|Year : 2017 | Volume
| Issue : 3 | Page : 108-114
Pattern of metabolic profile of latent autoimmune diabetes in adults (LADA) subgroup among type two diabetic patients attending tertiary health facility in Northern Nigeria
Salisu Babura Muazu1, Innocent Onoja Okpe2, Felicia Ehusani Anumah3, Adamu Girei Bakari2
1 Department of Medicine, Ahmadu Bello University, Zaria, Kaduna State, Nigeria
2 Department of Medicine, Faculty of Medicine, Ahmadu Bello University, Zaria, Kaduna State, Nigeria
3 Department of Medicine, College of Medicine, University of Abuja, Abuja, Nigeria
|Date of Submission||03-Jan-2017|
|Date of Acceptance||16-Aug-2017|
|Date of Web Publication||6-Oct-2017|
Salisu Babura Muazu
Consultant Physician and Endocrinologist/Visiting Lecturer, Department of Medicine, Jigawa State Specialist Hospital/Ahmadu Bello University, Zaria
Source of Support: None, Conflict of Interest: None
Aims: Insulin secretory defect, but not resistance, is the common feature of latent autoimmune diabetes in adults (LADAs), and insulin resistance is considered central in the pathophysiology of metabolic syndrome (MS). The aim of the study is to describe the pattern of the clinical and cardiometabolic characteristics of LADA in Northern Nigeria. Methods: This cross-sectional survey was conducted involving age- and sex-matched 48 LADA patients, 50 type 2 diabetes mellitus (T2DM) patients, and 52 normal controls,. The clinical and physical characteristics including weight, height, waist circumference, hip circumference, and blood pressure measurements were performed. The body mass index (BMI) and waist–hip ratio were also determined. A fasting blood test was taken for glucose, lipids, HbA1c, c-peptide, and glutamic acid decarboxylase antibody (GADA) estimation. ELISA method (Kronus kit, USA) was used for GADA estimation, >5.0 units/ml was considered positive while c-peptide value of <1.0 μ/ml is considered low. A clinical criterion for the diagnosis of LADA was used. The Modified International Diabetes Federation-ethnic criteria for classification of MS were used. The SPSS package version 20 was used to analyze the data with P < 0.05 as statistically significant level. Results: The mean ages for LADA and T2DM were 50.1 (11.3) and 51.2 (9.1) years, respectively, and the mean duration of disease was 6.1 (3.7) years in LADA and 7.0 (5.6) years in T2DM patients, P> 0.05. The BMI and WC were 22.1 (5.1) and 80.1 (12.4) cm for LADA and 27.3 (4.9) and 93.2 (10.9) cm for T2DM patients, respectively, P < 0.05. The LADA showed lower high-density lipoprotein-cholesterol (HDL-C), triglyceride (TGD), and blood pressure values, while the T2DM group had a better glucose control. The prevalence of MS was 5.7%, 19%, and 68% for the normal, LADA, and T2DM groups, respectively. Conclusions: It was found in this study that LADA subset of diabetes exhibited metabolic features consistent with both defective insulin secretion and insulin resistance. They were found to be lean with low TGD and HDL-C levels.
Keywords: High-density lipoprotein-cholesterol, latent autoimmune diabetes in adults, metabolic syndrome, Nigeria, triglyceride
|How to cite this article:|
Muazu SB, Okpe IO, Anumah FE, Bakari AG. Pattern of metabolic profile of latent autoimmune diabetes in adults (LADA) subgroup among type two diabetic patients attending tertiary health facility in Northern Nigeria. J Health Res Rev 2017;4:108-14
|How to cite this URL:|
Muazu SB, Okpe IO, Anumah FE, Bakari AG. Pattern of metabolic profile of latent autoimmune diabetes in adults (LADA) subgroup among type two diabetic patients attending tertiary health facility in Northern Nigeria. J Health Res Rev [serial online] 2017 [cited 2018 Feb 25];4:108-14. Available from: http://www.jhrr.org/text.asp?2017/4/3/108/216064
| Introduction|| |
Latent autoimmune diabetes in adults (LADA) is a form of diabetes subset that occurs in an adult population that is usually mistaken as type 2 diabetes mellitus (T2DM). It is characterized by islet beta cell loss due to autoimmune destruction and leading to gradual but absolute insulin deficiency, initial response to oral hypoglycemic agents, and aged between 30–40 years.
