In this editorial,we comment on the article by Liu et al published in the recent issue of the World Journal of Diabetes(Relationship between GCKR gene rs780094 polymorphism and type 2 diabetes with albuminuria).Type 2...In this editorial,we comment on the article by Liu et al published in the recent issue of the World Journal of Diabetes(Relationship between GCKR gene rs780094 polymorphism and type 2 diabetes with albuminuria).Type 2 diabetes mellitus(T2DM)is a chronic disorder characterized by dysregulated glucose homeostasis.The persistent elevated blood glucose level in T2DM significantly increases the risk of developing severe complications,including cardiovascular disease,re-tinopathy,neuropathy,and nephropathy.T2DM arises from a complex interplay between genetic,epigenetic,and environmental factors.Global genomic studies have identified numerous genetic variations associated with an increased risk of T2DM.Specifically,variations within the glucokinase regulatory protein(GCKR)gene have been linked to heightened susceptibility to T2DM and its associated complications.The clinical trial by Liu et al further elucidates the role of the GCKR rs780094 polymorphism in T2DM and nephropathy development.Their findings demonstrate that individuals carrying the CT or TT genotype at the GCKR rs780094 locus are at a higher risk of developing T2DM with albuminuria compared to those with the CC genotype.These findings highlight the importance of genetic testing and risk assessment in T2DM to develop effective preventive strategies and personalized treatment plans.展开更多
Positive diagnosis of diabetes is currently easy, but typing diagnosis of diabetes still remains a challenge for every clinician. It is currently accepted that types of diabetes apart from T1D and T2D can expand and i...Positive diagnosis of diabetes is currently easy, but typing diagnosis of diabetes still remains a challenge for every clinician. It is currently accepted that types of diabetes apart from T1D and T2D can expand and include several forms of diabetes mellitus;From gestational diabetes, to all forms of secondary diabetes mellitus due to medications, intercurrent disease but also infections, and finally monogenic diabetes, whose diagnosis is not always easy to establish. The aim is to reveal the difficulties that clinicians may face in the process of etiological diagnosis regarding the suspicion of this type of monogenic diabetes, through the study of 2 cases, in which MODY type diabetes was suspected. Today we recognize 17 different genetic mutations that can all lead to MODY diabetes, the most common mutation of which is GCK coding for the glucokinase, the real sensor of pancreatic Beta-cell. The truly stable glycemic profile, with an A1C ranging between 7% and 7.5%, confirmed with a TIR always above 70% and a good MAGE, but also the rarity of degenerative complications and pharmacological therapeutic abstention which can last for years, these would be the most striking clinical characteristics of a GCK MODY.展开更多
Hepatic GCK is a key enzyme in glucose homeostasis and, as such, is a potential target for treatment strategies of diabetes. We investigated the effect of Persian shallot (Allium hirtifolium Boiss) hydroalchoholic ext...Hepatic GCK is a key enzyme in glucose homeostasis and, as such, is a potential target for treatment strategies of diabetes. We investigated the effect of Persian shallot (Allium hirtifolium Boiss) hydroalchoholic extract on blood glucose level, plasma insulin level, GCK activity and its gene expression. Thirty two male rats were divided into 4 groups of 8, diabetic groups received 100 and 200 mg/kg Persian shallot extract, diabetic control and normal control received 0.9% saline for 30 days. Investigations of gene expression by Real-Time PCR showed that Persian shallot had led to gently increased GCK gene expression in diabetic rats. GCK activity increased significantly in Persian shallot treated group in dose dependent manner (P < 0.05). These results indicated that Persian shallot exhibited a significant potential as a hypoglycemic agent perhaps via its ability to enhance insulin secretion, GCK gene expression and its activity.展开更多
AIM： To observe the effect of berberine on insulin secretion in rat pancreatic islets and to explore its possible molecular mechanism. METHODS： Pdmary rat islets were isolated from male Sprague-Dawley rats by collag...AIM： To observe the effect of berberine on insulin secretion in rat pancreatic islets and to explore its possible molecular mechanism. METHODS： Pdmary rat islets were isolated from male Sprague-Dawley rats by collagenase digestion and treated with different concentrations （1, 3, 10 and 30 μmol/L） of berberine or 1 μmol/L Glibenclamide （GB） for 24 h. Glucose-stimulated insulin secretion （GSIS） assay was conducted and insulin was determined by radioimmunoassay. 3-（4,5-Dimethylthiazol-2-yl）- 2,5-diphenyltetrazolium bromide （MTT） assay was performed to evaluate cytotoxicity. The mRNA level of hepatic nuclear factor 4 alpha （HAIF4α） was determined by reverse transcription polymerase chain reaction （RT-PCR）. Indirect immunofluorescence staining and Western blot analysis were employed to detect protein expression of HNF4α in the islets. Glucokinase （GK） activity was measured by spectrophotometric method. RESULTS： Berberine enhanced GSIS rather than basal insulin secretion dose-dependently in rat islets and showed no significant cytotoxicity on islet cells at the concentration of 10 μmol/L. Both mRNA and protein expressions of HNF4α were up-regulated by berberine in a dose-dependent manner, and GK activity was also increased accordingly. However, GB demonstrated no regulatory effects on HNF4α expression or GK activity. CONCLUSION： Berberine can enhance GSIS in rat islets, and probably exerts the insulinotropic effect via a pathway involving HNF4α and GK, which is distinct from sulphonylureas （SUs）.展开更多
