p r i m a r y c a r e d i a b e t e s 9 ( 2 0 1 5 ) 231–236
Contents lists available at ScienceDirect
Primary Care Diabetes journal homepage: http://www.elsevier.com/locate/pcd
Original research
Latent autoimmune diabetes amongst adults with type 2 diabetes in a Nigerian tertiary hospital Arinola Ipadeola a,∗ , Jokotade O. Adeleye a , Kehinde S. Akinlade b a b
Department of Medicine, University College Hospital, Ibadan, Nigeria Department of Chemical Pathology, University College Hospital, Ibadan, Nigeria
a r t i c l e
i n f o
a b s t r a c t
Article history:
Aims: The aim was to investigate the frequency and characteristics of persons with latent
Received 14 June 2014
autoimmune diabetes in adults (LADA) amongst patients who had been clinically diagnosed
Received in revised form
as type 2 diabetes mellitus (CT2DM) in a tertiary care centre.
6 September 2014
Methodology: One hundred and sixty patients with CT2DM participated in this cross-sectional
Accepted 14 September 2014
study following selection by systematic random sampling. Demographic data, relevant clini-
Available online 11 October 2014
cal history and anthropometric measurements (weight, height, waist circumference and hip circumference) were taken and blood samples were obtained for analysis of fasting blood
Keywords:
glucose, glycated haemoglobin (HbA1c) and glutamic acid decarboxylase antibodies (GADA).
Type 2 diabetes mellitus
The results were analysed using SPSS version 16.
Latent autoimmune diabetes in
Results: Nineteen (11.9%) out of 160 persons with CT2DM were positive for GADA. 95(59.4%)
adults
of the total study population were females. The mean (SD) age, BMI, waist circumference,
Glutamic acid decarboxylase
were 60.49 (10.37) years, 26.47 (4.80) kg/m2 , 92.16 (11.50) cm respectively.
antibody
Subjects with CT2DM who were GADA positive had trend towards lower mean BMI (25.64 kg/m2 vs. 26.59 kg/m2 ) and waist circumference (89.80 kg/m2 vs. 92.47 kg/m2 ) than GADA negative subjects. GADA positive subjects also had a trend showing higher mean fasting blood glucose (144 mg/dl vs. 125 mg/dl, t = 2.20, p = 0.14), higher mean HbA1c (7% vs. 6.1%, t = 3.19, p = 0.077) and a higher proportion on insulin (31.6% vs. 22%, 2 = 0.07, p = 0.25) when compared with GADA negative patients. Conclusion: The prevalence of LADA amongst a subset of Nigerians with CT2DM was 11.9%. There were no distinguishing clinical features to help characterize persons with LADA. The above finding emphasizes the importance of GADA testing for appropriate classification of persons with CT2DM. Early diagnosis of LADA would help direct appropriate therapy to optimize glycaemic control. © 2014 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.
Abbreviations: ADA, American Diabetic Association; BMI, body mass index; BP, blood pressure; CT2DM, clinical type 2 diabetes mellitus; DCCT, Diabetes Control and Complications Trial; DM, diabetes mellitus; EDTA, ethylenediamine tetra acetic acid; GAD, glutamic acid decarboxylase; GADA, glutamic acid decarboxylase antibody; HbA1c, glycated haemoglobin; HLA, human leucocyte antigen; IAA, autoantibody to insulin; IA-2A, IA-2, autoantibody to tyrosine phosphatases; ICA, islet cell antibody; IDDM, insulin dependent diabetes mellitus; IDF, International Diabetes Federation; LADA, latent autoimmune diabetes in adults; MOP, Medical Outpatients Clinic; MRDM, malnutrition related diabetes mellitus; OHA, oral hypoglycaemic agents; Type 1 DM, type 1 diabetes mellitus; Type 2 DM, type 2 diabetes mellitus; UKPDS, United Kingdom Prospective Diabetes Study; WHO, World Health Organization. ∗ Corresponding author. Tel.: +234 8037024916. E-mail address: [email protected] (A. Ipadeola). http://dx.doi.org/10.1016/j.pcd.2014.09.003 1751-9918/© 2014 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.
232
1.
p r i m a r y c a r e d i a b e t e s 9 ( 2 0 1 5 ) 231–236
Introduction
In routine clinical practice, persons with diabetes are categorized as type 1 or type 2 on the basis of their mode of presentation and phenotypic appearance. Following such classification, the first line of management is usually lifestyle modification followed by medications which may be insulin therapy or oral hypoglycaemic agents (OHAs) or a combination of both. Some patients diagnosed clinically as persons with type 2 diabetes have surprisingly been shown to have autoantibodies, indicating diabetes of autoimmune aetiology. Latent autoimmune diabetes in adults (LADA) has been described as slowly progressive form of diabetes which results from autoimmune mediated destruction of the beta cells of the pancreas [1]. It is regarded as a sub-classification of type 1 diabetes mellitus (type 1 DM) but patients usually present with an insidious onset of disease suggestive of type 2 diabetes mellitus (type 2 DM). The presence of autoantibodies to islet cell antigens in adults clinically considered to have type 2 DM at the time of diagnosis has been found to be associated with gradual autoimmune  islet cell destruction [1]. Glutamic acid decarboxylase antibody (GADA) has been found to be the most prevalent antibody detected in LADA and in most cases the only detectable autoantibody [2]. The diagnosis of LADA is currently based on three criteria which include adult age at the time of diagnosis of diabetes, the presence of circulating autoantibody to pancreatic islet cell antigens, and the lack of requirement for insulin at the time of diagnosis of diabetes mellitus [3]. It is important to identify this group of patients who may have LADA because its natural history and treatment strategy are different from that of type 2 DM. They often experience marked loss of beta cell function within a few years of diagnosis and much earlier requirement for insulin compared with persons with type 2 DM. Therefore, early identification of LADA may help to convince patients and health care providers on the importance of a quicker and smoother transition to insulin therapy, rather than persistence with oral agents in the face of poor glycaemic control. These measures may help to improve metabolic control and reduce the risk of development of long term complications of DM.
