Linkage analysis using whole exome sequencing data implicates SLC17A1, SLC17A3, TATDN2 and TMEM131L in type 1 diabetes in Kuwaiti families.

Type 1 diabetes (T1D) is characterized by the progressive destruction of pancreatic ß-cells, leading to insulin deficiency and lifelong dependency on exogenous insulin. Higher estimates of heritability rates in monozygotic twins, followed by dizygotic twins and sib-pairs, indicate the role of genetics in the pathogenesis of T1D. The incidence and prevalence of T1D are alarmingly high in Kuwait. Consanguineous marriages account for 50-70% of all marriages in Kuwait, leading to an excessive burden of recessive allele enrichment and clustering of familial disorders. Thus, genetic studies from this Arab region are expected to lead to the identification of novel gene loci for T1D. In this study, we performed linkage analyses to identify the recurrent genetic variants segregating in high-risk Kuwaiti families with T1D. We studied 18 unrelated Kuwaiti native T1D families using whole exome sequencing data from 86 individuals, of whom 37 were diagnosed with T1D. The study identified three potential loci with a LOD score of ≥ 3, spanning across four candidate genes, namely SLC17A1 (rs1165196:pT269I), SLC17A3 (rs942379: p.S370S), TATDN2 (rs394558:p.V256I), and TMEM131L (rs6848033:p.R190R). Upon examination of missense variants from these genes in the familial T1D dataset, we observed a significantly increased enrichment of the genotype homozygous for the minor allele at SLC17A3 rs56027330_p.G279R accounting for 16.2% in affected children from 6 unrelated Kuwaiti T1D families compared to 1000 genomes Phase 3 data (0.9%). Data from the NephQTL database revealed that the rs1165196, rs942379, rs394558, and rs56027330 SNPs exhibited genotype-based differential expression in either glomerular or tubular tissues. Data from the GTEx database revealed rs942379 and rs394558 as QTL variants altering the expression of TRIM38 and IRAK2 respectively. Global genome-wide association studies indicated that SLC17A1 rs1165196 and other variants from SLC17A3 are associated with uric acid concentrations and gout. Further evidence from the T1D Knowledge portal supported the role of shortlisted variants in T1D pathogenesis and urate metabolism. Our study suggests the involvement of SLC17A1, SLC17A3, TATDN2, and TMEM131L genes in familial T1D in Kuwait. An enrichment selection of genotype homozygous for the minor allele is observed at SLC17A3 rs56027330_p.G279R variant in affected members of Kuwaiti T1D families. Future studies may focus on replicating the findings in a larger T1D cohort and delineate the mechanistic details of the impact of these novel candidate genes on the pathophysiology of T1D.

Intermediate hyperglycaemia, insulin resistance and metabolic syndrome among obese Arab children (12-17 years old) in Kuwait.

OBJECTIVE: To screen 97 obese Arab adolescents for metabolic risk factors. RESULTS: Insulin resistance, metabolic syndrome and intermediate hyperglycaemia was found in 56.7 %, 14.4 % and 27.8 % (HbA1c) while fasting plasma glucose was impaired in 0-16.5 %, using different cut-offs. Interventions to prevent obesity and diabetes are needed.

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.

Audit of glycemic control in patients with type 1 diabetes referred to a pediatric clinic in a specialized center in Kuwait.

INTRODUCTION: Intensive glycemic control reduces the risk of microvascular and macrovascular complications. Furthermore, optimal glycemic control is essential for normal growth and development. Thus, there is a need to monitor and evaluate glycemic control in patients with type 1 diabetes (T1D). Our aim was to audit glycemic control in patients with T1D in a specialized center as per the Society of Pediatric and Adolescent Diabetes (ISPAD) Hemoglobin A1C (HbA1C) target recommendations published in 2014. METHODS: This is a retrospective cross-sectional study reporting on glycemic control (HbA1C) of patients younger than 21 years of age and with T1D treated at Dasman Diabetes Institute (DDI) between January 2013 and December 2015. RESULTS: A total of 470 patients with T1D (250 males and 220 females) were included. Only 53 (11.3%) patients met the ISPAD target for optimal glycemic control with HbA1C < 7.5% (58 mmol/mol). Older age was positively associated with poor glycemic control (p = 0.001) while Continuous Subcutaneous Insulin Infusion (CSII) therapy was negatively associated with poor glycemic control, adjusted Odds Ratio (OR) 0.33 (95% confidence interval (CI): 0.16-0.66) for CSII and adjusted OR 0.42 (95% CI: 0.27-0.64) for shifting to CSII (p < 0.001). CONCLUSION: Achieving optimal glycemic control is a significant challenge for young patients with T1D. Glycemic control goals should be individualized to achieve such goals safely, realistically and with a better quality of life for patients with T1D.