Objective To establish a reliable platform for screening glucokinase activators （GKAs） in vitro. Methods Pancreatic glucokinase （PGK） protein expressed in a prokaryotic expression system as a histidine-tagged fusi...Objective To establish a reliable platform for screening glucokinase activators （GKAs） in vitro. Methods Pancreatic glucokinase （PGK） protein expressed in a prokaryotic expression system as a histidine-tagged fusion protein from Homo sapiens was produced. Then, response surface methodology （RSM） was used to optimize the microplate-based GKA screening platform. In the f＇trst step of optimization with Plackett-Burman design （PBD）, initial pH, reaction time and MgC12 were found to be important factors affecting the activity ratio of GKA （RO-28-1675） significantly. In the second step, a 23 full factorial central composite design （CCD） and RSM were applied to the optimal condition determination of each significant variable. A second-order polynomial was determined by a multiple regression analysis of the experimental data. Results The following optimal values for the critical factors were obtained： initial pH 0 （7.0）, reaction time-0.63 （13.7 min） and MgC12 0.11 （2.11 mmol/L） with a predicted value of the maximum activity ratio of 34.1%. Conclusion Under the optimal conditions, the practical activity ratio is 34.8%. The determination coefficient （R2） is 0.9442, ensuring adequate credibility of the model. LLAE3, extracted from Folium nelumbinis in our laboratory, has prominently activated effects on PGK.展开更多
This study aimed at acquiring knowledge on the hypoglycemic mechanisms of sodium metavanadate (SMV) showed that the liver glucokinase and muscle hexokinase activities increased rapidly after oral SMV was given, and th...This study aimed at acquiring knowledge on the hypoglycemic mechanisms of sodium metavanadate (SMV) showed that the liver glucokinase and muscle hexokinase activities increased rapidly after oral SMV was given, and that the blood glucose level was correlated closely with the activities of the two enzymes but not with the insulin level; which indicated that SMV could improve the altered glucose phosphorylation in diabetic mice independently of stimulating insulin secretion. This was probably one of the mechanisms of hypoglycemic effects of SMV.展开更多
Non insulin dependent diabetes mellitus (NIDDM) as a most common form of diabetes is a major public health problem;there is a subgroup of NIDDM patients who develop the disease at an early age and show a dominant mode...Non insulin dependent diabetes mellitus (NIDDM) as a most common form of diabetes is a major public health problem;there is a subgroup of NIDDM patients who develop the disease at an early age and show a dominant mode of inheritance. This type is nominates Maturity onset diabetes of the young (MODY). The prevalence of MODY is difficult to access, and patients with MODY genes mutations are often identified during routine screening for other purposes. MODY2 was linked to glucokinase gene (GCK) mutations, and accounted for 8% to 56% of MODY, with the highest prevalence found in the southern Europe. The aim of this study was to examine the prevalence and nature of mutations in GCK gene in Iranian paients. We have screened GCK mutations by polymerase chain reaction (PCR);single stranded conformation polymorphism (SSCP) technique in 12 Iranian families with clinical diagnosis of MODY, included 30 patients (8 males and 22 females) and their 21 family members. PCR products with abnormal mobility in denaturing gradient gel electrophoresis (DGGE) were directly sequenced. We identified 6 novel mutations in GCK gene in Iranian families (corresponding to 36.6% prevalence). Our findings and the last study on MODY1 highlight that in addition to GCK, other MODY genes such as MODY3 and MODYX may play a significant role in diabetes characterized by monogenic autosomal dominant transmission. There is an important point that the genetic recognation can be used to pre-symptomatically identify family members at risk for developing MODY.展开更多
