Diabetic Kidney Disease (DKD) is the leading cause of end-stage renal disease (ESRD) worldwide. Among individuals with type 1 diabetes mellitus (T1DM), 30–40% are at risk of developing DKD. This review focuses on the mechanistic processes, available and emerging biomarkers for diagnosing, monitoring, and preventing DKD, as well as treatment options targeted at DKD patients. A literature search was conducted on PubMed and Scopus using specific keywords. Inclusion and exclusion criteria were applied to select the articles used for this review. The literature highlights various mechanisms involved in the progression of DKD to more severe stages. Additionally, several biomarkers have been identified, which aid in diagnosing and monitoring the disease. Furthermore, numerous treatment approaches are being explored to address the underlying causes of DKD. Advanced research is exploring new medications to aid in DKD remission; sodium-glucose cotransport (SGLT2) inhibitors and finerenone, in particular, are gaining attention for their novel renoprotective effects. DKD is a major complication of diabetes, marked by complex and multifactorial mechanisms. Thus, understanding these processes is essential for developing targeted therapies to potentially reverse DKD progression. Biomarkers show promise for early diagnosis and monitoring of disease progression, while current treatment strategies underscore the importance of a multifaceted approach.

Background: Binge eating disorder (BED) is characterized by episodes of uncontrollable eating, defined by the rapid consumption of large quantities of food over a short period. This condition is associated with a variety of psychological and non-psychological factors, including behavioral, biological, genetic, neurological, and pharmacological influences, all of which adversely affect patients’ daily lives. BED is linked to numerous health consequences, such as obesity, atherosclerosis, diabetes, chronic pain, and hypertension. Although BED is not exclusive to individuals with obesity, it is more prevalent in this population, who also face a heightened risk of developing metabolic syndrome (MetS). The latter is a cluster of five risk factors—obesity, hyperlipidemia, hyperinsulinemia, hypertension, and hyperglycemia—that significantly increase the likelihood of chronic diseases. Methods: This narrative review synthesizes existing research to explore the association between BED and MetS, examining shared pathophysiological mechanisms and clinical implications. It also highlights the role of escalating food insecurity and ongoing political, economic, and health crises in the development of BED. Results: BED is significantly associated with MetS components, including hypertension, obesity, type 2 diabetes, and dyslipidemia, all contributing to increased morbidity and mortality. Beyond body weight, behavioral, genetic, biological, and neurological factors mediate this relationship. Conclusions: BED is strongly linked to MetS through shared behavioral, genetic, and biological pathways. Early detection, integrated management strategies, and further research are crucial to addressing the public health challenges posed by this association.

The intricate interplay of one-carbon metabolism (OCM) with various cellular processes has garnered substantial attention due to its fundamental implications in several biological processes. OCM serves as a pivotal hub for methyl group donation in vital biochemical reactions, influencing DNA methylation, protein synthesis, and redox balance. In the context of aging, OCM dysregulation can contribute to epigenetic modifications and aberrant redox states, accentuating cellular senescence and age-associated pathologies. Furthermore, OCM’s intricate involvement in cancer progression is evident through its capacity to provide essential one-carbon units crucial for nucleotide synthesis and DNA methylation, thereby fueling uncontrolled cell proliferation and tumor development. In neurodegenerative disorders like Alzheimer’s and Parkinson’s, perturbations in OCM pathways are implicated in the dysregulation of neurotransmitter synthesis and mitochondrial dysfunction, contributing to disease pathophysiology. This review underscores the profound impact of OCM in diverse disease contexts, reinforcing the need for a comprehensive understanding of its molecular complexities to pave the way for targeted therapeutic interventions across inflammation, aging and neurodegenerative disorders.

Lipid droplets (LDs) are highly specialized energy storage organelles involved in the maintenance of lipid homoeostasis by regulating lipid flux within white adipose tissue (WAT). The physiological function of adipocytes and LDs can be compromised by mutations in several genes, leading to NEFA-induced lipotoxicity, which ultimately manifests as metabolic complications, predominantly in the form of dyslipidemia, ectopic fat accumulation, and insulin resistance. In this review, we delineate the effects of mutations and deficiencies in genes — CIDEC, PPARG, BSCL2, AGPAT2, PLIN1, LIPE, LMNA, CAV1, CEACAM1, and INSR — involved in lipid droplet metabolism and their associated pathophysiological impairments, highlighting their roles in the development of lipodystrophies and metabolic dysfunction.

