes in youth onset diabetes patients from east Delhi and neighboring NCR region, Diab Met Syndr: Clin Res Rev (2017), http://dx.doi.org/10.1016/j.dsx.2017.08.016
G Model DSX 862 No. of Pages 4
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B.K. Mishra et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews xxx (2017) xxx–xxx
Table 1 Demographic and glycemic profile of study subjects. Variables
T1DM (n = 102)
T2DM (n = 26)
Unknown (n = 58)
Double diabetes (n = 14)
P-value
Age (years) Male/female (%) Duration of diabetes (years)
16.9 6.7 62.5/37.4 3.0 3.9 (0–16)
20.6 7.7 43.5/56.5 2.65 3.7 (0–15)
19.4 7.4 62.1/37.9 5.4 4.5 (0–19)
22.2 9.7 42.8/57.2 1.8 2.1 (0–7)
BMI (kg/m2) Positive family history of diabetes (%) Fasting plasma glucose (mg/dl) Postprandial plasma glucose (mg/ dl) Fasting serum insulin (m IU/ml)
16.6 3.7 15.0
19.3 4.1 19.3
18.0 4.6 24.1
19.8 5.7 28.7
a,b,d,e,f = > 0.05, c = 0.05 – a,c,e = > 0.05, b = < 0.001, d, f = < 0.05 a,b,d,e,f = > 0.05, c = 0.05 –
249.8 106.6 292.2 104.6
231.5 95.6 273.7 122.6
262.1 130.4 299.8 125.3
217.1 127.7 253.6 83.2
a,b,c,d,e,f = > 0.05 a,b,c,d,e,f = > 0.05
12.2 10.1 (1.63– 52.0) 10.4 2.7
16.2 28.2 (1.84– 123.0) 9.3 3.4
12.7 12.2 (1.58– 61.4) 10.3 2.4
5.0 5.1 (1.99–18.1)
a,b,c,d,e,f = > 0.05
10.9 4.1
a,b,c,d,e,f = > 0.05
HbA1c (%)
a = T1DM vs T2DM, b = T1DM vs Unknown, c = T1DM vs DD, d = T2DM vs Unknown, e = T2DM vs DD, f = Unknown vs DD.
2. Methods
3. Results
Study was approved by Institutional ethics committee-Human research, University college of medical sciences, Delhi. Written consent was obtained from all study participants. 200 diabetes subjects with young age at onset i.e. below 25 years of age from east Delhi and neighboring NCR region were recruited from those enrolled under the project “Registry of people with diabetes with young age at onset” of Indian Council of Medical Research, New Delhi India. A structured questionnaire was filled to obtain data on socio-economic parameters and behavioural aspects. Anthropometric measurements were carried out. Family history was obtained to assess the role of genetic factors. Glycaemic measures i.e., fasting plasma glucose, postprandial plasma glucose (glucose oxidase peroxidase method) and HbA1c (HPLC method, BioRad Kit) were also done in all the study subjects. Serum C-peptide, insulin, Anti-IA2-antibody and Anti-GAD-antibody were measured in fasting samples. Serum C-peptide, insulin, Anti-IA2-antibody were measured using radioimmunoassay kits (Beckman Coulter, USA) and Anti-GAD-antibody were measured using ELISA kit (DRG, USA). Specificity, sensitivity, inter assay and intra assay precision of C-peptide kit was 97%, 0.011 ng/ml, <5.2% and <3.1%, insulin kit was 100%, 0.5 m IU/ml, <3.4% and <4.3%, Anti-IA2-antibody kit was 100%, 0.16 U/ml, <5.3% and <2.8% and Anti-GAD-antibody kit was 87.1%, 85.0%, <5.4% and <4.6% respectively. Youth onset diabetes subjects recruited in the study were initially classified on the basis of pre defined WHO criteria [14]. The study subjects were re-categorized as T1DM, T2DM and double diabetes based on their antibodies and C peptide concentrations (Anti-GAD-antibody, Anti-IA2-antibody, DKA and C-peptide levels). Subjects positive for Anti-GAD(>1.05 U/ml) and C-peptide levels more than 0.3 nmol/l were characterized as double diabetes subjects; subjects negative for Anti-GAD and C-peptide >0.3 nmol/ l were kept under the category of T2DM and subjects with Cpeptide <0.3 nmol/l and have any one of the following i.e. positive Anti-GAD-antibody, positive Anti-IA2-antibody or DKA were kept under the category of T1DM. Subjects who had low level of Cpeptide but were negative for Anti-GAD-antibody, Anti-IA2antibody or DKA were kept under the unknown category. Statistical analysis: One way ANOVA followed by Tukey’s test was used to compare age, duration of diabetes, BMI, fasting insulin, fasting and postprandial plasma glucose and HbA1c between the groups using SPSS 20.0. Data was considered significantly different if P-value was <0.05.
