Fasting pancreatic polypeptide predicts incident microvascular and macrovascular complications of type 2 diabetes: An observational study.

AIMS: Pancreatic polypeptide (PP) is elevated in people with vascular risk factors such as type 2 diabetes or increased visceral fat. We investigated potential relationships between PP and microvascular and macrovascular complications of diabetes. MATERIALS AND METHODS: Animal study: Subcutaneous PP infusion for 4 weeks in high fat diet mouse model. Retinal mRNA submitted for Ingenuity Pathway Analysis. Human study: fasting PP measured in 1478 participants and vascular complications recorded over median 5.5 (IQR 4.9-5.8) years follow-up. RESULTS: Animal study: The retinal transcriptional response to PP was indicative of cellular stress and damage, and this footprint matched responses described in previously published studies of retinal disease. Of mechanistic importance the transcriptional landscape was consistent with upregulation of folliculin, a recently identified susceptibility gene for diabetic retinopathy. Human study: Adjusting for established risk factors, PP was associated with prevalent and incident clinically significant retinopathy (odds ratio (OR) 1.289 (1.107-1.501) p = 0.001; hazard ratio (HR) 1.259 (1.035-1.531) p = 0.0213), albuminuria (OR 1.277 (1.124-1.454), p = 0.0002; HR 1.608 (1.208-2.141) p = 0.0011), and macrovascular disease (OR 1.021 (1.006-1.037) p = 0.0068; HR 1.324 (1.089-1.61), p = 0.0049), in individuals with type 2 diabetes, and progression to diabetes in non-diabetic individuals (HR 1.402 (1.081-1.818), p = 0.0109). CONCLUSIONS: Elevated fasting PP is independently associated with vascular complications of diabetes and affects retinal pathways potentially influencing retinal neuronal survival. Our results suggest possible new roles for PP-fold peptides in the pathophysiology of diabetes complications and vascular risk stratification.

Fine-Scale Genetic Structure in the United Arab Emirates Reflects Endogamous and Consanguineous Culture, Population History, and Geography.

The indigenous population of the United Arab Emirates (UAE) has a unique demographic and cultural history. Its tradition of endogamy and consanguinity is expected to produce genetic homogeneity and partitioning of gene pools while population movements and intercontinental trade are likely to have contributed to genetic diversity. Emiratis and neighboring populations of the Middle East have been underrepresented in the population genetics literature with few studies covering the broader genetic history of the Arabian Peninsula. Here, we genotyped 1,198 individuals from the seven Emirates using 1.7 million markers and by employing haplotype-based algorithms and admixture analyses, we reveal the fine-scale genetic structure of the Emirati population. Shared ancestry and gene flow with neighboring populations display their unique geographic position while increased intra- versus inter-Emirati kinship and sharing of uniparental haplogroups, reflect the endogamous and consanguineous cultural traditions of the Emirates and their tribes.

Cellular and functional evaluation of LDLR missense variants reported in hypercholesterolemic patients demonstrates their hypomorphic impacts on trafficking and LDL internalization.

