Search Results (107)

Background and Objectives: To provide, for the first time, statistical data on risk factors for proliferative diabetic retinopathy (PDR) in young-onset type 1 diabetes (T1D) in Croatia, and to develop a predictive health economic model to evaluate the clinical and financial impact of implementing a national diabetic retinopathy (DR) screening. Materials and Methods: A cross-sectional study at University Hospital Split (June 2020–June 2022) analyzed 58 suitable T1D patients out of 562 screened. Patients were classified based on detailed fundus exams and photos into PDR and non-PDR groups. Clinical, demographic, and laboratory data were collected and analyzed using logistic regression. A health economic model was established to project the number of preventable PDR cases and the potential cost savings under various screening scenarios. Results: PDR was found in 47% of patients. Its presence was statistically significantly linked to longer diabetes duration, poor glycemic control, onset before 18 years of age, and irregular eye exams. Irregular ophthalmologic examinations increased the odds of PDR by nearly 30-fold. Health-economic modeling for 10,000 young-onset T1D patients showed that annual screening with 60% uptake could prevent about 1973 PDR cases and save €14.2 million annually. Screening remained cost-effective even with moderate uptake or less frequent intervals. Conclusions: Strict glycemic control and regular eye examinations are critical for preventing PDR in young T1D, and establishing a national screening program would be cost-effective, especially in resource-limited settings like Croatia, where providing appropriate, timely treatment may be challenging. Full article

Background/Objectives: Young-onset dementia (YOD) is a form of dementia where symptoms appear before the age of 65 years with a worse course, a poorer prognosis, and a lower survival rate than late-onset dementia. Psychiatric disorders often entail confusion, which delays their diagnosis and management. This study emphasizes the risk factors and confounders that limit opportunities to provide adequate early diagnoses of YOD. Methods: A retrospective, analytical, and observational study was based on the clinical records of 191 patients with a diagnosis of probable YOD in a medium-complexity hospital between 2009 and 2024. Demographic variables and the characteristics of the population were analyzed. An explanatory linear regression analysis was conducted to highlight the time required for diagnosis beginning at the onset of symptoms. Results: A high proportion of initial misdiagnoses were identified, and most patients were initially diagnosed with psychiatric or neurological disorders other than dementia. The main preventable risk factors were high blood pressure (HBP), type 2 diabetes mellitus (T2DM), and traumatic brain injury (TBI). HBP and the presence of irritability were associated with earlier diagnosis, whereas T2DM and the initial diagnosis of an affective or anxiety disorder were associated with a longer delay prior to diagnosis. Conclusions: Due to delays in seeking care and initial misdiagnoses as affective or anxiety disorders, T2DM is associated with a delayed final dementia diagnosis. In contrast, HBP and irritability were linked to shorter diagnostic times. These findings underscore the need for improved diagnostic capacity, adapted clinical tools, and awareness strategies to promote the early recognition of YOD. Full article

Background: Maturity-onset diabetes of the young (MODY) is a heterogeneous group of monogenic diabetes forms that are frequently misclassified as type 1 or type 2 diabetes due to overlapping phenotypic features. The true prevalence of MODY is likely substantially underestimated. As DNA-based diagnostics become increasingly accessible, an expanding number of novel genetic variants are being identified. Objectives: The aim of this study was to characterize the clinical and genetic features of patients carrying rare variants in the BLK, KLF11, PAX4, PDX1, and CEL genes, with attention to population-specific aspects, family history, and treatment outcomes. Methods: Targeted next-generation sequencing (NGS) using a custom-designed panel covering 27 genes implicated in MODY, neonatal diabetes, and related hereditary syndromes was performed on the Illumina NovaSeq 6000 platform (Illumina). Results: We identified 21 variants in five genes associated with rare MODY subtypes among 24 unrelated patients. MODY9 was diagnosed in two unrelated patients of Russian ethnicity harboring an identical heterozygous missense mutation in exon 5 of the PAX4 gene (HG38, chr7:127615049G>A, c.191C>T, p.Thr64Ile), which has not been previously described in patients with diabetes. MODY11 was diagnosed in a patient carrying the c.773-1G>A variant in the BLK gene. A patient with a de novo c.40_41dupGC (p.Val15Glnfs*41) variant in the KLF11 gene was clinically diagnosed with type 1 diabetes. Conclusion: Our findings expand the current understanding of rare MODY subtypes and contribute to the growing body of evidence on the spectrum and frequency of potentially pathogenic variants in BLK, CEL, KLF11, PDX1, and PAX4 genes across ethnically diverse populations worldwide. Full article