Insulin resistance is considered the central component in the pathophysiology of both T2DM and metabolic syndrome (MS). MS is defined as a cluster of cardiometabolic risk factors in an individual including diabetes or raised fasting plasma glucose, abdominal obesity, low-level high-density cholesterol, raised triglyceride, and high blood pressure.,
Although LADA is characterized by islet beta cell loss following continuous autoimmune attack targeting the pancreatic beta cells, recently, some studies were reported to have shown some degree of insulin resistance in this class of diabetics , Hence, the name intermediate or one and a half (1.5) diabetes was given to LADA.
In view of the insulin resistance being central in the pathogenesis of MS and its complicity in LADA, it is thought that MS could also be found in LADA patients. Hence, the LADA subgroup of diabetics could have both the features of insulin secretory defect (T1DM) and that of insulin resistance as in T2DM. This is the rationale for classifying this form of diabetes as transitional, intermediate, or one and half (1.5) diabetes.
Recent studies have shown that the occurrence of MS among LADA patients is directly proportional to the body mass index (BMI) of an individual. The LADA patients who turned positive for all the three antibodies (Abs) (GAD, ICA, and IA2), i.e., strong autoimmune activity, tend to have less features of MS. These findings suggest that, the more lean the LADA patients are and the exhibition of higher autoimmune process, the less the bad metabolic features are seen.
This buttresses the fact that insulin resistance and obesity play a key role in the development of MS in all diabetic patients. The severity of the autoimmune process will depend on the number and amount of Abs present in a LADA patient and will in turn predict the waist circumference (WC) or BMI.
There may be varied intrinsic and extrinsic factors that may predispose a LADA patient to develop MS with consequent rise in the chances of developing coronary heart disease. It was shown that presence of a pre existing one or more metabolic syndrome components in a LADA patient was associated with poorer cardiovascular outcome.
Racial differences play a major role in the development of MS among populations., It was found that the West Africans population has greater insulin resistance than Caucasians and higher rates of obesity, hypertension, diabetes, and consequent increased cardiovascular morbidity and mortality.,, Both the West Africans and Caucasian T2DM patients share similar prevalence rates of LADA., The metabolic features of LADA will be expected to, some extent, be compounded by the degree of the insulin resistance in that individual.
Among the black population of Africa, a prevalence range of LADA was found to be 10%–14%., Muazu et al. documented a prevalence of 10.5% in Northern Nigeria. Similar value was also found among Caucasians as documented by Tuomi et al.; however, a lower value was reported among the Asians. This showed that a significant proportion of our diabetic population are LADA subgroup, and the magnitude is comparable to that of European population, hence the need to assess its metabolic profile.
The prevalence of MS among different T2DM patient populations ranges from 66% to 88.8%., However, prevalence rates of MS among LADA patients were much lower. Li et al. found a rate of 23.7% among Chinese T2DM patients while Hawa et al. working in action LADA 3 study among the European T2DM patients documented a rate as high as 41.9%.
Among the LADA patients, studies have showed that a significant proportion of them have bad metabolic indices leading to MS and its consequences. In view of this, there is a compelling need to characterize the LADA subgroup of diabetic for clinical categorization and development of appropriate management strategies. This will enhance early detection of LADA and institution of the most appropriate management modalities so as to reduce morbidity and mortality arising from the delay in identification of bad metabolic features.
There is scanty data on the identification and characterization of LADA subgroup of diabetics in Africa, especially among the West Africans, and there is none from Northern Nigeria.
The aim of the study is, therefore, to document the metabolic indices and characteristics of LADA in northwestern parts of Nigeria.
| Methods|| |
It was a cross-sectional observational study involving 48 LADA patients, who were selected based on the clinical criteria mentioned below and 50 T2DM patients attending a tertiary health institution in Northern Nigeria. Furthermore, 52 age- and sex-matched normal individuals served as control.
