Evaluation of HLA typing content of next-generation sequencing datasets from family trios and individuals of arab ethnicity.

Introduction: HLA typing is a critical tool in both clinical and research applications at the individual and population levels. Benchmarking studies have indicated HLA-HD as the preferred tool for accurate and comprehensive HLA allele calling. The advent of next-generation sequencing (NGS) has revolutionized genetic analysis by providing high-throughput sequencing data. This study aims to evaluate, using the HLA-HD tool, the HLA typing content of whole exome, whole genome, and HLA-targeted panel sequence data from the consanguineous population of Arab ethnicity, which has been underrepresented in prior benchmarking studies. Methods: We utilized sequence data from family trios and individuals, sequenced on one or more of the whole exome, whole genome, and HLA-targeted panel sequencing technologies. The performance and resolution across various HLA genes were evaluated. We incorporated a comparative quality control analysis, assessing the results obtained from HLA-HD by comparing them with those from the HLA-Twin tool to authenticate the accuracy of the findings. Results: Our analysis found that alleles across 29 HLA loci can be successfully and consistently typed from NGS datasets. Clinical-grade whole exome sequencing datasets achieved the highest consistency rate at three-field resolution, followed by targeted HLA panel, research-grade whole exome, and whole genome datasets. Discussion: The study catalogues HLA typing consistency across NGS datasets for a large array of HLA genes and highlights assessments regarding the feasibility of utilizing available NGS datasets in HLA allele studies. These findings underscore the reliability of HLA-HD for HLA typing in underrepresented populations and demonstrate the utility of various NGS technologies in achieving accurate HLA allele calling.

Extreme Temperatures and Stroke Mortality: Evidence From a Multi-Country Analysis.

BACKGROUND: Extreme temperatures contribute significantly to global mortality. While previous studies on temperature and stroke-specific outcomes presented conflicting results, these studies were predominantly limited to single-city or single-country analyses. Their findings are difficult to synthesize due to variations in methodologies and exposure definitions. METHODS: Within the Multi-Country Multi-City Network, we built a new mortality database for ischemic and hemorrhagic stroke. Applying a unified analysis protocol, we conducted a multinational case-crossover study on the relationship between extreme temperatures and stroke. In the first stage, we fitted a conditional quasi-Poisson regression for daily mortality counts with distributed lag nonlinear models for temperature exposure separately for each city. In the second stage, the cumulative risk from each city was pooled using mixed-effect meta-analyses, accounting for clustering of cities with similar features. We compared temperature-stroke associations across country-level gross domestic product per capita. We computed excess deaths in each city that are attributable to the 2.5% hottest and coldest of days based on each city's temperature distribution. RESULTS: We collected data for a total of 3 443 969 ischemic strokes and 2 454 267 hemorrhagic stroke deaths from 522 cities in 25 countries. For every 1000 ischemic stroke deaths, we found that extreme cold and hot days contributed 9.1 (95% empirical CI, 8.6-9.4) and 2.2 (95% empirical CI, 1.9-2.4) excess deaths, respectively. For every 1000 hemorrhagic stroke deaths, extreme cold and hot days contributed 11.2 (95% empirical CI, 10.9-11.4) and 0.7 (95% empirical CI, 0.5-0.8) excess deaths, respectively. We found that countries with low gross domestic product per capita were at higher risk of heat-related hemorrhagic stroke mortality than countries with high gross domestic product per capita (P=0.02). CONCLUSIONS: Both extreme cold and hot temperatures are associated with an increased risk of dying from ischemic and hemorrhagic strokes. As climate change continues to exacerbate these extreme temperatures, interventional strategies are needed to mitigate impacts on stroke mortality, particularly in low-income countries.

Angiopoietin-2 and Angiopoietin-like Proteins with a Prospective Role in Predicting Diabetic Nephropathy.