Aim: The management of type 2 diabetes mellitus is affected by the presence of comorbidities. This meta-analysis aimed to determine how likely it is for individuals with type 2 diabetes in the Middle East and North Africa (MENA) region to be living with additional chronic health conditions. Methods: We searched for studies published from January 2010 to December 2020 in the PubMed, Ovid MEDLINE®, Cochrane CENTRAL, Scopus, and Web of Science databases. Studies of adults with type 2 diabetes in the MENA region were included. We performed a random-effects meta-analysis of single proportions to calculate each comorbidity's overall prevalence/coprevalence. Results: Statistically significant co-prevalence was detected at p < 0.01 for angina (pooled proportion: 0.24, 95% CI: 0.06, 0.49), cerebrovascular accident (pooled proportion: 0.16, 95% CI: 0.08, 0.26), coronary artery disease (pooled proportion: 0.25, 95% CI: 0.16, 0.35), coronary heart disease (pooled proportion: 0.05, 95% CI: 0.01, 0.12), peripheral vascular disease (pooled proportion: 0.19, 95% CI: 0.13, 0.26), hypertension (pooled proportion: 0.56, 95% CI: 0.43, 0.69), renal impairment (pooled proportion: 0.19, 95% CI: 0.10, 0.29), in addition to hyperlipidemia and overweight/ obesity. Conclusion: There is evidence of co-prevalence of several comorbidities in patients with type 2 diabetes, highlighting the importance of enhancing communication among healthcare professionals to develop the optimal management plan for each patient.

Diabetic cardiomyopathy (DCM) is a major complication of type 2 diabetes mellitus (T2DM) that leads to significant morbidity and mortality. The alteration in the signaling mechanism in diabetes leading to cardiomyopathy remains unclear. The purpose of this study is to investigate the role of tauopathy in myocardial dysfunction observed in T2DM. In that regard, diabetic Sprague Dawley rats were treated with intraperitoneal injections of lithium chloride (LiCl), inhibiting tau phosphorylation. Cardiac function was evaluated, and molecular markers of myocardial fibrosis and the TGF-β signaling were analyzed. T2DM rats exhibited a decline in ejection fraction and fractional shortening that revealed cardiac function abnormalities and increased myocardial fibrosis. These changes were associated with tau hyperphosphorylation. Treating diabetic rats with LiCl attenuated cardiac fibrosis and improved myocardial function. Inhibition of GSK-3β leads to the suppression of tau phosphorylation, which is associated with a decrease in TGF-β expression and regulation of the pro-inflammatory markers, suggesting that tau hyperphosphorylation is parallelly associated with fibrosis and inflammation in the diabetic heart. Our findings provide evidence of a possible role of tau hyperphosphorylation in the pathogenesis of DCM through the activation of TGF-β and by inducing inflammation. Targeting the inhibition of tau phosphorylation may offer novel therapeutic approaches to reduce DCM burden in T2DM patients.

Background Transvenous pacemakers (TVP) and leadless pacemakers (LP) are two reliable permanent modalities for the treatment of heart rhythm disorders. Several observational studies explored the safety and efficacy of the two devices. The aim of this meta-analysis study is to present a comparative analysis of the safety of leadless versus transvenous pacemakers. Methods The study protocol was registered in PROSPERO registry (CRD42024520647). A comprehensive and systematic search was conducted across PubMed, Embase, Cochrane Library, Web of Science and ClinicalTrials.gov, spanning from inception until just before the final analysis. SPSS was used for statistical analysis. Relative risks (RR) and odds ratio (OR) were used to evaluate the outcomes with a 95% confidence interval (CI). Results Nineteen studies met the inclusion criteria and were analyzed, in which the overall effect estimate showed increased risk of major complications in the TVP group (LogOR= -0.27, 95% CI: [-0.63, 0.10]) compared to the LP group. Among the nineteen studies, seven studies showed that TVP significantly increase the risk of reintervention (LogOR= -0.73, 95% CI: [-1.15, -0.31]) and thirteen studies showed a higher risk of mortality among patients receiving TVP (Cohen’s d= -0.11, 95% CI: [-0.22, 0.01]) compared to those receiving LP. Conversely, a higher risk of pericardial effusion or tamponade and thromboembolic events was among patients receiving LP with (LogOR= 1.01, 95% CI: [0.55, 1.46]) and (LogOR= 0.45, 95% CI: [-0.33, 1.23]) respectively. Conclusion This study showed that leadless pacemakers tend to be safer compared to transvenous pacemakers, with reduced risks of major complications, reintervention, generator malfunction, device or lead dislodgement, pneumothorax and hemothorax, infections rates, and mortality. However, higher odds of cardiac perforation and tamponade and thromboembolic events were observed among patients receiving LP. The lack of both randomized clinical trials and long term follow up studies limits our assessment and emphasizes the need for ongoing investigation to understand the extended complications associated with these devices amidst advancing technology.