Maturity-Onset Diabetes of the Young Type 5 (MODY5) is caused by heterozygous pathogenic variants in the HNF1B gene, encoding the transcription factor hepatocyte nuclear factor-1β. HNF1B haploinsufficiency typically leads to young-onset non-immune diabetes and highly variable renal involvement, whose more frequent features are bilateral kidney cysts and renal hypodysplasia. Kidney cysts or echogenic kidneys can be identified by ultrasonography in the prenatal period, but the renal involvement can also start in childhood or later. Notably, a recurrent microdeletion syndrome at 17q12 (deleting HNF1B plus ~15 neighboring genes) accounts for ~40–50% of cases. The 17q12 deletion is a contiguous gene syndrome and affected individuals present with a complex phenotype, including neurodevelopmental disorders, liver and pancreas abnormalities, and other congenital defects. When counseling the patient and the parents, the clinician must consider multiple factors, including the molecular defect and the age of onset of the symptoms, with particular attention to prenatal diagnosis. A multidisciplinary approach and an early diagnosis are essential for the management of these conditions. Full article

Maturity-onset diabetes of the young type 10 (MODY10) is a monogenic diabetes subtype caused by heterozygous mutations in the insulin gene (INS), leading to defective proinsulin processing, endoplasmic reticulum (ER) stress, and β-cell dysfunction. Current management relies on sulfonylureas or insulin therapy, but these fail to address the underlying genetic defect. Recent research has elucidated the molecular mechanisms of MODY10, including ER stress induced by proinsulin misfolding, activation of the unfolded protein response (UPR), and β-cell apoptosis. Emerging therapies such as Adeno-Associated Virus (AAV)-mediated gene delivery to induce the glucose-responsive hepatic insulin expression, plasmid-based single-chain insulin analogs, and cell-based therapies show promise in preclinical studies. However, critical challenges remain, including immune responses to AAV vectors, incomplete correction of dominant-negative mutant effects, and the need for long-term safety data. This review summarizes current knowledge on MODY10 genetics, pathophysiology, and therapeutic innovations, while identifying key gaps for future research to enable precision medicine approaches. Full article

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disorder characterized by the destruction of insulin-producing pancreatic beta cells, resulting in lifelong insulin dependence. While genetic susceptibility—particularly human leukocyte antigen (HLA) class II alleles—is a major risk factor, accumulating evidence implicates viral infections as potential environmental triggers in disease onset and progression. This narrative review synthesizes current findings on the role of viral pathogens in T1DM pathogenesis. Enteroviruses, especially Coxsackie B strains, are the most extensively studied and show strong epidemiological and mechanistic associations with beta-cell autoimmunity. Large prospective studies—including Diabetes Virus Detection (DiViD), The environmental determinans of diabetes in the young (TEDDY), Miljøfaktorer i utvikling av type 1 diabetes (MIDIA), and Diabetes Autoimmunity Study in the Young (DAISY)—consistently demonstrate correlations between enteroviral presence and the initiation or acceleration of islet autoimmunity. Other viruses—such as mumps, rubella, rotavirus, influenza A (H1N1), and SARS-CoV-2—have been investigated for their potential involvement through direct cytotoxic effects, immune activation, or molecular mimicry. Interestingly, certain viruses like varicella-zoster virus (VZV) and cytomegalovirus (CMV) may exert modulatory or even protective influences on disease progression. Proposed mechanisms include direct beta-cell infection, molecular mimicry, bystander immune activation, and dysregulation of innate and adaptive immunity. Although definitive causality remains unconfirmed, the complex interplay between genetic predisposition, immune responses, and viral exposure underscores the need for further mechanistic research. Elucidating these pathways may inform future strategies for targeted prevention, early detection, and vaccine or antiviral development in at-risk populations. Full article