The Ethics Committee of Jigawa State Specialist hospital approved the study with Ethical committee number ABUTH/MED/SURV/2015/209 dated Tuesday February 2, 2015. The consent of the willing participants was also sought before co-opting them.
A pro forma form containing age, sex, and duration of disease was filled. All patients had clinical examination. Weight was measured to the nearest 0.5 kg and height in meters using a stadiometer. BMI was calculated from weight and height. WC was measured to the nearest centimeter at the midpoint between the lower most rib and the anterosuperior iliac spine while hip circumference was measured at the level of greater trochanter, and waist–hip ratio was determined using ratio of waist size (cm) over hip size in centimeters.
The patients were then asked to come for the next visit after fasting for 8–12 h.
During the next visit, a 10 ml of fasting blood was taken and analyzed for plasma glucose, lipids, glycated hemoglobin, c-peptide, and glutamic acid decarboxylase (GAD).
The GAD-Ab estimation was done using Kronus anti-GAD ELISA kit (Boise, USA). The reading of final absorbance at two wavelengths (450 nm and 405 nm) was done. Measuring range (4–200 units/ml of the WHO reference preparation) ≥5 units/ml is considered positive.
C-peptide estimation was done using Kronus ELISA kit (Boise, USA) and reading was done at 450 nm with value <1.0 μ/ml which is considered as low.
Latent autoimmune diabetes in adults
- GAD positivity of ≥5.0 units
- Age >30 years
- Not dependent on insulin for survival
- Lean patients.
The International Diabetes Federation criteria for the diagnosis of MS ethnic specific recommended for black Africans were used.
- Central obesity defined by WC in centimeters, >94 cm in males or >80 cm in females plus any two of the following confirms the diagnosis of MS
- TG ≥150 mg/dl (1.7 mmol/L)
- HDL ≤40 mg/dl (1.03 mmol/L) in males and ≤50 mg/dl (1.29 mmol/L) in females
- Hypertension ≥130/85 mmHg
- Fasting blood glucose ≥100 mg/dl (5.6 mmol/L).
The Statistical Package for the Social Sciences (SPSS), version 20, software (IBM, USA) was deployed to analyze the data where mean (standard deviation) was compared using Student's t-test and Chi–square test for nominal values. Logistic regression was used to ascertain the association of variables and LADA. P < 0.05 was considered statistically significant.
| Results|| |
The mean ages for LADA and T2DM were 50.1 (11.3) and 51.2 (9.1) years, respectively, and comprised equal proportions of males (40%) and females (60%) (P < 0.05). The duration of disease is shorter, i.e., 6.1 years (3.7) in LADA group than T2DM group, i.e., 7.0 years (5.6) (P > 0.05).
[Table 1] summarizes the clinical and biochemical characteristics of the two groups against the control group. The BMI and WC were significantly lower in LADA patients than that in T2DM patients [Table 2] and [Figure 2]. The c-peptide, as a marker of secretory function of the beta cells, was markedly reduced, i.e., 0.84 (0.05) in LADA when compared with T2DM, i.e., 1.72 (0.43) (P < 0.05).
|Table 1: Comparison of clinical and metabolic characteristics of normal, latent autoimmune diabetes in adult and type 2 diabetes mellitus|
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|Figure 2: The indices of obesity among the normal, latent autoimmune diabetes in adults and type two diabetes mellitus groups. BMI: Body mass index, WC: Waist circumference, WHR: Waist hip ratio, LADA: Latent autoimmune diabetes in adults, T2DM: Type two diabetes mellitus|
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The LADA group had poorer glycemic control as evidenced by higher HbA1c of 8.3 (1.4) compared to 7.0 (2.1) of T2DM group (P < 0.05). The blood pressure measurements, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol, and triglyceride (TGD) were all low in LADA group compared to T2DM group.
