Association of interleukin-4, interleukin-13 gene polymorphisms, HLA-DQ and DR genotypes with genetic susceptibility of type-1 Diabetes Mellitus in Kuwaiti children.

Background: Type-1 diabetes mellitus (T1DM) is a complex multifactorial disease with an autoimmune etiology and is thought to result from an interaction between genetic and non-genetic factors. Cytokines play a crucial role in the pathogenesis of autoimmune diseases due to their effector and regulatory functions in immune responses. Interleukin-4 (IL4) and Interleukin-13 (IL13) are anti-inflammatory cytokines and are considered as important mediators in pathology of the autoimmune diseases. Methods: We have determined the genotype frequency of IL4 gene promoter polymorphism (-590C/T, rs2243250), IL13 gene polymorphism p.(Arg130Glu, rs20541) and human leukocyte antigen, HLA-DQ and DR genotypes in Kuwaiti children with T1DM to investigate their role in genetic susceptibility. This study included 261 Kuwaiti children with T1DM and 214 healthy controls. The genotypes for IL4 (-590C/T) and IL13 p.(Arg130Glu) gene polymorphisms were detected by PCR-RFLP methods. HLA-DQ and DR genotypes were determined by sequence-specific PCR methods. Results: The CC genotype of IL4 gene polymorphism (-590C/T) was significantly related to the risk for T1DM in Kuwaiti patients (OR 1.64). The homozygous AA (QQ) and heterozygous AG (RQ) genotypes of IL13 gene polymorphism p.(Arg130Glu), also manifested a statistically significant association with T1DM (OR 2.92 and 4.79). In 55% T1DM patients, the HLA genotype was either DQ2/DQ2 or in combination with a DQ8 allele. Collectively, 91% Kuwaiti T1DM patients had either DQ2 or DQ8 alleles in different combinations highlighting them as the high risk-genotypes in comparison to the controls. In the case of HLA-DR, the genotypes DR3/DRB5, DR3/DR4, DR3/DR7 and DR4/DR4 showed highest frequency amongst the Kuwaiti T1DM patients and thus can be considered as high-risk genotypes when compared to the controls. A high degree of co-inheritance (>80%) was detected between IL4 and IL13 gene polymorphism genotypes (CC and QQ) and the high-risk HLA-DQ and DR genotypes amongst the Kuwaiti T1DM patients. Conclusions: We have identified the association of IL4 and IL13 gene polymorphisms with susceptibility to T1DM in Kuwaiti children and the co-inheritance of these polymorphisms with high-risk HLA genotypes. The findings may contribute to early identification of childhood diabetes.

Incidence of Type 2 Diabetes in Kuwaiti Children and Adolescents: Results From the Childhood-Onset Diabetes Electronic Registry (CODeR).

Background: Type 2 Diabetes (T2D) in children and adolescents has become an important public health concern due to the increase in childhood obesity worldwide. The urgency to address T2D is evident as children and adolescents are at a higher risk of complications due to prolonged disease duration. We aimed to estimate the incidence rate (IR) of T2D in Kuwaiti children and adolescents aged 14 years and younger between 2011 and 2013 and to describe their clinical characteristics at the time of diagnosis. Material and Methods: All newly diagnosed patients were registered through the Childhood-Onset Diabetes electronic Registry implemented in Kuwait. Cases who met the 2018 ISPAD guidelines for diagnosis of T2D were included. Results: A total of 32 patients were included, equally distributed gender-wise, with a mean age 12.2 years (±1.7 SD), lower for females than males (11.5 vs. 12.2, p < 0.025). Data ascertainment was 94.1% (95%CI; 91.6-96.6%). Overall IR was 2.56 (95% CI; 1.78-3.56) per 100,000 Kuwaiti children and adolescents per year. Most of the patients (n = 30; 93.8%) presented with T2D between the ages 10-14 years, with age-specific IR of 8.0 (95%CI; 5.5-11.3). No statistically significant difference between males and females with regards to BMI z scores or HbA1C at diagnosis. Conclusion: The true incidence of T2D in Kuwaiti children and adolescents is expected to be considerably higher as we have reported only symptomatic cases. Future research should focus on screening children and adolescents at risk to enable accurate estimates. More efforts are needed to better understand the clinical course of T2D early in life to improve management, prevent complications and improve quality of life.

Relationship of four vitamin D receptor gene polymorphisms with type 1 diabetes mellitus susceptibility in Kuwaiti children.