Objective:To examine the effects of Sapium ellipticum(SE) leaf extract on the hepatic activities of glucokinase and glucose-6-phosphatase in streptozotocin-induced diabetic Wistar rats.Methods:STZ-induced diabetic Wis...Objective:To examine the effects of Sapium ellipticum(SE) leaf extract on the hepatic activities of glucokinase and glucose-6-phosphatase in streptozotocin-induced diabetic Wistar rats.Methods:STZ-induced diabetic Wistar rats(four groups,n = 8) were used in this study.SE was assessed at two different doses,400 and 800 mg/kg BW,in comparison with metformin(METF)(12 mg/kg BW) as a reference antidiabetic drug.All treatments were done orally(p.o),twice daily at 8 h interval for a period of 21 days.Glucokinase and glucose-6-phosphatase activities were respectively determined using standard protocols.Hepatic and muscle glycogen contents were estimated as well.Results:STZ caused significant decrease in glucose-6-phosphatase activity and concomitant increase in glucokinase activity.SE extract especially at 400 mg dosage significantly reversed the alterations by increasing glucokinase activity by 40.31% and inhibiting glucose-6-phosphatase activity by 37.29% compared to diabetic control animals.However,the effects were significantly lower than that of METF which enhanced glucokinase activity by94.76% and simultaneously inhibited glucose-6-phosphatase activity by 49.15%.The extract also improved hepatic glycogen level by 32.37 and 27.06% at 400 and 800 mg dosage respectively.HPLC-MS analysis of some SE fractions in dynamic MRM mode(using the optimized compound-specific parameters) revealed among other active compounds,the presence of amentoflavone,which has been associated with antidiabetic function.Conclusions:The ability of SE extract to concurrently inhibit glucose-6-phosphatase and activate glucokinase in this study suggests that it may be a treatment option for type 2 diabetes patients,and the presence of amentoflavone in the plant extract may account for its anti-diabetic potential.展开更多
BACKGROUND Diabetic kidney disease is one of the common complications of type 2 diabetes(T2D).There are no typical symptoms in the early stage,and the disease will progress to moderate and late stage when albuminuria ...BACKGROUND Diabetic kidney disease is one of the common complications of type 2 diabetes(T2D).There are no typical symptoms in the early stage,and the disease will progress to moderate and late stage when albuminuria reaches a high level.Treatment is difficult and the prognosis is poor.At present,the pathogenesis of diabetic kidney disease is still unclear,and it is believed that it is associated with genetic and environmental factors.AIM To explore the relationship between the glucokinase regulatory protein(GCKR)gene rs780094 polymorphism and T2D with albuminuria.METHODS We selected 252 patients(126 males and 126 females)with T2D admitted to our hospital from January 2020 to October 2020,and 66 healthy people(44 females and 22 males).According to the urinary albumin/creatinine ratio,the subjects were divided into group I(control),group II(T2D with normoalbuminuria),group III(T2D with microalbuminuria),and group IV(T2D with macroalbuminuria).Additionly,the subjects were divided into group M(normal group)or group N(albuminuria group)according to whether they developed albuminuria.We detected the GCKR gene rs780094 polymorphism(C/T)of all subjects,and measured the correlation between GCKR gene rs780094 polymorphism(C/T)and T2D with albuminuria.RESULTS Gene distribution and genotype distribution among groups I-IV accorded with the Hardy-Weinberg equilibrium.Genotype frequency was significantly different among the four groups (P = 0.048, χ^(2)= 7.906). T allele frequency in groups II, III, and IV was significantly higherthan that in group I. Logistic regression analysis of the risk factors for T2D with albuminuria showed that the CT +TT genotype (odds ratio = 1.710, 95% confidence interval: 1.172-2.493) was a risk factor.CONCLUSION CT + TT genotype is a risk factor for T2D with albuminuria. In the future, we can assess the risk of individualscarrying susceptible genes to delay the onset of T2D.展开更多
基金Supported by the Kuwait Foundation for the Advancement of Sciences(KFAS)and Dasman Diabetes Institute,No.RACB-2021-007.
文摘In this editorial,we comment on the article by Liu et al published in the recent issue of the World Journal of Diabetes(Relationship between GCKR gene rs780094 polymorphism and type 2 diabetes with albuminuria).Type 2 diabetes mellitus(T2DM)is a chronic disorder characterized by dysregulated glucose homeostasis.The persistent elevated blood glucose level in T2DM significantly increases the risk of developing severe complications,including cardiovascular disease,re-tinopathy,neuropathy,and nephropathy.T2DM arises from a complex interplay between genetic,epigenetic,and environmental factors.Global genomic studies have identified numerous genetic variations associated with an increased risk of T2DM.Specifically,variations within the glucokinase regulatory protein(GCKR)gene have been linked to heightened susceptibility to T2DM and its associated complications.The clinical trial by Liu et al further elucidates the role of the GCKR rs780094 polymorphism in T2DM and nephropathy development.Their findings demonstrate that individuals carrying the CT or TT genotype at the GCKR rs780094 locus are at a higher risk of developing T2DM with albuminuria compared to those with the CC genotype.These findings highlight the importance of genetic testing and risk assessment in T2DM to develop effective preventive strategies and personalized treatment plans.