2.
Methods
This was a cross-sectional study of 160 consenting persons with type 2 diabetes mellitus based on clinical presentation. It was carried out over a 3-month period after ethical clearance had been obtained from the Joint Institution Review Committee (IRC) of the University College Hospital and the College of Medicine, University of Ibadan. (UI/IRC/07/0068).
3.
Sampling technique
The study was conducted at the Medical outpatient clinic, University College Hospital, Ibadan. The calculated sample size was 138 patients using the formula by Lesie & Kisch n = Z2 pq/d. An average of 14 patients was selected weekly using systematic random sampling. The first patient was randomly selected
and every third patient who satisfied the inclusion criteria was recruited into the study, after obtaining consent. Anthropometric measurements were taken which included weight (kg), height (m), waist circumference (cm) and hip circumference (cm). Blood samples were obtained for analysis of fasting plasma glucose (FPG), HbA1c and antibodies to glutamic acid decarboxylase.
4.
Clinical assessment
4.1.
Weight and height measurement
Weight was measured (in kilograms) using a beam balance scale with subjects in light clothing and without shoes on. Height was also measured (in metres) using a portable height/length measuring board without the subjects wearing footwear, caps or other head gear. The head was kept in anatomical position and the highest point was taken as the height. Body mass index (BMI) was then calculated using the formula BMI = Weight/Height2 (kg/m2 ). A BMI of 18.5–24.9 was taken as normal. Values of 25–29.9 was in keeping with overweight and obesity with a value >30 [4].
4.2.
Waist circumference measurement
The waist circumference was measured using a flexible inelastic tape measure with the subject standing and breathing normally using the protocol recommended by the World Health Organization (WHO expert committee 1995). Standing to the side of the subject, without belts or heavy outer clothing, measurement was made directly over the skin. The subject stood comfortably with weight evenly distributed on both feet, and the feet apposed together. The arms hung loosely at the sides while the inferior margin (lowest point) of the last rib and the iliac crest (top of the hip bone) was located and marked with an erasable pen. The midpoint was determined with the use of a tape measure and the point marked. The tape rule was then applied over the marked midpoint and a check was made to ensure that the tape was horizontal across the back and front of the subject. The waist circumference was measured and read at the level of the tape to the nearest 0.1 cm. A waist circumference of ≥80 cm in females and ≥94 cm in males was taken as indicative of truncal obesity [5].
4.3.
Hip circumference measurement
The hip circumference was measured with the arms relaxed at the sides and standing with their feet together. The measuring tape was placed around the maximum circumference over the buttocks according to the WHO STEPS instrument [6]. The hip circumference was then measured and read at this level to the nearest 0.1 cm. This was measured only once and recorded on the subject’s questionnaire. The waist to hip ratio was also calculated and recorded in the questionnaire.
4.4.
Blood pressure measurement
Blood pressure was measured with the patients seated after at least 5 min rest. A mercury sphygmomanometer with a
p r i m a r y c a r e d i a b e t e s 9 ( 2 0 1 5 ) 231–236
standard adult cuff size of 12 cm was wrapped round the patient’s arm and placed at the heart level. The cuff was applied closely to the upper arm with the lower end about 2.5 cm above the cubital fossa. The patient was seated with the back resting on the chair; the non-dominant arm used was resting on the table while both feet were resting on the floor. Korotkoff sounds phases I and V were taken as the systolic and diastolic blood pressures respectively and values were recorded to the nearest 2 mmHg. Two readings were taken 2 min apart and the average was recorded. Patients with systolic or diastolic blood pressure of ≥140 and ≥90 mmHg respectively were regarded as having hypertension. In addition, patients on treatment for previously diagnosed hypertension were also regarded as having hypertension [7].
4.5.
Laboratory evaluation
Subjects were requested to come to the MOP after an overnight fast of 8–14 h. After being seated and allowed to rest for 5 min, a venepuncture was performed after cleaning the skin with 70% methylated spirit, using a new sterile disposable needle and syringe. Ten millilitres of blood was collected out of which 3 ml was put in a fluoride oxalate bottle for fasting blood glucose estimation, 3 ml into an EDTA bottle for HbA1c analysis and the remainder was transferred into a plain bottle for GADA estimation. Samples were centrifuged at 10–15,000 rpm for 5 min soon after to obtain serum which were batched and stored at −20 ◦ C until analysis.
4.6.
Blood glucose estimation
Blood glucose estimation was carried out using the glucose oxidase enzymatic method. A fasting plasma glucose of >120 mg/dl was taken as indicative of poor glycaemic control.
4.7.
HbA1c of ≤6.5% was taken as good control, while >6.5% was taken as poor glycaemic control.
4.9.
Data analysis
Results obtained were analysed using SPSS package version 16. Associations between variables were tested using the chi square for qualitative variables and the Student’s t-tests for quantitative variables. Statistical significance of the tests of association was set at p value of less than 0.05.
5.
Results
5.1.