Gastric cancer traditionally affects older adults, and its precursor lesions and risk factors are well-documented in this population. Helicobacter pylori (H. pylori) infection remains highly prevalent in Saudi Arabia and contributes to gastric pathology. However, early-onset gastric cancer (EOGC), diagnosed in individuals aged ≤ 45 years, presents unique challenges and remains poorly understood in young populations. Therefore, we conducted an observational cohort study using a prospective longitudinal design (2021–2024) involving 1823 Saudi nationals aged 18–45 years who underwent zoom high-definition chromoendoscopy to evaluate the prevalence of premalignant gastric lesions (PGLs) and EOGC. We found a high H. pylori prevalence (78.0%) with PGLs in 1.9% of participants and EOGC-adenocarcinoma in 0.7% of patients. All EOGC cases arose from dysplasia, with most PGLs being classified as OLGA/OLGIM stage II/III. Multiple risk factorswere significantly associated with PGLs and EOGC, including H. pylori infection (p = 0.022), increasing age (p < 0.001), a family history of gastric cancer (p < 0.001), poor dietary habits (p < 0.001), obesity (p < 0.001), and smoking (p < 0.001). Additional EOGC risk factors include dage of 36–45 years (p = 0.018), EBV infection (p = 0.016), and diabetes mellitus (p = 0.001). These findings demonstrate the notable presence of PGLs and EOGC in young Saudi adults and emphasize the importance of early detection and risk factor management in this vulnerable population. Full article

Maturity-onset diabetes of the young (MODY)—a monogenic form of diabetes—accounts for approximately 1–2% of all diabetes cases, with GCK-MODY being the second most commonly diagnosed type. Although the inherited nature of the disease implies that the interplay between maternal glycemia and fetal genotype directly influences neonatal outcomes, clinical guidelines for MODY-complicated pregnancies remain underdeveloped. A systematic literature search in the PubMed, Scopus, Web of Science, and Cochrane databases was conducted following the PRISMA guidelines. The study protocol has been logged in the PROSPERO registry with the identification number CRD42024609390. Data, such as MODY type, the gestational age at delivery, mode of delivery, insulin administration, mutational status of the fetus, fetal birthweight (FBW), occurrence of small-/large-for-gestational age fetus, shoulder dystocia, and neonatal hypoglycemia, were extracted and evaluated. Among 19 studies selected for the final analysis, 15 investigated perinatal outcomes in the GCK-MODY variant. Women diagnosed with GCK-MODY treated with insulin delivered approximately 1–2 weeks earlier than those managed with diet alone. FBW was significantly higher in GCK-negative as compared to GCK-positive offspring. Accordingly, fetal macrosomia was notably more common among unaffected neonates. In GCK-affected fetuses, insulin therapy was associated with a significantly lower FBW. Fetal genotype critically modifies perinatal outcomes in GCK-MODY pregnancies. In the absence of fetal genotyping, conservative management should be prioritized to mitigate the risks of fetal growth restriction and iatrogenic prematurity. As data regarding other types of MODY in pregnancy remain sparse, there is an urgent need for more research in this area. Full article