Angiopoietins are crucial growth factors for maintaining a healthy, functional endothelium. Patients with type 2 diabetes (T2D) exhibit significant levels of angiogenic markers, particularly Angiopoietin-2, which compromises endothelial integrity and is connected to symptoms of endothelial injury and failure. This report examines the levels of circulating angiopoietins in people with T2D and diabetic nephropathy (DN) and explores its link with ANGPTL proteins. We quantified circulating ANGPTL3, ANGPTL4, ANGPTL8, Ang1, and Ang2 in the fasting plasma of 117 Kuwaiti participants, of which 50 had T2D and 67 participants had DN. The Ang2 levels increased with DN (4.34 ± 0.32 ng/mL) compared with T2D (3.42 ± 0.29 ng/mL). This increase correlated with clinical parameters including the albumin-to-creatinine ratio (ACR) (r = 0.244, p = 0.047), eGFR (r = -0.282, p = 0.021), and SBP (r = -0.28, p = 0.024). Furthermore, Ang2 correlated positively to both ANGPTL4 (r = 0.541, p < 0.001) and ANGPTL8 (r = 0.41, p = 0.001). Multiple regression analysis presented elevated ANGPTL8 and ACRs as predictors for Ang2's increase in people with DN. In people with T2D, ANGPTL4 positively predicted an Ang2 increase. The area under the curve (AUC) in receiver operating characteristic (ROC) analysis of the combination of Ang2 and ANGPTL8 was 0.77 with 80.7% specificity. In conclusion, significantly elevated Ang2 in people with DN correlated with clinical markers such as the ACR, eGFR, and SBP, ANGPTL4, and ANGPTL8 levels. Collectively, this study highlights a close association between Ang2 and ANGPTL8 in a population with DN, suggesting them as DN risk predictors.

Ethnic Variations in the Levels of Bone Biomarkers (Osteoprostegerin, Receptor Activator of Nuclear Factor Kappa-Β Ligand and Glycoprotein Non-Metastatic Melanoma Protein B) in People with Type 2 Diabetes.

The global incidence of Type 2 diabetes (T2D) is on the rise, fueled by factors such as obesity, sedentary lifestyles, socio-economic factors, and ethnic backgrounds. T2D is a multifaceted condition often associated with various health complications, including adverse effects on bone health. This study aims to assess key biomarkers linked to bone health and remodeling-Osteoprotegerin (OPG), Receptor Activator of Nuclear Factor Kappa-Β Ligand (RANKL), and Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB)-among individuals with diabetes while exploring the impact of ethnicity on these biomarkers. A cross-sectional analysis was conducted on a cohort of 2083 individuals from diverse ethnic backgrounds residing in Kuwait. The results indicate significantly elevated levels of these markers in individuals with T2D compared to non-diabetic counterparts, with OPG at 826.47 (405.8) pg/mL, RANKL at 9.25 (17.3) pg/mL, and GPNMB at 21.44 (7) ng/mL versus 653.75 (231.7) pg/mL, 0.21 (9.94) pg/mL, and 18.65 (5) ng/mL in non-diabetic individuals, respectively. Notably, this elevation was consistent across Arab and Asian populations, except for lower levels of RANKL observed in Arabs with T2D. Furthermore, a positive and significant correlation between OPG and GPNMB was observed regardless of ethnicity or diabetes status, with the strongest correlation (r = 0.473, p < 0.001) found among Arab individuals with T2D. Similarly, a positive and significant correlation between GPNMB and RANKL was noted among Asian individuals with T2D (r = 0.401, p = 0.001). Interestingly, a significant inverse correlation was detected between OPG and RANKL in non-diabetic Arab individuals. These findings highlight dysregulation in bone remodeling markers among individuals with T2D and emphasize the importance of considering ethnic variations in T2D-related complications. The performance of further studies is warranted to understand the underlying mechanisms and develop interventions based on ethnicity for personalized treatment approaches.

Evaluating the correlation of sclerostin levels with obesity and type 2 diabetes in a multiethnic population living in Kuwait.