Sociodemographic data
One hundred and sixty adult patients clinically diagnosed to have type 2 diabetes mellitus (CT2DM) participated in the study. These patients with CT2DM included 65 (40.6%) males and 95(59.4%) females. The mean age (SD) of the patients was 60.49 (10.37) years. Those in the age group of 60–69 years constituted the largest number of subjects (36.2%), while those in the 30–39 years age group were the least, accounting for only 3.8%. The mean (SD) age at DM diagnosis was 51.80 (10.53) years, with the range between 30 years and 74 years. The median DM duration amongst the subjects was 8 years.
5.2. Prevalence of latent autoimmune diabetes in adults Nineteen (11.9%) of the 160 patients with CT2DM were positive for GADA. Twelve (63.2%) were females and 7 (36.8%) were males. Out of the total number of females with CT2DM, 12.8% were GADA positive while 10.6% of the total number of males was GADA positive. (2 = 0.17, p = 0.068). The mean age (SD) in GADA positive and GADA negative patients with CT2DM were similar: 60.26 (10.09) years and 60.46 (10.53) years respectively (t = 0.01, p = 0.92) (Fig. 1).
Glutamic acid decarboxylase antibody estimation 5.3.
This was carried out using Enzyme linked immunosorbent assay kit from RSR Ltd., UK. This is a sensitive non-isotopic assay for GAD antibody estimation which offers even higher disease specificity and sensitivity than GADA isotopic assays. The assays were carried out in duplicates to ensure that assay drift was minimal. A cut-off of ≥10 units/ml was taken as positive according to the reference range provided by the manufacturer.
4.8.
233
Anthropometric parameters
Both groups were however noted to have mean BMI in the overweight range. GADA positive persons had a trend
Glycated haemoglobin estimation
Blood samples were obtained from 122 patients with CT2DM and stored at 2–8 ◦ C. Analysis was done within 1 week of storage using the HbA1c ionic exchange chromatographic method (DIALAB, AUSTRIA). When this method was compared to the US National Glycohaemoglobin Standardization Programme certified method (NGSP) which is DCCT referenced some correlation was obtained. The following formula was used to obtain DCCT referenced values: HbA1c (NGSP) (%) = 0.86 HbA1c − Dialab (%) + 0.24.
Fig. 1 – Percentage of clinically diagnosed type 2 DM patients positive for GADA. This figure shows the proportion of patients with CT2DM found to be positive and negative for GADA.
234
p r i m a r y c a r e d i a b e t e s 9 ( 2 0 1 5 ) 231–236
Table 1 – Characteristics of GADA positive compared with GADA negative patients amongst patients with clinically diagnosed type 2 DM. GADA positive n = 19 Mean (SD) Age (years) Age of onset of DM (years) Duration of DM (years) Weight (kg) Height (m) Body mass index (kg/m2 ) Waist circumference (cm) Hip circumference (cm) Waist–hip ratio Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Average fasting plasma glucose (mg/dl) HbA1c (%/mmol/mol) n = 122
60.26 (10.10) 50.79 (10.03) 9.47 (7.54) 68.68 (11.25) 1.64 (0.08) 25.64 (4.26) 89.8 (11.40) 96.87 (8.88) 0.93 (0.06) 140.84 (23.65) 81.89 (10.92) 144.23 (81.25) 7.0 (3.12) 53
GADA negative n = 141 Mean (SD)
t value
p value
60.52 (10.44) 52.11 (10.50) 8.42 (7.52) 69.74 (13.07) 1.62 (0.08) 26.59 (4.87) 92.47 (11.52) 99 (10.60) 0.94 (0.11) 135.56 (23.25) 81.02 (12.28) 125.8 (45.48) 6.10 (1.53) 42
0.91 0.268 0.312 0.113 0.888 0.65 0.903 0.702 0.223 0.86 0.087 2.199 3.185
0.918 0.606 0.57 0.737 0.347 0.421 0.343 0.403 0.638 0.355 0.769 0.14 0.077
This table shows that the mean age was similar in both groups but GADA positive persons with CT2DM, had trend towards lower mean BMI and waist circumference and waist–hip ratio but higher systolic blood pressure, fasting blood glucose and glycated haemoglobin compared with their GADA negative counterparts.
towards lower mean BMI (25.64 kg/m2 vs. 26.59 kg/m2 , p > 0.05) and lower waist circumference (89.80 kg/m2 vs. 92.47 kg/m2 , p > 0.05) than GADA negative subjects. Approximately 58% of the GADA positive patients had normal BMI as compared with 42.1% of GADA negative group, however showing no statistical significance difference (2 = 2.03, p = 0.378). When reviewed according to gender, males and females who were GADA positive showed a trend towards lower mean BMI and waist circumference when compared with their GADA negative counterparts. However, none of these observed differences attained statistical significance.
5.4.
Biochemical parameters
GADA positive subjects also had a higher mean fasting plasma glucose (144 mg/dl vs. 125 mg/dl, t = 2.20, p = 0.14), and a higher mean HbA1c levels (7% vs. 6.1% t = 3.19, p = 0.077). None of these findings were statistically significant (Table 1).
5.5.
Medication use
Approximately 37% of GADA positive patients were on a combination of sulphonylurea and biguanide therapy, while 31.6% were on insulin alone compared with 43.3% and 22% respectively in the GADA negative group. Although a larger proportion of patients who were GADA positive were receiving insulin therapy, the observed difference was also not statistically significant (2 = 0.25, p = 0.618).
6.
