BACKGROUND: This study aims to evaluate the effects of sodium-glucose cotransporter 1 inhibitors (SGLT1i) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) on neurodegenerative disorders and to investigate the role of hemoglobin A1c (HbA1c) levels.
METHODS: Utilizing drug target Mendelian randomization, we employed single nucleotide polymorphisms (SNPs) proximal to the SLC5A1 and SLC5A2 genes to analyze the influence of SGLT1i and SGLT2i on Alzheimer\'s disease (AD), Parkinson\'s disease (PD), multiple sclerosis (MS), frontotemporal dementia (FTD), Lewy body dementia (LBD), and amyotrophic lateral sclerosis (ALS), with type 2 diabetes (T2D) as a positive control. An additional analysis examined the impact of HbA1c levels on the same disorders.
RESULTS: SGLT1i exhibited a significant association with decreased risk for ALS and MS. Conversely, SGLT2i were linked to an increased risk of AD, PD, and MS. Elevated HbA1c levels, independent of SGLT1 and SGLT2 effects, were associated with an increased risk of PD. Sensitivity analyses supported the robustness of these findings.
CONCLUSIONS: Our study suggests that SGLT1i may confer protection against ALS and MS, whereas SGLT2i could elevate the risk of AD, PD, and MS. Additionally, elevated HbA1c levels emerged as a risk factor for PD. These findings underscore the importance of personalized approaches in the utilization of SGLT inhibitors, considering their varying impacts on the risks of neurodegenerative diseases.

BACKGROUND: Some glucoside drugs can be transported via intestinal glucose transporters (IGTs), and the presence of carbohydrate excipients in pharmaceutical formulations may influence the absorption of them. This study, using gastrodin as probe drug, aimed to explore the effects of fructose, lactose, and arabic gum on intestinal drug absorption mediated by the glucose transport pathway.
METHODS: The influence of fructose, lactose, and arabic gum on gastrodin absorption was assessed via pharmacokinetic experiments and single-pass intestinal perfusion. The expression of sodium-dependent glucose transporter 1 (SGLT1) and sodium-independent glucose transporter 2 (GLUT2) was quantified via RT‒qPCR and western blotting. Alterations in rat intestinal permeability were evaluated through H&E staining, RT‒qPCR, and immunohistochemistry.
RESULTS: Fructose reduced the area under the curve (AUC) and peak concentration (Cmax) of gastrodin by 42.7% and 63.71%, respectively (P < 0.05), and decreased the effective permeability coefficient (Peff) in the duodenum and jejunum by 58.1% and 49.2%, respectively (P < 0.05). SGLT1 and GLUT2 expression and intestinal permeability remained unchanged. Lactose enhanced the AUC and Cmax of gastrodin by 31.5% and 65.8%, respectively (P < 0.05), and increased the Peff in the duodenum and jejunum by 33.7% and 26.1%, respectively (P < 0.05). SGLT1 and GLUT2 levels did not significantly differ, intestinal permeability increased. Arabic gum had no notable effect on pharmacokinetic parameters, SGLT1 or GLUT2 expression, or intestinal permeability.
CONCLUSIONS: Fructose, lactose, and arabic gum differentially affect intestinal drug absorption through the glucose transport pathway. Fructose competitively inhibited drug absorption, while lactose may enhance absorption by increasing intestinal permeability. Arabic gum had no significant influence.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) and SGLT1 inhibitors may have additional beneficial metabolic effects on circulating metabolites beyond glucose regulation, which could contribute to a reduction in the burden of cerebral small vessel disease (CSVD). Accordingly, we used Mendelian Randomization (MR) to examine the role of circulating metabolites in mediating SGLT2 and SGLT1 inhibition in CSVD.
METHODS: Genetic instruments for SGLT1/2 inhibition were identified as genetic variants, which were both associated with the expression of encoding genes of SGLT1/2 inhibitors and glycated hemoglobin A1c (HbA1c) level. A two-sample two-step MR was used to determine the causal effects of SGLT1/2 inhibition on CSVD manifestations and the mediating effects of 1400 circulating metabolites linking SGLT1/2 inhibition with CSVD manifestations.
RESULTS: A lower risk of deep cerebral microbleeds (CMBs) and small vessel stroke (SVS) was linked to genetically predicted SGLT2 inhibition. Better white matter structure integrity was also achieved, as evidenced by decreased mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), as well as lower deep (DWMH) and periventrivular white matter hyperintensity (PWMH) volume. Inhibiting SGLT2 could also lessen the incidence of severe enlarged perivascular spaces (EPVS) located at white matter, basal ganglia (BG) and hippocampus (HIP). SGLT1 inhibition could preserve white matter integrity, shown as decreased MD of white matter and DWMH volume. The effect of SGLT2 inhibition on SVS and MD of white matter through the concentration of 4-acetamidobutanoate and the cholesterol to oleoyl-linoleoyl-glycerol (18:1 to 18:2) ratio, with a mediated proportion of 30.3% and 35.5% of the total effect, respectively.
CONCLUSIONS: SGLT2 and SGLT1 inhibition play protective roles in CSVD development. The SGLT2 inhibition could lower the risk of SVS and improve the integrity of white matter microstructure via modulating the level of 4-acetamidobutanoate and cholesterol metabolism. Further mechanistic and clinical studies research are needed to validate our findings.

