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Lactate elevation is a well-characterized biomarker of mitochondrial dysfunction, but its role in diabetic kidney disease (DKD) is not well defined. Urine lactate was measured in patients with type 2 diabetes (T2D) in 3 cohorts (HUNT3, SMART2D, CRIC). Urine and plasma lactate were measured during euglycemic and hyperglycemic clamps in participants with type 1 diabetes (T1D). Patients in the HUNT3 cohort with DKD had elevated urine lactate levels compared with age- and sex-matched controls. In patients in the SMART2D and CRIC cohorts, the third tertile of urine lactate/creatinine was associated with more rapid estimated glomerular filtration rate decline, relative to first tertile. Patients with T1D demonstrated a strong association between glucose and lactate in both plasma and urine. Glucose-stimulated lactate likely derives in part from proximal tubular cells, since lactate production was attenuated with sodium-glucose cotransporter-2 (SGLT2) inhibition in kidney sections and in SGLT2-deficient mice. Several glycolytic genes were elevated in human diabetic proximal tubules. Lactate levels above 2.5 mM potently inhibited mitochondrial oxidative phosphorylation in human proximal tubule (HK2) cells. We conclude that increased lactate production under diabetic conditions can contribute to mitochondrial dysfunction and become a feed-forward component to DKD pathogenesis.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P

Background: Diabetic nephropathy (DN) has been a major factor in the outbreak of end-stage renal disease for decades. As the underlying mechanisms of DN development remains unclear, there is no ideal methods for the diagnosis and therapy. Objective: We aimed to explore the key genes and pathways that affect the rate progression of DN. Methods: Nanopore-based full-length transcriptome sequencing was performed with serum samples from DN patients with slow progression (DNSP, n = 5) and rapid progression (DNRP, n = 6). Results: Here, transcriptome proclaimed 22,682 novel transcripts and obtained 45,808 simple sequence repeats, 1,815 transcription factors, 5,993 complete open reading frames, and 1,050 novel lncRNA from the novel transcripts. Moreover, a total of 341 differentially expressed transcripts (DETs) and 456 differentially expressed genes (DEGs) between the DNSP and DNRP groups were identified. Functional analyses showed that DETs mainly involved in ferroptosis-related pathways such as oxidative phosphorylation, iron ion binding, and mitophagy. Moreover, Functional analyses revealed that DEGs mainly involved in oxidative phosphorylation, lipid metabolism, ferroptosis, autophagy/mitophagy, apoptosis/necroptosis pathway. Conclusion: Collectively, our study provided a full-length transcriptome data source for the future DN research, and facilitate a deeper understanding of the molecular mechanisms underlying the differences in fast and slow progression of DN. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a chronic metabolic disorder affecting millions of people worldwide and causes serious complications such as diabetic nephropathy. Curcumin, a natural polyphenol derived from turmeric, has demonstrated antidiabetic, anti‐inflammatory, and antioxidant properties. However, the molecular mechanisms underlying curcumin's anti‐diabetic effects remain incompletely understood. This study employed network pharmacology, molecular docking, and simulation techniques to explore the potential targets, and key pathways of curcumin in the treatment of diabetes. Using SwissTarget prediction and Superpred databases, we predicted the molecular targets for curcumin, while diabetes‐associated genes were obtained from DisGeNet. We identified 60 common targets for curcumin in diabetes. Protein‐protein interaction (PPI) analysis revealed three sub‐networks and ten hub genes with AKT1, TNF‐α, EGFR, and STAT3 identified as key hub genes that could serve as potential biomarkers. Gene enrichment analysis indicated that these genes primarily regulate insulin resistance and other metabolic pathways. Quantum‐polarized ligand docking (QPLD) showed that curcumin establishes multiple hydrogen and hydrophobic interactions with the essential amino acids of these hub targets. Molecular simulation results demonstrated stable dynamic behavior, a compact structure, and variations in residue flexibility. Binding free energy calculations using MM/GBSA and MM/PBSA methods validate curcumin's strong binding to the potential targets. Total binding free energy using MM/GBSA ranged from −21.35 to −30.94 kcal/mol while MM/PBSA calculations showed total binding free energy values between −19.80 and −26.66 kcal/mol. Altogether, this study provides valuable insights into the molecular targets of curcumin in diabetes and lays the foundation for future advancements in diabetes treatment. [ABSTRACT FROM AUTHOR]

