BACKGROUND Sodium-dependent glucose transporter 2 inhibitors(SGLT2i)have shown efficacy in reducing heart failure(HF)burden in a very heterogeneous groups of patients,raising doubts about some contemporary assumptions...BACKGROUND Sodium-dependent glucose transporter 2 inhibitors(SGLT2i)have shown efficacy in reducing heart failure(HF)burden in a very heterogeneous groups of patients,raising doubts about some contemporary assumptions of their mechanism of action.We previously published a prospective observational study that evaluated mechanisms of action of SGLT2i in patients with type 2 diabetes who were in HF stages A and B on dual hypoglycemic therapy.Two groups of patients were included in the study:the ones receiving SGLT2i as an add-on agent to metformin and the others on dipeptidyl peptidase-4 inhibitors as an add-on to metformin due to suboptimal glycemic control.AIM To evaluate the outcomes regarding natriuretic peptide,oxidative stress,inflammation,blood pressure,heart rate,cardiac function,and body weight.METHODS The study outcomes were examined by dividing each treatment arm into two subgroups according to baseline parameters of global longitudinal strain(GLS),N-terminal pro-brain natriuretic peptide,myeloperoxidase(MPO),high-sensitivity C-reactive protein(hsCRP),and systolic and diastolic blood pressure.To evaluate the possible predictors of observed changes in the SGLT2i arm during follow-up,a rise in stroke volume index,body mass index(BMI)decrease,and lack of heart rate increase,linear regression analysis was performed.RESULTS There was a greater reduction of MPO,hsCRP,GLS,and blood pressure in the groups with higher baseline values of mentioned parameters irrespective of the therapeutic arm after 6 months of follow-up.Significant independent predictors of heart rate decrease were a reduction in early mitral inflow velocity to early diastolic mitral annular velocity at the interventricular septal annulus ratio and BMI,while the predictor of stroke volume index increase was SGLT2i therapy itself.CONCLUSION SGLT2i affect body composition,reduce cardiac load,improve diastolic/systolic function,and attenuate the sympathetic response.Glycemic control contributes to the improvement of heart function,blood pressure control,oxidative stress,and reduction in inflammation.展开更多
We comment on an article by GrubićRotkvićet al published in the recent issue of the World Journal of Cardiology.We specifically focused on possible factors affecting the therapeutic effectiveness of sodium-dependent g...We comment on an article by GrubićRotkvićet al published in the recent issue of the World Journal of Cardiology.We specifically focused on possible factors affecting the therapeutic effectiveness of sodium-dependent glucose transporter inhibitors(SGLT2i)in patients with type 2 diabetes mellitus(T2DM)and their impact on comorbidities.SGLT2i inhibits SGLT2 in the proximal tubules of the kidneys,lowering blood glucose levels by inhibiting glucose reabsorption by the kidneys and causing excess glucose to be excreted in the urine.Previous studies have demonstrated a role of SGLT2i in cardiovascular function in patients with diabetes who take metformin but still have poor glycemic control.In addition,SGLT2i has been shown to be effective in anti-apoptosis,weight loss,and cardiovascular protection.Accordingly,it is feasible to treat patients with T2DM with cardiovascular or renal diseases using SGLT2i.展开更多
Sodium-dependent glucose transporter 2 inhibitors(SGLT2i)have been increa-singly used with proven efficacy in patients with heart failure(HF),regardless of diabetes status.GrubićRotkvićet al recently published an obse...Sodium-dependent glucose transporter 2 inhibitors(SGLT2i)have been increa-singly used with proven efficacy in patients with heart failure(HF),regardless of diabetes status.GrubićRotkvićet al recently published an observational study on SGLT2i therapy in patients with type 2 diabetes mellitus and asymptomatic HF.They found that the use of SGLT2i led to reduced cardiac load and improved cardiovascular performance,reinforcing the evolving paradigm that SGLT2i are not merely glucose-lowering agents but are integral to the broader management of cardiovascular risk in patients with type 2 diabetes mellitus.The study by GrubićRotkvićet al contributes to the growing body of literature supporting the early use of SGLT2i in patients with diabetic cardiomyopathy,offering a potential strategy to mitigate the progression of HF.Future larger studies should be con-ducted to confirm these findings,and explore the long-term cardiovascular bene-fits of SGLT2i,particularly in asymptomatic patients at risk of developing HF.展开更多
