Hubungan antara Status Kontrol Glikemik, Vitamin D dan Gizi pada Anak Diabetes Melitus Tipe 1 Relationship between Glycemic, Vitamin D and Nutrition Status Control in Children with Type 1 Diabetes Mellitus

In some western countries, type-1 diabetes cases are 5-10% of diabetes cases, and more than 90% of diabetics in children and adolescents are type 1 DM. Vitamin D plays an important role in building and maintaining bone mineralization. Vitamin D deficiency can cause bone turnover suppression, thus causing height growth disorders. Poor glycemic control in the form of high HbA1c can cause weight and height not to increase adequately. This study aimed to prove the relationship among control glycemic status (HbA1c), vitamin D status (25(OH)D), and nutritional status in children with type-1 DM. The study design was a cross-sectional study conducted on 28 research subjects, namely children with type 1 DM aged 1-18 years who underwent outpatient care at the Endocrinology Polyclinic of Dr. Saiful Anwar General Hospital Malang. The exclusion criteria were suffering from other autoimmune diseases, severe infections, liver disorders, impaired kidney function, and anemia. Variables measured were nutritional status, HbA1c, and 25(OH)D levels. To find out the differences in the mean levels of 25(OH)D and HbA1c based on nutritional status, Kruskal wallis test and Spearman correlation test were used. Of the 28 subjects 68% of children were found with good nutritional status, 64% of children with bad metabolic control, and 61% of children with 25(OH)D deficiency/insufficiency. There is no significant relationship between nutritional status, glycemic control, and vitamin D.


INTRODUCTION
decreased insulin levels (7)(8)(9). If the insulin level drops, hyperglycemia will occur which, if chronic, results in Type 1 diabetes mellitus (DM) is one of the chronic increasing HbA1c as an indicator of glycemic control. In diseases that until recently could not be cured (1,2). This uncontrolled type-1 DM, a disruption of nutritional status disease is a chronic disease with disrupted metabolism of occurs. Insulin deficiency in type-1 DM will reduce glucose carbohydrate, fat, and protein due to insulin deficiency as uptake by muscles, soft tissue, splanic tissue, and there will a result of autoimmune pancreatic beta cell destruction be an increase in glycogenolysis and gluconeogenesis, (3). reduced amino acid uptake and protein synthesis, resulting The incidence of type 1 DM varies greatly among countries in less muscle nitrogen fulfillment. Protein catabolism also and within a country. In several western countries, type 1 increases, so clinically muscle mass in the peripheral tissue DM cases are 5-10% of all diabetes cases, and more than decreases resulting in weight loss (4). 90% of diabetics in children and adolescents are type 1 Children with diabetes are at risk of developing growth diabetes mellitus. The highest incidence is in Finland that disorders due to the disease process or its complications. is 43/100,000 and the lowest incidence is in Japan at 1. 5-Poor metabolic control can result in impaired growth 2/100,000 among children below 15 years old (2,3). The (weight and height do not adequately increase) and late incidence of type 1 diabetes is higher in Caucasians development of puberty (Mauriac syndrome) (4,13). A compared to other races. It is estimated that throughout study in India showed children with type 1 diabetes aged 4the world 80,000 children aged below 15 years will 16 years had a lower height velocity than healthy children develop type 1 diabetes mellitus. Until 2014, the national (14). Growth monitoring needs to be done in children with registry data of type 1 diabetes mellitus in children from diabetes so that adequate management can be carried out, the Board of Central Indonesian Medical Association thus they can achieve optimal final height according to the revealed 1021 cases (4). At Dr. Saiful Anwar Hospital general population (4). (RSSA) Malang from 2011 to 2016, there were 60 type 1 diabetes mellitus patients aged 1-18 years (5).
