Identification of Maturity-Onset-Diabetes of the Young (MODY) mutations in a country where diabetes is endemic.

Genetic variants responsible for Maturity-Onset-Diabetes of the Young (MODY) in Kuwait were investigated. A newly established a National Referral Clinic, the Dasman Diabetes Institute (DDI-NRC), assessed forty-five members from 31 suspected MODY families by whole exome sequencing. Thirty-three of the 45 samples were independently sequenced at the DDI-NRI, Exeter University, UK ( https://www.diabetesgenes.org/ ) using targeted 21-gene panel approach. Pathogenic mutations in GCK, HNF1A, HNF1B, HNF4A, and PDX1 confirmed MODY in 7 families, giving an overall positivity rate of 22.6% in this cohort. Novel variants were identified in three families in PDX1, HNF1B, and HNF1B. In this cohort, Multiplex Ligation-dependent Probe Amplification assay did not add any value to MODY variant detection rate in sequencing negative cases. In highly selected familial autoantibody negative diabetes, known MODY genes represent a minority and 77.3% of the familial cases have yet to have a causal variant described.

Cultural Adaptation of Health Literacy Measures: Translation Validation of the Newest Vital Sign in Arabic-Speaking Parents of Children With Type 1 Diabetes in Kuwait.

PURPOSE: The purpose of the study was to assess the feasibility of use and reliability of the Arabic version of the Newest Vital Sign (NVS-Ar) in parents of children with type 1 diabetes (T1D). METHODS: The final translated version of NVS-Ar was administered to 175 adult caregivers of children with T1D who are native Arabic speakers. The association between NVS-Ar scores for the parents/legal guardians and A1C for their children was assessed. The internal consistency was evaluated by Cronbach's α, and reliability was assessed by test-retest method. RESULTS: The median (interquartile range) score was 4.0 (3-5). The internal consistency of the NVS-Ar was moderate (α = .58). The intraclass correlation coefficient was .61. There was no correlation between NVS-Ar score and A1C (Spearman's ρ = .055; P = .62). Furthermore, there was significant inverse association between adequate health literacy and optimal glycemic control among the children, which remained evident even after adjusting for the duration of T1D, age, or education of the parents/guardians. However, it lost statistical significance after adjustment for treatment regimen. CONCLUSION: Study findings indicate that the NVS is unlikely to be a predictive tool for functional health literacy in Arabic settings and that there is a need to properly translate and validate other tools such as the Test of Functional Health Literacy in Adults or, alternatively, to develop a reliable tool.

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.

Rabson-Mendenhall Syndrome in a brother-sister pair in Kuwait: Diagnosis and 5 year follow up.

AIM: To report on Rabson-Mendenhall Syndrome (RMS) diagnosed in Kuwait. METHODS: A toddler (18 months old) was referred with high plasma insulin and dysmorphic features suggestive of RMS including coarse facial features with globular nose, full lips and furrowed tongue. His skin was hyperkeratotic with hypertrichosis. His sister (aged 13.5 years) was diagnosed with diabetes at 9 years of age and treated with metformin and insulin. She presented with similar dysmorphic features, extensive acanthosis nigricans, dental abnormalities and bilateral nephrocalcinosis. The children were born to non-consanguineous parents. Blood samples were sent for genetic testing in a reference laboratory. RESULTS: Both children were found to be homozygous for the p.Arg141Trp missense variant (p.Arg114Trp if numbered according to pro-receptor sequence) in the alpha subunit of the insulin receptor. CONCLUSIONS: These cases demonstrate the importance of raising awareness among healthcare professionals to ensure rapid referral of patients with characteristic physical features of RMS and severe insulin resistance for genetic testing. Unfortunately, treatment of RMS patients remains a challenge with poor prognosis and short life expectancy usually caused by diabetes-related complications. Genetic testing confirms the diagnosis and allows informed genetic counseling of parents considering future pregnancies.

