Mohammed Al Dubayee

Background Hypophosphatemic rickets (HR) and osteomalacia related to fibroblast growth factor 23 (FGF23) are rare, lifelong disorders characterized by phosphate wasting, resulting in defective bone mineralization, multisystem manifestations, and reduced quality of life (QoL). Excess FGF23 is central to the pathophysiology of many HR subtypes, including X-linked hypophosphatemia (XLH). Supplementation with oral phosphate and active vitamin D analogs is often ineffective and associated with side effects. Burosumab, a fully humanized monoclonal immunoglobulin G1 antibody that inhibits FGF23, has been approved in the Gulf Cooperation Council (GCC) countries for the treatment of XLH and tumor-induced osteomalacia. Epidemiological, treatment, resource utilization, and outcomes data on FGF23-related HR and osteomalacia are limited in the Middle East region. Methods We present a 10-year, multicenter, non-interventional registry of patients with FGF23-related HR/osteomalacia at 14 sites across the Gulf Cooperation Council (GCC) countries. Up to 200 patients of any age or sex with a confirmed diagnosis of FGF23-related HR/osteomalacia have been enrolled over five years (June 2020 to June 2025), with follow-up extending five years post-enrollment. Retrospective data include a three-year look-back period from the date of diagnosis; prospective data will be collected biannually during routine clinical visits. The study will generate up to ten years of real-world data, with the last patient follow-up concluding in 2030. The primary study objective is to characterize the burden, progression, treatment patterns, and long-term outcomes of FGF23-related HR/osteomalacia. Secondary objectives include evaluations of treatment effectiveness, safety, and QoL, using patient-reported outcome tools – the Short Form-36 (SF-36) for adults and the Pediatric Quality of Life Inventory (PedsQL) for children <18 years – completed approximately every six months during routine visits. Exploratory analyses will focus on healthcare resource utilization. All reporting will be consistent with the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) Initiative checklist for cohort studies. Conclusions This 10-year regional rare disease registry aims to fill critical knowledge gaps regarding epidemiology, real-world treatment, and outcomes of FGF23-related HR and osteomalacia in the GCC. Insights will seek to inform clinical decision-making, optimize management strategies, and improve patient outcomes. Findings will also contribute to the global understanding of FGF23-related disorders.

Background: Type 2 diabetes (T2D) is a growing health concern among adolescents, driven by rising obesity rates. Early identification of prediabetes, particularly impaired fasting glucose (IFG), can guide interventions to reduce long‐term risks. Despite the global burden of diabetes, limited data exist on Saudi adolescents, a population experiencing high rates of obesity. Objective: To determine the prevalence and associated factors for IFG in a representative sample of Saudi adolescents. Methods: We conducted a cross‐sectional analysis on a subgroup of participants from the national Jeeluna study (2011–2012), which sampled adolescents aged 10–19 years from all 13 regions of Saudi Arabia. Anthropometric measurements, fasting plasma glucose levels, and lifestyle data were collected. Dysglycemia (IFG or diabetes) was defined using American Diabetes Association (ADA) criteria. A logistic regression analysis was conducted to identify factors associated with dysglycemia. Results: The study included 5,421 participants (50.8% females; mean ± SD age was 15.9 ± 1.8 years). Prevalence of dysglycemia was 4.8% (IFG: 4.1%; diabetes: 0.7%). Dysglycemia was more prevalent in obese adolescents (8.2%) compared to overweight (4.8%) and nonobese/nonoverweight peers (4.1%), p < 0.0001. Regional differences were noted with the highest prevalence in Mecca (6.1%). Compared with nondysglycemic patients, those who were dysglycemic had higher proportion of individuals consuming fast food meals per week ( p = 0.03), body mass index (BMI) ( p < 0.0001), tri‐ponderal mass (TMI) ( p < 0.001), waist‐to‐height ratio ( p = 0.001) and systolic BP ( p < 0.001) and lower triglycerides ( p < 0.0001). Factors independently associated with dysglycemia included systolic BP (OR = 1.03; 95% CI 1.01–1.04, p < 0.0001), triglyceride levels (OR = 1.60; 95% CI 1.27–2.00, p < 0.0001) and geographical region (Mecca OR = 1.54, 95% CI 1.07–196, Riyadh OR = 0.61,95% CI 0.42–0.89, p < 0.001, compared with other regions combinedly). Conclusion: Our study highlights the prevalence of dysglycemia (4.8%) among Saudi adolescents, particularly in those with obesity. Risk factors included higher BMI and increased fast food consumption. Notably, regional differences were observed, with Mecca reporting the highest prevalence. Our findings underscore the need for targeted interventions in obesity, focusing on promoting healthy lifestyles and early screening for T2D in this vulnerable population.