Background/Objective: Early-onset diabetes (EOD), diagnosed at ≤35 years, is a growing public health crisis in low- and middle-income countries, including Pakistan. Identifying modifiable and non-modifiable risk factors is critical for developing effective prevention strategies. This study aimed to investigate the risk factors associated with EOD in Sindh, Pakistan, focusing on genetic, lifestyle, and metabolic determinants. Methods: A multicenter cross-sectional study was conducted across diabetic clinics in Sindh, with primary data collection at Baqai Institute of Diabetology and Endocrinology (Karachi, Pakistan) and secondary sites in Hyderabad, Larkana, and Sukkur. Following institutional ethical approval and informed consent, we enrolled 754 individuals (type 1 and type 2 diabetes, age at diagnosis: 15–35 years). Data on anthropometric, clinical, biochemical, and lifestyle parameters were collected via structured questionnaires. Statistical analyses included Pearson’s Chi Square tests and multivariate logistic regression in determining associations. Results: Logistic regression revealed key predictors of early-onset diabetes (EOD). A two-generation diabetes family history showed a strong association (aOR:1.86, 1.12–3.43). Significant lifestyle risks included physical inactivity (OR:1.40, 1.03–1.90), frequent sugary beverage intake (OR:1.93, 1.89–1.98), and abnormal sleep duration (<6 h: OR:1.58, 1.04–2.40; >8 h: OR:1.86, 1.21–2.85). Hypertension was a major metabolic predictor (elevated BP: OR:1.79, 1.28–1.54; Stage I: OR:1.81, 1.34–1.77). Cardiovascular disease and uncontrolled fasting glucose lost significance after adjustment, indicating confounding effects. Conclusions: This study highlights familial predisposition, sedentary behavior, poor diet, sleep disturbances, and hypertension as key contributors to EOD in young Pakistani adults. Early screening and targeted lifestyle interventions are urgently needed to mitigate this escalating epidemic. Full article

Maturity-onset diabetes of the young (MODY) is a rare genetic condition that affects children, adolescents, and adults. Studies have shown that genetic changes in the HNF1A gene are associated with MODY-3. However, most of the causative variants and the molecular mechanisms remain underexplored. This study aims to better understand MODY-3 by investigating HNF1A-missense variants with clinical uncertainty. Various bioinformatics tools were utilised to address the clinical uncertainty of missense variants in the HNF1A gene that have not been linked with HNF1A-related conditions, sourced from the Genome Aggregation Database (GnomAD v4.1.0). Among the clinically uncertain 2444 variants, only 138 were classified as missense with clinically uncertain significance. Results show that four variants (Arg168Cys, Glu275Ala, Gly375Asp and Val411Phe) were consistently predicted as pathogenic by all tools. The allele frequency (AF) of the commonly predicted disease-causing variants was very low in the global population. The assessment of the secondary structure of filtered variants indicates that variants (Arg168Cys and Glu275Ala) are located in the helical region of the HNF1A protein. At the same time (Gly375Asp and Val411Phe) are found in the protein’s coil, suggesting structural changes at the site of variations. The prediction of protein stability was conducted using I-Mutant and MuPro. Both tools collectively indicate decreased protein stability for the variants (Arg168Cys, Glu275Ala, Gly375Asp and Val411Phe). Predicting the protein’s 3D structure for the HNF1A wild-type and mutants indicates potential structural damages in Arg168Cys and Gly375Asp. Additionally, results show that the amino acids at the variation sites of the variants (Arg168Cys, Glu275Ala, Gly375Asp and Val411Phe) were highly conserved. To conclude, 4 out of the 138 missense variants labelled as uncertain significance were found to be consistently pathogenic using in silico tools in this study. Our findings aim to support variant interpretation, understand the genotype–phenotype association of diabetes, and provide better healthcare services for patients with diabetes. Full article

