The beneficial cardiorenal outcomes of sodium-glucose cotransporter 2 inhibitors(SGLT2i)in patients with type 2 diabetes mellitus(T2DM)have been substantiated by multiple clinical trials,resulting in increased interes...The beneficial cardiorenal outcomes of sodium-glucose cotransporter 2 inhibitors(SGLT2i)in patients with type 2 diabetes mellitus(T2DM)have been substantiated by multiple clinical trials,resulting in increased interest in the multifarious pathways by which their mechanisms act.The principal effect of SGLT2i(-flozin drugs)can be appreciated in their ability to block the SGLT2 protein within the kidneys,inhibiting glucose reabsorption,and causing an associated osmotic diuresis.This ameliorates plasma glucose elevations and the negative cardiorenal sequelae associated with the latter.These include aberrant mitochondrial metabolism and oxidative stress burden,endothelial cell dysfunction,pernicious neurohormonal activation,and the development of inimical hemodynamics.Positive outcomes within these domains have been validated with SGLT2i administration.However,by modulating the sodium-glucose cotransporter in the proximal tubule(PT),SGLT2i consequently promotes sodium-phosphate cotransporter activity with phosphate retention.Phosphatemia,even at physiologic levels,poses a risk in cardiovascular disease burden,more so in patients with type 2 diabetes mellitus(T2DM).There also exists an association between phosphatemia and renal impairment,the latter hampering cardiovascular function through an array of physiologic roles,such as fluid regulation,hormonal tone,and neuromodulation.Moreover,increased phosphate flux is associated with an associated increase in fibroblast growth factor 23 levels,also detrimental to homeostatic cardiometabolic function.A contemporary commentary concerning this notion unifying cardiovascular outcome trial data with the translational biology of phosphate is scant within the literature.Given the apparent beneficial outcomes associated with SGLT2i administration notwithstanding negative effects of phosphatemia,we discuss in this review the effects of phosphate on the cardiometabolic status in patients with T2DM and cardiorenal disease,as well as the mechanisms by which SGLT2i counteract or overcome them to achieve their net effects.Content drawn to develop this conversation begins with proceedings in the basic sciences and works towards clinical trial data.展开更多
The circadian system plays an immense role in controlling physiological processes in our body.The suprachiasmatic nucleus (SCN) supervises this system,regulating and harmonising the circadian rhythms in our body.Most ...The circadian system plays an immense role in controlling physiological processes in our body.The suprachiasmatic nucleus (SCN) supervises this system,regulating and harmonising the circadian rhythms in our body.Most neurons present in the SCN are GABAergic neurons.Although GABA is considered the main inhibitory neurotransmitter of the CNS,recent studies have shown that excitatory responses were recorded in this area.These responses are enabled by an increase in intracellular chloride ions[Cl;];levels.The chloride (Cl;) levels in GABAergic neurons are controlled by two solute carrier 12 (SLC12)cation-chloride-cotransporters (CCCs):Na^(+)/K^(+)/Cl^(-)co-transporter (NKCC1) and K^(+)/Cl^(-)cotransporter (KCC2),that respectively cause an influx and efflux of Cl^(-).Recent works have found altered expression and/or activity of either of these co-transporters in SCN neurons and have been associated with circadian rhythms.In this review,we summarize and discuss the role of CCCs in circadian rhythms,and highlight these recent advances which attest to CCC’s growing potential as strong research and therapeutic targets.展开更多
Objective This study aimed to investigate the susceptibility of mice with streptozotocin（STZ）-induced diabetes mellitus（TIDM） to the uptake of pentavalent inorganic arsenic（iAs^V） and the possible molecular mech...Objective This study aimed to investigate the susceptibility of mice with streptozotocin（STZ）-induced diabetes mellitus（TIDM） to the uptake of pentavalent inorganic arsenic（iAs^V） and the possible molecular mechanism. Methods TIDM was induced in mice by STZ. TIDM and normal mice were treated with 15.0 mg/kg Na2HAsO4·12H2O by intragastric administration. Then, the concentrations of arsenic in various tissues were measured by atomic fluorescence spectrometry. The gene expression levels of Pit1 and Pit2 were quantified by real-time RT-PCR, and their protein levels were detected by Western blotting in mouse heart, kidney, and liver tissues. Results The concentrations of arsenic in STZ-induced TIDM mouse tissues were higher at 2 h after intragastric administration of Na2HAsO4·12H2O. Compared with the levels in normal mice, PIT1 and PIT2, which play a role in the uptake of iAs^V, were upregulated in the livers and hearts of TIDM mice. PIT1 but not PIT2 was higher in TIDM mouse kidneys. The upregulation of Pit1 and Pit2 expression could be reversed by insulin treatment. Conclusion The increased uptake of iAs^V in TIDM mouse tissues may be associated with increased PIT1 and/or PIT2 expression.展开更多