Background: Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by increased LDL-cholesterol levels. About 85% of FH cases are caused by LDLR mutations encoding the low-density lipoprotein receptor (LDLR). LDLR is synthesized in the endoplasmic reticulum (ER) where it undergoes post-translational modifications and then transported through Golgi apparatus to the plasma membrane. Over 2900 LDLR variants have been reported in FH patients with limited information on the pathogenicity and functionality of many of them. This study aims to elucidate the cellular trafficking and functional implications of LDLR missense variants identified in suspected FH patients using biochemical and functional methods. Methods: We used HeLa, HEK293T, and LDLR-deficient-CHO-ldlA7 cells to evaluate the subcellular localization and LDL internalization of ten LDLR missense variants (p.C167F, p.D178N, p.C243Y, p.E277K, p.G314R, p.H327Y, p.D477N, p.D622G, p.R744Q, and p.R814Q) reported in multiethnic suspected FH patients. We also analyzed the functional impact of three variants (p.D445E, p.D482H, and p.C677F), two of which previously shown to be retained in the ER. Results: We show that p.D622G, p.D482H, and p.C667F are largely retained in the ER whereas p.R744Q is partially retained. The other variants were predominantly localized to the plasma membrane. LDL internalization assays in CHO-ldlA7 cells indicate that p.D482H, p.C243Y, p.D622G, and p.C667F have quantitatively lost their ability to internalize Dil-LDL with the others (p.C167F, p.D178N, p.G314R, p.H327Y, p.D445E, p.D477N, p.R744Q and p.R814Q) showing significant losses except for p.E277K which retained full activity. However, the LDL internalization assay is only to able evaluate the impact of the variants on LDL internalization and not the exact functional defects such as failure to bind LDL. The data represented illustrate the hypomorphism nature of variants causing FH which may explain some of the variable expressivity of FH. Conclusion: Our combinatorial approach of in silico, cellular, and functional analysis is a powerful strategy to determine pathogenicity and FH disease mechanisms which may provide opportunitites for novel therapeutic strategies.

Monogenic diabetes variants in Emirati women with gestational diabetes are associated with risk of non-autoimmune diabetes within 5 years after pregnancy.

Aims: To investigate the prevalence of pathogenic variants in monogenic diabetes genes in Emirati women with gestational diabetes (GDM) and examine the risk of developing hyperglycemia during follow-up in carriers and non-carriers. Methods: Female patients with GDM (n = 370) were identified. Selected monogenic diabetes genes, GCK, HNF1A, HNF4A, HNF1B, INS, ABCC8 and KCNJ1I, were examined by sequencing and identified variants were classified. Anthropometrics and subsequent diagnosis of diabetes were extracted from hospital records. Median follow-up time was 6-years. Results: A total of 34 variants were detected. Seven women (2%) were carriers of pathogenic variants in GCK, HNF1A, INS, ABCC8 or KCNJ11. A significantly larger fraction of women carrying pathogenic variants were diagnosed with any form of hyperglycemia or diabetes postpartum (risk ratio = 1.8 (1.1-2.9), p = 0.02) or 2.5 (1.3-4.8; p = 0.009), respectively) and they had a shorter disease-free period after GDM compared to women without such variants. There were no significant associations between carrying pathogenic variants and anthropometric measures or C-peptide. Conclusions: Pathogenic variants were found in known monogenic diabetes genes in two percent of Emirati women with GDM, allowing for precision medicine utilisation in these women both during and outside pregnancy. Carriers were at an increased risk of being diagnosed with hyperglycemia or type 2 diabetes mellitus within 5 years after pregnancy.

Obesity and Diabetes in an Arab population: Role of Adenovirus 36 Infection.

Prior infection with adenovirus 36 (Adv36) has been associated with increased adiposity, improved insulin sensitivity, and a lower prevalence of diabetes. This study investigated the prevalence of Adv36 seropositivity and its association with obesity and diabetes among adults attending a diabetes centre in the UAE.Participants (N = 973) with different weight and glucose tolerance categories were recruited. Adv36 seropositivity (Adv36 + ) was assessed using ELISA. Differences among groups were analyzed using statistical tests as appropriate to the data. Prevalence of Adv36+ in the study population was 47%, with no significant difference in obese and non-obese subgroups (42.5% vs 49.6% respectively; p=non-significant). Females were more likely to be Adv36+ compared to males (odds ratio 1.78; 95% CI 1.36-2.32, p < 0.001). We found no significant association between Adv36 seropositivity and different BMI categories, or glucose tolerance status. In our population, the effect of Adv36 infection on lipid profile varied between healthy individuals and individuals with obesity. Adv36 infection is more prevalent in the UAE than in other countries but has no association with obesity. Our study found that females were more likely to be Adv36 positive regardless of weight or diabetes status.

Parameters of Bone and Cardiovascular Health Related to 25-Hydroxyvitamin D Status in Emirati Nationals attending Primary Care and Diabetes services: a retrospective cohort study.

