Diabetes/Metabolism Research and Reviews最新文献

Diabetic kidney disease (DKD) is the most severe complication of diabetes mellitus and has poor prognosis, often progressing to end-stage renal disease, causing substantial morbidity and mortality globally. While the pathogenesis of DKD has been extensively characterised, including glomerular hyperfiltration, podocyte injury, and tubulointerstitial fibrosis, recent findings underscore renal tubular injury as a pivotal contributor to DKD progression. High glucose levels and lipid accumulation result in tubular injury, followed by oxidative stress, endoplasmic reticulum stress, inflammation, activation of the renin–angiotensin–aldosterone system, programmed cell death, epithelial–mesenchymal transition, and intercellular crosstalk, all of which exacerbate tubular dysfunction in DKD. Notably, biomarkers of renal tubular injury, including kidney injury molecule-1, cystatin C, neutrophil gelatinase-associated lipocalin, liver fatty acid-binding protein, monocyte chemoattractant protein-1, N-acetyl-beta-glucosidase, and retinol-binding protein, along with other promising novel biomarkers, emerge earlier than microalbuminuria and serve as novel diagnostic indicators for early DKD detection. Therapeutically, we critically evaluate both established agents and emerging strategies, including hypoglycemic agents, anti-oxidative stress therapies, anti-inflammatory therapies, anti-cell death therapies, and stem cell therapy, showing promise for mitigating DKD-related tubular damage. This comprehensive review constructs a logical framework linking molecular mechanisms, novel biomarkers, and emerging therapeutic strategies for renal tubular injury in DKD. By bridging molecular mechanisms with actionable therapeutic strategies, this review highlights the pivotal role of tubulopathy in DKD pathogenesis and its implications for early diagnosis and intervention strategies.

Disease-modifying therapies have been used to treat the underlying causes of autoimmune diseases for over half a century. However, until recently, type 1 diabetes (T1D), the autoimmune form of diabetes, had not entered this therapeutic landscape. The approval of teplizumab, an anti-CD3 monoclonal antibody and the first disease-modifying therapy for use in individuals with preclinical T1D, has caused a major shift in the way healthcare providers can treat the T1D disease course. In this review, we discuss the chronic autoimmune nature of T1D and provide an overview of disease-modifying therapies that are under investigation to target the autoimmune mechanisms in T1D to preserve residual beta-cell function and prevent disease progression. The considerations for implementing these therapies into clinical practice are also discussed.

Obesity is highly correlated to muscle insulin resistance (IR), which significantly impacts metabolic health. One of the primary mechanisms connecting obesity to muscle IR is the accumulation of intramyocellular lipids (IMCL). Excessive lipid accumulation in muscle cells, that is, muscle lipotoxicity, leads to the formation of lipid metabolites, such as diacylglycerol (DAG) and ceramides, which disrupt insulin signalling pathways. These metabolites activate protein kinase C (PKC) and other kinases that inhibit insulin receptor substrate (IRS) proteins, subsequently impairing the insulin signalling cascade and reducing glucose uptake in skeletal muscle cells. This lipid-induced IR is a critical factor in the development of metabolic disorders associated with obesity. Furthermore, inflammation and oxidative stress may play significant roles in linking obesity with muscle IR. Obesity-induced inflammation is characterised by increased levels of pro-inflammatory cytokines, which activate signalling pathways, such as NF-κB and JNK. This transcription factor and stress protein further impair insulin signalling by promoting serine phosphorylation of IRS proteins. Concurrently, oxidative stress, resulting from an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, exacerbates insulin resistance. Elevated ROS levels associated with damaging cellular components, including proteins, lipids, and DNA, may activate stress-sensitive signalling pathways, inhibiting insulin action. The current review analyses evidence on the interplay between IMCL accumulation, inflammation, and oxidative stress, establishing this interconnected triad as a vicious cycle: lipid metabolites activate inflammatory kinases, while inflammation and ROS further promote lipid deposition and mitochondrial inefficiency. This triad of mechanisms explains why muscle IR in obesity is both a cause and consequence of metabolic disease progression. Understanding these pathways is clinically urgent, as they represent actionable targets for therapies (e.g., peroxisome proliferator-activated receptor gamma [PPARγ] agonists to reduce ceramides, anti-inflammatory strategies to preserve insulin signalling). This synthesis of current evidence highlights how obesity-induced muscle IR propagates systemic metabolic risk, offering a framework for future translational research.