Obesity and Type 2 Diabetes Mellitus (T2DM) are intricate metabolic disorders with a multifactorial etiology, often leading to a spectrum of complications. Recent research has highlighted the impact of these conditions on bone health, with a particular focus on the role of sclerostin (SOST), a protein molecule integral to bone metabolism. Elevated circulating levels of SOST have been observed in patients with T2DM compared to healthy individuals. This study aims to examine the circulating levels of SOST in a multiethnic population living in Kuwait and to elucidate the relationship between SOST levels, obesity, T2DM, and ethnic background. The study is a cross-sectional analysis of a large cohort of 2083 individuals living in Kuwait. The plasma level of SOST was measured using a bone panel multiplex assay. The study found a significant increase in SOST levels in individuals with T2DM (1008.3 pg/mL, IQR-648) compared to non-diabetic individuals (710.6 pg/mL, IQR-479). There was a significant gender difference in median SOST levels, with males exhibiting higher levels than females across various covariates (diabetes, IR, age, weight, and ethnicity). Notably, SOST levels varied significantly with ethnicity: Arabs (677.4 pg/mL, IQR-481.7), South Asians (914.6 pg/mL, IQR-515), and Southeast Asians (695.2 pg/mL, IQR-436.8). Furthermore, SOST levels showed a significant positive correlation with gender, age, waist circumference, systolic and diastolic blood pressure, fasting blood glucose, HbA1c, insulin, total cholesterol, triglycerides, HDL, LDL, ALT, and AST (p-Value ≥0.05). South Asian participants, who exhibited the highest SOST levels, demonstrated the most pronounced associations, even after adjusting for age, gender, BMI, and diabetes status (p-Value ≥0.05). The observed correlations of SOST with various clinical parameters suggest its significant role in the diabetic milieu, particularly pronounced in the South Asian population compared to other ethnic groups.

Investigating the Role of FABP4 in Diabetes and Obesity and the Influence of Age and Ethnicity: A Comprehensive Analysis of a Cohort from the KEDP-Study.

Adipocyte P2 (aP2), also known as FABP4, is an adipokine that adipose tissue produces and expresses in macrophages. Its primary role is to facilitate the transportation of fatty acids across cell membranes. Numerous studies have reported associations between FABP4 and the development of metabolic disorders. However, there is limited knowledge regarding FABP4 expression in diabetes and obesity, especially about different age groups, genders, and ethnicities. This study aims to investigate the association between FABP4 levels, diabetes mellitus, and obesity within various ethnic groups. We measured plasma FABP4 concentrations in a cohort of 2083 patients from the KDEP study and gathered anthropometric data. Additionally, we collected and analyzed clinical, biochemical, and glycemic markers using multivariate regression analysis. The average FABP4 concentration was significantly higher in female participants than in males (18.8 ng/mL vs. 14.4 ng/mL, p < 0.001, respectively), and in those over 50 years old compared to those under 50 years of age (19.3 ng/mL vs. 16.2 ng/mL, p < 0.001, respectively). In this study, significant positive associations were found between the plasma level of FABP4 and obesity markers: BMI (r = 0.496, p < 0.001), hip circumference (r = 0.463, p < 0.001), and waist circumference (WC) (r = 0.436, p < 0.001). Similar observations were also seen with glycemic markers, which included HbA1c (r = 0.126, p < 0.001), fasting blood glucose (FBG) (r = 0.184, p < 0.001), fasting insulin (r = 0.326, p < 0.001), and HOMA-IR (r = 0.333, p < 0.001). Importantly, these associations remained significant even after adjusting for age, gender, and ethnicity. Furthermore, FABP4 levels were negatively associated with male gender (ß: -3.85, 95% CI: -4.92, -2.77, p < 0.001), and positively associated with age (ß: 0.14, 95% CI: 0.096, 0.183, p < 0.001), BMI (ß: 0.74, 95% CI: 0.644, 0.836, p < 0.001), and fasting insulin (ß: 0.115, 95% CI: 0.091, 0.138, p < 0.001). In this study, plasma FABP4 levels were significantly higher in diabetic and obese participants, and they were strongly influenced by age, gender, and ethnicity. These findings suggest that FABP4 may serve as a valuable prognostic and diagnostic marker for obesity and diabetes, particularly among female patients, individuals over 50 years old, and specific ethnic groups.

Therapeutic advances in obesity management: an overview of the therapeutic interventions.