Glycemic control is associated with microvascular and macrovascular complications. Good glycemic control can The etiology of multifactorial type 1 DM includes genetic improve the life quality of patients with type 1 diabetes. A factors, environment, and immune system. The high level of HbA1c indicates poor glycemic control. mechanism of β cell destruction is still under debate, but it Vitamin D status is one of the factors associated with is clear that the involvement of the immune system, i.e. glycemic control in children and adolescents with Type 1 macrophages and T cells, and cytokines is very big. DM (15). Poor metabolic control can result in impaired Inflammatory factors, reactive oxygen species, and nutritional status and growth. Vitamin D has an important autoimmune reactions appear as pathogenic effectors of role in bone growth. This study was conducted to type 1 DM (6)(7)(8)(9).
determine the relationship among vitamin D status (25 Vitamin D deficiency can increase the risk of developing (OH) D), glycemic control status, and nutritional status in autoimmune diseases including type 1 DM due to the loss children with type 1 DM. of vitamin D modulation to the immune system and inflammatory reactions in diabetes (6,10,11). In vitro studies have shown that vitamin D is immunosuppressive METHOD or as an immunomodulator while studies on experimental This study was an analytical observational study with a models of autoimmune diseases, including type 1 DM, cross-sectional design that measured vitamin D level show that vitamin D is protective. Other observational (25(OH)D), HbA1c, and nutritional status (based on body studies also showed a positive correlation among vitamin weight and height) in children with type 1 DM. The D level, insulin sensitivity, and pancreatic beta cell population of this study was type 1 DM children who function (11). In the skeleton, vitamin D has a very underwent outpatient care at the Endocrinology Clinic of important role in building and maintaining bone Dr. Saiful Anwar General Hospital Malang from October mineralization. Bone growth requires calcium and 2017 to December 2017 and routinely got insulin therapy 1,25(OH) D to build optimal bone osteoblastic formation 2 and have not received vitamin D supplementation therapy. (12).
In accordance with the calculation, the minimum sample The involvement of genetic factors, environment, and size was 13 samples (16), in this study 28 samples were autoimmune process is a mechanism that plays a role in involved. Sample inclusion criteria included type 1 DM the occurrence of type 1 DM. The interaction between classified, aged between 2 to 18 years, and parents agreed genetic factors and environment triggers an immune to take part in the study. Patients with type 1 diabetes response in a form of an autoimmune process. Vitamin D mellitus who suffer from other autoimmune diseases, is a hormone that is synthesized in the body and acts on severe liver disorders, kidney function disorders, and various organs through vitamin D receptor (VDR). Most anemia were not included in this study. Type 1 DM patients people with type 1 DM experience vitamin D deficiency, were determined based on one of the following criteria, i.e. because of either lacking UV exposure or inadequate (1) hyperglycemia symptoms including polyuria, vitamin D intake. A low 25(OH)D level can affect the polydipsia, weight loss, and random blood plasma glucose immune system in various ways, thus resulting in level >200 mg/dl (11.1 mmol/L), (2) fasting blood glucose pathogenic immune response and triggering pancreatic β (> 8 hours) ≥126 mg/dl (≥7.0 mmol/L), (3) in patients with cell destruction. In the process of pancreatic β cell asymptomatic, random blood glucose level was > destruction, there are infiltrations to Langerhans islands by inflammatory cells through selective and specific 200mg/dl or fasting blood glucose level was higher than destruction of pancreatic β cells thus causing insulitis and normal with more than one examination of impaired glucose tolerance tests. This research was approved by the status was carried out using the Kruskal-Wallis test because Ethics Commission of Saiful Anwar Hospital Malang No. the data were not normally distributed. Spearman rank 4000/01/K.3/302/2018. correlation analysis was used to test the correlation between nutritional status and vitamin D status and Vitamin D level was the 25(OH)D level that was measured nutritional status with glycemic control status. in plasma using the enzyme-linked Immuno Assay (ELISA) method. Serum 25(OH)D level was classified into: normal > 30ng/ml, insufficiency 21-29ng/ml, and deficiency < RESULTS 20ng/ml. HbA1c was glucose bound to hemoglobin Table 1 shows the comparison of the gender ratio of male (glycated hemoglobin) which served to see the average to female was 3: 4. The most age group (57%) was >12-18 blood glucose level in 3 months. The examination was TM years while the age group of 5-12 years was 12 people, the measured by using Bio-Rad D-10 at the Clinical mean age was 12.64±3.19 years, and approximately half Pathology Central Laboratory RSSA Malang. The following were in puberty. Clinically most subjects had good criteria were used to group the HbA1c levels: <7.5% (good nutrition, experienced insufficiency and deficiency of metabolic control), 7.5% -9% (suboptimal metabolic vitamin D, and poor glycemic control. control), and >9% (poor metabolic control). The weight of the children was measured using a standing scale. Before weighing, an inspection was carried out to ensure the device was balance (the needle showed the number 0). The children were weighed in a standing position without shoes and with minimal clothing. Height measurement of the children was carried out in a standing position without assistance; height was measured using a stadiometer. In measuring height, the children were measured without footwear or socks and with minimal clothing, when measured, the child must stand upright, both feet were touching each other, heels, buttocks and back of the head touched the stadiometer and stared forward at a flat level. Weight was measured in kilograms, and height was measured in centimeters, and then plotted on the CDC or WHO curve according to the age of the patient.