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.

Corrigendum: Caveolin-1 Variant Is Associated With the Metabolic Syndrome in Kuwaiti Children.

[This corrects the article DOI: 10.3389/fgene.2018.00689.].

Glycaemic control in native Kuwaiti Arab patients with type 2 diabetes.

AIMS: To evaluate the influence of age at diabetes diagnosis, diabetes duration, BMI, comorbidity with hypertension and medication regimen on glycaemic control in native Kuwaiti Arab patients with T2D. METHODS: This cross-sectional study considered 7657 patients from Kuwait Diabetes Registry and analysed data from their laboratory and hospital records. RESULTS: HbA1c and prevalence of hypertension increased significantly with diabetes duration. Duration of diabetes (ß=0.034; P<0.001) and age at diagnosis (ß=-0.03; P<0.001) were independently associated with HbA1c. Inadequate glycaemic control was more likely in patients diagnosed at <60 than in those ≥60 years of age (OR:1.80, 95%-CI:1.39-2.31). Increasing duration of diabetes witnessed decrease in metformin prescription and increase in sulfonylureas prescription; proportion of patients treated with insulin increased from 5.6% to 44.4% in 9 years of diagnosis. Patients with 9-years duration of diabetes or with combination therapy of insulin-metformin-sulfonylureas differed in mean BMI for adequate or inadequate glycaemic control (29.5 versus 31.2kg/m2; P<0.001 and 29.8 versus 33.2; P<0.01, respectively). CONCLUSIONS: Only 25.6% of the T2D patients in this ethnic cohort exhibited adequate glycaemic control. The delineated relationship of inadequate glycaemic control with diabetes duration, onset age, obesity and hypertension prevalence has a bearing on diabetes management programs for Arabs.

Caveolin-1 Variant Is Associated With the Metabolic Syndrome in Kuwaiti Children.

Caveolin-1 (CAV1) variants have been suggested to be associated with obesity and related metabolic disorders, but information based on human studies is limited. In the present study, we aimed to investigate the potential association between the CAV1 rs1997623 C/A variant and metabolic syndrome (MetS) in Kuwaiti children. DNA from saliva samples collected from 1313 Kuwaiti children (mean age: 12 years) were genotyped using the TaqMan SNP genotyping assay. The classification of MetS was based on the presence/absence of four indicators; (1) central obesity, (2) elevated systolic or diastolic blood pressure, (3) low salivary high-density lipoprotein cholesterol (HDLC), and (4) high salivary glucose. In this study, children with MetS scored ≥3, children in the intermediate metabolic group scored 1 or 2 and children without MetS scored 0. About one-third of the children were obese. A total of 246 children (18.7%) were classified as having MetS; 834 children (63.5%) were in the intermediate metabolic group, and 233 children (17.7%) had no indication of MetS. Obesity was highly prevalent in the MetS group (91.9%) while 26.8% of children were obese in the intermediate metabolic group. None of the children were obese in the group without MetS. Analysis of the CAV1 rs1997623 variant revealed a significant association of the A-allele (p = 0.01, Odds Ratio (OR) = 1.66) and the heterozygous CA-genotype (p = 0.005, OR = 1.88) with MetS. Consistently, the A-allele (p = 0.002, OR = 1.71) and CA-genotype (p = 0.005, OR = 1.70) also showed significant association with the intermediate metabolic group. Furthermore, the A-allele (p = 0.01, OR = 1.33) and the CA-genotype (p = 0.008, OR = 1.55) were associated with low levels of saliva HDLC. Individuals who were heterozygous or homozygous for the variant (CA/AA) showed significantly lower levels of high HDLC compared to those harboring the CC-genotype (p = 0.023). Our study revealed a novel association of the CAV1 rs1997623 variant with the MetS and with low saliva HDLC levels in young Kuwaiti children and indicated the need for further in-depth studies to unravel the role of CAV1 gene in the genetic etiology of MetS.