The demographic details and glycemic profile of study subjects under various categories has been presented in Table 1. Mean age of study subjects was 18.2 7.1 years. Seven percent (7%, n = 14) of the subjects were classified as DD, 51% (n = 102) as T1DM, 13% (n = 26) as T2DM and 29% (n = 58) were kept under the unknown category as per our study criteria defined on the basis of Anti-GAD, Anti IA2, DKA and C-peptide (Fig. 1). Three out of 14 subjects with DD were characterized as T2DM clinically and 11 were characterized as type 1 diabetes mellitus clinically. Twenty nine percent (29%, n = 58) of the subjects with low C-peptide level were found negative for all antibodies and were also negative for DKA. These cases were kept under the unknown category. Anti GAD was the most prominent (29.5%) type of antibody followed by Anti IA2 (13%) found in the present study. C-peptide was found to be high in 20% of the subjects. Data of family history shows that 28.7% of subjects with DD had a positive family history of diabetes (first degree relative). Antibody positivity rates in DOY (diabetes of young) subjects with increasing duration of diabetes has been shown in Table 2. There was a progressive decline in Anti-GAD and Anti-IA2 antibodies concentrations with increase in duration of diabetes. Fifty percent (50%, n = 7) of the subjects with DD, 30.3% subjects with T2DM, 29.8% subjects of unknown category and 17.52% subjects with T1DM had diabetes related complications. Ten (10) out of 14 subjects were on insulin, 3 on oral antidiabetic agents (OADs) and 1 on insulin plus OADs in the DD group. Ninty three (93) out of 102 subjects with T1DM were on insulin and 9 on OADs.
Fig. 1. Various categories of youth onset diabetes subjects. n = 200. T1DM; type 1 diabetes mellitus, T2DM; type 2 diabetes mellitus, DD; double diabetes.
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Table 2 Autoantibody positivity according to duration of youth onset diabetes. Duration of diabetes (years)
Antibody positive (Anti-GAD and Anti-IA2 antibody)
0–2.5 2.5–5 5–7.5 >7.5
60/118 (50.84%) 14/31 (45.16%) 4/18(22.22%) 6/33(18.18%)
Eighteen (18) out of 26 subjects were on OADs and 8 on insulin plus OADs in T2DM group. In unknown group, 54 out of 58 were on insulin and 4 on OADs. 4. Discussion Present study in subjects of diabetes with young age at onset in the age group 03-32 years found 7% of subjects who had the characteristics of both type 1 and type2 diabetes and were labelled as double diabetes. This is the first study from India to report on the prevalence of double diabetes in the subjects with young age at onset. It would help to better characterize diabetes in younger subjects particularly those who have phenotypes of both T1DM and T2DM. Prevalence of double diabetes was found to be 32% in Caucasian populations [10] and 4.61% in the study conducted in continental Italy [1] as compared to 7% in our study indicating the role of geographic variance and genetic factors. However Reinehr et al. who reported a higher prevalence of double diabetes (32%) have not mentioned the duration of diabetes in their study. It is unclear whether shorter duration of diabetes in these subjects resulted in a higher rate of antibody positivity [15,16], which might be an important factor underlying the difference in prevalence of double diabetes from our study. When the subjects in our study were analyzed considering the duration of diabetes we found highest antibody positive with shorter duration of diabetes mellitus. This could also explain the absence of Anti GAD antibodies in a significant number of clinically diagnosed T1DM in our study as many (29%) of those subjects had diabetes for more than 5 years. Antibody profiling done in the initial stage after the onset of diabetes to obtain the actual autoimmune status could characterize diabetes subjects more accurately. Double diabetes subjects were older, more obese and had a stronger family history of diabetes as compared with T1DM subjects. They also had a higher proportion of females and a relatively shorter duration of diabetes at diagnosis. 