Background/Objectives: Understanding the metabolic responses to different macronutrients is crucial for assessing their impacts on health. This study aims to investigate the postprandial metabolomic profiles of healthy individuals following the consumption of glucose, protein, and lipids. Methods: Twenty-three healthy, normal-weight adults participated in the study, randomly assigned to consume 300 kcal from glucose, protein, or lipids after an overnight fast. Blood samples were collected at baseline and at 1, 2, and 3 h post-ingestion. An untargeted metabolomic approach using mass spectrometry was employed to analyze plasma metabolites. Results: In total, 21, 59, and 156 dysregulated metabolites were identified after glucose, protein, and lipid intake, respectively. Notably, 3’-O-methylguanosine levels decreased significantly after glucose consumption while remaining stable during lipid intake before increasing at 2 h. Common metabolites shared between glucose and lipid groups included 3’-O-methylguanosine, 3-oxotetradecanoic acid, poly-g-D-glutamate, and triglyceride (TG) (15:0/18:4/18:1). Conclusions: The findings highlight distinct metabolic responses to macronutrient intake, emphasizing the role of specific metabolites in regulating postprandial metabolism. These insights contribute to understanding how dietary components influence metabolic health and insulin sensitivity.

The Saudi National Diabetes Registry focuses mainly on adult patients. In 2020, the National Guard Health Authority (NGHA) launched the Saudi Pediatric and Youth Diabetes Registry (SPYDR), for children and adolescents with diabetes. This report is about the first data and the challenges we faced during SPYDR initiation. Patients were identified from the electronic medical records of the Saudi NGHA hospitals using the International Classification of Disease (ICD-10). A trained coordinator verified the diagnosis and entered patients' details into the registry and a random sample was validated by experienced endocrinologists. The data were analyzed according to patients' demography, diabetes subtypes, duration, control, and complications. The challenges faced by the team were identified and addressed. At the time of manuscript submission, 2,344 individuals were enrolled. Their mean age at diagnosis was 9.08 (±4.27) years and 1,136 (48.46%) were females. Of these, 91.3% have type 1 (T1D), and 6.4% have type 2 diabetes (T2D). The mean HbA1c was 10.45% (±2.36) and duration of diabetes was 5.31 (±3.05) years. The main challenges included the COVID-19 pandemic, data validation, and centers' participation. However, within 12 months of initiation enrolled subjects matched the expected number. Despite the challenges, the first step of SPYDR was achieved. The initial data confirmed that T1D is the most common form of childhood diabetes, and the frequency of T2D is comparable to regional and international data. SPYDR provides the infrastructure for data sharing and collaborative research with the enrollment of patients from other Saudi healthcare institutes.