AIM： TO investigate the effects of the somatostatin analogue, octreotide, on maltose and sucrase activities and expression of glucose transporter type 2 （GLUT2） in obese rat intestinal mucosa. METHODS： We divided ...AIM： TO investigate the effects of the somatostatin analogue, octreotide, on maltose and sucrase activities and expression of glucose transporter type 2 （GLUT2） in obese rat intestinal mucosa. METHODS： We divided 49 Sprague-Dawley rats into a group of 31 high fat diet-induced obese rats and a group of 18 normal controls. The obese rats were separated into an octreotide treated group 9f 16 rats and an obese group of 15. The intervention （：jroup was injected with octreotide at 40 ±g/kg body weight every 12 h for 8 d. Rat body weight was measured weekly to calculate Lee＇s index. After euthanization, maltase and sucrase activities in the small intestine were measured by activity assays, and the fasting plasma glucose level was measured. The expression of GLUT2 in small intestinal mucosa was analyzed by immunohistochemistry, reverse transcriptase polymerase chain reaction and Western blotting assays. RESULTS： Body weight, Lee＇s index, fasting plasma glucose level, maltase activity in small intestinal mucosa, mucosa and apical GLUT2, GLUT2 mRNA and protein expression levels were all significantly higher in the obese group than in the normal control group （605.61 ± 141.00 vs 378.54 ±111.75, 337.61 ± 10.82 vs 318.73 ± 20.10, 8.60± 1.38 vs 7.33 ± 0.70, 156.01 ± 58.81 vs 50.43 ± 30.49, 390 744.2± 62 469.21 vs 170 546.50 ± 50 646.14, 26 740.18 ±3809.60 vs 354.98± 57.19, 0.26± 0.11 vs 0.07± 0.02, and 2.08 ± 0.59 vs 1.27 ± 0.38, respectively, all P 〈 0.01）. Sucrase activity did not differ between the two groups. Octreotide intervention significantly decreased the body weight and fasting plasma glucose level of obese rats （508.27 ± 94.39 vs 605.61 ± 141.00, 7.58 ± 1.51 vs 8.60±1.38, respectively, all P 〈 0.05）. The intestinal mucosa and apical GLUT2, expression of GLUT2 mRNA and protein were also significantly lower in the octreotide intervention group than in the obese group （269 975.2 ± 53 730.94 vs 390 744.2 ± 62 469.21, 3758.06 ± 364.51 vs 26 740.18 ± 3809.60, 0.08 ± 0.02 vs 0.26 ±0.11, and 1.31 ± 0.27 vs 2.08 ±0.59, respectively, all P 〈 0.01）. CONCLUSION： High fat dietinduced obesity is associated with elevated intestinal maltase activity, GLUT2 expression, and permanent apical GLUT2 in the small intestinal mucosa of rats. Octreotide can inhibit these effects.展开更多
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent cause of chronic liver disease worldwide. NAFLD is considerably more frequent in patients with type 2 diabetes mellitus (T2DM) than in the general populat...Nonalcoholic fatty liver disease (NAFLD) is the most prevalent cause of chronic liver disease worldwide. NAFLD is considerably more frequent in patients with type 2 diabetes mellitus (T2DM) than in the general population and is also more severe histologically in this group. Sodium-glucose co-transporter-2 (SGLT2) inhibitors, the newest class of antidiabetic agents, appear to represent a promising option for the management of NAFLD in patients with T2DM. In a number of studies, treatment with SGLT2 inhibitors resulted in a reduction in hepatic steatosis and in transaminase levels. However, existing studies are small, their follow-up period was short and none evaluated the effects of SGLT2 inhibitors on liver histology. Accordingly, larger studies are needed to verify these preliminary results and define the role of SGLT2 inhibitors in the treatment of NAFLD in patients with T2DM.展开更多