BACKGROUND: The incidence of type 1 diabetes mellitus (T1DM) in Kuwait is amongst the highest in the world. Vitamin D is considered to be involved in immune modulation and its deficiency contribute to autoimmune destruction of insulin producing beta cells in T1DM patients. Vitamin D has been shown to exert its effects via a nuclear vitamin D receptor (VDR) and therefore, VDR gene may be considered a candidate for T1DM susceptibility. METHODS: The genotypes of four VDR gene polymorphisms were determined in 253 Kuwaiti Arab T1DM patients and 214 healthy controls by PCR-RFLP analysis. Serum concentrations of three autoantibodies i.e. ICA (Islet cell autoantibody), GADA (Glutamic acid decarboxylase) and INS (Insulin autoantibody) were determined by radio-immunoassays. RESULTS: Statistically significant differences were detected between the genotypes of two VDR gene polymorphisms (FokI, C > T, rs10735810 and TaqI, C > T, rs731236) between T1DM patients and controls (P < 0.0001). In both, the frequency of variant alleles was considerably high in T1DM than in the controls. In contrast, the VDR gene ApaI (G > T, rs7975232) and BsmI (A > G, rs1544410) polymorphisms did not show association with T1DM. The homozygous variant genotypes of FokI, ApaI and TaqI polymorphisms show significant differences between various age-of-onset subgroups while no such association was detected in the case of BsmI polymorphism. Significant differences were also noted between heterozygous genotypes of all four polymorphisms especially between 4-6y and > 6y age-of-onset subgroups of T1DM patients. Three autoantibodies, ICA (Islet cell), GADA (glutamate decarboxylase) and INS (insulin) were positively associated to, varying degrees, with T1DM in Kuwaiti Arabs harboring different VDR gene polymorphism genotypes. CONCLUSIONS: Our results demonstrate a significant effect of two VDR gene polymorphisms (FokI and TaqI) and three autoantibodies on genetic susceptibility of T1DM in Kuwaiti Arabs along with other factors.

Association of protein tyrosine phosphatase non-receptor type 22 gene functional variant C1858T, HLA-DQ/DR genotypes and autoantibodies with susceptibility to type-1 diabetes mellitus in Kuwaiti Arabs.

The incidence of type-1 Diabetes Mellitus (T1DM) has increased steadily in Kuwait during recent years and it is now considered amongst the high-incidence countries. An interaction between susceptibility genes, immune system mediators and environmental factors predispose susceptible individuals to T1DM. We have determined the prevalence of protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene functional variant (C1858T; R620W, rs2476601), HLA-DQ and DR alleles and three autoantibodies in Kuwaiti children with T1DM to evaluate their impact on genetic predisposition of the disease. This study included 253 Kuwaiti children with T1DM and 214 ethnically matched controls. The genotypes of PTPN22 gene functional variant C1858T (R620W; rs2476601) were detected by PCR-RFLP method and confirmed by DNA sequencing. HLA-DQ and DR alleles were determined by sequence-specific PCR. Three autoantibodies were detected in the T1DM patients using radio-immunoassays. A significant association was detected between the variant genotype of the PTPN22 gene (C1858T, rs2476601) and T1DM in Kuwaiti Arabs. HLA-DQ2 and DQ8 alleles showed a strong association with T1DM. In T1DM patients which carried the variant TT-genotype of the PTPN22 gene, 93% had at least one DQ2 allele and 60% carried either a DQ2 or a DQ8 allele. Amongst the DR alleles, the DR3-DRB5, DR3-3, DR3-4 and DR4-4 showed a strong association with T1DM. Majority of T1DM patients who carried homozygous variant (TT) genotype of the PTPN22 gene had either DR3-DRB5 or DRB3-DRB4 genotypes. In T1DM patients who co-inherited the high risk HLA DQ, DR alleles with the variant genotype of PTPN22 gene, the majority were positive for three autoantibodies. Our data demonstrate that the variant T-allele of the PTPN22 gene along with HLA-DQ2 and DQ8 alleles constitute significant determinants of genetic predisposition of T1DM in Kuwaiti children.

Low serum vitamin-D status is associated with high prevalence and early onset of type-1 diabetes mellitus in Kuwaiti children.