Osteoarthritis (OA), caused by the long-term use of joints, is a representative degenerative disease in the elderly. However, recently, the age of onset has been decreasing owing to excessive activities among young people in their 20s and 30s. Gynostemma pentaphyllum (Thunb.) Makino (GP), a perennial herb of the Cucurbitaceae family, has been used since the Ming dynasty as a medicinal material to treat various ailments, such as rheumatism, liver disease, and diabetes. In this study, we investigated the anti-arthritic effects of heat-processed Gynostemma pentaphyllum extract (Actiponin (AP)) and its derivatives, damulin A (DA) and damulin B (DB), using in vitro (primary rat chondrocytes and SW1353 cells) and in vivo (destabilization of the medial meniscus (DMM)-induced OA model) systems. Histological analysis results from the in vivo study showed that the group that underwent DMM surgery induced degeneration by the loss of proteoglycan and the destruction of cartilage (OARSI score 14 ± 0.57), whereas the group that received AP daily for 8 weeks maintained an intact condition (OARSI score 5 ± 0.28 at 200 mg/kg, p < 0.001). In addition, cartilage thickness and chondrocytes were reduced in the DMM group, but were restored in the AP-administered group. Furthermore, the von Frey analysis results showed that the pain threshold of the DMM group was considerably low (54.5 g at 8 weeks), whereas that of the AP group was dose-dependently increased (65.5, 69.5, 70.3, and 71.8 at 8 weeks for 30, 50, 100, and 200 mg/kg, respectively). In vitro studies showed that AP, DA, and DB reduced the expression of interleukin-1β alone-induced nitrite; inducible nitric oxide synthase; cyclooxygenase-2; matrix metallopeptidase 1/3/13; and a disintegrin and metalloproteinase with thrombospondin motifs 4/5. They also restored the expression of collagen type II and aggrecan, which are components of the extracellular matrix. The anti-arthritic effects of AP, DA, and DB were confirmed to be mediated by the mitogen-activated protein kinase and nuclear factor kappa-light-chain-enhancer of activated B cell signaling pathways. Collectively, these results suggest that AP is a potential therapeutic agent for mitigating OA progression and chondroprotection. Full article

Analyzing the genetic architecture of hereditary forms of diabetes in different populations is a critical step toward optimizing diagnostic and preventive algorithms. This requires consideration of regional and population-specific characteristics, including the spectrum and frequency of pathogenic variants in targeted genes. As part of this study, we used a custom-designed NGS panel to screen for mutations in 28 genes associated with the pathogenesis of hereditary diabetes mellitus in 506 unrelated patients from Russia. The study identified 180 pathogenic or likely pathogenic variants across 13 genes (GCK, HNF1A, HNF1B, HNF4A, ABCC8, INS, INSR, KCNJ11, PAX4, PDX1, ZFP57, BLK, WFS1), representing 46.44% of the analyzed cohort (235 individuals). The glucokinase gene (GCK) had the highest number of identified variants, with 111 variants detected in 161 patients, 20 of which were identified for the first time. In the tissue-specific transcription factor genes HNF1A, HNF4A, and HNF1B, 34 variants were found in 38 patients, including 13 that were previously unreported. Seventeen variants were identified in the ABCC8 gene, which encodes the ATP-binding cassette transporter 8 of subfamily C, each found in a different patient; four of these were novel discoveries. Nine pathogenic or likely pathogenic variants were identified in the insulin gene (INS) and its receptor gene (INSR), including four previously unreported variants. Additionally, we identified 10 previously unreported variants in six other genes among 11 patients. Variants in the genes GCK, HNF1A, HNF1B, HNF4A, ABCC8, INS, and INSR were the main contributors to the genetic pathogenesis of hereditary diabetes mellitus in the Russian cohort. These findings enhance our understanding of the molecular mechanisms underlying the disease and provide a solid basis for future studies aimed at improving diagnostic accuracy and advancing personalized therapeutic strategies. This knowledge provides a foundation for developing region-specific genetic testing algorithms and personalized therapeutic strategies, which are critical for future initiatives in precision medicine. Full article