[Figure 1] depicts the prevalence of MS among the control, LADA, and T2DM patients as 5.7% (3/52), 19% (9/48), and 68% (34/50), respectively (P < 0.05).
|Figure 1: The prevalence rates of metabolic syndrome among the Normal, latent autoimmune diabetes in adults and type two diabetes mellitus subjects|
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In T2DM patients, females had more MS than the male counterparts (83.0% vs. 45.5%, respectively, P < 0.05); however, there was no gender difference noticed in the LADA with MS group.
[Table 3] summarizes the comparison of individual cardiometabolic risk factors among the two groups. The HDL-C level was lower in the LADA group and contributed by 97.5% to making a diagnosis of MS. The TGD in LADA was so reduced (low normal) that it has not contributed in making a diagnosis of MS [Figure 3]. All the other metabolic profiles in the LADA group were lower than that in T2DM group.
|Table 3: The percentage distribution of risk factors of metabolic syndrome among the two groups|
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|Figure 3: Individual metabolic risk factors among latent autoimmune diabetes in adults and type two diabetes mellitus. MS: Metabolic syndrome, WC: Waist circumference, FBG: Fasting blood glucose, HDL: High density lipoprotein cholesterol, TGD: Triglyceride, SBP: Systolic blood pressure, DBP: Diastolic blood pressure, LADA: Latent autoimmune diabetes in adults, T2DM: Type two diabetes mellitus|
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[Table 4] showed the result of logistic regression where Age, BMI, WC, TG were negatively associated with LADA while HbA1c exhibited a positive linear relationship with LADA.
|Table 4: Odds ratio estimates for risk factors of latent autoimmune diabetes in adult|
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The occurrence of low HDL cholesterol and hyperglycemia, with WC as determinant, constitutes the majority in making the diagnosis of MS among both the LADA and T2DM groups. The TGD levels were low and, as a criterion for diagnosis, contributed only in T2DM group.
| Discussion|| |
In this study, the prevalence of MS among the LADA group was significantly lower (19%) than in T2DM group (69%) and higher than in controls (5.7%). This rate is lower than in a Chinese study of LADA and MS where they documented 23.7% and much lower than that reported among the European LADA study group, involving five countries of 41.9%.
The observed difference between this study and the others may not be unconnected with the virtually low normal values of TGD recorded in this study, hence contributed less toward making a diagnosis of MS. It has been documented that the black race develop less of MS, due to low TGD, despite having higher incidence of insulin resistance, diabetes, and hypertension, as compared to Caucasian population.,,
The lower MS in LADA recorded in this study is in concordance with the risk factors documented. The lower blood pressure, BMI, and TG values supported the low incidence of MS as compared with T2DM. In contrast, the HDL values were very low, contributing majorly in all the documented cases of MS seen in this study. This is not in concordance with a study in central Europe where the values of HDL and TG observed were high and low, respectively, among LADA patients.
The pathophysiology of LADA is that of gradual beta cell damage and absolute insulin deficiency rather than insulin resistance seen in T2DM patients. However, some studies , have reported that LADA patients also exhibit some degree of insulin resistance state as in T2DM patients. Furthermore population-based studies , among Swedish communities showed that high intake of sweetened beverages and low birth weight increase the risk of LADA of the same strength as for T2DM, suggesting a common pathway possibly involving insulin resistance. In our survey, we documented substantial patients with MS than in normal cohorts which is in keeping with the above theories.
Another study showed that the prevalence of MS among LADA patients is inversely related to the quantity of the auto-Abs present and the clinical phenotype dependent on the pattern of autoantibody positivity.,
The study which was carried out among large cohorts in the UAE showed that those LADA with IA2 antibody positive only are phenotypically more of T2DM while those with multiple Abs positive are more closely to T1DM. In our study, the LADA patients exhibited features more of T1DM than T2DM, probably suggesting that they are multiple auto-Abs' positive.
The mean age was lower in LADA group than that of T2DM group and there was no gender difference noted. This finding supported the fact that advancing age  is associated with MS. The lack of gender difference in this study is curious but may be attributed to the smaller sample size in this study.
The MS patients in LADA group in this study exhibited significant poorer glycemic control and were lean compared to MS patients in T2DM. This supports the fact that LADA has more of defective beta cell function than insulin resistance and closer to T1DM. The continual autoimmune attack on small beta cell mass in LADA will accelerate the defective secretory process and lead to absolute insulin deficiency.