Obesity has become a global epidemic in the modern world, significantly impacting the global healthcare economy. Lifestyle interventions remain the primary approach to managing obesity, with medical therapy considered a secondary option, often used in conjunction with lifestyle modifications. In recent years, there has been a proliferation of newer therapeutic agents, revolutionizing the treatment landscape for obesity. Notably, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide, liraglutide, and the recently approved dual GLP-1/GIP RAs agonist tirzepatide, have emerged as effective medications for managing obesity, resulting in significant weight loss. These agents not only promote weight reduction but also improve metabolic parameters, including lipid profiles, glucose levels, and central adiposity. On the other hand, bariatric surgery has demonstrated superior efficacy in achieving weight reduction and addressing overall metabolic imbalances. However, with ongoing technological advancements, there is an ongoing debate regarding whether personalized medicine, targeting specific components, will shape the future of developing novel therapeutic agents for obesity management.

Neutral Sphingomyelinase 2 Inhibition Limits Hepatic Steatosis and Inflammation.

Non-alcoholic fatty liver disease (NAFLD) is manifested by hepatic steatosis, insulin resistance, hepatocyte death, and systemic inflammation. Obesity induces steatosis and chronic inflammation in the liver. However, the precise mechanism underlying hepatic steatosis in the setting of obesity remains unclear. Here, we report studies that address this question. After 14 weeks on a high-fat diet (HFD) with high sucrose, C57BL/6 mice revealed a phenotype of liver steatosis. Transcriptional profiling analysis of the liver tissues was performed using RNA sequencing (RNA-seq). Our RNA-seq data revealed 692 differentially expressed genes involved in processes of lipid metabolism, oxidative stress, immune responses, and cell proliferation. Notably, the gene encoding neutral sphingomyelinase, SMPD3, was predominantly upregulated in the liver tissues of the mice displaying a phenotype of steatosis. Moreover, nSMase2 activity was elevated in these tissues of the liver. Pharmacological and genetic inhibition of nSMase2 prevented intracellular lipid accumulation and TNFα-induced inflammation in in-vitro HepG2-steatosis cellular model. Furthermore, nSMase2 inhibition ameliorates oxidative damage by rescuing PPARα and preventing cell death associated with high glucose/oleic acid-induced fat accumulation in HepG2 cells. Collectively, our findings highlight the prominent role of nSMase2 in hepatic steatosis, which could serve as a potential therapeutic target for NAFLD and other hepatic steatosis-linked disorders.

Association between risk of obstructive sleep apnea severity and risk of severe COVID-19 symptoms: insights from salivary and serum cytokines.

Objectives: Obstructive sleep apnea (OSA) can adversely affect the immune response through clinical factors such as hypoxia, inflammation, and sleep disturbance. Since SARS-CoV-2 heavily relies on local and systemic host immune responses, this study aims to examine the links between the severity of OSA risk, cytokine levels, and the severity of symptoms associated with SARS-CoV-2 infection. Methods: Saliva and blood samples from 50 COVID-19 patients and 30 non-infected hospital staff members were collected. Using Luminex multiplex analysis, 65 blood and salivary cytokines were examined from the collected samples. Ordinal logistic regression analysis was utilized to examine the association between the self-reported risk of OSA, assessed through the STOP-Bang questionnaire, and the likelihood of experiencing severe symptoms of COVID-19. Mann-Whitney test was then performed to compare the cytokine levels between individuals with moderate to severe risk of OSA to those with a mild risk of OSA. Results: Ordinal logistic regression analysis revealed that individuals with a moderate to severe risk of OSA were 7.60 times more likely to experience more severe symptoms of COVID-19 compared to those with a mild risk of OSA (OR = 7.60, 95%CI: 3.03, 19.06, p < 0.001). Moreover, among COVID-19-positive patients with a moderate to severe risk of OSA, there was a statistically significant negative correlation with serum IL-6 (p < 0.05), Eotaxin (CCL11) (p = 0.04), and salivary MIP-3α/CCL20 (p = 0.04). In contrast, individuals without COVID-19 who had a moderate to severe risk of OSA exhibited a significant positive correlation with serum IL-6 (p = 0.04). Conclusion: Individuals with moderate to severe risk of OSA were more likely to experience severe COVID-19 symptoms than those with mild risk for OSA. Additional analysis from the present studies revealed distinct patterns of oral and systemic immune responses between individuals with mild and moderate to severe risk of OSA. Findings from the present study underscores the importance of early detection and management of OSA to improve clinical outcomes, particularly when faced with the subsequent superimposed infection such as COVID-19.

