Emerging Plant-Based Nanotechnological Advances and Molecular Insights for Type‑2 Diabetes, Diagnosis and Treatments-Recent Trends and Future Prospects

Abstract

Type-2 diabetes, characterized by aberrant insulin secretion or increased hepatic glucose synthesis, accounts for approximately 90% of diabetes issues. This study explores current molecular and cellular advances related to T2D pathogenesis. Recent research on T2D about intracellular signaling cascades, inflammation, autophagy, genetics, and epigenetic changes is explained discretely. The present review discusses the available antidiabetic therapeutic strategies currently commercialized as well as their limitations that need to be acknowledged. Specifically, the review discusses how nanotechnology-based approaches nullify conventional antidiabetic therapeutics' inadequacy and heterogeneous nanoparticulate systems have been explored in diabetes research, and they're also listed in a tabular format. Furthermore, the research offers many strategic hypotheses as a potential application of nanotechnology in the future to improve the management of type-2 diabetes by developing a targeted nanodelivery system. In particular, attempts have been made to develop new treatment approaches based on nanotechnology that take advantage of autophagy and inflammasome target sites that have been previously identified. An explanation of how a smart targeted nano delivery system can inhibit the Wnt signaling pathway (inhibiting Gsk-3β), inhibit the inflammasome (inhibiting NLRP3), and activate autophagy target points (protecting the Atg3/Atg7 complex from oxidative stress) is provided through graphical description, which may mitigate the severity of type-2 diabetes.

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Mechanistic pathways of hyperglycemia-induced diabetic complications. Several pathways are stimulated by increased glucose levels, including the polyol pathway, hexosamine pathway, activation of PKC (protein kinase-C), and AGE (advanced glycation end product) formation, which result in excessive ROS (reactive oxygen species) production. Exacerbated ROS induces DNA damage, lipid peroxidation, oxidation of LDL (low-density lipoprotein), inflammation through TNF-α (tumor necrosis factor-alpha), IL-6 (interleukin-6), VEGF (vascular endothelial growth factor), ICAM-1 (intercellular adhesion molecule-1), TGF-β (transforming growth factor-beta) signaling, and apoptosis. These all sum up to matrix remodeling, fibrosis, and endothelial dysfunction through GAPDH (glyceraldehyde-3-phosphate dehydrogenase)-reduced activity and eventually result in diabetic complications. Antioxidant enzymes like SOD (superoxide dismutase), GPx (glutathione peroxidase), and AR (aldose reductase) try to neutralize oxidative stress but prove inadequate under chronic hyperglycemia.

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Mechanisms involved for the pharmaceutical management of Type-2 Diabetes (T2D) and its progression. Meglitinides and sulfonylureas, metformin and thiazolidinedione, α-glucosidase inhibitors, DPP-4 inhibitors, sodium glucose transporter (SGLT) inhibitors, and GLP-1 receptor agonists are some pharmacological therapies involved in the treatment of type-2 diabetes. Each of these medications acts on a specific site in the insulin resistance mechanism in type-2 diabetes.

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Diabetes therapy. Advantages (black) and limitations (red) of cellular diabetes therapy. ESC: embryonic stem cell, iPSC: induced pluripotent stem cell, and MSC: mesenchymal stem cell.

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Deterioration of the β-cell response to insulin resistance due to genetic predisposition and environmental influences. The development, maturation, and function of β-cells in the pancreas are crucially regulated by a variety of transcription factors (TFs), such as Pancreatic Duodenal Homeobox-1 (Pdx1), Forkhead Box A2 (FOXA2), Pancreas Transcription Factor 1A (PTF1A), FOXA1/2, Sex Determining Region Y-box 9 (SOX9), Hepatocyte Nuclear Factor (HNF) 1β, GATA-binding protein (GATA4/6), Neuronal Differentiation 1 (NeuroD1), Nk class of Homeodomain-encoding genes 2.2 (Nkx2.2), Nkx-6.1, V-Maf musculoaponeurotic fibro sarcoma oncogene family protein B (MafB), and GliSimilar 3 (Glis3). Also, Pdx1-expressing cells decreased β-cells and elevated fetal corticosteroid secretion.

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Current and updated applications of nanoparticles in diabetes diagnosis and therapeutics monitoring.

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Mechanistic management of diabetes using phytofabricated nanoparticles in Rin-5F pancreatic β-cells exposed to streptozotocin. STZ enters β-cells via GLUT2 transporters, leading to increase ROS (reactive oxygen species) and NOS (nitric oxide) species induction, mitochondrial membrane cleavage, free radical generation, DNA fragmentation, cell cycle arrest, cytotoxicity, and apoptosis. Nanoparticles modulate these effects by altering oxidative stress markers and serum testosterone levels, reducing oxidative damage and cellular dysfunction.

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Polymeric nanodelivery system (PNDS) activation of Wnt signaling pathway in vivo: without the Wnt molecule, the active β-catenin degradation complex breaks down β-catenin and inhibits the growth of β-cells in the Islets of Langerhans. Gsk-3β, which is essential for the stability of the degradation complex, may be degraded in the nucleus by PNDS-mediated targeting and release of antisense RNA, such as Gsk-3β. β-catenin may go to the nucleus to express genes if Gsk-3β is absent.

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Schematic representation of the significance of the NLRP3 inflammasome in type-2 diabetes and its inhibition by nanoparticles. Metabolic stress triggers the activation of the NLRP3 inflammasome through DAMPs (damage-associated molecular patterns) such as fatty acids, ATP, and ROS. This leads to caspase-1 activation, secretion of inflammatory cytokines (IL-1β, IL-18), and induction of pyroptosis. As a result, pancreatic islet mass decreases and insulin resistance increases.