Discussion
Several studies done in various groups of patients with CT2DM in Finland, Australia, New Zealand, United States, United Kingdom, Germany, and Sweden have found the frequency of GADA positivity to range between 2 and 21% [1,2,8]. The UKPDS study, which is one of the largest studies done in patients with type 2 DM, reported a prevalence of 9.4% [9]. Studies conducted
amongst Africans have reported the prevalence of GADA in CT2DM as 2.5% amongst South Africans, while in Tanzania the prevalence was 5.3% [10,11]. In a study done in West Africa on the genetics of diabetes, with Ghana and Nigeria as centres, 10% of the patients with CT2DM were found to be positive for GADA [12]. This study found the prevalence of LADA as defined by GADA positivity amongst patients with CT2DM to be 11.9% and is about the same percentage found by AgyeiFrempong et al. in Kumasi, Ghana [13]. A recent study in a Lagos, Nigeria gave a prevalence of 14% which is similar to our finding [14]. Interestingly, the Lagos study was in a tertiary care centre like ours but more cosmopolitan in setting. The differences in prevalence from the various studies may be as a result of racial and ethnic variability, differences in sample selection techniques, the use of different assay techniques for detection of GADA and varying diagnostic criteria or cut off points. Also, population based studies have reported lower prevalence of islet autoantibodies (including GADA) when compared with hospital based studies [15,16]. A similar percentage of males and females in this study were GADA positive suggesting that there is no gender predilection for LADA which was also corroborated by reports from the Lagos study [14]. Abiru et al. [17] also reported equal gender distribution amongst GADA positive CT2DM patients in Japan, while Hamaguchi et al. [18] and Kim et al. [19] found a higher proportion of GADA positive males than females amongst CT2DM patients, in studies carried out in Japan and Korea respectively. Falorni et al. [20] reported that more females were GADA positive amongst persons with CT2DM. Gender distribution would have been a useful criterion in determining patient selection for antibody testing if there had been a difference. Although the mean weight, BMI, waist circumference and waist–hip ratio were above the normal cut-off points in this study, there was a trend towards lower values in GADA positive persons with CT2DM compared with GADA negative ones. In fact, a higher proportion of GADA positive persons in this study had normal BMI. Many studies have reported that GADA
p r i m a r y c a r e d i a b e t e s 9 ( 2 0 1 5 ) 231–236
positivity was not related to BMI, with similar prevalence rates in the obese and none obese groups of patients with type 2 DM. The Lagos study however, found that LADA patients were more likely to be overweight or obese which is in contrast to our finding, although the mean BMI in their LADA and GADA negative group were similar [14]. On the other hand, several studies have reported significantly lower BMI in GADA positive patients, irrespective of the ethnicity, age or gender distribution of the population studied [8,18,21]. A review of previous studies to relate clinical features with LADA found significant correlation between clinical findings and LADA in only 2 out of 184 studies [22]. In this study, there were no significant set of clinical phenotypic features that characterized the GADA positive persons with CT2DM. Latent autoimmune diabetes in adults has often been reported to be diagnosed in people who develop diabetes between 30 and 50 years of age [17]. The mean age of persons with LADA in this study was 60 years which was also the average age of the study population. Juneja et al. [23] suggested that the age may not be an important diagnostic factor in the diagnosis of LADA. However, some studies have suggested that increasing age may be a predisposing factor for LADA but the exact mechanism is yet to be determined [24]. Persons with CT2DM who were GADA positive in this study had a trend towards higher mean fasting blood glucose, higher mean HbA1c concentration and a higher proportion of persons with HbA1c above the optimal target range when compared with the GADA negative subjects. These findings are important because patients with LADA often experience marked loss of beta cell function within a few years of diagnosis, require increasing doses of oral hypoglycaemic medication and earlier use of insulin. If not recognized early metabolic and chronic complications may supervene. Also, a higher proportion of GADA positive patients were receiving insulin therapy when compared with those who were GADA negative. Similar findings have been reported in the Fremantle Diabetes Study report, where GADA positive CT2DM patients were reported to have higher glycosylated haemoglobin levels, and were more likely to be taking insulin, than GADA-negative CT2DM subjects [16].
7.
Conclusion
The prevalence of LADA amongst Nigerian patients clinically diagnosed as type 2 DM was 11.9% with no significant phenotypic differences observed. Clinical/phenotypic appearances may therefore not be adequate to differentiate adult Nigerians with LADA. GAD antibody testing is therefore important in our practice settings, so as to appropriately classify and manage adult patients with diabetes mellitus. The detection of GAD antibodies in persons with CT2DM may influence therapeutic options leading to improved glycaemic control, thus reducing long term complications of diabetes mellitus. Larger multicentre studies amongst persons with CT2DM would be necessary to further define the prevalence and clinical correlates of LADA in our practice settings.
8.
235
Limitations
Some limitations recognized in this study must be mentioned. Serum C-peptide levels were not measured due to cost related constraints. This could have helped in determining the degree of beta cell function and direct treatment, as regards identification of persons who are at a high risk of early progression to insulin dependency. Also, it would have been informative to test for other pancreatic autoantibodies especially islet cell antibody (ICA), as its presence along with GADA, has been reported to be highly predictive of insulin dependency. However ICA levels wane with longer duration of DM while GADA usually persists for several years. GADA is the more easily assayed of the two autoantibodies, with a higher sensitivity and specificity than ICA.
Authors’ contribution AI was responsible for the conception, design, acquisition of data, analysis, and drafting of manuscript. JOA was involved in design, acquisition of data, drafting of manuscript and revising it critically for important intellectual content. KSA was involved in design, drafting of manuscript and revising it critically for important intellectual content. All authors read and approved the final manuscript.
Conflict of interest The authors state that they have no conflict of interest.