Fasting during the holy month of Ramadan among older children and adolescents with type 1 diabetes in Kuwait.

Background To evaluate the safety of fasting during the holy month of Ramadan among children and adolescent with type 1 diabetes (T1D). Methods A retrospective cohort study of 50 children and adolescents with T1D whose mean age was 12.7 ± 2.1 years was conducted. Twenty-seven patients (54%) were on multiple daily injections (MDI) insulin regimen and 23 (46%) were on insulin pump therapy. Before fasting for Ramadan, children and their families were evaluated and educated about diabetes management during Ramadan. Hemoglobin A1c (HbA1c), weight, number of days fasted, hypoglycemia and hyperglycemia episodes, and emergency hospital visits were collected and analyzed after completing the month. Participants were compared according to the insulin treatment regimen and their glycemic control level before Ramadan. Results The children were able to fast 20 ± 9.9 days of Ramadan, and the most common cause for breaking the fast was mild hypoglycemia (7.8% among all cases). There was no significant difference between the two insulin regimen groups in breaking fast days, frequency of hypo- or hyperglycemia, weight and HbA1c changes post Ramadan. Patients with HbA1c ≤ 8.5% were able to fast more days during Ramadan with significantly less-frequent hypoglycemic attacks as compared to patients with HbA1c > 8.5 (1.2 ± 1.5 vs. 3.3 ± 2.9 days of hypoglycemia, p = 0.01, respectively). Conclusions Fasting for children with T1D above the age of 10 years is feasible and safe in both pump and non-pump users, and well-controlled patients are less likely to develop complications. Education of the families and their children before Ramadan, along with intensive monitoring of fasting children during the month are crucial.

The Complex Etiology of Childhood Obesity in Arabs Is Highlighted by a Combination of Biological and Socio-Economic Factors.

Objectives: To identify predictors of childhood and adolescent obesity in Kuwaitis with Arab ethnicity. Methods: A cross-sectional sample of 6-18 year-old schoolchildren was randomly selected from 244 public schools across all six governorates in the State of Kuwait. Anthropometric data were measured from 6,574 Arab Kuwaiti schoolchildren, and a structured questionnaire was used to collect information on possible risk factors associated with obesity. Overweight and obesity were defined in accordance with the Center for Disease Control and Prevention criteria. Results: The prevalence of overweight and obesity in children (aged 6-18 years) were 17.7% and 33.7%, respectively. The likelihood of childhood obesity increased with birth weights >4.0 Kg [odds ratio (OR) = 2.3; p < 0.0001], maternal employment (OR = 1.26, p = 0.0006), maternal age at pregnancy >30 years (OR = 1.24; p = 0.0016) and family size of <6 members (OR = 1.16, p = 0.0106). Conclusions: Public health professionals should be aware that advanced maternal age, maternal employment, smaller family size, and high birthweight may predict the risk of obesity in Kuwaiti Arab children and adolescents.

An Audit of Clinical Practice in a Single Centre in Kuwait: Management of Children on Continuous Subcutaneous Insulin Infusion and Cardiovascular Risk Factors Screening.

OBJECTIVES: To audit the current clinical practice of continuous subcutaneous insulin infusion (CSII) for the treatment of type 1 diabetes mellitus (T1D) in children and adolescents attending a single centre in Kuwait. METHODS: A one year retrospective audit was performed in children and adolescents with T1D on CSII, who attended the paediatric diabetes clinic, Dasman Diabetes Institute during 2012. The primary outcome measure was glycaemic control as evidenced by glycated haemoglobin (HbA1c) level and the secondary outcome measures were the frequency of monitoring of the risk for microvascular complications and occurrence of acute complications and adverse events. RESULTS: 58 children and adolescents (mean age ± SD: 12.6 ± 4.1 years) were included. Mean HbA1c at baseline was 8.8% (72.7 mmol/mol) and 8.9% (73.8 mmol/mol) at the end of a 12 months observation period. Children with poor control (HbA1c >9.5% (80 mmol/mol) had a significant 1.4% reduction in HbA1c compared with the overall reduction of 0.1% (p=0.7). Rate of screening for cardiovascular risk factors and for long term complications were well documented. However, there was underreporting of acute complications such as severe hypoglycaemia and diabetic ketoacidosis. Only 1.7% of patients discontinued the pump. CONCLUSION: There was no significant change in HbA1c values at the end of 12 months follow up. However, HbA1c values in poorly controlled children improved. CSII requires care by skilled health professionals as well as education and selection of motivated parents and children.