Vitamin D deficiency is endemic in people living in the Gulf states. We performed a retrospective analysis of data gathered at the first attendance of 82,396 Emirati nationals to outpatient diabetes, endocrinology and general primary care services at two centres in the United Arab Emirates during 2012-2016. Our aim was to explore associations between vitamin D status and markers of cardiovascular and bone health. In the study population, 67.1% of men and 73.5% of women had serum 25(OH)D of less than 50 nmol/L, with the lowest levels being found in young adults. Among Emirati adults with type 2 diabetes, serum 25(OH)D < 50 nmol/L was associated with an increased risk of a coexisting adverse total cholesterol:HDL (TC:HDL) ratio (odds ratio 2.13 (1.60-2.84), p < 0.001). Correcting for age, sex, body mass index, HbA1c and statin therapy, an increase in 25(OH)D of 1 nmol/L was associated with a 0.01 unit reduction in TC:HDL in this population. In a subset of 1064 adult individuals, 25(OH)D < 25 nmol/L was associated with a reduction in DEXA-measured z-score of -0.29 (-0.44 to -0.15, p < 0.001) at the femoral neck and of -0.25(-0.45 to -0.05, p = 0.015) at L1-4, corrected for body mass index, compared with individuals with 25(OH)D ≥ 75 nmol/L. Our findings raise concerns regarding lifetime burden of cardiovascular disease and bone health for young Emiratis with vitamin D deficiency.

The effects of Ramadan fasting on activity and energy expenditure.

Background: Fasting during the month of Ramadan entails abstinence from eating and drinking between dawn and sunset and a major shift in meal times and patterns with associated changes in several hormones and circadian rhythms; whether there are accompanying changes in energy metabolism is unclear. Objective: We have investigated the impact of Ramadan fasting on resting metabolic rate (RMR), activity, and total energy expenditure (TEE). Design: Healthy nonobese volunteers (n = 29; 16 women) fasting during Ramadan were recruited. RMR was measured with the use of indirect calorimetry. In subgroups of participants, activity (n = 11; 5 women) and TEE (n = 10; 5 women) in free-living conditions were measured with the use of accelerometers and the doubly labeled water technique, respectively. Body composition was measured with the use of bioelectrical impedance. Measurements were repeated after a wash-out period of between 1 and 2 mo after Ramadan. Nonparametric tests were used for comparative statistics. Results: Ramadan fasting did not result in any change in RMR (mean ± SD: 1365.7 ± 230.2 compared with 1362.9 ± 273.6 kcal/d for Ramadan and post-Ramadan respectively, P = 0.713, n = 29). However, controlling for the effects of age, sex, and body weight, RMR was higher in the first week of Ramadan than in subsequent weeks. During Ramadan, the total number of steps walked were significantly lower (n = 11, P = 0.001), while overall sleeping time was reduced and different sleeping patterns were seen. TEE did not differ significantly between Ramadan and post-Ramadan (mean ± SD: 2224.1 ± 433.7 compared with 2121.0 ± 718.5 kcal/d for Ramadan and post-Ramadan, P = 0.7695, n = 10). Conclusions: Ramadan fasting is associated with reduced activity and sleeping time, but no significant change in RMR or TEE. Reported weight changes with Ramadan in other studies are more likely to be due to differences in food intake. This trial is registered at clinicaltrials.gov as NCT02696421.

Indeterminate Thyroid Nodules: A Pragmatic Approach.