Long-Term Mortality and SGLT2 Inhibitors in Type 2 Diabetes with and without Renal Impairment: An Observational Cohort Study.

AIM: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have emerged as a vital part of management of type 2 diabetes, as they have been shown to have both cardiovascular and renal benefits along with an improved survival rate in several randomized clinical trials. We designed a retrospective cohort study to investigate the impact of SGLT2 inhibitors on mortality among type 2 diabetes patients. METHODS: Patients with type 2 diabetes who presented to the Dasman Diabetes Institute in Kuwait were followed from January 1st, 2015, until January 20th, 2023. To control for non-random allocation of SGLT2 inhibitors and measured confounders, we performed one-to-one propensity score matching and evaluated outcomes in the matched cohorts using a Cox proportional hazards model. The primary treatment variable was SGLT2 inhibitor use; time to mortality from any cause was used as the outcome of interest. RESULTS: 1,551 patients were taking SGLT2 inhibitors, and 1,687 patients were not. After propensity score matching, 845 patients were on SGLT2 inhibitors, and 845 patients were not. In post-matching analysis, all-cause mortality was higher among patients who did not take SGLT2 inhibitors compared to patients taking SGLT2 inhibitors (5.2 vs. 2.1%, p = 0.0012). The hazard ratio of all-cause mortality in patients taking SGLT2 inhibitors was 0.42 (95% confidence interval [95% CI], 0.24-0.72). Additional adjustment of matching factors did not change the results. CONCLUSION: This observational study demonstrated substantial long-term reduction in mortality risk among patients with type 2 diabetes treated with SGLT2 inhibitors. This is irrespective of the stage of their renal diseases or GLP1 agonist.

Global analysis of urinary extracellular vesicle small RNAs in autosomal dominant polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent monogenic renal disease progressing to end-stage renal disease. There is a pressing need for the identification of early ADPKD biomarkers to enable timely intervention and the development of effective therapeutic approaches. Here, we profiled human urinary extracellular vesicles small RNAs by small RNA sequencing in patients with ADPKD and compared their differential expression considering healthy control individuals to identify dysregulated small RNAs and analyze downstream interaction to gain insight about molecular pathophysiology. METHODS: This is a cross-sectional study where urine samples were collected from a total of 23 PKD1-ADPKD patients and 28 healthy individuals. Urinary extracellular vesicles were purified, and small RNA was isolated and sequenced. Differentially expressed Small RNA were identified and functional enrichment analysis of the critical miRNAs was performed to identify driver genes and affected pathways. RESULTS: miR-320b, miR-320c, miR-146a-5p, miR-199b-3p, miR-671-5p, miR-1246, miR-8485, miR-3656, has_piR_020497, has_piR_020496 and has_piR_016271 were significantly upregulated in ADPKD patient urine extracellular vesicles and miRNA-29c was significantly downregulated. Five 'driver' target genes (FBRS, EDC3, FMNL3, CTNNBIP1 and KMT2A) were identified. CONCLUSIONS: The findings of the present study make significant contributions to the understanding of ADPKD pathogenesis and to the identification of novel biomarkers and potential drug targets aimed at slowing disease progression in ADPKD.

Differential effects of fish-oil and cocoa-butter based high-fat/high-sucrose diets on endocrine pancreas morphology and function in mice.