Measurement of Weight, Height, and Nutritional Status
Nutritional status was determined based on body weight and height, for ages below 5 years WHO chart was used, and ages above 5 years were using CDC charts. Subjects were called malnutrition if BW/BH -3 SD up to -2 SD according to WHO or 70-90% BW/BH according to CDC, good nutrition if -2SD up to +2SD according to WHO or BW/BH 90 -110 % according to CDC, over nutrition if BW/BH +2SD up to +3SD or BW/BH >110-120% according to CDC, and obesity if BW/BH +3SD or BW/BH >120% according to CDC. Subjects with BW/BH >110% were analyzed further by measuring body mass index (BMI) 2 with a formula of BW (kg)/BH (meter) and plotted to BMI charts according to age and sex.

Examination of HbA1c and 25(OH)D levels
Examination of HbA1c level using whole blood sample was Table 2 shows nearly the same HbA1c levels in different TM examined by Bio-Rad D-10 device using a highnutritional statuses with the lowest level in over nutritional performance liquid chromatography (HPLC) method.
status. Vitamin D levels in the three groups of nutritional Examination of vitamin D level (25 (OH) D) using plasma status were also almost the same as the lowest level in samples by the Enzyme-linked Immuno Assay (ELISA) malnutrition status. Statistically, there were no differences method was carried out at the Clinical Pathology in HbA1c or vitamin D levels in subjects with type 1 DM in Laboratory in Saiful Anwar Hospital Malang. The kit used children with three different nutritional statuses. was the Alegria Human Vitamin D kit catalog number ORG 270 in ng/mL unit.   (20). In type 1 DM, a decrease in insulin secretion that occurs is a result of autoimmune disease, not because of a decrease in insulin sensitivity as in other types of DM, so that nutritional status does not have a direct effect (21). Diabetic children with adequate insulin therapy and improved metabolic control will experience weight gain. Too much weight gain indicates excess diet above their needs and the possibility of excessive insulin doses (22).
In this study 54% of 28 subjects had experienced puberty, the average dose of insulin used in this study was 1.14 ± Correlation test found no significant correlation between 0.26 IU/kg/day. There were two children with more nutritional status and vitamin D status with glycemic nutritional status with an insulin dose range of 0.5-1 control status ( Table 4). Most of the subjects showed poor IU/kg/day. More nutritional status in this study can be glycemic control even with good nutritional status. The caused by excess diet above the needs of children, but the proportion of subjects with vitamin D deficiency and number of diets that can affect children's nutritional status sufficiency was balanced.
was not examined in this study. Onset, peak work, and the length of work of insulin are the determining factors in the management of DM patients. Insulin dose adjustment Table 4

. Relationship between nutritional status and vitamin
aims to achieve optimal metabolic control, without D with glycemic control status increasing the risk of hypoglycemia and without neglecting the life quality of patients both short and long terms. During the "honeymoon" period, the total daily insulin dose is <0.5 IU/kgBW/day, children before puberty (excluding the "honeymoon" period) in the dose range of 0.7-1 IU/kgBW/day. During puberty, the need for insulin increases into above 1 IU up to 2 IU/kgBW/day. In adolescence, the need for insulin increases because of the work of sex steroid hormones, increased amplitude, and frequency of growth hormone secretion, all of them are anti-insulin hormones (4). Children with type 1 diabetes have a lower height velocity than healthy children, one risk factor of growth failure is the younger the age when diagnosed (Parthasaray). The duration of illness and HbA1C level affect height velocity (14).