Background: The pathogenesis of type 2 diabetes mellitus is somewhat associated with lipid metabolism. We aim to assess the impact of lipid-lowering drugs (HMGCR inhibitors, PCSK9 inhibitors, and NPC1L1 inhibitors) on type 2 diabetes mellitus and its complications through a two-sample Mendelian randomization (MR) study. Method: We identified suitable genetic instruments from the GWAS database that represent the expression levels of three genes, interpreting reduced genetically proxied gene expression as indicative of lipid-lowering drug use. We evaluated the causal relationships among these variables employing a two-sample Mendelian randomization approach, with the Inverse Variance Weighted (IVW) analysis serving as the primary method. Coronary artery disease was utilized as a positive control to validate the reliability of the selected genetic instruments. Result: Increased genetically proxied HMGCR expression is significantly associated with a reduced risk of type 2 diabetes mellitus (OR = 0.64, 95%CI = 0.55–0.74), which was replicated in the FinnGen study with consistent results (OR = 0.65, 95%CI = 0.53–0.80). Increased genetically proxied HMGCR expression is associated with a reduced risk of diabetic retinopathy (OR = 0.23, 95%CI = 0.12–0.44) and diabetic nephropathy (OR = 0.35, 95%CI = 0.17–0.71). In contrast, increased genetically proxied PCSK9 expression is associated with a decreased risk of diabetic coma (OR = 0.70, 95%CI = 0.50–0.98), diabetic neuropathy (OR = 0.24, 95%CI = 0.14–0.42), diabetic retinopathy (OR = 0.67, 95%CI = 0.48–0.96), diabetic cardiovascular diseases (OR = 0.62, 95%CI = 0.38–0.99), and diabetic nephropathy (OR = 0.62, 95%CI = 0.41–0.95). Conclusions: This Mendelian randomization study suggests an association between HMGCR and the pathogenesis of type 2 diabetes mellitus, with increased genetically proxied HMGCR expression reducing the risk of type 2 diabetes mellitus, while PCSK9 and NPC1L1 show no significant association with type 2 diabetes mellitus. These findings may offer more reasonable lipid-lowering drug options for patients with dyslipidemia. Highlights: • Many studies have found that certain lipid-lowering drugs increase the risk of some diseases. • Observational study finds HMGCR inhibitors increase the risk of type 2 diabetes mellitus. •HMGCR inhibitor use increased the risk of type 2 diabetes in both of two different populations. [ABSTRACT FROM AUTHOR]

In recent years, with the rapid development of omics technologies, researchers have shown that interactions between the intestinal flora and bile acids are closely related to the progression of diabetic kidney disease (DKD). By regulating bile acid metabolism and receptor expression, the intestinal flora affects host metabolism, impacts the immune system, and exacerbates kidney injury in DKD patients. To explore interactions among the gut flora, bile acids and DKD, as well as the related mechanisms, in depth, in this paper, we review the existing literature on correlations among the gut flora, bile acids and DKD. This review also summarizes the efficacy of bile acids and their receptors as well as traditional Chinese medicines in the treatment of DKD and highlights the unique advantages of bile acid receptors in DKD treatment. This paper is expected to reveal a new and important potential strategy for the clinical treatment of DKD. [ABSTRACT FROM AUTHOR]