Introduction: A high-fat/high-sucrose diet leads to adverse metabolic changes that affect insulin sensitivity, function, and secretion. The source of fat in the diet might inhibit or increase this adverse effect. Fish oil and cocoa butter are a significant part of our diets. Yet comparisons of these commonly used fat sources with high sucrose on pancreas morphology and function are not made. This study investigated the comparative effects of a fish oil-based high-fat/high-sucrose diet (Fish-HFDS) versus a cocoa butter-based high-fat/high-sucrose diet (Cocoa-HFDS) on endocrine pancreas morphology and function in mice. Methods: C57BL/6 male mice (n=12) were randomly assigned to dietary intervention either Fish-HFDS (n=6) or Cocoa-HFDS (n=6) for 22 weeks. Intraperitoneal glucose and insulin tolerance tests (IP-GTT and IP-ITT) were performed after 20-21 weeks of dietary intervention. Plasma concentrations of c-peptide, insulin, glucagon, GLP-1, and leptin were measured by Milliplex kit. Pancreatic tissues were collected for immunohistochemistry to measure islet number and composition. Tissues were multi-labelled with antibodies against insulin and glucagon, also including expression on Pdx1-positive cells. Results and discussion: Fish-HFDS-fed mice showed significantly reduced food intake and body weight gain compared to Cocoa-HFDS-fed mice. Fish-HFDS group had lower fasting blood glucose concentration and area under the curve (AUC) for both GTT and ITT. Plasma c-peptide, insulin, glucagon, and GLP-1 concentrations were increased in the Fish-HFDS group. Interestingly, mice fed the Fish-HFDS diet displayed higher plasma leptin concentration. Histochemical analysis revealed a significant increase in endocrine pancreas ß-cells and islet numbers in mice fed Fish-HFDS compared to the Cocoa-HFDS group. Taken together, these findings suggest that in a high-fat/high-sucrose dietary setting, the source of the fat, especially fish oil, can ameliorate the effect of sucrose on glucose homeostasis and endocrine pancreas morphology and function.

Glucose intolerance induces anxiety-like behaviors independent of obesity and insulin resistance in a novel model of nutritional metabolic stress.

OBJECTIVES: Type 2 diabetes (T2D) is a metabolic disease of major public health concern. It impacts peripheral tissues and the central nervous system, leading to systemic dysmetabolism and neurocognitive impairments, including memory deficits, anxiety, and depression. The metabolic determinants of these neurocognitive impairments remain unidentified. Here, we sought to address this question by developing a proprietary (P-) high-fat diet (HFD), in which glucose intolerance precedes weight gain and insulin resistance. METHODS: The P-HFD model was nutritionally characterized, and tested in vivo in mice that underwent behavioral and metabolic testing. The diet was benchmarked against reference models. . RESULTS: P-HFD has 42% kcal from fat, high monounsaturated/polyunsaturated fatty acid ratio, and 10% (w/v) sucrose in drinking water. When administered, from the early stages of glucose intolerance alone, animals exhibit anxiety-like behavior, without depression nor recognition memory deficits. Long-term P-HFD feeding leads to weight gain, brain glucose hypometabolism as well as impaired recognition memory. Using an established genetic model of T2D (db/db) and of diet-induced obesity (60% kcal from fat) we show that additional insulin resistance and obesity are associated with depressive-like behaviors and recognition memory deficits. DISCUSSION: Our findings demonstrate that glucose intolerance alone can elicit anxiety-like behavior. Through this study, we also provide a novel nutritional model (P-HFD) to characterize the discrete effects of glucose intolerance on cognition, behavior, and the physiology of metabolic disease.

PKD1 Truncating Mutations Accelerate eGFR Decline in Autosomal Dominant Polycystic Kidney Disease Patients.

INTRODUCTION: Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic disease characterized by the accumulation of fluid-filled cysts in the kidneys, leading to renal volume enlargement and progressive kidney function impairment. Disease severity, though, may vary due to allelic and genetic heterogeneity. This study aimed to determine genotype-phenotype correlations between PKD1 truncating and non-truncating mutations and kidney function decline in ADPKD patients. METHODS: We established a single-center retrospective cohort study in Kuwait where we followed every patient with a confirmed PKD1-ADPKD diagnosis clinically and genetically. Renal function tests were performed annually. We fitted generalized additive mixed effects models with random intercepts for each individual to analyze repeated measures of kidney function across mutation type. We then calculated survival time to kidney failure in a cox proportional hazards model. Models were adjusted for sex, age at visit, and birth year. RESULTS: The study included 22 truncating and 20 non-truncating (42 total) patients followed for an average of 6.6 years (range: 1-12 years). Those with PKD1 truncating mutations had a more rapid rate of eGFR decline (-4.7 mL/min/1.73 m2 per year; 95% CI: -5.0, -4.4) compared to patients with PKD1 non-truncating mutations (-3.5 mL/min/1.73 m2 per year; 95% CI: -4.0, -3.1) (p for interaction <0.001). Kaplan-Meier survival analysis of time to kidney failure showed that patients with PKD1 truncating mutations had a shorter renal survival time (median 51 years) compared to those with non-truncating mutations (median 56 years) (P for log-rank = 0.008). CONCLUSION: In longitudinal and survival analyses, patients with PKD1 truncating mutations showed a faster decline in kidney function compared to patients PKD1 non-truncating mutations. Early identification of patients with PKD1 truncating mutations can, at best, inform early clinical interventions or, at least, help suggest aggressive monitoring.