Vitamin D status DISCUSSION
Vitamin D status in this study sample was dominated by This study identified 28 subjects of children with type 1 abnormal level of 25(OH)D, both deficiencies as much as diabetes mellitus, most of whom were females with the 39% and insufficiency as much as 21% of the 28 subjects. highest age range of 13-18 years. In this study, 28 children There was no significant differences in the 25(OH)D level in with type I diabetes mellitus were identified as the the nutritional status group. Research by Hasan also subjects of the study. The age characteristics of subjects identified vitamin D deficiency in children with type 1 DM were in the age range of 7-17 years with a mean age of 12 was as much as 91.67%, and obtained no significant years. This is in line with the previous epidemiology that correlation between serum vitamin D, serum calcium, the peak incidence of type 1 DM is 5-7 years old and at the phosphorus, anthropometric status, duration of diabetes, age of 10-14 years or puberty (2.8). Based on gender mean of HbA1c, insulin dose, and sunray exposure (23). A distribution, the females were higher than males (4: 3).
cross-sectional study in the Netherlands showed that 60-This is consistent with data from a study in the United 84% of patients with type 1 DM had vitamin D deficiency States that the highest incidence is in the age range of 9-12 (10). A study in America, of the 128 type 1 DM patients, years, and girls are twice as many as boys (17). In contrast, revealed 15% of patients with 25(OH)D deficiency, 61% data from IDF in 2011 stated that men were 1.5 times with insufficient 25(OH)D level, and 24% sufficient higher than women. ISPAD data in the same year stated 25(OH)D level (15). Another study in Saudi Arabia, North that gender differences in the incidence of type 1 DM in India, and Australia reported that children with type 1 DM some countries were not different (3). The existence of had low level of 25(OH)D compared to the normal this difference is caused by differences in population, race, 3 population (11,24). Research conducted in Indonesia also metabolic control while the other 18 children were in poor found similar results that type 1 DM patients experienced metabolic control (HbA1c> 9%). HbA1c examination is vitamin D deficiency and insufficiency. One study used to describe long-term glucose control, describing the conducted in RSSA Malang found 90% of children with condition of 8-12 weeks before, because half-life of type 1 DM had low level of 25(OH)D (25). Based on erythrocytes is 120 days (33). 3 nutritional status, there were two patients with over The possibility that can cause a high HbA1c level is the nutrition (BMI >110) with a BMI >25. In these patients, relationship between the limited availability of insulin and one of the vitamin D level was in a deficiency state, and the a lack of independent blood sugar monitoring. Insulin other one was insufficiency. In obese patients there is a storage may affect the effects of insulin, such as storing decrease in vitamin bioavailability due to the presence of insulin in the freezer or exposure to insulin in direct sunray vitamin D sequestration in fat tissue (26).
(34). From several studies, there was a significant Vitamin D deficiency is influenced by genetic factors and correlation between independent monitoring and environmental factors. Indonesia as a tropical country glycemic control. Blood glucose levels should be measured located on the equator with sunray exposure obtained several times per day to avoid hypoglycemia and throughout the year, thus it makes Indonesia sufficient for hyperglycemia, as well as adjusting insulin doses. vitamin D synthesis (27). Decreased synthesis of vitamin D Preprandial, postprandial, and midnight blood glucose is caused by the use of sunscreen, dark skin pigments, age, levels are indispensable for adjusting insulin doses (4). In season, latitude that is away from the equator, the this study the frequency of blood glucose monitoring was amount of sunray exposure duration, closed dressing 1-2 per day in all study samples, this indicates a lack of choice, and lesions on the skin. Decreased bioavailability monitoring. of vitamin D can be caused by malabsorption and obesity. Increased catabolism of vitamin D can be triggered by the A retrospective study of the effect of type 1 DM on growth use of drugs such as anticonvulsants and glucocorticoids.
by Korcan et al. showed a negative correlation of HbA1C Decreased synthesis of vitamin D can be due to liver with height at three years after diagnosis (35). Studies in disorders. Loss of vitamin D through urine can occur in Iran showed that in the early onset of type 1 DM, 44.6% nephrotic syndrome. The presence of chronic kidney experienced KAD, the mean of HbA1C was 8.89%. disease can reduce the vitamin D synthesis. In children, Significant differences in SDS weight were only seen in the most common cause of vitamin D deficiency is patients with good and bad metabolic controls. Poor breastfeeding without vitamin D supplementation, lack of metabolic control can reduce growth in height and slightly sunray exposure, and a diet lacking vitamin D (26,28).