The influence of SGLT-1 on perivascular preadipocytes (PVPACs) and vascular remodeling is not well understood. This study aimed to elucidate the role and mechanism of SGLT-1-mediated PVPACs bioactivity. PVPACs were cultured in vitro and applied ex vivo to the carotid arteries of mice using a lentivirus-based thermosensitive in situ gel (TISG). The groups were treated with Lv-SGLT1 (lentiviral vector, overexpression), Lv-siSGLT1 (RNA interference, knockdown), or specific signaling pathway inhibitors. Assays were conducted to assess changes in cell proliferation, apoptosis, glucose uptake, adipogenic differentiation, and vascular remodeling in the PVPACs. Protein expression was analyzed by Western blotting, immunocytochemistry, and/or immunohistochemistry. The methyl thiazolyl tetrazolium (MTT) assay and Hoechst 33342 staining indicated that SGLT-1 overexpression significantly promoted PVPACs proliferation and inhibited apoptosis in vitro. Conversely, SGLT-1 knockdown exerted the opposite effect. Oil Red O staining revealed that SGLT-1 overexpression facilitated adipogenic differentiation, while its inhibition mitigated these effects. 3H-labeled glucose uptake experiments demonstrated that SGLT-1 overexpression enhanced glucose uptake by PVPACs, whereas RNA interference-mediated SGLT-1 inhibition had no significant effect on glucose uptake. Moreover, RT-qPCR, Western blotting, and immunofluorescence analyses revealed that SGLT-1 overexpression upregulated FABP4 and VEGF-A levels and activated the Akt/mTOR/p70S6K signaling pathway, whereas SGLT-1 knockdown produced the opposite effects. In vivo studies corroborated these findings and indicated that SGLT-1 overexpression facilitated carotid artery remodeling. Our study demonstrates that SGLT-1 activation of the Akt/mTOR/p70S6K signaling pathway promotes PVPACs proliferation, adipogenesis, glucose uptake, glucolipid metabolism, and vascular remodeling.NEW & NOTEWORTHY SGLT-1 is expressed in PVPACs and can affect preadipocyte glucolipid metabolism and vascular remodeling. SGLT-1 promotes the biofunctions of PVPACs mediated by Akt/mTOR/p70S6K signaling pathway. Compared with caudal vein or intraperitoneal injection, the external application of lentivirus-based thermal gel around the carotid artery is an innovative attempt at vascular remodeling model, it may effectively avoid the transfection of lentiviral vector into the whole body of mice and the adverse effect on experimental results.

The present study aimed to investigate the effects of deoxynivalenol (DON) stimulation on inflammatory injury and the expression of the glucose transporters sodium-dependent glucose transporter 1 (SGLT1) and glucose transporter protein 2 (GLU2) in porcine small intestinal epithelial cells (IPEC-J2). Additionally, the study aimed to provide initial insights into the connection between the expression of glucose transporters and the inflammatory injury of IPEC-J2 cells. DON concentration and DON treatment time were determined using the CCK‑8 assay. Accordingly, 1.0 µg/mL DON and treatment for 24 h were chosen for subsequent experiments. Then IPEC-J2 cells were treated without DON (CON, N = 6) or with 1 μg/mL DON (DON, N = 6). Lactate dehydrogenase (LDH) content, apoptosis rate, and proinflammatory cytokines including interleukin (IL)-1β, Il-6, and tumor necrosis factor α (TNF-α) were measured. Additionally, the expression of AMP-activated protein kinase α1 (AMPK-α1), the content of glucose, intestinal alkaline phosphatase (AKP), and sodium/potassium-transporting adenosine triphosphatase (Na+/K+-ATPase) activity, and the expression of SGLT1 and GLU2 of IPEC-J2 cells were also analyzed. The results showed that DON exposure significantly increased LDH release and apoptosis rate of IPEC-J2 cells. Stimulation with DON resulted in significant cellular inflammatory damage, as evidenced by a significant increase in proinflammatory cytokines (IL-1β, IL-6, and TNF-α). Additionally, DON caused damage to the glucose absorption capacity of IPEC-J2 cells, indicated by decreased levels of glucose content, AKP activity, Na+/K+-ATPase activity, AMPK-α1 protein expression, and SGLT1 expression. Correlation analysis revealed that glucose absorption capacity was negatively correlated with cell inflammatory cytokines. Based on the findings of this study, it can be preliminarily concluded that the cell inflammatory damage caused by DON may be associated with decreased glucose absorption.
Glucose is one of the most basic nutrients necessary to sustain animal life and plays a crucial role in animal body composition and energy metabolism. Previous studies suggested a link between glucose absorption and inflammatory injury. In the present study, deoxynivalenol (DON) stimulation caused severe inflammatory injury and reduced the glucose absorption capacity of IPEC-J2 cells. Pearson’s correlation analysis revealed a negative correlation between glucose absorption capacity and cell inflammatory cytokines. Ultimately, it can be speculated that the cellular inflammatory response triggered by DON may be related to the altered expression of glucose transporters.