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.

Total Energy Expenditure in Obese Kuwaiti Primary School Children Assessed by the Doubly-Labeled Water Technique.

The aim of this pilot study was to assess body composition and total energy expenditure (TEE) in 35 obese 7-9 years old Kuwaiti children (18 girls and 17 boys). Total body water (TBW) and TEE were assessed by doubly-labeled water technique. TBW was derived from the intercept of the elimination rate of deuterium and TEE from the difference in elimination rates of 18O and deuterium. TBW was used to estimate fat-free mass (FFM), using hydration factors for different ages and gender. Fat mass (FM) was calculated as the difference between body weight and FFM. Body weight was not statistically different but TBW was significantly higher (p = 0.018) in boys (44.9% ± 3.3%) than girls (42.4% ± 3.0%), while girls had significantly higher estimated FM (45.2 ± 3.9 weight % versus 41.6% ± 4.3%; p = 0.014). TEE was significantly higher in boys (2395 ± 349 kcal/day) compared with girls (1978 ± 169 kcal/day); p = 0.001. Estimated physical activity level (PAL) was significantly higher in boys; 1.61 ± 0.167 versus 1.51 ± 0.870; p = 0.034. Our results provide the first dataset of TEE in 7-9 years old obese Kuwaiti children and highlight important gender differences to be considered during the development of school based interventions targeted to combat childhood obesity.

Total body water measurement using the 2H dilution technique for the assessment of body composition of Kuwaiti children.

OBJECTIVE: The 2H dilution technique is the reference method to estimate total body water for body composition assessment. The aims of the present study were to establish the total body water technique at the Kuwait Institute for Scientific Research and assess body composition of Kuwaiti children. DESIGN: The isotope ratio mass spectrometer was calibrated with defined international reference water standards. A non-random sampling approach was used to recruit a convenience sample of Kuwaiti children. A dose of 2H2O, 1-3 g, was consumed after an overnight fast and 2H enrichment in baseline and post-dose urine samples was measured. Total body water was calculated and used to estimate fat-free mass. Fat mass was estimated as body weight minus fat-free mass. SETTING: The total body water study was implemented in primary schools. SUBJECTS: Seventy-five boys and eighty-three girls (7-9 years). RESULTS: Measurements of the isotope ratio mass spectrometer were confirmed to be accurate and precise. Children were classified as normal weight, overweight or obese according to the WHO based on BMI-for-age Z-scores. Normal-weight and overweight girls had significantly higher percentage body fat (median (range): 32·4 % (24·7-39·3 %) and 38·3 % (29·3-44·2 %), respectively) compared with boys (median (range): 26·5 % (14·2-37·1 %) and 34·6 % (29·9-40·2 %), respectively). No gender difference was found in obese children (median 46·5 % v. 45·6 %). CONCLUSIONS: The establishment of a state-of-the-art stable isotope laboratory for assessment of body composition provides an opportunity to explore a wide range of applications to better understand the relationship between body size, body composition and risk of developing non-communicable diseases in Kuwait.

The aetiology of anaemia during pregnancy: a study to evaluate the contribution of iron deficiency and common infections in pregnant Ugandan women.