Silencing ANGPTL8 reduces mouse preadipocyte differentiation and insulin signaling.

ANGPTL8, expressed mainly in the liver and adipose tissue, regulates the activity of lipoprotein lipase (LPL) present in the extracellular space and triglyceride (TG) metabolism through its interaction with ANGPTL3 and ANGPTL4. Whether intracellular ANGPTL8 can also exert effects in tissues where it is expressed is uncertain. ANGPTL8 expression was low in preadipocytes and much increased during differentiation. To better understand the role of intracellular ANGPTL8 in adipocytes and assess whether it may play a role in adipocyte differentiation, we knocked down its expression in normal mouse subcutaneous preadipocytes. ANGPTL8 knockdown reduced adipocyte differentiation, cellular TG accumulation and also isoproterenol-stimulated lipolysis at day 7 of differentiation. RNA-Seq analysis of ANGPTL8 siRNA or control siRNA transfected SC preadipocytes on days 0, 2, 4 and 7 of differentiation showed that ANGPTL8 knockdown impeded the early (day 2) expression of adipogenic and insulin signaling genes, PPARγ, as well as genes related to extracellular matrix and NF-κB signaling. Insulin mediated Akt phosphorylation was reduced at an early stage during adipocyte differentiation. This study based on normal primary cells shows that ANGPTL8 has intracellular actions in addition to effects in the extracellular space, like modulating LPL activity. Preadipocyte ANGPTL8 expression modulates their differentiation possibly via changes in insulin signaling gene expression.

Targeting the Metabolic Paradigms in Cancer and Diabetes.

Dysregulated metabolic dynamics are evident in both cancer and diabetes, with metabolic alterations representing a facet of the myriad changes observed in these conditions. This review delves into the commonalities in metabolism between cancer and type 2 diabetes (T2D), focusing specifically on the contrasting roles of oxidative phosphorylation (OXPHOS) and glycolysis as primary energy-generating pathways within cells. Building on earlier research, we explore how a shift towards one pathway over the other serves as a foundational aspect in the development of cancer and T2D. Unlike previous reviews, we posit that this shift may occur in seemingly opposing yet complementary directions, akin to the Yin and Yang concept. These metabolic fluctuations reveal an intricate network of underlying defective signaling pathways, orchestrating the pathogenesis and progression of each disease. The Warburg phenomenon, characterized by the prevalence of aerobic glycolysis over minimal to no OXPHOS, emerges as the predominant metabolic phenotype in cancer. Conversely, in T2D, the prevailing metabolic paradigm has traditionally been perceived in terms of discrete irregularities rather than an OXPHOS-to-glycolysis shift. Throughout T2D pathogenesis, OXPHOS remains consistently heightened due to chronic hyperglycemia or hyperinsulinemia. In advanced insulin resistance and T2D, the metabolic landscape becomes more complex, featuring differential tissue-specific alterations that affect OXPHOS. Recent findings suggest that addressing the metabolic imbalance in both cancer and diabetes could offer an effective treatment strategy. Numerous pharmaceutical and nutritional modalities exhibiting therapeutic effects in both conditions ultimately modulate the OXPHOS-glycolysis axis. Noteworthy nutritional adjuncts, such as alpha-lipoic acid, flavonoids, and glutamine, demonstrate the ability to reprogram metabolism, exerting anti-tumor and anti-diabetic effects. Similarly, pharmacological agents like metformin exhibit therapeutic efficacy in both T2D and cancer. This review discusses the molecular mechanisms underlying these metabolic shifts and explores promising therapeutic strategies aimed at reversing the metabolic imbalance in both disease scenarios.

New-Generation Glucokinase Activators: Potential Game-Changers in Type 2 Diabetes Treatment.