Pulmonary arterial hypertension (PAH) was a devastating disease characterized by artery remodeling, ultimately resulting in right heart failure. The aim of this study was to investigate the effects of canagliflozin (CANA), a sodium-glucose cotransporter 2 inhibitor (SGLT2i) with mild SGLT1 inhibitory effects, on rats with PAH, as well as its direct impact on pulmonary arterial smooth muscle cells (PASMCs). PAH rats were induced by injection of monocrotaline (MCT) (40 mg/kg), followed by four weeks of treatment with CANA (30 mg/kg/day) or saline alone. Pulmonary artery and right ventricular (RV) remodeling and dysfunction in PAH were alleviated with CANA, as assessed by echocardiography. Hemodynamic parameters and structural of pulmonary arteriole, including vascular wall thickness and wall area, were reduced by CANA. RV hypertrophy index, cardiomyocyte hypertrophy, and fibrosis were decreased with CANA treatment. PASMCs proliferation was inhibited by CANA under stimulation by platelet-derived growth factor (PDGF)-BB or hypoxia. Activation of AMP kinase (AMPK) was induced by CANA treatment in cultured PASMCs in a time- and concentration-dependent manner. These effects of CANA were attenuated when treatment with compound C, an AMPK inhibitor. Abundant expression of SGLT1 was observed in PASMCs and pulmonary arteries, while SGLT2 expression was undetectable. SGLT1 increased in response to PDGF-BB or hypoxia stimulation, while PASMCs proliferation was inhibited and beneficial effects of CANA were counteracted by knockdown of SGLT1. Our research demonstrated for the first time that CANA inhibited the proliferation of PASMCs by regulating SGLT1/AMPK signaling and thus exerted an anti-proliferative effect on MCT-induced PAH.

YG1699 is a novel inhibitor of sodium-glucose cotransporter 1 (SGLT1) and SGLT2. This double-blind, 3-way crossover trial compared YG1699 to dapagliflozin as an adjunct to insulin in people with type 1 diabetes (T1D) on insulin pump therapy. Treatment periods included four mixed meal tolerance tests (MMTTs) and insulin withdrawal tests per person. Nineteen adults with T1D were randomized to YG1699 10 mg, YG1699 25 mg, and dapagliflozin 10 mg once daily for 1 week in different orders. The primary end point was the difference in area under the curve (AUC) in plasma glucose (AUC0-120min) after an MMTT between treatment groups. Mean change in plasma glucose after an MMTT (AUC0-120min) was lower for YG1699 10 mg vs. dapagliflozin (89.51% of baseline vs. 102.13%, 90% confidence interval (CI) vs. dapagliflozin, -6% to -16%, P = 0.0003) and for YG1699 25 mg (84.83% vs. 102.13%, 90% CI vs. dapagliflozin -13% to -22%, P < 0.0001). At 120 minutes, mean glucose values on no treatment, dapagliflozin, YG1699 10 mg, and YG1699 25 mg were 149 (SE 7.6), 141 (SE 6.1), 128 (SE 6.9), and 115 (SE 7.8) mg/dL, respectively. Insulin dose requirements were lower for YG1699 10 mg and 25 mg vs. dapagliflozin for bolus insulin, and for YG1699 10 mg vs. dapagliflozin for total daily insulin. Safety profiles were similar between treatment groups. YG1699 reduced post-prandial glucose more than dapagliflozin in people with T1D on insulin pump therapy. The results were consistent with dual SGLT1/SGLT2 inhibition by YG1699.

