Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a key treatment for type 2 diabetes mellitus (T2DM), with cardiorenal effects that extend beyond glycemic management. One important mechanism und Show more
Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a key treatment for type 2 diabetes mellitus (T2DM), with cardiorenal effects that extend beyond glycemic management. One important mechanism underpinning these pleiotropic effects is their interaction with AMP-activated protein kinase (AMPK), a crucial regulator of cellular energy balance. This review summarizes the strong evidence that SGLT2 inhibitors activate AMPK via both shared and drug-specific mechanisms. Empagliflozin induces on-target energetic stress, dapagliflozin activates the FGFR1-LKB1 axis, and canagliflozin inhibits mitochondrial complex I off-target. We describe how AMPK activation coordinates a protective network that includes PGC-1α-mediated mitochondrial biogenesis, ULK1-driven autophagy, Nrf2-antioxidant responses, and mTOR/NF-κB signaling inhibition. This interaction leads to enhanced insulin sensitivity, decreased oxidative stress, and sustained heart, kidney, and liver function. Furthermore, we conduct a comparative investigation of the distinct AMPK-modulatory profiles of prominent SGLT2 inhibitors and explore the practical applicability of these processes, including possible drawbacks such as the theoretical risk of muscle atrophy associated with persistent AMPK activation. By thoroughly describing the SGLT2-AMPK axis, this review emphasizes its importance as a therapeutic target and offers a framework for understanding the entire range of SGLT2 inhibitor activity in diabetes and associated consequences. Show less
Obesity is one of the risk factors concerns of colorectal cancer (CRC), the most common type of gastrointestinal cancer, due to the changing lifestyle and especially diet. There are various molecular Show more
Obesity is one of the risk factors concerns of colorectal cancer (CRC), the most common type of gastrointestinal cancer, due to the changing lifestyle and especially diet. There are various molecular pathways associated with obesity and the risk of CRC incidence, such as insulin resistance or elevated plasma free fatty acids, which alter the signaling pathways of intestinal epithelial cells. The aim of this study was to better understand the significance of unsaturated fatty acid biosynthesis on pathogenesis of colon cancer in obese. Based on GSE20931 dataset, obese individuals affected by CRC had higher increased gene expression than non-obese individuals. The analysis showed that in obese individuals, the 16 signaling pathway genes were activated and increased (FDR <0.05) significantly. The biosynthetic pathway of unsaturated fatty acids showed a cross-talk with the arachidonic acid metabolism pathway and the PPAR signaling pathway is influenced and regulated via these pathways. The biosynthetic pathway of unsaturated fatty acids consisting of 22 genes, were analyzed using GEO data and revealed that 4 genes (HSD17B12, TECR, FADS2, ELOVL5) from this pathway were significantly increased (FDR <0.05). These data were validated based on TCGA data (Adj.p.value <0.001). The expression level of candidate genes in HT-29 cells decreased significantly (P.value <0.01), and PPARγ expression increased under linoleic acid treatment (200 μM) compared to control cells. Moreover, in presence of linoleic acid treatment, migration, colony formation, and proliferation decreased (P.value <0.01) in presence of treatment. In summary, the Biosynthesis pathway of unsaturated fatty acids is an interesting and critical pathway in CRC. Show less