The Saudi National Diabetes Registry focuses mainly on adult patients. In 2020, the National Guard Health Authority (NGHA) launched the Saudi Pediatric and Youth Diabetes Registry (SPYDR), for children and adolescents with diabetes. We report on the first data and the challenges we faced during SPYDR initiation. Patients were identified from the electronic medical records of the Saudi NGHA hospitals using International Classification of Disease (ICD-10). A trained coordinator verified the diagnosis and entered patients' details into the registry and a random sample was validated by experienced endocrinologists. The data were analyzed according to patients' demography, diabetes subtypes, duration, control, and complications. The challenges faced the team were identified and addressed. At the time of manuscript submission, 2344 individuals were enrolled. Their mean age at diagnosis was 9.08 (±4.27) years and 1,136 (48.46%) were females. Of these, 91.3% have type 1 (T1D) and 6.4% have type 2 diabetes (T2D). The mean HbA1c was 10.45% (±2.36) and duration of diabetes was 5.31 (±3.05) years. The main challenges included COVID-19 pandemic, data validation and centers' participation. However, within 12 months of initiation enrolled subjects matched the expected number. Despite the challenges, the first step of SPYDR was achieved. The initial data confirmed that T1D is the commonest form of childhood diabetes, and the frequency of T2D is comparable to regional and international data. SPYDR provides infrastructure to data sharing and collaborative research; hence; we plan to expand it to enroll patients from other Saudi healthcare institutes.

Metformin is the first-line oral medication for treating type 2 diabetes mellitus (T2DM). In the current study, an untargeted lipidomic analytical approach was used to investigate the alterations in the serum lipidome of a cohort of 89 participants, including healthy lean controls and obese diabetic patients, and to examine the alterations associated with metformin administration. A total of 115 lipid molecules were significantly dysregulated (64 up-regulated and 51 down-regulated) in the obese compared to lean controls. However, the levels of 224 lipid molecules were significantly dysregulated (125 up-regulated and 99 down-regulated) in obese diabetic patients compared to the obese group. Metformin administration in obese diabetic patients was associated with significant dysregulation of 54 lipid molecule levels (20 up-regulated and 34 down-regulated). Levels of six molecules belonging to five lipid subclasses were simultaneously dysregulated by the effects of obesity, T2DM, and metformin. These include two putatively annotated triacylglycerols (TGs), one plasmenyl phosphatidylcholine (PC), one phosphatidylglycerol (PGs), one sterol lipid (ST), and one Mannosyl-phosphoinositol ceramide (MIPC). This study provides new insights into our understanding of the lipidomics alterations associated with obesity, T2DM, and metformin and offers a new platform for potential biomarkers for the progression of diabetes and treatment response in obese patients.

Background: Obesity and type 2 diabetes mellitus (T2DM) are characterized by underlying low-grade chronic inflammation. Metformin has been used as the first line of therapy in T2DM as it decreases hepatic glucose production and glucose intestinal absorption, enhances insulin sensitivity and weight loss, and is known to ameliorate inflammation. The mechanisms through which metformin exerts its effect remain unclear. Proteomics has emerged as a unique approach to explore the biological changes associated with diseases, including T2DM. It provides insight into the circulating biomarkers/mediators which could be utilized for disease screening, diagnosis, and prognosis. Methods: This study evaluated the proteomic changes in obese (Ob), obese diabetics (OD), and obese diabetic patients on metformin (ODM) using a 2D DIGE MALDI-TOF mass spectrometric approach. Results: Significant changes in sixteen plasma proteins (15 up and 1 down, ANOVA, p ≤ 0.05; fold change ≥ 1.5) were observed in the ODM group when compared to the Ob and OD groups. Bioinformatic network pathway analysis revealed that the majority of these altered plasma proteins are involved in distinct pathways involving acute-phase response, inflammation, and oxidative response and were centered around HNF4A, ERK, JNK, and insulin signaling pathways. Conclusions: Our study provides important information about the possible biomarkers altered by metformin treatment in obese patients with and without T2DM. These altered plasma proteins are involved in distinct pathways involving acute-phase response, inflammation, and oxidative response and were centered around HNF4A, ERK, JNK, and insulin signaling pathways. The presented proteomic profiling approach may help in identifying potential biomarkers/mediators affected by metformin treatment in T2DM and inform the understanding of metformin’s mechanisms of action.