Acknowledgements Special thanks to Prof. Olaleye, Dr. Odaibo, Dr. Bakare and Mr. Omoruyi, all of Virology department for their assistance with the storage and analysis of blood specimen for GADA. Sincere appreciation also goes to Dr. Obioma Uchendu and Mr. Adewole for assisting with the statistical analysis.
references
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Contents lists available at ScienceDirect
Primary Care Diabetes journal homepage: http://www.elsevier.com/locate/pcd
Original research
Latent autoimmune diabetes amongst adults with type 2 diabetes in a Nigerian tertiary hospital Arinola Ipadeola a,∗ , Jokotade O. Adeleye a , Kehinde S. Akinlade b a b
Department of Medicine, University College Hospital, Ibadan, Nigeria Department of Chemical Pathology, University College Hospital, Ibadan, Nigeria
a r t i c l e
i n f o
a b s t r a c t
Article history:
Aims: The aim was to investigate the frequency and characteristics of persons with latent
Received 14 June 2014
autoimmune diabetes in adults (LADA) amongst patients who had been clinically diagnosed
Received in revised form
as type 2 diabetes mellitus (CT2DM) in a tertiary care centre.
6 September 2014
Methodology: One hundred and sixty patients with CT2DM participated in this cross-sectional
Accepted 14 September 2014
study following selection by systematic random sampling. Demographic data, relevant clini-
Available online 11 October 2014
cal history and anthropometric measurements (weight, height, waist circumference and hip circumference) were taken and blood samples were obtained for analysis of fasting blood
Keywords:
glucose, glycated haemoglobin (HbA1c) and glutamic acid decarboxylase antibodies (GADA).
Type 2 diabetes mellitus
The results were analysed using SPSS version 16.
Latent autoimmune diabetes in
Results: Nineteen (11.9%) out of 160 persons with CT2DM were positive for GADA. 95(59.4%)
adults
of the total study population were females. The mean (SD) age, BMI, waist circumference,
Glutamic acid decarboxylase
were 60.49 (10.37) years, 26.47 (4.80) kg/m2 , 92.16 (11.50) cm respectively.
antibody
Subjects with CT2DM who were GADA positive had trend towards lower mean BMI (25.64 kg/m2 vs. 26.59 kg/m2 ) and waist circumference (89.80 kg/m2 vs. 92.47 kg/m2 ) than GADA negative subjects. GADA positive subjects also had a trend showing higher mean fasting blood glucose (144 mg/dl vs. 125 mg/dl, t = 2.20, p = 0.14), higher mean HbA1c (7% vs. 6.1%, t = 3.19, p = 0.077) and a higher proportion on insulin (31.6% vs. 22%, 2 = 0.07, p = 0.25) when compared with GADA negative patients. Conclusion: The prevalence of LADA amongst a subset of Nigerians with CT2DM was 11.9%. There were no distinguishing clinical features to help characterize persons with LADA. The above finding emphasizes the importance of GADA testing for appropriate classification of persons with CT2DM. Early diagnosis of LADA would help direct appropriate therapy to optimize glycaemic control. © 2014 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.
Abbreviations: ADA, American Diabetic Association; BMI, body mass index; BP, blood pressure; CT2DM, clinical type 2 diabetes mellitus; DCCT, Diabetes Control and Complications Trial; DM, diabetes mellitus; EDTA, ethylenediamine tetra acetic acid; GAD, glutamic acid decarboxylase; GADA, glutamic acid decarboxylase antibody; HbA1c, glycated haemoglobin; HLA, human leucocyte antigen; IAA, autoantibody to insulin; IA-2A, IA-2, autoantibody to tyrosine phosphatases; ICA, islet cell antibody; IDDM, insulin dependent diabetes mellitus; IDF, International Diabetes Federation; LADA, latent autoimmune diabetes in adults; MOP, Medical Outpatients Clinic; MRDM, malnutrition related diabetes mellitus; OHA, oral hypoglycaemic agents; Type 1 DM, type 1 diabetes mellitus; Type 2 DM, type 2 diabetes mellitus; UKPDS, United Kingdom Prospective Diabetes Study; WHO, World Health Organization. ∗ Corresponding author. Tel.: +234 8037024916. E-mail address: [email protected] (A. Ipadeola). http://dx.doi.org/10.1016/j.pcd.2014.09.003 1751-9918/© 2014 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.
232
1.
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Introduction
In routine clinical practice, persons with diabetes are categorized as type 1 or type 2 on the basis of their mode of presentation and phenotypic appearance. Following such classification, the first line of management is usually lifestyle modification followed by medications which may be insulin therapy or oral hypoglycaemic agents (OHAs) or a combination of both. Some patients diagnosed clinically as persons with type 2 diabetes have surprisingly been shown to have autoantibodies, indicating diabetes of autoimmune aetiology. Latent autoimmune diabetes in adults (LADA) has been described as slowly progressive form of diabetes which results from autoimmune mediated destruction of the beta cells of the pancreas [1]. It is regarded as a sub-classification of type 1 diabetes mellitus (type 1 DM) but patients usually present with an insidious onset of disease suggestive of type 2 diabetes mellitus (type 2 DM). The presence of autoantibodies to islet cell antigens in adults clinically considered to have type 2 DM at the time of diagnosis has been found to be associated with gradual autoimmune  islet cell destruction [1]. Glutamic acid decarboxylase antibody (GADA) has been found to be the most prevalent antibody detected in LADA and in most cases the only detectable autoantibody [2]. The diagnosis of LADA is currently based on three criteria which include adult age at the time of diagnosis of diabetes, the presence of circulating autoantibody to pancreatic islet cell antigens, and the lack of requirement for insulin at the time of diagnosis of diabetes mellitus [3]. It is important to identify this group of patients who may have LADA because its natural history and treatment strategy are different from that of type 2 DM. They often experience marked loss of beta cell function within a few years of diagnosis and much earlier requirement for insulin compared with persons with type 2 DM. Therefore, early identification of LADA may help to convince patients and health care providers on the importance of a quicker and smoother transition to insulin therapy, rather than persistence with oral agents in the face of poor glycaemic control. These measures may help to improve metabolic control and reduce the risk of development of long term complications of DM.
