Gestational diabetes mellitus (GDM) is characterized by an inadequate pancreatic β-cell response to pregnancy-induced insulin resistance, resulting in hyperglycemia. The pathophysiology involves reduced incretin hormone secretion and signaling, specifically decreased glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), impairing insulinotropic effects. Pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), impair insulin receptor substrate-1 (IRS-1) phosphorylation, disrupting insulin-mediated glucose uptake. β-cell dysfunction in GDM is associated with decreased pancreatic duodenal homeobox 1 (PDX1) expression, increased endoplasmic reticulum stress markers (CHOP, GRP78), and mitochondrial dysfunction leading to impaired ATP production and reduced glucose-stimulated insulin secretion. Excessive gestational weight gain exacerbates insulin resistance through hyperleptinemia, which downregulates insulin receptor expression via JAK/STAT signaling. Additionally, hypoadiponectinemia decreases AMP-activated protein kinase (AMPK) activation in skeletal muscle, impairing GLUT4 translocation. Placental hormones such as human placental lactogen (hPL) induce lipolysis, increasing circulating free fatty acids which activate protein kinase C, inhibiting insulin signaling. Placental 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) overactivity elevates cortisol levels, which activate glucocorticoid receptors to further reduce insulin sensitivity. GDM diagnostic thresholds (≥92 mg/dL fasting, ≥153 mg/dL post-load) are lower than type 2 diabetes to prevent fetal hyperinsulinemia and macrosomia. Management strategies focus on lifestyle modifications, including dietary carbohydrate restriction and exercise. Pharmacological interventions, such as insulin or metformin, aim to restore AMPK signaling and reduce hepatic glucose output. Emerging therapies, such as glucagon-like peptide-1 receptor (GLP-1R) agonists, show potential in improving glycemic control and reducing inflammation. A mechanistic understanding of GDM pathophysiology is essential for developing targeted therapeutic strategies to prevent both adverse pregnancy outcomes and the progression to overt diabetes in affected women.

Type 1 diabetes (T1D) is an autoimmune condition characterized by the destruction of insulin-producing pancreatic beta cells, leading to lifelong insulin dependence and significant complications. Early detection of T1D is essential to delay disease onset and improve outcomes. Recent advancements in artificial intelligence (AI) and machine learning (ML) have provided powerful tools for predicting and diagnosing T1D. This systematic review evaluates the current landscape of AI/ML-based approaches for early T1D detection. A comprehensive search across PubMed, EMBASE, Science Direct, and Scopus identified 1447 studies, of which 10 met the inclusion criteria for narrative synthesis after screening and full-text review. The studies utilized diverse ML models, including logistic regression, support vector machines, random forests, and artificial neural networks. The datasets encompassed clinical parameters, genetic risk markers, continuous glucose monitoring (CGM) data, and proteomic and metabolomic biomarkers. The included studies involved a total of 49,172 participants and employed case–control, retrospective cohort, and prospective cohort designs. Models integrating multimodal data achieved the highest predictive accuracy, with area under the curve (AUC) values reaching up to 0.993 in sex-specific models. CGM data and plasma biomarkers, such as CXCL10 and IL-1RA, also emerged as valuable tools for identifying at-risk individuals. While the results highlight the potential of AI/ML in revolutionizing T1D risk stratification and diagnosis, challenges remain. Data heterogeneity and limited model generalizability present barriers to widespread implementation. Future research should prioritize the development of universal frameworks and real-world validation to enhance the reliability and clinical integration of these tools. Ultimately, AI/ML technologies hold transformative potential for clinical practice by enabling earlier diagnosis, guiding targeted interventions, and improving long-term patient outcomes. These advancements could support clinicians in making more informed, timely decisions, thus reducing diagnostic delays and paving the way for personalized prevention strategies in both pediatric and adult populations.

Type 1 Diabetes (T1D) is a progressive autoimmune disease often identified in childhood or adolescence, with early stages detectable through pre-diabetic markers such as autoantibodies and subclinical beta-cell dysfunction. The identification of the pre-T1D stage is critical for preventing complications, such as diabetic ketoacidosis, and for enabling timely interventions that may alter disease progression. This review examines the multifaceted approach to managing T1D risk in adolescents and teens, emphasizing early detection, nutritional interventions, beta-cell preservation strategies, and psychosocial support. Screening for T1D-associated autoantibodies offers predictive insight into disease risk, particularly when combined with education and family resources that promote lifestyle adjustments. Although nutritional interventions alone are not capable of preventing T1D, certain lifestyle interventions, such as weight management and specific nutritional choices, have shown the potential to preserve insulin sensitivity, reduce inflammation, and mitigate metabolic strain. Pharmacological strategies, including immune-modulating drugs like teplizumab, alongside emerging regenerative and cell-based therapies, offer the potential to delay disease onset by protecting beta-cell function. The social and psychological impacts of a T1D risk diagnosis are also significant, affecting adolescents’ quality of life, family dynamics, and mental health. Supportive interventions, including counseling, cognitive-behavioral therapy (CBT), and group support, are recommended for managing the emotional burden of pre-diabetes. Future directions call for integrating universal or targeted screening programs within schools or primary care, advancing research into nutrition and psychosocial support, and promoting policies that enhance access to preventive resources. Advocacy for the insurance coverage of screening, nutritional counseling, and mental health services is also crucial to support families in managing T1D risk. By addressing these areas, healthcare systems can promote early intervention, improve beta-cell preservation, and support the overall well-being of adolescents at risk of T1D.