文摘The beneficial cardiorenal outcomes of sodium-glucose cotransporter 2 inhibitors(SGLT2i)in patients with type 2 diabetes mellitus(T2DM)have been substantiated by multiple clinical trials,resulting in increased interest in the multifarious pathways by which their mechanisms act.The principal effect of SGLT2i(-flozin drugs)can be appreciated in their ability to block the SGLT2 protein within the kidneys,inhibiting glucose reabsorption,and causing an associated osmotic diuresis.This ameliorates plasma glucose elevations and the negative cardiorenal sequelae associated with the latter.These include aberrant mitochondrial metabolism and oxidative stress burden,endothelial cell dysfunction,pernicious neurohormonal activation,and the development of inimical hemodynamics.Positive outcomes within these domains have been validated with SGLT2i administration.However,by modulating the sodium-glucose cotransporter in the proximal tubule(PT),SGLT2i consequently promotes sodium-phosphate cotransporter activity with phosphate retention.Phosphatemia,even at physiologic levels,poses a risk in cardiovascular disease burden,more so in patients with type 2 diabetes mellitus(T2DM).There also exists an association between phosphatemia and renal impairment,the latter hampering cardiovascular function through an array of physiologic roles,such as fluid regulation,hormonal tone,and neuromodulation.Moreover,increased phosphate flux is associated with an associated increase in fibroblast growth factor 23 levels,also detrimental to homeostatic cardiometabolic function.A contemporary commentary concerning this notion unifying cardiovascular outcome trial data with the translational biology of phosphate is scant within the literature.Given the apparent beneficial outcomes associated with SGLT2i administration notwithstanding negative effects of phosphatemia,we discuss in this review the effects of phosphate on the cardiometabolic status in patients with T2DM and cardiorenal disease,as well as the mechanisms by which SGLT2i counteract or overcome them to achieve their net effects.Content drawn to develop this conversation begins with proceedings in the basic sciences and works towards clinical trial data.
基金supported by a Commonwealth Ph D Scholarship(S.S.J.)NSFC grants to Y.W.(31771188,31471027)+1 种基金the University of Exeter Medical School start-up fund(J.Z.)NIH Grants R01 NS109358(J.Z.)。
文摘The circadian system plays an immense role in controlling physiological processes in our body.The suprachiasmatic nucleus (SCN) supervises this system,regulating and harmonising the circadian rhythms in our body.Most neurons present in the SCN are GABAergic neurons.Although GABA is considered the main inhibitory neurotransmitter of the CNS,recent studies have shown that excitatory responses were recorded in this area.These responses are enabled by an increase in intracellular chloride ions[Cl;];levels.The chloride (Cl;) levels in GABAergic neurons are controlled by two solute carrier 12 (SLC12)cation-chloride-cotransporters (CCCs):Na^(+)/K^(+)/Cl^(-)co-transporter (NKCC1) and K^(+)/Cl^(-)cotransporter (KCC2),that respectively cause an influx and efflux of Cl^(-).Recent works have found altered expression and/or activity of either of these co-transporters in SCN neurons and have been associated with circadian rhythms.In this review,we summarize and discuss the role of CCCs in circadian rhythms,and highlight these recent advances which attest to CCC’s growing potential as strong research and therapeutic targets.
基金supported by the National Natural Science Foundation of China[grant numbers 21277078,21407082]the Natural Science Foundation of Jiangsu Province[grant numbers BK20140426]+1 种基金the Natural Science Fund Project of Colleges in Jiangsu Province[grant numbers 16KJB330007]the National Undergraduate Innovation Experiment Project[grant numbers 201510304037Z]
文摘Objective This study aimed to investigate the susceptibility of mice with streptozotocin（STZ）-induced diabetes mellitus（TIDM） to the uptake of pentavalent inorganic arsenic（iAs^V） and the possible molecular mechanism. Methods TIDM was induced in mice by STZ. TIDM and normal mice were treated with 15.0 mg/kg Na2HAsO4·12H2O by intragastric administration. Then, the concentrations of arsenic in various tissues were measured by atomic fluorescence spectrometry. The gene expression levels of Pit1 and Pit2 were quantified by real-time RT-PCR, and their protein levels were detected by Western blotting in mouse heart, kidney, and liver tissues. Results The concentrations of arsenic in STZ-induced TIDM mouse tissues were higher at 2 h after intragastric administration of Na2HAsO4·12H2O. Compared with the levels in normal mice, PIT1 and PIT2, which play a role in the uptake of iAs^V, were upregulated in the livers and hearts of TIDM mice. PIT1 but not PIT2 was higher in TIDM mouse kidneys. The upregulation of Pit1 and Pit2 expression could be reversed by insulin treatment. Conclusion The increased uptake of iAs^V in TIDM mouse tissues may be associated with increased PIT1 and/or PIT2 expression.