Ethnic differences in association of high body mass index with early onset of Type 1 diabetes - Arab ethnicity as case study.

OBJECTIVE: The "accelerator hypothesis" predicts early onset of Type 1 diabetes (T1D) in heavier children. Studies testing direction of correlation between body mass index (BMI) and age at onset of T1D in different continental populations have reported differing results-inverse, direct, and neutral. Evaluating the correlation in diverse ethnic populations is required to generalize the accelerator hypothesis. METHODS: The study cohort comprised 474 Kuwaiti children of Arab ethnicity diagnosed with T1D at age 6 to 18 years during 2011-2013. Age- and sex-adjusted BMI z-scores were calculated by comparing the BMI measured at diagnosis with Kuwaiti pediatric population reference data recorded during comparable time-period. Multiple linear regression and Pearson correlation analyses were performed. RESULTS: BMI z-score was seen inversely associated with onset age (r,-0.28; p-value<0.001). Children with BMI z-score>0 (i.e. BMI >national average) showed a stronger correlation (r,-0.38; p-value<0.001) than those with BMI z-score<0 (r,-0.19; p-value<0.001); the former group showed significantly lower mean onset age than the latter group (9.6±2.4 versus 10.5±2.7; p-value<0.001). Observed inverse correlation was consistent with that seen in Anglo-saxon, central european, caucasian, and white children while inconsistent with that seen in Indian, New Zealander, and Australian children. CONCLUSIONS: The accelerator hypothesis generalizes in Arab pediatric population from Kuwait.

Incidence of type 1 diabetes has doubled in Kuwaiti children 0-14 years over the last 20 years.

AIMS: This study had 2 aims: to report data on the incidence of childhood-onset type 1 diabetes in Kuwaiti children aged 0-14 years during 2011 to 2013 and to compare the recent data with those collected during 1992 to 1997. METHODS: All newly diagnosed patients were registered through the Childhood-Onset Diabetes eRegistry (CODeR) in 2011-2013, based on the DiaMond protocol used in 1992-1997. RESULTS: A total of 515 Kuwaiti children (247 boys and 268 girls) aged 0-14 years newly diagnosed with type 1 diabetes were registered from 1 January 2011 to 31 December 2013. Data ascertainment were 96.7%. The mean age ± SD at diagnosis was 8.7 ± 3.4 years in boys and 7.9 ± 3.1 years in girls. The crude incidence rate (95% CI) was 40.9 (37.4-44.6) and the age standardized rate 41.7 (95% 38.1-45.4) per 100,000 per year, 39.3 (34.6-44.4) among boys and 44.1 (39.0-49.7) among girls. A statistically significant increasing trend in incidence was observed as the overall crude incidence rose from 17.7 in 1992-1994 to 40.9 per 100,000 per year in 2011-2013. The Poisson regression model depicting the trend in incidence revealed that, the incidence rates adjusted for age and sex in 2011 to 2013 was 2.3 (95% CI 1.9-2.7) times higher than 1992-1997. CONCLUSIONS: The incidence of type 1 diabetes in Kuwaiti children 0-14 years has doubled in the last 2 decades. The reasons for this increase requires further investigation.

Ketoacidosis at first presentation of type 1 diabetes mellitus among children: a study from Kuwait.

We examined the frequency and severity of diabetic ketoacidosis (DKA) in 679 children and adolescents (0-14 years) at diagnosis of Type 1 Diabetes Mellitus (T1DM) in Kuwait. Between 1(st) January 2011 and 31(st) December 2013, all newly diagnosed children with diabetes were registered prospectively in a population-based electronic register. DKA was diagnosed using standard criteria based on the levels of venous pH and serum bicarbonate. At the time of diagnosis, mild/moderate DKA was present in 24.8% of the children, while severe DKA was present in 8.8%. Incidence of ketoacidosis was significantly higher in young children less than 2 (60.7% vs 32.4% p = <0.005) compared to children 2-14 years old, and a higher proportion presented with severe DKA (21.4% vs 8.3% p = <0.05). No association was seen with gender. Significant differences were found in the incidence of DKA between Kuwaiti and non-Kuwaiti children (31.1% vs 39.8%; p < 0.05). Family history of diabetes had a protective effect on the occurrence of DKA (OR = 0.44; 95% CI = 0.27-0.71). Incidence of DKA in children at presentation of T1DM remains high at 33.6%. Prevention campaigns are needed to increase public awareness among health care providers, parents and school teachers in Kuwait.