11 out of 14 DD subjects were clinically T1DM it may be possible that these subjects may have susceptible genes for T2DM also. Obesity in double diabetes could be the result of weight gain in T1DM subjects [5–8] or as a result of development of autoimmunity in primarily obese T2DM subjects [9–13]. In T1DM, insulin can be considered as a factor associated with weight gain and obesity which further results in Insulin resistance, a characteristic of T2DM [6]. Obesity is also seen to be associated autoimmunity as fat cells attracts the macrophages which carries cytokines and reduces the sensitivity of insulin receptors causing insulin resistance a typical characteristic of T2DM and increases the chance of conversion of T1DM to DD10. As per the accelerator hypothesis both type 1 as well as type 2 diabetes mellitus depends upon insulin resistance and beta cell destruction, the only difference is rate of occurrence [11]. Similarly in T2DM subjects chronic inflammation raises due to the obesity which is associated with insulin resistance. T cell mediated immunity and circulating inflammatory proteins like IL-6 and IL1b leads to the functional and structural destruction of beta cells. Cytokine-associated reaction in the form of innate immune response has also been shown to be associated with T2DM [9–13]. Lifestyle modifications, including diet and exercise, which are relevant for the prevention of type 2 diabetes, may be important
modifiable environmental factors also for type 1 diabetes prevention in subjects with double diabetes1.In double diabetes subjects the risk of complication of both types of diabetes increases and consequently these subjects will be more prone to microvascular, macrovascular and metabolic complication which will further worsen the condition [17]. A precise treatment including a combination of life style measures and adequate insulin is required to be made for this class of subjects for improving their glycemic control and prevent diabetes related complications. In conclusion, double diabetes is an important occurrence among youth onset diabetes subjects. A strong positive family history and higher BMI can be clinical indicators to identify such cases among those with apparent TIDM. Funding Financial grant for this research work was provided by Indian Council of Medical Research (ICMR), New Delhi, India. Grant ID: 55/ 3/5/Registry/2012-NCD-II Conflict of interest All authors declare no conflict of interest. References [1] Pozzilli P, Chiara G, Sonia C, Buzzetti R, et al. Obesity, autoimmunity, and double diabetes in youth. Diab Care 2011;34(Supplement 2):S166–70. [2] Pozzilli P, Buzzetti R. A new expression of diabetes: double diabetes. Trends Endocrinol Metab 2007;18(2):52–7. [3] Pozzilli P, Chiara G, Ekaterina P, Elena P. Double or hybrid diabetes associated with an increase in type 1 and type 2 diabetes in children and youths. Pediatr Diab 2007;8(s9):88–95. [4] Pozzilli P, Guglielmi C. Double diabetes: a mixture of type 1 and type 2 diabetes in youth. Karger 2009;14:151–66. [5] Cleland J, Fisher BM, Colhoun HM, Sattar N, Petrie JR. Insulin resistance in type 1 diabetes: what is ‘double diabetes’ and what are the risks? Diabetologia 2013;56(7):1462–70. [6] Kilpatrick ES, Rigby AS, Atkin SL. Insulin resistance, the metabolic syndrome, and complication risk in type 1 diabetes double diabetes in the diabetes control and complications trial. Diab Care 2007;30(3):707–12. [7] Conway B, Miller R, Costacou T, Fried L, Kelsey S, Evans RW. Temporal patterns in overweight and obesity in type 1 diabetes. Diabet Med 2010;27(4):398–404. [8] Kahn Barbara B, Flier Jeffrey S. Obesity and insulin resistance. J Clin Invest 2000;106(4):473–81. [9] Man'kovs' kyı B, Urbanovych A. The blood leptin and the activity of the system inflammatory response in patients with diabetes mellitus type 2 with different body weight and disease duration. Fiziolohichnyizhurnal (Kiev, Ukraine: 1994) 2013;60(4):56–60. [10] Reinehr T, Schober E, Wiegand S, Thon A, Holl R. b-Cell autoantibodies in children with type 2 diabetes mellitus: subgroup or misclassification? Arch Dis Child 2006;91(6):473–7. [11] Wilkin T. The accelerator hypothesis: a review of the evidence for insulin resistance as the basis for type I as well as type II diabetes. Int J Obes 2009;33 (7):716–26. [12] Brooks-Worrell B, Palmer P. Immunology in the clinic review series; focus on metabolic diseases: development of islet autoimmune disease in type 2 diabetes patients: potential sequelae of chronic inflammation. J Transl Immunol 2011;167:40–6. [13] Pietropaolo M, Barinas-Mitchell E, Pietropaolo S, Kuller HL, Trucco M. Evidence of islet cell autoimmunity in elderly patients with type 2 diabetes. Diabetes 2000;49:32–6. [14] Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: report of a WHO/IDF consultation. Geneva: World Health Organization; 2006.
Please cite this article in press as: B.K. Mishra, et al., Prevalence of double diabetes in youth onset diabetes patients from east Delhi and neighboring NCR region, Diab Met Syndr: Clin Res Rev (2017), http://dx.doi.org/10.1016/j.dsx.2017.08.016
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Please cite this article in press as: B.K. Mishra, et al., Prevalence of double diabetes in youth onset diabetes patients from east Delhi and neighboring NCR region, Diab Met Syndr: Clin Res Rev (2017), http://dx.doi.org/10.1016/j.dsx.2017.08.016