The HDL cholesterol and TG levels were low in both the LADA and T2DM groups. The same scenario was reported in some community surveys of MS , among black ethnic populations. The low normal TGD values recorded in this study might also be explained by this racial difference and may warrant redefining the limits of the values used in the diagnosis of MS among black population.
The blood pressure reading was lower in LADA and was in concordance with the previous studies. This is because insulin resistance also plays a pivotal role in the pathophysiology of high blood pressure, and insulin resistance is less in autoimmune diabetes than in T2DM. However, low HDL values were recorded in our study, in contrast to most studies.
The clustering of cardiometabolic risk factors appeared in the order of WC, low HDL-C, raised blood glucose, and systolic BP. The HDL-C and TGD values were unusually low in both the LADA and T2DM groups; this may be related to peculiar patient characteristics.
| Conclusions|| |
Therefore, it is concluded among the population studied in this region of the country that LADA subset of patients are lean and have low TGD, greatly reduced HDL-C values, low blood pressure readings, no sex preference, and poor beta cell secretory function, with consequent poor blood glucose control. The prevalence of MS in LADA group was significantly lower than in T2DM and much higher than in normal population.
The occurrence of substantial MS among the LADA group above the normal controls, in this study, may further support the contribution of insulin resistance to that effect. This may explain the inclusion of insulin sensitizers in the management of LADA in previous studies.,
The strength of the study lies on the fact that both the patients and controls were drawn from the same community, sharing the same population characteristics, and no similar survey was carried out before in this region. The measurements, sample collection, and analysis were done by the same investigators and reagents, therefore reducing intra-assay bias and variability. The study was limited by the small sample size and it was conducted in one region of the country, insulin resistance was not measured and only one autoantibody was assessed.
The low TGD recorded in this study needs to be further explored that whether the cutoff value, used in the diagnosis of MS, is appropriate for all races and to find its relationship with other cardiometabolic risk factors, especially among black population. The very low HDL values recorded and low blood pressure measurements in this study are not compatible, as HDL value is inversely related to blood pressure or a predictor of cardiovascular disease.
It is, therefore, recommended that future studies on HDL and TG values, among black populations, as cardiovascular risk factors and use in the diagnosis of MS, respectively, should be further explored. It will be worthwhile to conduct a similar study with larger sample size in different regions to look into insulin resistance and beta cell function among LADA patients.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Alberti KG, Zimmet P, Shaw J. Metabolic syndrome – A new world-wide definition. A Consensus statement from the international diabetes federation. Diabet Med 2006;23:469-80.
Chiu HK, Tsai EC, Juneja R, Stoever J, Brooks-Worrell B, Goel A, et al.
Equivalent insulin resistance in latent autoimmune diabetes in adults (LADA) and type 2 diabetic patients. Diabetes Res Clin Pract 2007;77:237-44.
Li X, Zhou Z, Huang G, Su H, Yan X, Yang L, et al.
Metabolic syndrome in adult-onset latent autoimmune diabetes. Metab Syndr Relat Disord 2005;3:174-80.
Blaslov K, Bulum T, Knežević-Ćuća J, Duvnjak L. Relationship between autoantibodies combination, metabolic syndrome components and diabetic complications in autoimmune diabetes in adults. Endocrine 2015;48:551-6.
Sattar N, Gaw A, Scherbakova O, Ford I, O'Reilly DS, Haffner SM, et al.
Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland coronary prevention study. Circulation 2003;108:414-9.
Saad MF, Lillioja S, Nyomba BL, Castillo C, Ferraro R, De Gregorio M, et al.
Racial differences in the relation between blood pressure and insulin resistance. N Engl J Med 1991;324:733-9.
Anderson PJ, Critchley JA, Chan JC, Cockram CS, Lee ZS, Thomas GN, et al.
Factor analysis of the metabolic syndrome: Obesity vs insulin resistance as the central abnormality. Int J Obes Relat Metab Disord 2001;25:1782-8.