BACKGROUND Colorectal cancer(CRC)is a worldwide problem,which has been associated with changes in diet and lifestyle pattern.As a result of colonic fermentation of dietary fibres,short chain free fatty acids are gener...BACKGROUND Colorectal cancer(CRC)is a worldwide problem,which has been associated with changes in diet and lifestyle pattern.As a result of colonic fermentation of dietary fibres,short chain free fatty acids are generated which activate free fatty acid receptors(FFAR)2 and 3.FFAR2 and FFAR3 genes are abundantly expressed in colonic epithelium and play an important role in the metabolic homeostasis of colonic epithelial cells.Earlier studies point to the involvement of FFAR2 in colorectal carcinogenesis.AIM To understand the role of short chain FFARs in CRC.METHODS Transcriptome analysis console software was used to analyse microarray data from CRC patients and cell lines.We employed short-hairpin RNA mediated down regulation of FFAR2 and FFAR3 genes,which was validated using quantitative real time polymerase chain reaction.Assays for glucose uptake and cyclic adenosine monophosphate(cAMP)generation was done along with immunofluorescence studies to study the effects of FFAR2/FFAR3 knockdown.For measuring cell proliferation,we employed real time electrical impedancebased assay available from xCELLigence.RESULTS Microarray data analysis of CRC patient samples showed a significant down regulation of FFAR2 gene expression.This prompted us to study the FFAR2 in CRC.Since,FFAR3 shares significant structural and functional homology with FFAR2,we knocked down both these receptors in CRC cell line HCT 116.These modified cell lines exhibited higher proliferation rate and were found to have increased glucose uptake as well as increased level of glucose transporter 1.Since,FFAR2 and FFAR3 signal through G protein subunit(Gαi),knockdown of these receptors was associated with increased cAMP.Inhibition of protein kinase A(PKA)did not alter the growth and proliferation of these cells indicating a mechanism independent of cAMP/PKA pathway.CONCLUSION Our results suggest role of FFAR2/FFAR3 genes in increased proliferation of colon cancer cells via enhanced glucose uptake and exclude the role of PKA mediated cAMP signalling.Alternate pathways could be involved that would ultimately result in increased cell proliferation as a result of down regulated FFAR2/FFAR3 genes.This study paves the way to understand the mechanism of action of short chain FFARs in CRC.展开更多
BACKGROUND:The glucose transporter-1(Glut-1),a key ratelimiting factor in the transport and metabolism of glucose in cancer cells,is over-expressed in many human cancer cells and this overexpression is correlated with...BACKGROUND:The glucose transporter-1(Glut-1),a key ratelimiting factor in the transport and metabolism of glucose in cancer cells,is over-expressed in many human cancer cells and this overexpression is correlated with poor biological behavior. The increased levels of Glut-1 expression in hepatocellular carcinoma(HCC)cells functionally affect tumorigenicity.This study was undertaken to investigate effects of suppressing Glut-1 by an antisense oligodeoxynucleotide(AS-ODN)on the growth of human hepatocellular carcinoma(HepG-2)cells. METHODS:We used AS-ODN targeting against the Glut-1 gene in a HepG-2 cell line.There were four experimental groups: empty pcDNA3.1 vector(mock transfection),pcDNA3.1-anti-Glut(+),pcDNA3.1-Glut(+),and non-transfected HepG-2 cells. The Glut-1 mRNA expression was detected by RT-PCR and the Glut-1 protein expression by Western blotting after cell culture, and the glucose uptake was detected after glucose stimulation in each group. RESULTS:Compared with non-transfected HepG-2 or Glut-1 pcDNA3.1,a down-regulation of Glut-1 mRNA in HepG-2 cells transfected with anti-Glut-1 pcDNA3.1 was noted(P<0.05).Glut-1 protein in HepG-2 cells transfected with Glut-1 AS-ODN was decreased compared with non-transfected HepG-2,Glut-1 pcDNA3.1,or empty vectors. Glucose uptake by the HepG-2 cells transfected with AS-ODN was decreased at 1 hour after glucose stimulation.CONCLUSIONS:The application of Glut-1 AS-ODN can down-regulate the expression of Glut-1 at mRNA and protein,and inhibit glucose uptake partially in HepG-2 cells.The Glut-1 gene maybe a potential therapeutic target for HCC.展开更多