BACKGROUND: Fine needle aspiration (FNA) cytology fails to provide a conclusive diagnosis in a subset of thyroid lesions labeled as "indeterminate" (Thy3). In this study, we aimed at ascertaining the prevalence of Thy3 thyroid nodules in a hitherto unreported ethnic group (residents of the United Arab Emirates). METHODS: We retrospectively examined 688 FNA of the thyroid performed on 584 patients. Samples were reported using the Royal College of Physicians' (RCP) Thy classification. The results of the FNA were correlated with the final surgical specimens. Ultrasonography (US) risk stratification was calculated using a web-based US risk of malignancy calculator. RESULTS: Overall sample adequacy was 97%. The indeterminate group Thy3 was found in 7% of the samples. The overall risk of malignancy in the Thy3 category was 20%. This risk was very similar in the 2 subgroups of Thy3 (17% in Thy 3a and 22% in Thy3f). Subdividing the Thy3 group into subgroups becomes less necessary if the US scoring is <24.5% since the negative predictive value, in this case, is 100%. Applying this criterion to our population would have had the potential of reducing the percentage of patients referred to surgery from 61 to 43%. CONCLUSIONS: Proper risk stratification of Thy3 lesions should be based on the combined risk assessment of clinical, cytological, radiological, and molecular data. Such a pragmatic approach is expected to reduce the percentage of inappropriate referrals to surgery.

Environmental determinants of previtamin D synthesis in the United Arab Emirates.

Despite abundant sunshine throughout the year, vitamin D deficiency is endemic in the UAE. Solar radiation within the UVB range of the spectrum is required for the photosynthesis of previtamin D3 in the skin. Atmospheric transmission of UVB is strongly influenced by atmospheric conditions and solar zenith angle. We investigated the effects of diurnal and seasonal variation on the availability of sufficient UVB radiation for adequate previtamin D3 synthesis using an established in vitro model. Borosilicate ampoules of 7-dehydrocholesterol, the precursor of previtamin D3, in ethanol (50 µg/mL) were exposed to direct sunlight in an urban area of Abu Dhabi, at one hourly intervals between 0800 and 1700, on one day of each month over a period of one year. Conversion to previtamin D3, vitamin D3 and metabolically inactive photoisomers was analyzed using high performance liquid chromatography. The efficiency of 7-dehydrocholesterol conversion to previtamin D3 varied estimated UVB intensity. At the latitude of Abu Dhabi (24.2 N) previtamin D3 synthesis can occur throughout the year. However very little if any previtamin D3 was produced before 0900 hrs.and after 1600 hrs. Local conditions in Abu Dhabi are likely sufficient to maintain vitamin D levels throughout the year given adequate sun exposure.

Latent Autoimmune Diabetes in Adults in the United Arab Emirates: Clinical Features and Factors Related to Insulin-Requirement.

AIMS: To describe and to characterize clinical features of latent autoimmune diabetes in adults (LADA) compared to type 1 and type 2 diabetes in the UAE. METHODS: In this cross-sectional study a dataset including 18,101 subjects with adult-onset (>30 years) diabetes was accessed. 17,072 subjects fulfilled the inclusion/exclusion criteria. Data about anthropometrics, demographics, autoantibodies to Glutamic Acid Decarboxylase (GADA) and to Islet Antigen 2 (anti-IA2), HbA1c, cholesterol and blood pressure were extracted. LADA was diagnosed according to GADA and/or anti-IA2 positivity and time to insulin therapy. RESULTS: 437 (2.6%) patients were identified as LADA and 34 (0.2%) as classical type 1 diabetes in adults. Mean age at diagnosis, BMI, waist circumference, systolic blood pressure and HbA1c significantly differed between, LADA, type 2 and type 1 diabetes, LADA showing halfway features between type 2 and type 1 diabetes. A decreasing trend for age at diagnosis and waist circumference was found among LADA subjects when subdivided by positivity for anti-IA2, GADA or for both antibodies (p=0.013 and p=0.011 for trend, respectively). There was a gradual downward trend in autoantibody titre in LADA subjects requiring insulin within the first year from diagnosis to subjects not requiring insulin after 10 years of follow-up (p<0.001). CONCLUSIONS: This is the first study describing the clinical features of LADA in the UAE, which appear to be different from both type 1 and type 2 diabetes. Furthermore, we showed that the clinical phenotype of LADA is dependent on different patterns of antibody positivity, influencing the time to insulin requirement.