Background: Podocyte injury is crucial in diabetic kidney disease (DKD) progression, and the mechanism remains unclear. The previous studies indicated Diosgenin played a key role in inhibiting podocyte injury progression. However, more research is needed to explore Diosgenin in inhibiting-molecular mechanisms in the process of podocyte injury. Methods: The content of Diosgenin in HeShenwan was detected by High-Performance Liquid Chromatography-mass spectrometry (HPLC-MS) method. The podocyte injury model was constructed by high glucose (HG)-induced mpc5 cells. The Cell Counting Kit-8 (CCK-8) assay was utilized to evaluate the activity of mpc5 cells. Pyroptosis in mpc5 cells was assessed using flow cytometry. Molecular docking studies of Diosgenin and Nrf2 were carried out using VINA 1.1.2 software. The levels of Superoxide dismutase (SOD), Malondialdehyde (MDA), Reactive oxygen species (ROS), Interleukin 1β (IL-1β), Interleukin 18 (IL-18), Lactate dehydrogenase (LDH) and High mobility group protein B1 (HMGB1) were assessed using related kits. The levels of Nod-like receptor protein 3 (NLRP3), Nuclear factor erythroid-2-related factor 2 (Nrf2), Cysteinyl aspartate specific proteinase 1 (Caspase-1), Gasdermin (GSDMD), and Apoptosis-associated speck-like protein contain a CARD (ASC) were detected. Results: The Diosgenin content was the highest in HeShenwan. The addition of Diosgenin enhanced HG-induced mpc5 cell activity and reduced oxidative stress and pyroptosis. Molecular docking results showed that Diosgenin bound to the Nrf2 through hydrogen bonds and hydrophobic interactions, regulating the Nrf2 expression. Overexpression of Nrf2 reduced the levels of NLRP3, reducing oxidative stress and inhibiting pyroptosis in mpc5 cells. Knockdown of Nrf2 reduced HG-induced mpc5 cell activity and increased pyroptosis and oxidative stress. Diosgenin inhibited pyroptosis in mpc5 cells by regulating the Nrf2/NLRP3 pathway. Conclusion: Diosgenin inhibited HG-induced pyroptosis in mpc5 cells by regulating the Nrf2/NLRP3 pathway. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is one of microvascular complication associated with diabetes. Circular RNAs (circRNAs) have been shown to be involved in DN pathogenesis. Hence, this work aimed to explore the role and mechanism of circ_Arf3 in DN. Mouse mesangial cells (MCs) cultured in high glucose (HG) condition were used for functional analysis. Cell proliferation was determined using 5-ethynyl-2'-deoxyuridine (EdU) and cell counting kit-8 assays. Western blotting was used to measure the levels of proliferation indicator PCNA and fibrosis-related proteins α-smooth muscle actin (α-SMA), collagen I (Col I), fibronectin (FN), and collagen IV (Col IV). The binding interaction between miR-107-3p and circ_Arf3 or Tmbim6 (transmembrane BAX inhibitor motif containing 6) was confirmed using dual-luciferase reporter and pull-down assays. Circ_Arf3 is a stable circRNA, and the expression of circ_Arf3 was decreased after HG treatment in MCs. Functionally, ectopic overexpression of circ_Arf3 protected against HG-induced proliferation and elevation of fibrosis-related proteins in MCs. Mechanistically, circ_Arf3 directly bound to miR-107-3p, and Tmbim6 was a target of miR-107-3p. Further rescue assay showed miR-107-3p reversed the protective action of circ_Arf3 on MCs function under HG condition. Moreover, inhibition of miR-107-3p suppressed HG-induced proliferation and fibrosis, which were attenuated by Tmbim6 knockdown in MCs. CircRNA Arf3 could suppress HG-evoked mesangial cell proliferation and fibrosis via miR-107-3p/Tmbim6 axis, indicating the potential involvement of this axis in DN progression. Highlight: Circ_Arf3 expression was decreased after HG treatment in MCs. Ectopic overexpression of circ_Arf3 suppresses MC proliferation and fibrosis under HG condition. Circ_Arf3 can indirectly regulate Tmbim6 expression via sponging miR-107-3p. The miR-107-3p/Tmbim6 axis mediates the protective effects of circ_Arf3 on MC function in the presence of HG. [ABSTRACT FROM AUTHOR]