BACKGROUND Uncarboxylated osteocalcin(GluOC)has been reported to improve glucose metabolism,prevent type 2 diabetes,and decrease the severity of obesity in mice with type 2 diabetes.GluOC can increase glucose uptake i...BACKGROUND Uncarboxylated osteocalcin(GluOC)has been reported to improve glucose metabolism,prevent type 2 diabetes,and decrease the severity of obesity in mice with type 2 diabetes.GluOC can increase glucose uptake in a variety of cells.Glucose metabolism is the main source of energy for osteoblast proliferation and differentiation.We hypothesized that decarboxylated osteocalcin(dcOC),a kind of GluOC,can increase glucose uptake in MG63 cells(osteoblast-like osteosarcoma cells)and influence their proliferation and differentiation.AIM To investigate the effects of dcOC on glucose uptake in human osteoblast-like osteosarcoma cells and the possible signaling pathways involved.METHODS MG63 cells(human osteoblast-like osteosarcoma cells)were treated with dcOC(0,0.3,3,10,or 30 ng/mL)for 1 and 72 h,and glucose uptake was measured by flow cytometry.The effect of dcOC on cell proliferation was measured with a CCK-8 assay,and alkaline phosphatase(ALP)enzyme activity was measured.PI3K was inhibited with LY294002,and hypoxia-inducible factor 1 alpha(HIF-1α)was silenced with siRNA.Then,GPRC6A(G protein-coupled receptor family C group 6 subtype A),total Akt,phosphorylated Akt,HIF-1α,and glucose transporter 1(GLUT1)levels were measured by Western blot to elucidate the possible pathways by which dcOC modulates glucose uptake.RESULTS The glucose uptake of MG63 cells was significantly increased compared with that of the paired control cells after short-term(1 h)treatment with dcOC at different concentrations(0.3,3,and 10 ng/mL groups,P<0.01;30 ng/mL group,P<0.05).Glucose uptake of MG63 cells was significantly increased compared with that of the paired control cells after long-term(72 h)treatment with dcOC at different concentrations(0.3,3,and 10 ng/mL groups,P<0.01;30 ng/mL group,P<0.05).DcOC triggered Akt phosphorylation in a dose-dependent manner,and the most effective stimulatory concentration of dcOC for short-term(1 h)was 3 ng/mL(P<0.01).LY294002 abolished the dcOC-mediated(1 h)promotion of Akt phosphorylation and glucose uptake without affecting GLUT1 protein expression.Long-term dcOC stimulation triggered Akt phosphorylation and increased the protein levels of HIF-1α,GLUT1,and Runx2 in a dose-dependent manner.Inhibition of HIF-1αwith siRNA abolished the dcOC-mediated glucose uptake and substantially decreased GLUT1 protein expression.DcOC interven-tion promoted cell proliferation in a time-and dose-dependent manner as determined by the CCK-8 assay.Treatment with both 3 ng/mL and 10 ng/mL dcOC affected the ALP activity in MG63 cells after 72 h(P<0.01).CONCLUSION Short-and long-term dcOC treatment can increase glucose uptake and affect proliferation and ALP activity in MG63 cells.This effect may occur through the PI3K/Akt,HIF-1α,and GLUT1 signaling factors.展开更多
Heart failure(HF)is a major global health challenge,particularly among indi-viduals with type 2 diabetes mellitus(T2DM),who are at significantly higher risk of developing HF.Diabetic cardiomyopathy,a unique form of he...Heart failure(HF)is a major global health challenge,particularly among indi-viduals with type 2 diabetes mellitus(T2DM),who are at significantly higher risk of developing HF.Diabetic cardiomyopathy,a unique form of heart disease,often progresses silently until advanced stages.Recent research has focused on sodium-dependent glucose transporter 2 inhibitors(SGLT2i),originally developed for hyperglycemia,which have shown potential in reducing cardiovascular risks,including HF hospitalizations,irrespective of diabetic status.In this editorial we comment on the article by GrubićRotkvićet al published in the recent issue of the World Journal of Cardiology.The investigators examined the effects of SGLT2i on myocardial function in T2DM patients with asymptomatic HF,finding significant improvements in stroke volume index and reductions in systemic vascular resis-tance,suggesting enhanced cardiac output.Additionally,SGLT2i demonstrated anti-inflammatory and antioxidant effects,as well as blood pressure reduction,though the study’s limitations—such as small sample size and observational design—necessitate larger randomized trials to confirm these findings.The study underscores the potential of early intervention with SGLT2i in preventing HF progression in T2DM patients.展开更多