Background and Objectives: Visceral obesity is associated with chronic low-grade inflammation that predisposes to metabolic syndrome. Indeed, infiltration of adipose tissue with immune–inflammatory cells, including ‘classical’ inflammatory M1 and anti-inflammatory ‘alternative’ M2 macrophages, causes the release of a variety of bioactive molecules, resulting in the metabolic complications of obesity. This study examined the relative expression of macrophage phenotypic surface markers, cholesterol efflux proteins, scavenger receptors, and adenosine receptors in human circulating peripheral blood mononuclear cells (PBMCs), isolated from patients with type 2 diabetes mellitus (T2DM), with the aim to phenotypically characterize and identify biomarkers for these ill-defined cells. Materials and Methodology: PBMCs were isolated from four groups of adults: Normal-weight non-diabetic, obese non-diabetic, newly diagnosed with T2DM, and T2DM on metformin. The mRNA expression levels of macrophage phenotypic surface markers (interleukin-12 (IL-12), C-X-C motif chemokine ligand 10 (CXCL10), C-C motif chemokine ligand 17 (CCL17), and C-C motif receptor 7 (CCR7)), cholesterol efflux proteins (ATP-binding cassette transporter-1 (ABCA1), ATP binding cassette subfamily G member 1 (ABCG1), and sterol 27-hydroxylase (CYP27A)), scavenger receptors (scavenger receptor-A (SR-A), C-X-C motif ligand 16 (CXCL16), and lectin-like oxidized LDL receptor-1 (LOX-1)), and adenosine receptors (adenosine A2A receptor (A2AR) and adenosine A3 receptor (A3R)) were measured using qRT-PCR. Results: In PBMCs from T2DM patients, the expression of IL-12, CCR7, ABCA1, and SR-A1 was increased, whereas the expression of CXCL10, CCL17, ABCG1,27-hydroxylase, LOX-1, A2AR and A3R was decreased. On the other hand, treatment with the antidiabetic drug, metformin, reduced the expression of IL-12 and increased the expression of 27-hydroxylase, LOX-1, CXCL16 and A2AR. Conclusions: PBMCs in the circulation of patients with T2DM express phenotypic markers that are different from those typically present in adipose tissue M1 and M2 macrophages and could be representative of metabolically activated macrophages (MMe)-like cells. Our findings suggest that metformin alters phenotypic markers of MMe-like cells in circulation.

Objective. Puberty has a significant contribution to the final height. Therefore, it is crucial to understand the normal variations in the onset and tempo of puberty in a specific population. In this study, we aimed to provide normative data on the timing of puberty and late pubertal height (LPH) in Saudi schoolboys in Riyadh. Methods. This is a cross-sectional field study (20112013) including Saudi schoolboys (grades 112; aged 6 to 19 years). Schools were chosen to represent the population from urban and rural areas in the Riyadh region. Pubertal maturity staging for gonads was assessed by measuring testicular size using a Prader orchidometer and assessing the Tanner staging of pubic hair. The marginal mean age was calculated using regression analysis. Results. We recruited 1086 schoolboys. The estimated mean age of pubertal onset at G2 was 11.8 (95 CI 11.6012.0) years, for gonadal development at G3 was 13.2 (95 CI 12.913.5), G4=15.0 (95 CI 14.715.2), and G5=16.1 (95 CI 15.916.3) years, and for pubic hair stage 2 (PH2) was 12.6 (95 CI 12.412.9) years. The estimated time from G2/PH2 to G5/PH5 was 4.3 and 3.9years, respectively. At the onset of puberty, the mean height was 144.7cm and it reached 167.8cm at G5 with a pubertal height gain of 23.1cm. Conclusion. Our data present the norms of the timing of puberty and LPH in Saudi schoolboys. Saudi adolescent males are shorter than some European and American comparatives mainly due to shortness during childhood. However, they could have shorter LPH than Turkish, Greek, Thai, and Japanese due to a less pubertal height gain.