This study aimed to analyze the relationship between cutaneous microcirculation reactivity, retinal circulation, macrocirculation function, and specific adhesion molecules in young patients with uncomplicated type 1 diabetes. Fifty-five patients with type 1 diabetes mellitus (T1DM), aged 8 to 18 years, were divided into subgroups based on skin microcirculation reactivity. The cutaneous microcirculatory vessels were considered reactive if post-test PORH coverage increased compared to pre-test coverage. Optical coherence tomography (OCT) was conducted to detect early retinopathic changes. Macrocirculation was described using pulsatility indices (PIs) determined for common carotid (CCA) and peripheral arteries of the upper and lower limbs. The ankle–brachial index was also assessed. There were no significant differences in retinal circulation and macrocirculation between the studied subgroups. However, there were significant differences between the various subgroups concerning the age at onset of diabetes and the sP-selectin levels but not ICAM-1 and sVCAM-1. The sP-selectin differences remained true after adjusting for age at onset. The sP-selectin level was significantly higher in the subgroup of patients with non-reactive cutaneous microcirculation. The results of our study indicate that sP-selectin may be considered as an immunological marker for cutaneous abnormalities, which serve as an early indicator of endothelial dysfunction in young patients with type 1 diabetes in the absence of classical complication. Full article

The HNF1B gene, located on chromosome 17q12, encodes a transcription factor essential for the development of several organs. It regulates the expression of multiple genes in renal, pancreatic, hepatic, neurological, and genitourinary tissues during prenatal and postnatal development, influencing processes such as nephrogenesis, cellular polarity, tight junction formation, cilia development, ion transport in the renal tubule, and renal metabolism. Mutations that alter the function of Hnf1b deregulate those processes, leading to various pathologies characterized by both renal and extrarenal manifestations. The main renal diseases that develop are polycystic kidney disease, hypoplastic or dysplastic kidneys, structural abnormalities, Congenital Anomalies of the Kidney and Urinary Tract (CAKUT), and electrolyte imbalances such as hyperuricemia and hypomagnesemia. Extrarenal manifestations include Maturity-Onset Diabetes of the Young (MODY), hypertransaminasemia, genital and urinary tract malformations, Autism Spectrum Disorder (ASD), and other neurodevelopmental disorders. Patients with HNF1B alterations typically carry either punctual mutations or a monoallelic microdeletion in the 17q12 region. Future research on the molecular mechanisms and genotype–phenotype correlations in HNF1B-related conditions will enhance our understanding, leading to improved clinical management, genetic counseling, monitoring, and patient care. Full article

Monogenic defects of beta cell function refer to a group of rare disorders that are characterized by early-onset diabetes mellitus due to a single gene mutation affecting insulin secretion. It accounts for up to 5% of all pediatric diabetes cases and includes transient or permanent neonatal diabetes, maturity-onset diabetes of the young (MODY), and various syndromes associated with diabetes. Causative mutations have been identified in genes regulating the development or function of the pancreatic beta cells responsible for normal insulin production and/or release. To date, more than 40 monogenic diabetes subtypes have been described, with those caused by mutations in HNF1A and GCK genes being the most prevalent. Despite being caused by a single gene mutation, each type of monogenic diabetes, especially MODY, can appear with various clinical phenotypes, even among members of the same family. This clinical heterogeneity, its rarity, and the fact that it shares some features with more common types of diabetes, can make the clinical diagnosis of monogenic diabetes rather challenging. Indeed, several cases of MODY or syndromic diabetes are accurately diagnosed in adulthood, after having been mislabeled as type 1 or type 2 diabetes. The recent widespread use of more reliable sequencing techniques has improved monogenic diabetes diagnosis, which is important to guide appropriate treatment and genetic counselling. The current review aims to summarize the latest knowledge on the clinical presentation, genetic confirmation, and therapeutic approach of the various forms of monogenic defects of beta cell function, using three imaginary clinical scenarios and highlighting clinical and laboratory features that can guide the clinician in reaching the correct diagnosis. Full article