2.
Methods
This was a cross-sectional study of 160 consenting persons with type 2 diabetes mellitus based on clinical presentation. It was carried out over a 3-month period after ethical clearance had been obtained from the Joint Institution Review Committee (IRC) of the University College Hospital and the College of Medicine, University of Ibadan. (UI/IRC/07/0068).
3.
Sampling technique
The study was conducted at the Medical outpatient clinic, University College Hospital, Ibadan. The calculated sample size was 138 patients using the formula by Lesie & Kisch n = Z2 pq/d. An average of 14 patients was selected weekly using systematic random sampling. The first patient was randomly selected
and every third patient who satisfied the inclusion criteria was recruited into the study, after obtaining consent. Anthropometric measurements were taken which included weight (kg), height (m), waist circumference (cm) and hip circumference (cm). Blood samples were obtained for analysis of fasting plasma glucose (FPG), HbA1c and antibodies to glutamic acid decarboxylase.
4.
Clinical assessment
4.1.
Weight and height measurement
Weight was measured (in kilograms) using a beam balance scale with subjects in light clothing and without shoes on. Height was also measured (in metres) using a portable height/length measuring board without the subjects wearing footwear, caps or other head gear. The head was kept in anatomical position and the highest point was taken as the height. Body mass index (BMI) was then calculated using the formula BMI = Weight/Height2 (kg/m2 ). A BMI of 18.5–24.9 was taken as normal. Values of 25–29.9 was in keeping with overweight and obesity with a value >30 [4].
4.2.
Waist circumference measurement
The waist circumference was measured using a flexible inelastic tape measure with the subject standing and breathing normally using the protocol recommended by the World Health Organization (WHO expert committee 1995). Standing to the side of the subject, without belts or heavy outer clothing, measurement was made directly over the skin. The subject stood comfortably with weight evenly distributed on both feet, and the feet apposed together. The arms hung loosely at the sides while the inferior margin (lowest point) of the last rib and the iliac crest (top of the hip bone) was located and marked with an erasable pen. The midpoint was determined with the use of a tape measure and the point marked. The tape rule was then applied over the marked midpoint and a check was made to ensure that the tape was horizontal across the back and front of the subject. The waist circumference was measured and read at the level of the tape to the nearest 0.1 cm. A waist circumference of ≥80 cm in females and ≥94 cm in males was taken as indicative of truncal obesity [5].
4.3.
Hip circumference measurement
The hip circumference was measured with the arms relaxed at the sides and standing with their feet together. The measuring tape was placed around the maximum circumference over the buttocks according to the WHO STEPS instrument [6]. The hip circumference was then measured and read at this level to the nearest 0.1 cm. This was measured only once and recorded on the subject’s questionnaire. The waist to hip ratio was also calculated and recorded in the questionnaire.
4.4.
Blood pressure measurement
Blood pressure was measured with the patients seated after at least 5 min rest. A mercury sphygmomanometer with a
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standard adult cuff size of 12 cm was wrapped round the patient’s arm and placed at the heart level. The cuff was applied closely to the upper arm with the lower end about 2.5 cm above the cubital fossa. The patient was seated with the back resting on the chair; the non-dominant arm used was resting on the table while both feet were resting on the floor. Korotkoff sounds phases I and V were taken as the systolic and diastolic blood pressures respectively and values were recorded to the nearest 2 mmHg. Two readings were taken 2 min apart and the average was recorded. Patients with systolic or diastolic blood pressure of ≥140 and ≥90 mmHg respectively were regarded as having hypertension. In addition, patients on treatment for previously diagnosed hypertension were also regarded as having hypertension [7].
4.5.
Laboratory evaluation
Subjects were requested to come to the MOP after an overnight fast of 8–14 h. After being seated and allowed to rest for 5 min, a venepuncture was performed after cleaning the skin with 70% methylated spirit, using a new sterile disposable needle and syringe. Ten millilitres of blood was collected out of which 3 ml was put in a fluoride oxalate bottle for fasting blood glucose estimation, 3 ml into an EDTA bottle for HbA1c analysis and the remainder was transferred into a plain bottle for GADA estimation. Samples were centrifuged at 10–15,000 rpm for 5 min soon after to obtain serum which were batched and stored at −20 ◦ C until analysis.
4.6.
Blood glucose estimation
Blood glucose estimation was carried out using the glucose oxidase enzymatic method. A fasting plasma glucose of >120 mg/dl was taken as indicative of poor glycaemic control.
4.7.
HbA1c of ≤6.5% was taken as good control, while >6.5% was taken as poor glycaemic control.
4.9.
Data analysis
Results obtained were analysed using SPSS package version 16. Associations between variables were tested using the chi square for qualitative variables and the Student’s t-tests for quantitative variables. Statistical significance of the tests of association was set at p value of less than 0.05.
5.
Results
5.1.