文摘BACKGROUND Sodium-dependent glucose transporter 2 inhibitors(SGLT2i)have shown efficacy in reducing heart failure(HF)burden in a very heterogeneous groups of patients,raising doubts about some contemporary assumptions of their mechanism of action.We previously published a prospective observational study that evaluated mechanisms of action of SGLT2i in patients with type 2 diabetes who were in HF stages A and B on dual hypoglycemic therapy.Two groups of patients were included in the study:the ones receiving SGLT2i as an add-on agent to metformin and the others on dipeptidyl peptidase-4 inhibitors as an add-on to metformin due to suboptimal glycemic control.AIM To evaluate the outcomes regarding natriuretic peptide,oxidative stress,inflammation,blood pressure,heart rate,cardiac function,and body weight.METHODS The study outcomes were examined by dividing each treatment arm into two subgroups according to baseline parameters of global longitudinal strain(GLS),N-terminal pro-brain natriuretic peptide,myeloperoxidase(MPO),high-sensitivity C-reactive protein(hsCRP),and systolic and diastolic blood pressure.To evaluate the possible predictors of observed changes in the SGLT2i arm during follow-up,a rise in stroke volume index,body mass index(BMI)decrease,and lack of heart rate increase,linear regression analysis was performed.RESULTS There was a greater reduction of MPO,hsCRP,GLS,and blood pressure in the groups with higher baseline values of mentioned parameters irrespective of the therapeutic arm after 6 months of follow-up.Significant independent predictors of heart rate decrease were a reduction in early mitral inflow velocity to early diastolic mitral annular velocity at the interventricular septal annulus ratio and BMI,while the predictor of stroke volume index increase was SGLT2i therapy itself.CONCLUSION SGLT2i affect body composition,reduce cardiac load,improve diastolic/systolic function,and attenuate the sympathetic response.Glycemic control contributes to the improvement of heart function,blood pressure control,oxidative stress,and reduction in inflammation.
文摘We comment on an article by GrubićRotkvićet al published in the recent issue of the World Journal of Cardiology.We specifically focused on possible factors affecting the therapeutic effectiveness of sodium-dependent glucose transporter inhibitors(SGLT2i)in patients with type 2 diabetes mellitus(T2DM)and their impact on comorbidities.SGLT2i inhibits SGLT2 in the proximal tubules of the kidneys,lowering blood glucose levels by inhibiting glucose reabsorption by the kidneys and causing excess glucose to be excreted in the urine.Previous studies have demonstrated a role of SGLT2i in cardiovascular function in patients with diabetes who take metformin but still have poor glycemic control.In addition,SGLT2i has been shown to be effective in anti-apoptosis,weight loss,and cardiovascular protection.Accordingly,it is feasible to treat patients with T2DM with cardiovascular or renal diseases using SGLT2i.
文摘Sodium-dependent glucose transporter 2 inhibitors(SGLT2i)have been increa-singly used with proven efficacy in patients with heart failure(HF),regardless of diabetes status.GrubićRotkvićet al recently published an observational study on SGLT2i therapy in patients with type 2 diabetes mellitus and asymptomatic HF.They found that the use of SGLT2i led to reduced cardiac load and improved cardiovascular performance,reinforcing the evolving paradigm that SGLT2i are not merely glucose-lowering agents but are integral to the broader management of cardiovascular risk in patients with type 2 diabetes mellitus.The study by GrubićRotkvićet al contributes to the growing body of literature supporting the early use of SGLT2i in patients with diabetic cardiomyopathy,offering a potential strategy to mitigate the progression of HF.Future larger studies should be con-ducted to confirm these findings,and explore the long-term cardiovascular bene-fits of SGLT2i,particularly in asymptomatic patients at risk of developing HF.