In eukaryotic cells, membrane proteins play a crucial role. They fall into three categories: intrinsic proteins, extrinsic proteins, and proteins that are essential to the human genome (30% of which is devoted to encoding them). Hydrophobic interactions inside the membrane serve to stabilize integral proteins, which span the lipid bilayer. This review investigates a number of computational and experimental methods used to study membrane proteins. It encompasses a variety of technologies, including electrophoresis, X-ray crystallography, cryogenic electron microscopy (cryo-EM), nuclear magnetic resonance spectroscopy (NMR), biophysical methods, computational methods, and artificial intelligence. The link between structure and function of membrane proteins has been better understood thanks to these approaches, which also hold great promise for future study in the field. The significance of fusing artificial intelligence with experimental data to improve our comprehension of membrane protein biology is also covered in this paper. This effort aims to shed light on the complexity of membrane protein biology by investigating a variety of experimental and computational methods. Overall, the goal of this review is to emphasize how crucial it is to understand the functions of membrane proteins in eukaryotic cells. It gives a general review of the numerous methods used to look into these crucial elements and highlights the demand for multidisciplinary approaches to advance our understanding.

Background: Current guidelines recommend that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) with proven cardiovascular benefit should be considered for first-line therapy in patients with type 2 diabetes (T2D) who have/are at high risk of atherosclerotic cardiovascular disease (CVD). Summary: Only one GLP-1 RA – dulaglutide – has demonstrated superiority versus placebo in reducing cardiovascular risk in patients with T2D with or without a history of CVD in a cardiovascular outcomes trial (CVOT). This trial – REWIND – is the only GLP-1 RA-based CVOT that recruited patients with a CVD prevalence (31%) that is similar to the estimated prevalence in primary care T2D populations in the Gulf and Levant region. In contrast, baseline CVD prevalence in all other GLP-1 RA-based CVOTs ranged from 73 to 100%. REWIND’s results provided the European Association for the Study of Diabetes and American Diabetes Association with data on which to base updated guidelines. These organisations subsequently recommended that GLP-1 RAs should be considered for primary CVD prevention in high cardiovascular-risk patients with T2D, and acknowledged that present evidence supporting GLP-1 RAs for primary prevention of CVD in T2D is strongest for dulaglutide but limited for other GLP-1 RAs. The Emirates Diabetes Society guidelines also support the use of GLP-1 RAs for primary cardiovascular prevention in patients with T2D. The cardiovascular benefit conferred by dulaglutide in patients with no CVD history, and the close alignment of the REWIND cohort with patient populations in the Gulf and Levant region, may better inform physicians in the early use of dulaglutide in patients with T2D and multiple cardiovascular-risk factors, regardless of CVD history. Utilizing published data and author opinion, this review explores the importance of taking a cardiocentric approach to T2D management, and discusses the clinical implications of REWIND for people with T2D in the Gulf and Levant region. Key Messages: Guideline recommendations, including those of the Emirates Diabetes Society, state that GLP-1 RAs with proven cardiovascular benefit should be considered for primary CVD prevention in high cardiovascular-risk patients with T2D. This recommendation was informed, in part, by REWIND; REWIND was the only CVOT to show that a GLP-1 RA (dulaglutide) reduces cardiovascular risk in patients with T2D with or without established CVD. Demonstration of cardiovascular benefit in the REWIND cohort, which aligns closely with patient populations in the Gulf and Levant region, may better inform physicians in the early use of dulaglutide in patients with T2D, regardless of CVD history.