Sumner AE. Ethnic differences in triglyceride levels and high-density lipoprotein lead to under diagnosis of the metabolic syndrome in black children and adults. J Pediatr 2009;155:S7.e7-11.
Gaillard T, Schuster D, Osei K. Metabolic syndrome in Black people of the African diaspora: The paradox of current classification, definition and criteria. Ethn Dis 2009;19 2 Suppl 2:S2-1-7.
Osei K. Metabolic syndrome in West Africans: Are the criteria right? Curr Diab Rep 2010;10:199-208.
Ipadeola A, Adeleye JO, Akinlade KS. Latent autoimmune diabetes amongst adults with type 2 diabetes in a Nigerian tertiary hospital. Prim Care Diabetes 2015;9:231-6.
Tuomi T, Carlsson A, Li H, Isomaa B, Miettinen A, Nilsson A, et al.
Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Diabetes 1999;48:150-7.
Agyei-Frempong MT, Titty FV, Owiredu WK, Eghan BA. The prevalence of autoimmune diabetes among diabetes mellitus patients in Kumasi, Ghana. Pak J Biol Sci 2008;11:2320-5.
Muazu SB, Okpe I, Anumah F. The prevalence and characteristics of latent autoimmune diabetes in adults subset among type two diabetes mellitus patients in Northern Nigeria. Ann Afr Med 2016;15:163-70.
] [Full text]
Hwangbo Y, Kim JT, Kim EK, Khang AR, Oh TJ, Jang HC, et al.
Prevalence and clinical characteristics of recently diagnosed type 2 diabetes patients with positive anti-glutamic acid decarboxylase antibody. Diabetes Metab J 2012;36:136-43.
Chakraborty SN, Roy SK, Rahaman MA. Epidemiological predictors of metabolic syndrome in urban West Bengal, India. J Family Med Prim Care 2015;4:535-8.
] [Full text]
Hawa MI, Thivolet C, Mauricio D, Alemanno I, Cipponeri E, Collier D, et al.
Metabolic syndrome and autoimmune diabetes: Action LADA 3. Diabetes Care 2009;32:160-4.
Li X, Zhou ZG, Yang L, Huang G, Yan X. Metabolic syndrome and latent autoimmune diabetes in adults. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2003;25:676-9.
Martinka E, Rončáková M, Mišániková M, Davani A. Autoimmune insulitis in patients with type 2 diabetes mellitus A randomized clinical trial in hospitalized patients. Vnitr Lek Fall; 62:521-33.
Löfvenborg JE, Andersson T, Carlsson PO, Dorkhan M, Groop L, Martinell M, et al.
Sweetened beverage intake and risk of latent autoimmune diabetes in adults (LADA) and type 2 diabetes. Eur J Endocrinol 2016;175:605-14.
Hjort R, Alfredsson L, Carlsson PO, Groop L, Martinell M, Storm P, et al.
Low birthweight is associated with an increased risk of LADA and type 2 diabetes: Results from a Swedish case-control study. Diabetologia 2015;58:2525-32.
Maddaloni E, Lessan N, Al Tikriti A, Buzzetti R, Pozzilli P, Barakat MT, et al.
Latent autoimmune diabetes in adults in the United Arab Emirates: Clinical features and factors related to insulin-requirement. PLoS One 2015;10:e0131837.
U.K. Prospective diabetes study 16. Overview of 6 years' therapy of type II diabetes: A progressive disease. U.K. Prospective diabetes study group. Diabetes 1995;44:1249-58.
Rhee EJ, Byrne CD, Sung KC. The HDL cholesterol/apolipoprotein A-I ratio: An indicator of cardiovascular disease. Curr Opin Endocrinol Diabetes Obes 2017;24:148-53.
Leslie RD, Williams R, Pozzilli P. Clinical review: Type 1 diabetes and latent autoimmune diabetes in adults: One end of the rainbow. J Clin Endocrinol Metab 2006;91:1654-9.
Hamilton J, Cummings E, Zdravkovic V, Finegood D, Daneman D. Metformin as an adjunct therapy in adolescents with type 1 diabetes and insulin resistance: A randomized controlled trial. Diabetes Care 2003;26:138-43.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]