基金Supported by Grants from the National Natural Sciences Foundation of China,No.30870919Sichuan Provincial Department of Science and Technology,No.2010SZ0176
文摘AIM： TO investigate the effects of the somatostatin analogue, octreotide, on maltose and sucrase activities and expression of glucose transporter type 2 （GLUT2） in obese rat intestinal mucosa. METHODS： We divided 49 Sprague-Dawley rats into a group of 31 high fat diet-induced obese rats and a group of 18 normal controls. The obese rats were separated into an octreotide treated group 9f 16 rats and an obese group of 15. The intervention （：jroup was injected with octreotide at 40 ±g/kg body weight every 12 h for 8 d. Rat body weight was measured weekly to calculate Lee＇s index. After euthanization, maltase and sucrase activities in the small intestine were measured by activity assays, and the fasting plasma glucose level was measured. The expression of GLUT2 in small intestinal mucosa was analyzed by immunohistochemistry, reverse transcriptase polymerase chain reaction and Western blotting assays. RESULTS： Body weight, Lee＇s index, fasting plasma glucose level, maltase activity in small intestinal mucosa, mucosa and apical GLUT2, GLUT2 mRNA and protein expression levels were all significantly higher in the obese group than in the normal control group （605.61 ± 141.00 vs 378.54 ±111.75, 337.61 ± 10.82 vs 318.73 ± 20.10, 8.60± 1.38 vs 7.33 ± 0.70, 156.01 ± 58.81 vs 50.43 ± 30.49, 390 744.2± 62 469.21 vs 170 546.50 ± 50 646.14, 26 740.18 ±3809.60 vs 354.98± 57.19, 0.26± 0.11 vs 0.07± 0.02, and 2.08 ± 0.59 vs 1.27 ± 0.38, respectively, all P 〈 0.01）. Sucrase activity did not differ between the two groups. Octreotide intervention significantly decreased the body weight and fasting plasma glucose level of obese rats （508.27 ± 94.39 vs 605.61 ± 141.00, 7.58 ± 1.51 vs 8.60±1.38, respectively, all P 〈 0.05）. The intestinal mucosa and apical GLUT2, expression of GLUT2 mRNA and protein were also significantly lower in the octreotide intervention group than in the obese group （269 975.2 ± 53 730.94 vs 390 744.2 ± 62 469.21, 3758.06 ± 364.51 vs 26 740.18 ± 3809.60, 0.08 ± 0.02 vs 0.26 ±0.11, and 1.31 ± 0.27 vs 2.08 ±0.59, respectively, all P 〈 0.01）. CONCLUSION： High fat dietinduced obesity is associated with elevated intestinal maltase activity, GLUT2 expression, and permanent apical GLUT2 in the small intestinal mucosa of rats. Octreotide can inhibit these effects.
文摘Nonalcoholic fatty liver disease (NAFLD) is the most prevalent cause of chronic liver disease worldwide. NAFLD is considerably more frequent in patients with type 2 diabetes mellitus (T2DM) than in the general population and is also more severe histologically in this group. Sodium-glucose co-transporter-2 (SGLT2) inhibitors, the newest class of antidiabetic agents, appear to represent a promising option for the management of NAFLD in patients with T2DM. In a number of studies, treatment with SGLT2 inhibitors resulted in a reduction in hepatic steatosis and in transaminase levels. However, existing studies are small, their follow-up period was short and none evaluated the effects of SGLT2 inhibitors on liver histology. Accordingly, larger studies are needed to verify these preliminary results and define the role of SGLT2 inhibitors in the treatment of NAFLD in patients with T2DM.