Background: The triglyceride-glucose (TyG) index is identified as an alternative indicator of insulin resistance (IR) and is associated with macro- and micro-vascular diseases among patients with type 2 diabetes mellitus. The relationship between the TyG index and IR and its impact on diabetic kidney disease (DKD) remains unclear among adults with type 1 diabetes mellitus(T1DM). Methods: This study comprised a cross-sectional analysis using data from the Guangdong T1DM Translational Medicine Study (GTT) and a longitudinal analysis using data from the type 1 diabetes (T1D) Exchange registry study. Correlation analysis was used to investigate the association between the TyG index and IR. Logistic regression and Cox proportional hazards regression were performed to explore the impact of the TyG index on DKD risk. Results: The GTT Study included 836 adults (216 with DKD and 620 without DKD). A significant correlation existed between the TyG index and the estimated glucose disposal rate (r=-0.64, p < 0.01). The TyG index was a risk factor for DKD after confounder adjustment (OR = 1.34, 95% CI:1.03–1.74). The T1D Exchange registry study included 8,771 adults (2,050 with DKD and 6,721 without DKD). After adjusting confounding factors, the TyG index was identified as an independent risk factor for DKD at enrollment, with the highest risk of DKD incidence observed in the highest TyG tertile group (OR = 1.92, 95%CI:1.67–2.20). During a median follow-up of 44.58(21.84, 67.09) months, the risk of developing DKD was increased by 32% at every 1 SD increase of the TyG index over time among participants without DKD at enrollment. Conclusions: The TyG index could be used to assess IR and was identified as an independent risk factor of DKD among adults with T1DM. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN), a severe complication of type 2 diabetes mellitus (T2DM), is marked by heightened endoplasmic reticulum stress (ERS) and oxidative stress (OS) due to protein misfolding and free radical generation. We investigated the sodium‐glucose co‐transporter‐2 inhibitor (SGLT2i), canagliflozin (Cana), in alleviating ERS and OS in DN patients and THP‐1 cells under hyperglycemic condition. A total of 120 subjects were divided into four groups, with 30 subjects in each group: healthy controls, T2DM individuals, DN patients receiving standard treatment, and those treated with Cana. The control group had no history of diabetes, cardiovascular or renal diseases, or other comorbidities. Cana was administered at doses of either 100 or 300 mg per day based on the estimated glomerular filtration rate (eGFR) value of DN individuals, with a mean follow‐up of 6 months. Additionally, THP‐1 monocytes were exposed to HGM (33.3 mM glucose with a cytokine cocktail of TNF‐α and IFN‐γ at 50 ng/mL each) to evaluate the relative levels of ERS, OS markers, and nuclear factor erythroid 2‐related factor 2 (Nrf2), the transcription factor regulating cellular redox, which is downregulated in diabetes. Our results revealed that ERS markers GRP78 and PERK, as well as OS markers TXNIP and p22phox, were elevated in both DN patients and HGM‐treated THP‐1 monocytes and were reduced by Cana intervention. Furthermore, Cana regulated the phosphorylation of Nrf2, Akt, and EIF2α in HGM‐treated monocytes. In conclusion, our findings highlight the role of Cana in activating Nrf2, thereby attenuating ERS and OS to mitigate DN progression. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) associated with type 2 diabetes (T2DM) is a global challenge; progression to end‐stage kidney disease (ESKD) and increased risk of cardiovascular disease (CVD) associated with advancing nephropathy are a significant source of morbidity, mortality, and healthcare expenditure. Until recently, renin‐angiotensin system (RAS) blockade was the mainstay of pharmacotherapy in diabetic kidney disease (DKD), representing a therapeutic paradigm shift towards interventions that delay disease progression independently of antihypertensive effects. However, a significant residual risk of DKD progression persisted in patients established on RAS blockade, highlighting the need for additional treatment options. Sodium‐glucose cotransporter‐2 (SGLT2) inhibitors, originally licensed as glucose‐lowering agents in people with T2DM, serendipitously demonstrated beneficial renal and cardiovascular outcomes in clinical trials designed primarily to evaluate their cardiovascular safety. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial was the first to study the effect of SGLT2 inhibition on a primary composite renal endpoint of ESKD, doubling of serum creatinine, or renal or cardiovascular death in 4401 people with T2DM and CKD established on RAS blockade. The trial was stopped early due to efficacy, demonstrating a 30% relative risk reduction in the primary endpoint in the canagliflozin group (hazard ratio 0.70, 95% confidence interval 0.59–0.82; p = 0.00001). Through discussion of the primary analysis from CREDENCE, and selected post hoc analyses, we review the significant benefits highlighted by this landmark study, its role in shaping clinical guidelines, and in re‐establishing interest in interventions that reduce the residual risk of progression of DKD, alongside its interrelation with cardiovascular morbidity and heart failure. We also provide a brief narrative summary of key renal outcome trials since CREDENCE, which indicate emerging avenues for pharmacotherapy beyond SGLT2 inhibition. [ABSTRACT FROM AUTHOR]

Aim: Bile acids (BA) function as signalling molecules regulating glucose‐lipid homeostasis and energy expenditure. However, the expression of the apical sodium‐dependent bile acid transporter (ASBT) in the kidney, responsible for renal BA reabsorption, is downregulated in patients with diabetic kidney disease (DKD). Using the db/db mouse model of DKD, this study aimed to investigate the effects of rescuing ASBT expression via adeno‐associated virus‐mediated delivery of ASBT (AAVASBT) on kidney protection. Methods: Six‐week‐old male db/db mice received an intraparenchymal injection of AAVASBT at a dose of 1 × 1011 viral genomes (vg)/animal and were subsequently fed a chow diet for 2 weeks. Male db/m mice served as controls. For drug treatment, daily intraperitoneal (i.p.) injections of the farnesoid X receptor (FXR) antagonist guggulsterone (GS, 10 mg/kg) were administered one day after initiating the experiment. Results: AAVASBT treatment rescued renal ASBT expression and reduced the urinary BA output in db/db mice. AAVASBT treatment activated kidney mitochondrial biogenesis and ameliorated renal impairment associated with diabetes by activating FXR. In addition, the injection of FXR antagonist GS in DKD mice would reverse these beneficial effects by AAVASBT treatment. Conclusion: Our work indicated that restoring renal ASBT expression slowed the course of DKD via activating FXR. FXR activation stimulates mitochondrial biogenesis while reducing renal oxidative stress and lipid build up, indicating FXR activation's crucial role in preventing DKD. These findings further suggest that the maintenance of renal BA reabsorption could be a viable treatment for DKD. Summary at a glance: Restoring renal apical sodium‐dependent bile acid transporter (ASBT) expression attenuates diabetic kidney disease (DKD) progression through farnesoid X receptor activation, which promotes mitochondrial biogenesis and reduces oxidative stress and lipid accumulation.Modulating renal bile acid reabsorption via ASBT upregulation holds promise as a therapeutic approach for DKD management. [ABSTRACT FROM AUTHOR]

Aim: To estimate individual treatment effects (ITEs) of sodium‐glucose co‐transporter‐2 inhibitors (SGLT2is) on lowering the risk of developing chronic kidney disease (CKD) in patients with type 2 diabetes (T2D) and to identify those most probable to benefit from treatment. Methods: This study followed a T2D cohort from Ramathibodi Hospital, Thailand, from 2015 to 2022. A counterfactual model was constructed to predict factual and counterfactual risks of CKD if patients did/did not receive SGLT2is. ITEs were estimated by subtracting the factual risk from the counterfactual risk of CKD. Results: There were 1619 and 15 879 patients included in the SGLT2i and non‐SGLT2i groups, respectively. The estimated ITEs varied from −1.19% to −17.51% with a median of −4.49%, that is, 50% of patients had a 4.49% or greater lower CKD risk if they received an SGLT2i. Patients who gained the greatest benefit from SGLT2is were more probable to be male, aged at least 60 years, with a history of diabetes duration of at least 3 months, hypertension, peripheral arterial disease, diabetic retinopathy and low high‐density lipoprotein cholesterol. Conclusions: Our prediction model provides individualized information that helps target T2D patients who may benefit more from SGLT2is. This could help clinical decision making and implementation of personalized medicine in clinical practice, especially in resource‐limited settings. [ABSTRACT FROM AUTHOR]