A study of non-obese diabetes mellitus in adults in a tertiary care hospital in Kerala, India
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- Chandni, R., Paul, B.J., Udayabhaskaran, V. et al. Int J Diabetes Dev Ctries (2013) 33: 83. doi:10.1007/s13410-013-0113-7
The term Latent Autoimmune Diabetes in Adults (LADA) was introduced to define adult diabetic patients initially non–insulin-requiring but with immune markers of type 1 diabetes that, in a number of cases, progress to insulin dependency. This term has been largely used in the last few years when referring to autoimmune forms of diabetes not requiring insulin initially. In the present study we looked for the clinical, biochemical and immunological parameters of non-obese type 2 diabetes mellitus in adults and studied the frequency of antibodies to glutamic acid decarboxylase (GAD) and pancreatic islet cell antibodies (PICA). Subjects of 30 years or older with a history of diabetes of duration not more than 36 months and body mass index (BMI) of less than 23 kg/m2 were included. Fasting serum C-peptide, GAD antibody and islet cell auto antibody was estimated. GAD antibodies were positive in 25.81 %, ICA in 22.58 % and both in 9.70 % of lean diabetes. Fasting serum C-peptide was less than normal in 45.16 % of them.
KeywordsLatent autoimmune diabetes in adult (LADA)Lean diabetesGAD antibodyIslet cell antibody (ICA)Serum C-peptide
Even though Type 2 diabetes constitutes about 85 to 95 % of all diabetes, a subset are non-obese, similar in clinical presentation to obese type 2 diabetes mellitus but rapidly need insulin for glycemic control. With the discovery of glutamic acid decarboxylase (GAD) antibodies as another marker of type 1 diabetes mellitus, Paul Zimmet et al  introduced the term “Latent Autoimmune Diabetes in Adult” (LADA) to describe these patients with adult onset diabetes. Typical patients are positive for GAD antibodies, 35 years of age or older, non-obese, and present without ketoacidosis and weight loss. Although many maintain good glycemic control for several years with oral agents, they become “insulin dependent” more rapidly than antibody-negative type 2 diabetic patients. This form is called LADA . The presence of auto antibodies to Islet cell cytoplasm (ICAs) and/or to GAD 65 (GADAs) is the best predictor of the early insulin requirement . This study was planned with the following aims.
To study the clinical, biochemical and immunological parameters of non-obese type 2 diabetes mellitus in adults.
To study the frequency of antibodies to GAD and ICA in this group of patients.
Materials and methods
Patients of 30 years of age or older with diabetes duration not more than 36 months and BMI of less than 23 kg/m2 were included in this study. They did not have other co-existing illnesses or infections. Patients are selected from the general medicine out-patient departments of Medical College, Kozhikode, Kerala during the study period satisfying the inclusion criteria. Institutional Ethical Committee approval was obtained and informed consents were taken from all patients. Besides clinical evaluation, investigations included fasting and 2 h post-prandial blood glucose, urine albumin-creatinine ratio, blood urea, serum creatinine, HbA1c and fasting serum C-peptide measured by ADVIA Centaur C-peptide assay which was considered normal at 0.5–3.0 ng/ml. GAD antibodies assessed using GAD- Ig G Elisa kit were considered normal at <0.9 U/ml and positive >1.1 U/ml. ICA was estimated in all patients using immunoradiometric assay for in vitro determination of Anti-IA2 (IRMA Anti-IA2) was considered normal at <1.0U/ml value. Statistical analysis was done using SPSS version 16.
Thirty one patients were included in the study (13 men; 42 %, 18 women; 58 %) from May 2004 to April 2006. Gestational diabetes was reported in 3 (9.7 %) women. Mean (± SD, 95 % CI) values of clinical and biochemical parameters of the study subjects were, age 43.55 (± 10.67, CI 39.63–47.46), duration of diabetes 14.71 months (± 11.39, CI 10.53–18.89), BMI 18.74 kg/m2 (± 2.85, CI 17.7–19.79), waist circumference 74.74 cm (± 7.29, CI 72.07–77.41), systolic blood pressure 123.94 mm of Hg (± 10.84, CI 119.96–127.91), diastolic blood pressure 81.16 mm of Hg (± 6.94, CI 78.62–83.71). Fasting blood glucose 160.84 mg/dl (± 68.91, CI 135.56–186.12), post prandial blood glucose 244.06 mg/dl (± 82.71, 95 % 213.73–274.4) and HbA1c was 8.68 % (± 2.52).
Of the 31 patients, 13 (41.94 %) were on insulin, 17 (54.84 %) were on oral anti-diabetic drugs and 1 (3.22 %) on diet and exercise alone. Microvascular complications were uncommon, non-proliferative retinopathy was seen in two patients, proliferative retinopathy in one patient and diabetic maculopathy in three. GAD was positive in 8 (25.81 %), ICA in 7 (22.58 %) and both in 3 (9.7 %). Fasting serum C- peptide was less than normal in 14 (45.16 %).
Latent autoimmune diabetes in adults (LADA) is an immune mediated diabetes that occurs in adults and is marked by loss of beta cells that occurs more rapidly than in those without autoantibodies . Multiple autoantibodies in circulation to islet antigens found in Type 1 diabetes are also seen in the LADA subset of patients; single antibody positivity for GAD is more prevalent than IAA and IA-2A [2, 3]. LADA has been characterized in the early 1980s  and the name LADA has been used from 1990s [1, 2]. In the UK Prospective Diabetes study 13% of 25 to 44 year old people were positive for ICA and GAD and of these 94 % required insulin therapy by 6 years. Another study  examining 268 people with type 2 diabetes diagnosed age 18 to 45 years found 11.6 % had potential LADA. These people with apparent type 2 diabetes actually have a type 1 condition which will leave them requiring insulin within 6 years of diagnosis. These findings suggest that there are people with LADA requiring insulin treatment than with ‘classical’ type 1 diabetes.
There are few studies on the presence of LADA from India . The prevalence of LADA is not estimated in Northern Kerala. The type 2 diabetes mellitus and the co-existing metabolic syndrome have gained much attention stressing the need for preventive strategies. As LADA behaves more like type 1 diabetes, the management will include the need for early Insulin therapy for good glycemic control. However several epidemiological studies have demonstrated that LADA patients represent at least 10 % or more of those diagnosed with Type 2 diabetes . This proportion can vary from population to population. LADA behaves more like type 1 diabetes and the current management strategy is to institute early insulin therapy for good glycemic control.
In this study, GAD antibody and ICA positivity co-existed with insulin deficiency, suggesting a possible causative effect of autoimmunity in reducing the pancreatic β-cell function. It is now known that LADA is a slowly progressing adult onset type 1 diabetes. Patients with LADA may have single islet cell-specific autoantibody positivity , unlike in type 1 diabetes with multiple antibody positivity. C-peptide levels do not differ at onset but decreased gradually in LADA. However, the decline in residual β-cell function was progressive in majority LADA patients and this decline was not related to age, gender, BMI, antibody titres, HbA1c or treatment modality .
In conclusion, GAD antibodies were positive in 25.81 %, ICA in 22.58 % and both in 9.70 % of the lean diabetes from Northern Kerala. Fasting serum C-peptide was less than normal in 45.16 % in the present study. They must be screened for microvascular complications at presentation, as were a few patients had retinopathy by 3 years of diabetes.
Supported by a grant from the Research Society for the Study of Diabetes in India, Kerala chapter.
Conflict of interest
No conflicts of interest.