Sociodemographic data
One hundred and sixty adult patients clinically diagnosed to have type 2 diabetes mellitus (CT2DM) participated in the study. These patients with CT2DM included 65 (40.6%) males and 95(59.4%) females. The mean age (SD) of the patients was 60.49 (10.37) years. Those in the age group of 60–69 years constituted the largest number of subjects (36.2%), while those in the 30–39 years age group were the least, accounting for only 3.8%. The mean (SD) age at DM diagnosis was 51.80 (10.53) years, with the range between 30 years and 74 years. The median DM duration amongst the subjects was 8 years.
5.2. Prevalence of latent autoimmune diabetes in adults Nineteen (11.9%) of the 160 patients with CT2DM were positive for GADA. Twelve (63.2%) were females and 7 (36.8%) were males. Out of the total number of females with CT2DM, 12.8% were GADA positive while 10.6% of the total number of males was GADA positive. (2 = 0.17, p = 0.068). The mean age (SD) in GADA positive and GADA negative patients with CT2DM were similar: 60.26 (10.09) years and 60.46 (10.53) years respectively (t = 0.01, p = 0.92) (Fig. 1).
Glutamic acid decarboxylase antibody estimation 5.3.
This was carried out using Enzyme linked immunosorbent assay kit from RSR Ltd., UK. This is a sensitive non-isotopic assay for GAD antibody estimation which offers even higher disease specificity and sensitivity than GADA isotopic assays. The assays were carried out in duplicates to ensure that assay drift was minimal. A cut-off of ≥10 units/ml was taken as positive according to the reference range provided by the manufacturer.
4.8.
233
Anthropometric parameters
Both groups were however noted to have mean BMI in the overweight range. GADA positive persons had a trend
Glycated haemoglobin estimation
Blood samples were obtained from 122 patients with CT2DM and stored at 2–8 ◦ C. Analysis was done within 1 week of storage using the HbA1c ionic exchange chromatographic method (DIALAB, AUSTRIA). When this method was compared to the US National Glycohaemoglobin Standardization Programme certified method (NGSP) which is DCCT referenced some correlation was obtained. The following formula was used to obtain DCCT referenced values: HbA1c (NGSP) (%) = 0.86 HbA1c − Dialab (%) + 0.24.
Fig. 1 – Percentage of clinically diagnosed type 2 DM patients positive for GADA. This figure shows the proportion of patients with CT2DM found to be positive and negative for GADA.
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p r i m a r y c a r e d i a b e t e s 9 ( 2 0 1 5 ) 231–236
Table 1 – Characteristics of GADA positive compared with GADA negative patients amongst patients with clinically diagnosed type 2 DM. GADA positive n = 19 Mean (SD) Age (years) Age of onset of DM (years) Duration of DM (years) Weight (kg) Height (m) Body mass index (kg/m2 ) Waist circumference (cm) Hip circumference (cm) Waist–hip ratio Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Average fasting plasma glucose (mg/dl) HbA1c (%/mmol/mol) n = 122
60.26 (10.10) 50.79 (10.03) 9.47 (7.54) 68.68 (11.25) 1.64 (0.08) 25.64 (4.26) 89.8 (11.40) 96.87 (8.88) 0.93 (0.06) 140.84 (23.65) 81.89 (10.92) 144.23 (81.25) 7.0 (3.12) 53
GADA negative n = 141 Mean (SD)
t value
p value
60.52 (10.44) 52.11 (10.50) 8.42 (7.52) 69.74 (13.07) 1.62 (0.08) 26.59 (4.87) 92.47 (11.52) 99 (10.60) 0.94 (0.11) 135.56 (23.25) 81.02 (12.28) 125.8 (45.48) 6.10 (1.53) 42
0.91 0.268 0.312 0.113 0.888 0.65 0.903 0.702 0.223 0.86 0.087 2.199 3.185
0.918 0.606 0.57 0.737 0.347 0.421 0.343 0.403 0.638 0.355 0.769 0.14 0.077
This table shows that the mean age was similar in both groups but GADA positive persons with CT2DM, had trend towards lower mean BMI and waist circumference and waist–hip ratio but higher systolic blood pressure, fasting blood glucose and glycated haemoglobin compared with their GADA negative counterparts.
towards lower mean BMI (25.64 kg/m2 vs. 26.59 kg/m2 , p > 0.05) and lower waist circumference (89.80 kg/m2 vs. 92.47 kg/m2 , p > 0.05) than GADA negative subjects. Approximately 58% of the GADA positive patients had normal BMI as compared with 42.1% of GADA negative group, however showing no statistical significance difference (2 = 2.03, p = 0.378). When reviewed according to gender, males and females who were GADA positive showed a trend towards lower mean BMI and waist circumference when compared with their GADA negative counterparts. However, none of these observed differences attained statistical significance.
5.4.
Biochemical parameters
GADA positive subjects also had a higher mean fasting plasma glucose (144 mg/dl vs. 125 mg/dl, t = 2.20, p = 0.14), and a higher mean HbA1c levels (7% vs. 6.1% t = 3.19, p = 0.077). None of these findings were statistically significant (Table 1).
5.5.
Medication use
Approximately 37% of GADA positive patients were on a combination of sulphonylurea and biguanide therapy, while 31.6% were on insulin alone compared with 43.3% and 22% respectively in the GADA negative group. Although a larger proportion of patients who were GADA positive were receiving insulin therapy, the observed difference was also not statistically significant (2 = 0.25, p = 0.618).
6.