OBJECTIVE: To describe the aetiology of anaemia in pregnant Ugandan women and explore Fe deficiency and common infections as contributors to anaemia in this population. DESIGN: Cross-sectional study in which Hb, ferritin, transferrin receptor (sTfR), C-reactive protein, α-1 acid glycoprotein, hepcidin, malaria, hookworm infestation, syphilis and Helicobacter pylori infection were assessed. SETTING: Antenatal care clinic at Kawempe Health Centre, Kampala, Uganda. SUBJECTS: HIV-negative women (n 151) in their first or second pregnancy at 10-16 weeks' gestation. RESULTS: The prevalence of anaemia was 29·1 %. Fe deficiency was 40·4 % and 14·6 % based on ferritin 8·3 µg/ml. The prevalence of Fe-deficiency anaemia was 9·3 % based on ferritin 8·3 µg/ml. Hepcidin concentration was positively correlated with ferritin concentration (n 151, r=0·578, P1 g/l and/or C-reactive protein >5 mg/l. Malaria parasitaemia (OR=6·85; 95 % CI 1·25, 37·41, P=0·026) and Fe deficiency defined using sTfR (OR=5·58; 95 % CI 1·26, 24·80, P=0·024) were independently and positively associated with anaemia. Population-attributable risk factors for anaemia for raised C-reactive protein, Fe deficiency defined by sTfR >8·3 µg/ml and presence of malaria parasites were 41·6 (95 % CI 11·1, 72·2) %, 13·5 (95 % CI 2·0, 25·0) % and 12·0 (95 % CI 1·4, 22·6) %, respectively. CONCLUSIONS: Infections and inflammation are of greater significance than Fe deficiency in the aetiology of anaemia in pregnant Ugandan women during the first trimester.

Helicobacter pylori infection in pregnant women in four districts of Uganda: role of geographic location, education and water sources.

BACKGROUND: The prevalence of Helicobacter pylori infection varies in relation to geography, ethnicity and socioeconomic factors. Available data on the prevalence of Helicobacter pylori infection in Uganda are not representative of the general population. We sought to describe the epidemiology of this infection in pregnant women in Uganda to provide background data for a study into the effect of H. pylori infection during pregnancy on the hematological response to iron supplementation. METHODS: Using a cross-sectional design, H. pylori infection was assessed by the stool antigen test among 447 pregnant women attending antenatal care clinics in Apac, Mbale, Mbarara and Rakai Districts which are in different geographical regions in Uganda, and at Kawempe Health Center which serves a low-income densely populated area in Kampala City. Socio-demographic and household data were collected by face-to-face interviews using a questionnaire. Associations between H. pylori infection and socio-demographic and household characteristics were analyzed using logistic regression. RESULTS: The overall prevalence of H. pylori infection was 45.2% but varied by geographical location from 18.2% in Apac District to 60.5% at Kawempe Health Centre. At 18.4%, the Langi ethnic group, who were enrolled exclusively in Apac District, had the lowest prevalence of H. pylori infection while the Gisu had the highest prevalence (58.4%). H. pylori was independently associated with enrollment at clinics not in Apac (adjusted OR = 5.68; 95% CI: 3.02-10.7) and with using water from public wells, boreholes or springs (AOR = 3.20; 95% CI: 1.19-8.61) and from rivers, lakes or streams (AOR = 5.20; 95% CI: 1.58-17.05). Urban residence (AOR = 1.71; 95% CI: 1.13-2.60) and no formal education (AOR = 1.95; 95% CI: 1.03-3.67) were also independently associated with H. pylori infection. CONCLUSIONS: The unexpected variation in the prevalence of H. pylori infection in Uganda calls for population-based studies in the region and offers an opportunity to study the transmission dynamics of H. pylori infection. The association between H. pylori infection and surface water sources for household use suggests waterborne transmission of H. pylori infection highlighting the need for concerted efforts in environmental health in communities and at the household level.

Bioavailability of micronutrients: stable isotope techniques to develop effective food-based strategies to combat micronutrient deficiencies.

BACKGROUND: The prevalence of micronutrient deficiencies, in particular those of iron, vitamin A, iodine, and zinc, is unacceptably high, especially among infants, children, and women of childbearing age in developing countries. Effective food-based strategies to combat these public health problems are therefore urgently needed. OBJECTIVE: As only a fraction of dietary iron, zinc, and provitamin A carotenoids is absorbed and utilized, i.e., bioavailable, access to information on micronutrient bioavailability is crucial in the development of food fortification strategies and interventions based on dietary diversification. METHODS: Review of literature. RESULTS AND CONCLUSIONS: This overview highlights the usefulness of stable isotope techniques to assess the bioavailability of nonheme iron and provitamin A carotenoids and the importance of generating data on micronutrient bioavailability to move the agenda forward.