文摘BACKGROUND Colorectal cancer(CRC)is a worldwide problem,which has been associated with changes in diet and lifestyle pattern.As a result of colonic fermentation of dietary fibres,short chain free fatty acids are generated which activate free fatty acid receptors(FFAR)2 and 3.FFAR2 and FFAR3 genes are abundantly expressed in colonic epithelium and play an important role in the metabolic homeostasis of colonic epithelial cells.Earlier studies point to the involvement of FFAR2 in colorectal carcinogenesis.AIM To understand the role of short chain FFARs in CRC.METHODS Transcriptome analysis console software was used to analyse microarray data from CRC patients and cell lines.We employed short-hairpin RNA mediated down regulation of FFAR2 and FFAR3 genes,which was validated using quantitative real time polymerase chain reaction.Assays for glucose uptake and cyclic adenosine monophosphate(cAMP)generation was done along with immunofluorescence studies to study the effects of FFAR2/FFAR3 knockdown.For measuring cell proliferation,we employed real time electrical impedancebased assay available from xCELLigence.RESULTS Microarray data analysis of CRC patient samples showed a significant down regulation of FFAR2 gene expression.This prompted us to study the FFAR2 in CRC.Since,FFAR3 shares significant structural and functional homology with FFAR2,we knocked down both these receptors in CRC cell line HCT 116.These modified cell lines exhibited higher proliferation rate and were found to have increased glucose uptake as well as increased level of glucose transporter 1.Since,FFAR2 and FFAR3 signal through G protein subunit(Gαi),knockdown of these receptors was associated with increased cAMP.Inhibition of protein kinase A(PKA)did not alter the growth and proliferation of these cells indicating a mechanism independent of cAMP/PKA pathway.CONCLUSION Our results suggest role of FFAR2/FFAR3 genes in increased proliferation of colon cancer cells via enhanced glucose uptake and exclude the role of PKA mediated cAMP signalling.Alternate pathways could be involved that would ultimately result in increased cell proliferation as a result of down regulated FFAR2/FFAR3 genes.This study paves the way to understand the mechanism of action of short chain FFARs in CRC.
文摘BACKGROUND:The glucose transporter-1(Glut-1),a key ratelimiting factor in the transport and metabolism of glucose in cancer cells,is over-expressed in many human cancer cells and this overexpression is correlated with poor biological behavior. The increased levels of Glut-1 expression in hepatocellular carcinoma(HCC)cells functionally affect tumorigenicity.This study was undertaken to investigate effects of suppressing Glut-1 by an antisense oligodeoxynucleotide(AS-ODN)on the growth of human hepatocellular carcinoma(HepG-2)cells. METHODS:We used AS-ODN targeting against the Glut-1 gene in a HepG-2 cell line.There were four experimental groups: empty pcDNA3.1 vector(mock transfection),pcDNA3.1-anti-Glut(+),pcDNA3.1-Glut(+),and non-transfected HepG-2 cells. The Glut-1 mRNA expression was detected by RT-PCR and the Glut-1 protein expression by Western blotting after cell culture, and the glucose uptake was detected after glucose stimulation in each group. RESULTS:Compared with non-transfected HepG-2 or Glut-1 pcDNA3.1,a down-regulation of Glut-1 mRNA in HepG-2 cells transfected with anti-Glut-1 pcDNA3.1 was noted(P<0.05).Glut-1 protein in HepG-2 cells transfected with Glut-1 AS-ODN was decreased compared with non-transfected HepG-2,Glut-1 pcDNA3.1,or empty vectors. Glucose uptake by the HepG-2 cells transfected with AS-ODN was decreased at 1 hour after glucose stimulation.CONCLUSIONS:The application of Glut-1 AS-ODN can down-regulate the expression of Glut-1 at mRNA and protein,and inhibit glucose uptake partially in HepG-2 cells.The Glut-1 gene maybe a potential therapeutic target for HCC.
基金Supported by Provincial Science and Technology Department Natural Fund Guidance Project,No.2019-ZD-0774National Natural Science Foundation of China,No.81470998+1 种基金Liaoning Ministry of Education,No.LQNK201715and Liaoning Provincial Doctor Start up Fund,No.20180540008.