Achieving glycemic control and sustaining functional pancreatic ß-cell activity remains an unmet medical need in the treatment of type 2 diabetes mellitus (T2DM). Glucokinase activators (GKAs) constitute a class of anti-diabetic drugs designed to regulate blood sugar levels and enhance ß-cell function in patients with diabetes. A significant progression in GKA development is underway to address the limitations of earlier generations. Dorzagliatin, a dual-acting GKA, targets both the liver and pancreas and has successfully completed two phase III trials, demonstrating favorable results in diabetes treatment. The hepato-selective GKA, TTP399, emerges as a strong contender, displaying clinically noteworthy outcomes with minimal adverse effects. This paper seeks to review the current literature, delve into the mechanisms of action of these new-generation GKAs, and assess their efficacy and safety in treating T2DM based on published preclinical studies and recent clinical trials.

Clinical Application of Umbilical Cord Mesenchymal Stem Cells Preserves ß-cells in Type 1 Diabetes.

Type 1 diabetes (T1D) is a chronic autoimmune disease associated with complications that reduce the quality of life of affected individuals and their families. The therapeutic options for T1D are limited to insulin therapy and islet transplantation; these options are not focused on preserving ß-cell function and endogenous insulin. Despite the promising outcomes observed in current clinical trials involving allogeneic Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) infusion for the management of T1D, the precise underlying mechanism of action remains to be elucidated. In this correspondence, we propose prospective mechanisms of action of WJ-MSCs that may be mediating their observed capability to preserve ß-cell function and prevent T1D progression and provide recommendations for further investigations in clinical settings. We also highlight the efficacy of WJ-MSCs for therapeutic applications in comparison to other adult MSCs. Finally, we recommend the participation of muti-centers governed by international organizations to implement guidelines for the safe practice of cell therapy and patients' welfare.

Verapamil chronicles: advances from cardiovascular to pancreatic ß-cell protection.

Verapamil is a well-known drug used for treating angina and hypertension. Emerging data from current clinical trials suggest that this calcium channel blocker has a potential benefit for pancreatic ß-cells through the elevation and sustenance of C-peptide levels in patients with diabetes mellitus (DM). This is intriguing, given the fact that the current therapeutic options for DM are still limited to using insulin and incretins which, in fact, fail to address the underlying pathology of ß-cell destruction and loss. Moreover, verapamil is widely available as an FDA-approved, cost-effective drug, supported also by its substantial efficacy and safety. However, the molecular mechanisms underlying the ß-cell protective potentials of verapamil are yet to be fully elucidated. Although, verapamil reduces the expression of thioredoxin-interacting protein (TXNIP), a molecule which is involved in ß-cell apoptosis and glucotoxicity-induced ß-cell death, other signaling pathways are also modulated by verapamil. In this review, we revisit the historical avenues that lead to verapamil as a potential therapeutic agent for DM. Importantly, this review provides an update on the current known mechanisms of action of verapamil and also allude to the plausible mechanisms that could be implicated in its ß-cell protective effects, based on our own research findings.

Early autoantibody screening for type 1 diabetes: a Kuwaiti perspective on the advantages of multiplexing chemiluminescent assays.

Type 1 diabetes (T1D) incidence has increased globally over the last decades, alongside other autoimmune diseases. Early screening of individuals at risk of developing T1D is vital to facilitate appropriate interventions and improve patient outcomes. This is particularly important to avoid life-threatening diabetic ketoacidosis and hospitalization associated with T1D diagnosis. Additionally, considering that new therapies have been developed for T1D, screening the population and individuals at high risk would be of great benefit. However, adopting such screening approaches may not be feasible due to limitations, such as cost, adaptation of such programs, and sample processing. In this perspective, we explore and highlight the use of multiplexing chemiluminescent assays for T1D screening and emphasize on their advantages in detecting multiple autoantibodies simultaneously, maximizing efficiency, and minimizing sample volume requirements. These assays could be extremely valuable for pediatric populations and large-scale screening initiatives, providing a cost-efficient solution with increased diagnostic accuracy and deeper insights into T1D pathogenesis. Eventually, the adoption of such screening methods can help transform T1D diagnosis, especially in countries with high T1D prevalence, such as Kuwait, which will contribute to the development of novel therapeutic interventions, positively impacting the lives of those affected by T1D and other autoimmune diseases.