Type 2 diabetes (T2D) is a global health problem accompanied by an elevated risk of complications, the most common being cardiac and renal diseases. In Lebanon, the prevalence of T2D is estimated at 8–13%. Local medical practice generally suffers from clinical inertia, with gaps in the yearly assessment of clinical manifestations and suboptimal screening for major complications. The joint statement presented here, endorsed by five Lebanese scientific medical societies, aims at providing physicians in Lebanon with a tool for early, effective, and comprehensive care of patients with T2D. Findings from major randomized clinical trials of antidiabetic medications with cardio-renal benefits are presented, together with recommendations from international medical societies. Optimal care should be multidisciplinary and should include a multifactorial risk assessment, lifestyle modifications, and a regular evaluation of risks, including the risks for cardiovascular (CV) and renal complications. With international guidelines supporting a shift in T2D management from glucose-lowering agents to disease-modifying drugs, the present statement recommends treatment initiation with metformin, followed by the addition of sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide-1 receptor agonists due to their CV and renal protection properties, whenever possible. In addition to the selection of the most appropriate pharmacological therapy, efforts should be made to provide continuous education to patients about their disease, with the aim to achieve a patient-centered approach and to foster self-management and adherence to the medical plan. Increasing the level of patient engagement is expected to be associated with favorable health outcomes. Finally, this statement recommends setting an achievable individualized management plan and conducting regular follow-ups to monitor the patients’ glycemic status and assess their risks every 3–6 months.

INTRODUCTION:The identification and validation of a non-invasive prognostic marker for early detection of diabetic kidney disease (DKD) can lead to substantial improvement in therapeutic decision-making. OBJECTIVES:The main objective of this study is to assess the potential role of the arachidonic acid (AA) metabolite 20-hydroxyeicosatetraenoic (20-HETE) in predicting the incidence and progression of DKD. METHODS:Healthy patients and patients with diabetes were recruited from the Hamad General Hospital in Qatar, and urinary 20-HETE levels were measured. Data analysis was done using the Statistical Package for Social Sciences (SPSS). RESULTS:Our results show that urinary 20-HETE-to-creatinine (20-HETE/Cr) ratios were significantly elevated in patients with DKD when compared to patients with diabetes who did not exhibit clinical signs of kidney injury (p < 0.001). This correlation was preserved in the multivariate linear regression accounting for age, diabetes, family history of kidney disease, hypertension, dyslipidemia, stroke and metabolic syndrome. Urinary 20-HETE/Cr ratios were also positively correlated with the severity of kidney injury as indicated by albuminuria levels (p < 0.001). A urinary 20-HETE/Cr ratio of 4.6 pmol/mg discriminated between the presence and absence of kidney disease with a sensitivity of 82.2 % and a specificity of 67.1%. More importantly, a 10-unit increase in urinary 20-HETE/Cr ratio was tied to a 10-fold increase in the risk of developing DKD, suggesting a 20-HETE prognostic efficiency. CONCLUSION:Taken together, our results suggest that urinary 20-HETE levels can potentially be used as non-invasive diagnostic and prognostic markers for DKD.

This work introduces novel body-matched, vasculature-inspired, quasi-antenna-arrays that act as electromagnetic sensors to instantaneously, continuously, and wirelessly sense glucose variations in the bloodstream. The proposed sensors are personalized, leverage electromagnetic waves, and are coupled with a custom machine-learning-based signal-processing module. These sensors are flexible, and embedded in wearable garments such as socks, which provide conformity to curved skin surfaces and movement resilience. The entire wearable system is calibrated against temperature, humidity, and movement resulting in high accuracy in glucose variations tracking. In-Vivo experiments on diabetic rats and pigs exhibit a 100% diagnostic accuracy over a wide range of glucose variations. Human trials on patients with diabetes and healthy individuals reveal a clinical accuracy of continuous glucose monitoring of 99.01% in twenty-eight subjects who underwent Oral Glucose Tolerance Tests. Hence, our approach ensures the continuous tracking of glucose variations from hypo-to-hyper glycemic levels with great fidelity.