文摘BACKGROUND Uncarboxylated osteocalcin(GluOC)has been reported to improve glucose metabolism,prevent type 2 diabetes,and decrease the severity of obesity in mice with type 2 diabetes.GluOC can increase glucose uptake in a variety of cells.Glucose metabolism is the main source of energy for osteoblast proliferation and differentiation.We hypothesized that decarboxylated osteocalcin(dcOC),a kind of GluOC,can increase glucose uptake in MG63 cells(osteoblast-like osteosarcoma cells)and influence their proliferation and differentiation.AIM To investigate the effects of dcOC on glucose uptake in human osteoblast-like osteosarcoma cells and the possible signaling pathways involved.METHODS MG63 cells(human osteoblast-like osteosarcoma cells)were treated with dcOC(0,0.3,3,10,or 30 ng/mL)for 1 and 72 h,and glucose uptake was measured by flow cytometry.The effect of dcOC on cell proliferation was measured with a CCK-8 assay,and alkaline phosphatase(ALP)enzyme activity was measured.PI3K was inhibited with LY294002,and hypoxia-inducible factor 1 alpha(HIF-1α)was silenced with siRNA.Then,GPRC6A(G protein-coupled receptor family C group 6 subtype A),total Akt,phosphorylated Akt,HIF-1α,and glucose transporter 1(GLUT1)levels were measured by Western blot to elucidate the possible pathways by which dcOC modulates glucose uptake.RESULTS The glucose uptake of MG63 cells was significantly increased compared with that of the paired control cells after short-term(1 h)treatment with dcOC at different concentrations(0.3,3,and 10 ng/mL groups,P<0.01;30 ng/mL group,P<0.05).Glucose uptake of MG63 cells was significantly increased compared with that of the paired control cells after long-term(72 h)treatment with dcOC at different concentrations(0.3,3,and 10 ng/mL groups,P<0.01;30 ng/mL group,P<0.05).DcOC triggered Akt phosphorylation in a dose-dependent manner,and the most effective stimulatory concentration of dcOC for short-term(1 h)was 3 ng/mL(P<0.01).LY294002 abolished the dcOC-mediated(1 h)promotion of Akt phosphorylation and glucose uptake without affecting GLUT1 protein expression.Long-term dcOC stimulation triggered Akt phosphorylation and increased the protein levels of HIF-1α,GLUT1,and Runx2 in a dose-dependent manner.Inhibition of HIF-1αwith siRNA abolished the dcOC-mediated glucose uptake and substantially decreased GLUT1 protein expression.DcOC interven-tion promoted cell proliferation in a time-and dose-dependent manner as determined by the CCK-8 assay.Treatment with both 3 ng/mL and 10 ng/mL dcOC affected the ALP activity in MG63 cells after 72 h(P<0.01).CONCLUSION Short-and long-term dcOC treatment can increase glucose uptake and affect proliferation and ALP activity in MG63 cells.This effect may occur through the PI3K/Akt,HIF-1α,and GLUT1 signaling factors.
文摘Heart failure(HF)is a major global health challenge,particularly among indi-viduals with type 2 diabetes mellitus(T2DM),who are at significantly higher risk of developing HF.Diabetic cardiomyopathy,a unique form of heart disease,often progresses silently until advanced stages.Recent research has focused on sodium-dependent glucose transporter 2 inhibitors(SGLT2i),originally developed for hyperglycemia,which have shown potential in reducing cardiovascular risks,including HF hospitalizations,irrespective of diabetic status.In this editorial we comment on the article by GrubićRotkvićet al published in the recent issue of the World Journal of Cardiology.The investigators examined the effects of SGLT2i on myocardial function in T2DM patients with asymptomatic HF,finding significant improvements in stroke volume index and reductions in systemic vascular resis-tance,suggesting enhanced cardiac output.Additionally,SGLT2i demonstrated anti-inflammatory and antioxidant effects,as well as blood pressure reduction,though the study’s limitations—such as small sample size and observational design—necessitate larger randomized trials to confirm these findings.The study underscores the potential of early intervention with SGLT2i in preventing HF progression in T2DM patients.