The aim of this study was to use a combination of physiologically based pharmacokinetic (PBPK) modeling and urinary glucose excretion (UGE) modeling to predict the time profiles of pharmacokinetics (PK) and UGE for the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMP). Additionally, the study aims to explore the compensatory effect of SGLT1 in renal glucose reabsorption (RGR) when SGLT2 is inhibited. The PBPK-UGE model was developed using physicochemical and biochemical properties, renal physiological parameters, binding kinetics, glucose, and Na+ reabsorption kinetics by SGLT1/2. For area under the plasma concentration-time curve, maximum plasma concentration, and cumulative EMP excretion in urine, the predicted values fell within a range of 0.5-2.0 when compared to observed data. Additionally, the simulated UGE data also matched well with the clinical data, further validating the accuracy of the model. According to the simulations, SGLT1 and SGLT2 contributed approximately 13% and 87%, respectively, to RGR in the absence of EMP. However, in the presence of EMP at doses of 2.5 and 10 mg, the contribution of SGLT1 to RGR significantly increased to approximately 76%-82% and 89%-93%, respectively, in patients with type 2 diabetes mellitus. Furthermore, the model supported the understanding that the compensatory effect of SGLT1 is the underlying mechanism behind the moderate inhibition observed in total RGR. The PBPK-UGE model has the capability to accurately predict the PK and UGE time profiles in humans. Furthermore, it provides a comprehensive analysis of the specific contributions of SGLT1 and SGLT2 to RGR in the presence or absence of EMP.

Gastric bypass surgery has been shown to improve metabolic profiles via GLP1, which may also have cognitive benefits for Alzheimer\'s disease (AD) patients. However, the exact mechanism requires further investigation.
Roux-en-Y gastric bypass or sham surgery was performed on APP/PS1/Tau triple transgenic mice (an AD mice model) or wild type C57BL/6 mice. Morris Water Maze (MWM) test was used to evaluate the cognitive function of mice and animal tissue samples were obtained for measurements two months after the surgery. Additionally, STC-1 intestine cells were treated with siTAS1R2 and siSGLT1, and HT22 nerve cells were treated with Aβ, siGLP1R, GLP1 and siSGLT1 in vitro to explore the role of GLP1-SGLT1 related signaling pathway in cognitive function.
The MWM test showed that bypass surgery significantly improved cognitive function in AD mice as measured by navigation and spatial probe tests. Moreover, bypass surgery reversed neurodegeneration, down-regulated hyperphosphorylation of Tau protein and Aβ deposition, improved glucose metabolism, and up-regulated the expression of GLP1, SGLT1, and TAS1R2/3 in the hippocampus. Furthermore, GLP1R silencing down-regulated SGLT1 expression, whereas SGLT1 silencing increased Tau protein deposition and exacerbated dysregulated of glucose metabolism in HT22 cells. However, RYGB did not alter the level of GLP1 secretion in the brainstem (where central GLP1 is mainly produced). Additionally, GLP1 expression was upregulated by RYGB via TAS1R2/3-SGLT1 activation sequentially in the small intestine.
RYGB surgery could improve cognition function in AD mice through facilitating glucose metabolism and reducing Tau phosphorylation and Aβ deposition in the hippocampus, mediated by peripheral serum GLP1 activation of SGLT1 in the brain. Furthermore, RYGB increased GLP1 expression through sequential activation of TAS1R2/TAS1R3 and SGLT1 in the small intestine.

BACKGROUND: Ovarian cancer (OC) is the deadliest tumor in the female reproductive tract. And increased resistance to platinum-based chemotherapy represents the major obstacle in the treatment of OC currently. Robust and accurate gene expression models are crucial tools in distinguishing platinum therapy response and evaluating the prognosis of OC patients.
METHODS: In this study, 230 samples from The Cancer Genome Atlas (TCGA) OV dataset were subjected to mRNA expression profiling, single nucleotide polymorphism (SNP), and copy number variation (CNV) analysis comprehensively to screen out the differentially expressed genes (DEGs). An SVM classifier and a prognostic model were constructed using the Random Forest algorithm and LASSO Cox regression model respectively via R. The Gene Expression Omnibus (GEO) database was applied as the validation set.
RESULTS: Forty-eight differentially expressed genes (DEGs) were figured out through integrated analysis of gene expression, single nucleotide polymorphism (SNP), and copy number variation (CNV) data. A 10-gene classifier was constructed which could discriminate platinum-sensitive samples precisely with an AUC of 0.971 in the training set and of 0.926 in the GEO dataset (GSE638855). In addition, 8 optimal genes were further selected to construct the prognostic risk model whose predictions were consistent with the actual survival outcomes in the training cohort (p = 9.613e-05) and validated in GSE638855 (p = 0.04862). PNLDC1, SLC5A1, and SYNM were then identified as hub genes that were associated with both platinum response status and prognosis, which was further validated by the Fudan University Shanghai cancer center (FUSCC) cohort.
CONCLUSIONS: These findings reveal a specific risk model that could serve as effective biomarkers to identify patients\' platinum response status and predict survival outcomes for OC patients. PNLDC1, SLC5A1, and SYNM are the hub genes that may serve as potential biomarkers in OC treatment.