Background: Type 1 diabetes (T1D), a disease characterized by immune-mediated destruction of beta-cells, presents a significant global health challenge. Achieving therapeutic goals such as prevention of immune destruction, preservation of beta-cell mass, and automated insulin delivery remains complex due to the disease’s heterogeneity. Summary: This review explores the advancements and challenges in beta-cell replacement therapies, including pancreas and islet cell transplantation, stem cell-derived β-cell generation, and biotechnological innovations. Pancreas transplantation, especially simultaneous pancreas and kidney transplantation, has evolved significantly, offering insulin independence and improved quality of life despite surgical and immunological complications. Allogeneic islet transplantation, though less invasive, faces challenges such as donor scarcity, immunosuppressive therapy, and variable long-term success. Innovations in stem cell therapy, particularly using human embryonic stem cells and induced pluripotent stem cells, promise an unlimited source of β-cells. However, translating these advances into clinical applications involves overcoming technical, biological, and ethical hurdles. Strategies such as immunomodulation, encapsulation, and genetic engineering are critical to enhancing the viability and integration of transplanted cells. Key Messages: This review provides a comprehensive overview of the scientific intricacies and potential of β-cell replacement therapies, emphasizing the need for continued research to address the remaining challenges and improve diabetes care outcomes.

Alpha cells in the pancreas, traditionally known for their role in secreting glucagon to regulate blood glucose levels, are gaining recognition for their involvement in the pathophysiology of type 1 diabetes (T1D). In T1D, autoimmune destruction of beta cells results in insulin deficiency, which in turn may dysregulate alpha cell function, leading to elevated glucagon levels and impaired glucose homeostasis. This dysfunction is characterized by inappropriate glucagon secretion, augmenting the risk of life-threatening hypoglycemia. Moreover, insulin deficiency and autoimmunity alter alpha cell physiological responses, further exacerbating T1D pathophysiology. Recent studies suggest that alpha cells undergo transdifferentiation and interact with beta cells through mechanisms involving gamma-aminobutyric acid (GABA) signaling. Despite these advances, the exact pathways and interactions remain poorly understood and are often debated. Understanding the precise role of alpha cells in T1D is crucial, as it opens up avenues for developing new therapeutic strategies for T1D. Potential strategies include targeting alpha cells to normalize glucagon secretion, utilizing glucagon receptor antagonists, enhancing GABA signaling, and employing glucagon-like peptide-1 (GLP-1) receptor agonists. These approaches aim to improve glycemic control and reduce the risk of hypoglycemic events in individuals with T1D. This review provides an overview of alpha cell function in T1D, highlighting the emerging focus on alpha cell dysfunction in the context of historically well-developed beta cell research.

Background: Type 1 diabetes (T1D) is an autoimmune condition characterized by the destruction of insulin-producing beta cells in the pancreas. Anti-Thymocyte Globulin (ATG) has emerged as a promising immunomodulatory therapy aimed at preserving beta-cell function and altering the disease course. This systematic review synthesizes current evidence from the clinical trials evaluating the efficacy and safety of low-dose ATG in individuals with T1D. Methods: We conducted a comprehensive literature search of electronic databases, including PubMed (MEDLINE), Science Direct, Scopus, EMBASE, and ClinicalTrials.gov, to identify studies investigating ATG in T1D in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. The Joanna Briggs Institute (JBI) Critical Appraisal Tools for randomized clinical trials and case-control studies were used to assess the quality and evaluate the risk of bias in the eligible studies. Results: The primary outcomes assessed were preservation of C-peptide levels, glycemic control, and adverse events. Results indicated that ATG showed potential in preserving beta-cell function and improving clinical outcomes in recent-onset T1D. However, the incidence of adverse events, such as cytokine release syndrome and lymphopenia, necessitated careful monitoring and management. Conclusion: Low-dose ATG presents a promising therapeutic approach for modifying the progression of T1D. While early-phase trials demonstrate potential benefits in preserving beta-cell function, further large-scale, long-term studies are essential to establish optimal dosing regimens, long-term efficacy, and safety profiles. This review highlights the importance of continued research to fully elucidate the role of ATG in T1D management.