New frontiers in science and technology: nuclear techniques in nutrition.

The use of nuclear techniques in nutrition adds value by the increased specificity and sensitivity of measures compared with conventional techniques in a wide range of applications. This article provides a brief overview of well-established stable-isotope techniques to evaluate micronutrient bioavailability and assess human-milk intake in breastfed infants to monitor the transfer of micronutrients from the mother to the infant. Recent developments are highlighted in the use of nuclear techniques to evaluate biological interactions between food, nutrition, and health to move the agenda forward.

Effects of age on the temporal organization of working memory in deaf signers.

Deaf native signers have a general working memory (WM) capacity similar to that of hearing non-signers but are less sensitive to the temporal order of stored items at retrieval. General WM capacity declines with age, but little is known of how cognitive aging affects WM function in deaf signers. We investigated WM function in elderly deaf signers (EDS) and an age-matched comparison group of hearing non-signers (EHN) using a paradigm designed to highlight differences in temporal and spatial processing of item and order information. EDS performed worse than EHN on both item and order recognition using a temporal style of presentation. Reanalysis together with earlier data showed that with the temporal style of presentation, order recognition performance for EDS was also lower than for young adult deaf signers. Older participants responded more slowly than younger participants. These findings suggest that apart from age-related slowing irrespective of sensory and language status, there is an age-related difference specific to deaf signers in the ability to retain order information in WM when temporal processing demands are high. This may be due to neural reorganisation arising from sign language use. Concurrent spatial information with the Mixed style of presentation resulted in enhanced order processing for all groups, suggesting that concurrent temporal and spatial cues may enhance learning for both deaf and hearing groups. These findings support and extend the WM model for Ease of Language Understanding.

Regular consumption of a complementary food fortified with ascorbic acid and ferrous fumarate or ferric pyrophosphate is as useful as ferrous sulfate in maintaining hemoglobin concentrations >105 g/L in young Bangladeshi children.

BACKGROUND: Non-water-soluble iron compounds have been reported to be less well absorbed than ferrous sulfate in young children, and concern has been raised about their usefulness as food fortificants. OBJECTIVE: The objective was to evaluate the usefulness of ferrous fumarate and ferric pyrophosphate, compared with ferrous sulfate, in maintaining hemoglobin concentrations >105 g/L in Bangladeshi children. DESIGN: Two hundred thirty-five children aged 7-24 mo (hemoglobin >105 g/L) were randomly assigned in a double-blind study to receive an infant cereal fortified with ferrous fumarate, ferric pyrophosphate, or ferrous sulfate. One serving of cereal (9.3 mg Fe; molar ratio of ascorbic acid to iron of 3:1) was consumed per day, 6 d/wk, for 9 mo. Blood samples were drawn at 4.5 and 9 mo. RESULTS: Raw data were reformatted, and a "time to event" was calculated that corresponded to reaching the following thresholds: hemoglobin <105 g/L, plasma ferritin <12 microg/L, or plasma C-reactive protein >10 mg/L at baseline, 4.5 mo, or 9 mo. Data were censored when children did not reach the threshold or were lost to follow-up. A Kaplan-Meier approach was used to compare the 3 groups. No statistically significant differences were observed for hemoglobin <105 g/L (P = 0.943), plasma ferritin <12 microg/L (P = 0.601), or plasma C-reactive protein >10 mg/L (P = 0.508). CONCLUSIONS: Contrary to earlier concerns, these results do not indicate differences in usefulness between water-soluble and non-water-soluble iron compounds in maintaining hemoglobin concentrations and preventing iron deficiency. These data will be important in the development of food-fortification strategies to combat anemia and iron deficiency in highly vulnerable population groups.