affect body weight (36). A cohort study in Mexico 2016 showed 50% who faced growth failure. The results of In this study, low vitamin D level could be because of a lack multivariate analysis of factors associated with failure to of sunray exposure and a lack of vitamin D diet. This study grow was HbA1c level in the first year of diagnosis (37). did not examine how long the amount of sunray exposure was and did not measure the type of diet containing In this study, there was no significant correlation between vitamin D among the subjects. The most genetic vitamin D status (25(OH)D) and HbA1c status. Study by contribution of locus DM type 1 is the HLA class II gene Branco et al. also proved that there was no relationship located on chromosome 6p21.3. The HLA-DR and HLA-DQ between HbA1c and 25(OH)D level but vitamin D status locus in the class II region have a very strong risk of the differed significantly between sexes (38). Even, previous occurrence of type 1 DM (29). The presence of a research showed a negative correlation which meant that polymorphism in VDR (Vitamin D receptor) is associated the higher the level of 25(OH)D, the lower the level of with a number of diseases, one of which is diabetes (30).
HbA1c. This study was conducted in three months without The presence of VDR polymorphism causes vitamin D not the intervention of vitamin D administration (39). to be captured by receptors even though the levels are In DM type 1, there is an imbalance between pronormal. In addition, certain genetic influences and inflammatory cytokines and anti-inflammatory cytokines. different environmental influences in each patient can At the APC level, vitamin D inhibits the surface expression also affect vitamin D levels in patients.
of the MHC class II complex and co-stimulatory molecules, Individuals who are deficient in vitamin D have a higher and also the production of IL-12, which directs the risk of developing autoimmune disorders (31).
polarization of T cells from Th1 phenotype towards Th2. Suppression in bone turnover is a major characteristic of F u r t h e r m o r e , v i t a m i n D h a s a n i n d i r e c t bone disorders associated with type 1 DM and vitamin D immunomodulatory effect on the level of T cells, through deficiency. The states of hyperglycemia, hypoinsulinemia, inhibition of Th1 inflammatory cytokines, namely IL-2 and IFN-γ, and stimulates the production of Th2 cytokines, autoimmune inflammation, a low level of insulin-like namely IL-4, IL5, and IL10. Simultaneously, the growth factor-1, and low vitamin D level are thought to be immunomodulatory effects of vitamin D lead to the associated with bone turnover suppression. Risk factors of protection of target tissues such as beta cells (40). In this a decrease in bone mineralization in type 1 DM include: study, no inflammatory or anti-inflammatory cytokines the younger the age at the time of diagnosis, poor were examined to determine the effect on vitamin D glycemic control, diabetes complications, decreased ((25(OH)D) and glycemic control (HbA1c). kidney function, low BMI, and insulin doses (32).
The limitation of this study is to examine the levels of HbA1c levels HbA1c and vitamin D and nutritional status in one This study showed no significant difference in HbA1C measurement, serial measurements are needed in order levels between nutritional status groups. In this study, of to find out more about the relationship between research variables. This study was conducted only in the population 28 study subjects, only seven children were in good of type 1 DM children, and there was no control of healthy The results of the study illustrate that in children with type children. HbA1c level is influenced by a number of factors 1 DM there is a considerable amount of deficiency and is including levels of iron, vitamin B12, and folic acid that dominated by poor glycemic control despite having good were not examined in this study. The complicating factors nutritional status. that may arise in this study also have not been controlled There are no significant differences in HbA1c and vitamin D as ideal as possible, for example, low vitamin D diet levels based on nutritional status in type 1 DM children. factors, exposure to sunray, ethnicity/race, body surface There is no relationship between vitamin D status and areas, and drugs that can affect vitamin D status in the nutritional status of glycemic control with vitamin D status research subjects who might have a role in the occurrence in type 1 DM children. Further studies need to be of vitamin D deficiency which were not examined in this conducted using healthy control groups, periodic study. IGF-1 level measurement is needed to determine the relationship with bone growth that affects the child's monitoring, and considering the influence of height. environmental factors.