Diabetic Peripheral Neuropathy (DPN), highly prevalent among patients with diabetes, is characterized by peripheral nerve dysfunction. Reactive Oxygen Species (ROS) overproduction has been suggested to orchestrate diabetic complications including DPN. Untargeted antioxidant therapy has exhibited limited efficacy, highlighting a critical need to explore ROS sources altered in a cell-specific manner in DPN. Cytochromes P450 (CYP) enzymes are prominent sources of ROS. Particularly, the 20-HETE synthase, CYP4A, is reported to mediate diabetes-induced renal, retinal, and cardiovascular injuries. This work investigates the role of CYP4A/20-HETE in DPN and their mechanisms of action. Non-obese type 2 Diabetic mice (MKR) were used and treated with a CYP4A-inhibitor (HET0016) or AMPK-activator (Metformin). Peripheral nerves of MKR mice reflect increased CYP4A and 20-HETE levels, concurrent with altered myelin proteins and sensorimotor deficits. This was associated with increased ROS production and altered Beclin-1 and LC3 protein levels, indicative of disrupted autophagic responses in tandem with AMPK inactivation. AMPK activation via Metformin restored nerve integrity, reduced ROS production, and regulated autophagy. Interestingly, similar outcomes were revealed upon HET0016 treatment whereby ROS production, autophagic responses, and AMPK signaling were normalized in diabetic mice. Altogether, the results highlight hyperglycemia-mediated oxidative injury in DPN through a novel CYP4A/20-HETE/AMPK pathological axis. PERSPECTIVE: To our knowledge, this is the first study to highlight the role of CYPs/20-HETE-induced oxidative injury in the pathogenesis of diabetic peripheral neuropathy. Targeting the identified pathological axis CYP4A/20-HETE/AMPK may be of clinical potential in predicting and alleviating peripheral nerve injury in patients with Type 2 Diabetes Mellitus.

Diabetic kidney disease (DKD), a serious diabetic complication, results in podocyte loss and proteinuria through NADPH oxidases (NOX)-mediated ROS production. DUOX1 and 2 are NOX enzymes that require calcium for their activation which enters renal cells through the pivotal TRPC channels. Hypoglycemic drugs such as liraglutide can interfere with this deleterious mechanism imparting reno-protection. Herein, we aim to investigate the reno-protective effect of GLP1 receptor agonist (GLP1-RA), via its effect on TRPC6 and NADPH oxidases. To achieve our aim, control or STZ-induced T1DM Sprague–Dawley rats were used. Rats were treated with liraglutide, metformin, or their combination. Functional, histological, and molecular parameters of the kidneys were assessed. Our results show that treatment with liraglutide, metformin or their combination ameliorates DKD by rectifying renal function tests and protecting against fibrosis paralleled by restored mRNA levels of nephrin, DUOX1 and 2, and reduced ROS production. Treatment with liraglutide reduces TRPC6 expression, while metformin treatment shows no effect. Furthermore, TRPC6 was found to be directly interacting with nephrin, and indirectly interacting with DUOX1, DUOX2 and GLP1-R. Our findings suggest that treatment with liraglutide may prevent the progression of diabetic nephropathy by modulating the crosstalk between TRPC6 and NADPH oxidases.

Dia, Batoul; Noureldein, Mohamad; Azar, Sami; Ziyadeh, Fuad N.; Eid, Assaad Antoine Author Information

Immunotherapy is now a recognized treatment option for several types of cancer. However, some cancer patients treated with immune checkpoint inhibitors (ICIs) are subject to immune-related adverse events, including induced diabetes mellitus. The exact role and molecular/genetic action of ICIs in diabetes are still not well understood. Elucidating the underlying mechanisms in a proper fashion would allow better refining of biomarkers that would help diagnose patients at risk of altered immune system homeostasis, but would also hold the potential of new therapeutic options for diabetes. In the present narrative review, we propose to discuss the case of autoimmune diabetes following treatment with ICIs and the role of ICIs in the pathophysiology of diabetes. We also present some scarce available data on interesting potential immune therapies for diabetes.

Background: Lebanon is part of the global DISCOVER study, a global, noninterventional, multicentre, prospective study with 3-years of follow-up. Aims: The aim of this study is to describe real-world clinical practice in terms of type 2 diabetes mellitus (T2DM) disease management and treatment patterns within Lebanon. Methods: Baseline demographic and clinical parameters were captured on a standardized case report form, according to routine clinical practice at each clinical site. Results: We recruited 348 patients. At the initiation of second-line therapy, mean duration of diabetes was 6.7 [standard deviation (SD) 6.5] years; mean HbA1c and fasting plasma glucose levels were 8.5% (SD 1.6%) and 178.7 (SD 56.5) mg/dL respectively. Almost half the patients were hypertensive (45.1%) or had dyslipidaemia (48.6%). Metformin monotherapy was used as first-line therapy in 56.9% of the patients and upfront dual therapy in 25%. The primary reason for changing first line therapy was poor glycaemic control. The main factors in choosing the second-line therapy were efficacy, tolerability and hypoglycaemia. Conclusion: Clinical inertia was evident in this cohort of patients as they had suboptimal glycaemic control at the time of enrolment and the initiation of second-line therapy. Treatment intensification is required to reduce diabetes-related adverse outcomes.