BACKGROUND: Type 1 diabetes mellitus (T1DM) is highly prevalent in Kuwait with incidence of around 40.1/100,000 individuals. Evidence indicate that vitamin D plays an important role in modulating the immune system and could thus impact the onset and high prevalence of T1DM. We report serum vitamin D levels in Kuwaiti children with T1DM and non-diabetic controls to explore its relationship with prevalence and onset of the disease. METHODS: This study included 216 Kuwaiti Arab children with T1DM. The diagnosis of T1DM was based on the ISPAD criteria. The control subjects (204 Kuwaitis) were age and gender matched, healthy, non-diabetic, and had no close relative with T1DM. Vitamin D levels were determined in serum using an enzyme immunoassay (EIA) method. RESULTS: The age of onset of T1DM was <4y in 20 % of the T1DM cases, between 4 and 6y in 28 % cases and >6y in 52 % patients. In T1DM patient group, 84 % subjects were found to be deficient in serum vitamin D level compared to 77 % of the controls (p = 0.046). Collectively, the deficient and insufficient vitamin D status was detected in 99 % of the T1DM patients compared to 92 % of the controls (p = 0.027). The mean serum vitamin D levels were found to be significantly different in early onset cases (age <4y) compared to the late onset sub-group (p = 0.001). A significant correlation was found between some elements of socioeconomic status, SES (i.e. parent's profession and family's income) and lower vitamin D levels in Kuwaiti T1DM children. There was no significant difference between mean serum vitamin D levels during winter and summer months in the T1DM patients. CONCLUSIONS: The proportion of cases with a deficient vitamin D status was significantly high in Kuwaiti T1DM children compared to the controls. The serum vitamin D levels were found to be significantly different in early onset and late onset T1DM patients. Therefore, serum vitamin D status can be considered an important contributor in high prevalence of T1DM in Kuwaiti children.

A Comparison of Continuous Subcutaneous Insulin Infusion vs. Multiple Daily Insulin Injection in Children with Type I Diabetes in Kuwait: Glycemic Control, Insulin Requirement, and BMI.

OBJECTIVE: Continuous subcutaneous insulin infusion (CSII) and multiple daily insulin injections (MDI) are two methods currently used to manage type I diabetes mellitus (T1DM). Here we compare our experiences with CSII and MDI in a large cohort of pediatric patients in Kuwait. METHODS: Data on 326 patients with T1DM who were started on CSII between 2007 and 2012 were retrospectively compared with those of 326 patients on MDI. They were matched for sex, age at diagnosis, T1DM duration, glycemic control, insulin requirement, and body mass index (BMI). Data were collected at baseline and every three months and included glycated hemoglobin (HbA1c), insulin dose, and adverse events (severe hypoglycemia, diabetic ketoacidosis, and skin problems). RESULTS: The main reason for switching to CSII was to achieve better glycemic control (37%), followed by reducing hypoglycemia, and improving the quality of life (13.3% each). Although HbA1c decrease was most significant in the first year, it continued to be significantly lower in the CSII group compared to the MDI throughout the study period. Total daily insulin requirements were significantly lower in the CSII group. BMI increased in both groups, but the difference was significant only at the end of the fifth year. There was no significant change in the rate of diabetic ketoacidosis in either group. The CSII patients had more severe hypoglycemic episodes at baseline; however, it significantly decreased throughout the study period. Only five patients discontinued CSII therapy and two of these restarted within three months. CONCLUSION: CSII is a safe intensive insulin therapy in youngsters with T1DM and achieved markedly fewer severe hypoglycemic episodes and lower daily insulin requirements.

Successful transfer from insulin to oral sulfonylurea in a 3-year-old girl with a mutation in the KCNJ11 gene.

Neonatal diabetes mellitus is considered a rare disease that is diagnosed in the first six months of life, and can be either transient or permanent. Recent advances in molecular genetics have shown that activating mutations in KCNJ11 (the gene that encodes for the Kir6.2 subunit of the K ATP potassium channel of the pancreatic beta-cell) is a common cause of permanent neonatal diabetes mellitus. Patients with mutations in this gene may respond to oral sulfonylureas. We describe a 3-year-old girl with permanent neonatal diabetes mellitus with a mutation in the KCNJ11 gene (R201H), who was successfully transferred from subcutaneous insulin to oral glibenclamide, with a marked improvement in glycemic control. This is the first successful switch from insulin to oral sulfonylurea in a patient with R201H mutation, in the Arabian Gulf.