Discussion
Several studies done in various groups of patients with CT2DM in Finland, Australia, New Zealand, United States, United Kingdom, Germany, and Sweden have found the frequency of GADA positivity to range between 2 and 21% [1,2,8]. The UKPDS study, which is one of the largest studies done in patients with type 2 DM, reported a prevalence of 9.4% [9]. Studies conducted
amongst Africans have reported the prevalence of GADA in CT2DM as 2.5% amongst South Africans, while in Tanzania the prevalence was 5.3% [10,11]. In a study done in West Africa on the genetics of diabetes, with Ghana and Nigeria as centres, 10% of the patients with CT2DM were found to be positive for GADA [12]. This study found the prevalence of LADA as defined by GADA positivity amongst patients with CT2DM to be 11.9% and is about the same percentage found by AgyeiFrempong et al. in Kumasi, Ghana [13]. A recent study in a Lagos, Nigeria gave a prevalence of 14% which is similar to our finding [14]. Interestingly, the Lagos study was in a tertiary care centre like ours but more cosmopolitan in setting. The differences in prevalence from the various studies may be as a result of racial and ethnic variability, differences in sample selection techniques, the use of different assay techniques for detection of GADA and varying diagnostic criteria or cut off points. Also, population based studies have reported lower prevalence of islet autoantibodies (including GADA) when compared with hospital based studies [15,16]. A similar percentage of males and females in this study were GADA positive suggesting that there is no gender predilection for LADA which was also corroborated by reports from the Lagos study [14]. Abiru et al. [17] also reported equal gender distribution amongst GADA positive CT2DM patients in Japan, while Hamaguchi et al. [18] and Kim et al. [19] found a higher proportion of GADA positive males than females amongst CT2DM patients, in studies carried out in Japan and Korea respectively. Falorni et al. [20] reported that more females were GADA positive amongst persons with CT2DM. Gender distribution would have been a useful criterion in determining patient selection for antibody testing if there had been a difference. Although the mean weight, BMI, waist circumference and waist–hip ratio were above the normal cut-off points in this study, there was a trend towards lower values in GADA positive persons with CT2DM compared with GADA negative ones. In fact, a higher proportion of GADA positive persons in this study had normal BMI. Many studies have reported that GADA
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positivity was not related to BMI, with similar prevalence rates in the obese and none obese groups of patients with type 2 DM. The Lagos study however, found that LADA patients were more likely to be overweight or obese which is in contrast to our finding, although the mean BMI in their LADA and GADA negative group were similar [14]. On the other hand, several studies have reported significantly lower BMI in GADA positive patients, irrespective of the ethnicity, age or gender distribution of the population studied [8,18,21]. A review of previous studies to relate clinical features with LADA found significant correlation between clinical findings and LADA in only 2 out of 184 studies [22]. In this study, there were no significant set of clinical phenotypic features that characterized the GADA positive persons with CT2DM. Latent autoimmune diabetes in adults has often been reported to be diagnosed in people who develop diabetes between 30 and 50 years of age [17]. The mean age of persons with LADA in this study was 60 years which was also the average age of the study population. Juneja et al. [23] suggested that the age may not be an important diagnostic factor in the diagnosis of LADA. However, some studies have suggested that increasing age may be a predisposing factor for LADA but the exact mechanism is yet to be determined [24]. Persons with CT2DM who were GADA positive in this study had a trend towards higher mean fasting blood glucose, higher mean HbA1c concentration and a higher proportion of persons with HbA1c above the optimal target range when compared with the GADA negative subjects. These findings are important because patients with LADA often experience marked loss of beta cell function within a few years of diagnosis, require increasing doses of oral hypoglycaemic medication and earlier use of insulin. If not recognized early metabolic and chronic complications may supervene. Also, a higher proportion of GADA positive patients were receiving insulin therapy when compared with those who were GADA negative. Similar findings have been reported in the Fremantle Diabetes Study report, where GADA positive CT2DM patients were reported to have higher glycosylated haemoglobin levels, and were more likely to be taking insulin, than GADA-negative CT2DM subjects [16].
7.
Conclusion
The prevalence of LADA amongst Nigerian patients clinically diagnosed as type 2 DM was 11.9% with no significant phenotypic differences observed. Clinical/phenotypic appearances may therefore not be adequate to differentiate adult Nigerians with LADA. GAD antibody testing is therefore important in our practice settings, so as to appropriately classify and manage adult patients with diabetes mellitus. The detection of GAD antibodies in persons with CT2DM may influence therapeutic options leading to improved glycaemic control, thus reducing long term complications of diabetes mellitus. Larger multicentre studies amongst persons with CT2DM would be necessary to further define the prevalence and clinical correlates of LADA in our practice settings.
8.
235
Limitations
Some limitations recognized in this study must be mentioned. Serum C-peptide levels were not measured due to cost related constraints. This could have helped in determining the degree of beta cell function and direct treatment, as regards identification of persons who are at a high risk of early progression to insulin dependency. Also, it would have been informative to test for other pancreatic autoantibodies especially islet cell antibody (ICA), as its presence along with GADA, has been reported to be highly predictive of insulin dependency. However ICA levels wane with longer duration of DM while GADA usually persists for several years. GADA is the more easily assayed of the two autoantibodies, with a higher sensitivity and specificity than ICA.
Authors’ contribution AI was responsible for the conception, design, acquisition of data, analysis, and drafting of manuscript. JOA was involved in design, acquisition of data, drafting of manuscript and revising it critically for important intellectual content. KSA was involved in design, drafting of manuscript and revising it critically for important intellectual content. All authors read and approved the final manuscript.
Conflict of interest The authors state that they have no conflict of interest.
Acknowledgements Special thanks to Prof. Olaleye, Dr. Odaibo, Dr. Bakare and Mr. Omoruyi, all of Virology department for their assistance with the storage and analysis of blood specimen for GADA. Sincere appreciation also goes to Dr. Obioma Uchendu and Mr. Adewole for assisting with the statistical analysis.
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