文摘Positive diagnosis of diabetes is currently easy, but typing diagnosis of diabetes still remains a challenge for every clinician. It is currently accepted that types of diabetes apart from T1D and T2D can expand and include several forms of diabetes mellitus;From gestational diabetes, to all forms of secondary diabetes mellitus due to medications, intercurrent disease but also infections, and finally monogenic diabetes, whose diagnosis is not always easy to establish. The aim is to reveal the difficulties that clinicians may face in the process of etiological diagnosis regarding the suspicion of this type of monogenic diabetes, through the study of 2 cases, in which MODY type diabetes was suspected. Today we recognize 17 different genetic mutations that can all lead to MODY diabetes, the most common mutation of which is GCK coding for the glucokinase, the real sensor of pancreatic Beta-cell. The truly stable glycemic profile, with an A1C ranging between 7% and 7.5%, confirmed with a TIR always above 70% and a good MAGE, but also the rarity of degenerative complications and pharmacological therapeutic abstention which can last for years, these would be the most striking clinical characteristics of a GCK MODY.
文摘Hepatic GCK is a key enzyme in glucose homeostasis and, as such, is a potential target for treatment strategies of diabetes. We investigated the effect of Persian shallot (Allium hirtifolium Boiss) hydroalchoholic extract on blood glucose level, plasma insulin level, GCK activity and its gene expression. Thirty two male rats were divided into 4 groups of 8, diabetic groups received 100 and 200 mg/kg Persian shallot extract, diabetic control and normal control received 0.9% saline for 30 days. Investigations of gene expression by Real-Time PCR showed that Persian shallot had led to gently increased GCK gene expression in diabetic rats. GCK activity increased significantly in Persian shallot treated group in dose dependent manner (P < 0.05). These results indicated that Persian shallot exhibited a significant potential as a hypoglycemic agent perhaps via its ability to enhance insulin secretion, GCK gene expression and its activity.
基金The National Natural Science Foundation of China,No.30500685
文摘AIM： To observe the effect of berberine on insulin secretion in rat pancreatic islets and to explore its possible molecular mechanism. METHODS： Pdmary rat islets were isolated from male Sprague-Dawley rats by collagenase digestion and treated with different concentrations （1, 3, 10 and 30 μmol/L） of berberine or 1 μmol/L Glibenclamide （GB） for 24 h. Glucose-stimulated insulin secretion （GSIS） assay was conducted and insulin was determined by radioimmunoassay. 3-（4,5-Dimethylthiazol-2-yl）- 2,5-diphenyltetrazolium bromide （MTT） assay was performed to evaluate cytotoxicity. The mRNA level of hepatic nuclear factor 4 alpha （HAIF4α） was determined by reverse transcription polymerase chain reaction （RT-PCR）. Indirect immunofluorescence staining and Western blot analysis were employed to detect protein expression of HNF4α in the islets. Glucokinase （GK） activity was measured by spectrophotometric method. RESULTS： Berberine enhanced GSIS rather than basal insulin secretion dose-dependently in rat islets and showed no significant cytotoxicity on islet cells at the concentration of 10 μmol/L. Both mRNA and protein expressions of HNF4α were up-regulated by berberine in a dose-dependent manner, and GK activity was also increased accordingly. However, GB demonstrated no regulatory effects on HNF4α expression or GK activity. CONCLUSION： Berberine can enhance GSIS in rat islets, and probably exerts the insulinotropic effect via a pathway involving HNF4α and GK, which is distinct from sulphonylureas （SUs）.
基金supported by the Program for Changjiang Scholars and Innovative Research Team in University,PCSERT(No.IRT0540).
文摘Objective To establish a reliable platform for screening glucokinase activators （GKAs） in vitro. Methods Pancreatic glucokinase （PGK） protein expressed in a prokaryotic expression system as a histidine-tagged fusion protein from Homo sapiens was produced. Then, response surface methodology （RSM） was used to optimize the microplate-based GKA screening platform. In the f＇trst step of optimization with Plackett-Burman design （PBD）, initial pH, reaction time and MgC12 were found to be important factors affecting the activity ratio of GKA （RO-28-1675） significantly. In the second step, a 23 full factorial central composite design （CCD） and RSM were applied to the optimal condition determination of each significant variable. A second-order polynomial was determined by a multiple regression analysis of the experimental data. Results The following optimal values for the critical factors were obtained： initial pH 0 （7.0）, reaction time-0.63 （13.7 min） and MgC12 0.11 （2.11 mmol/L） with a predicted value of the maximum activity ratio of 34.1%. Conclusion Under the optimal conditions, the practical activity ratio is 34.8%. The determination coefficient （R2） is 0.9442, ensuring adequate credibility of the model. LLAE3, extracted from Folium nelumbinis in our laboratory, has prominently activated effects on PGK.
文摘This study aimed at acquiring knowledge on the hypoglycemic mechanisms of sodium metavanadate (SMV) showed that the liver glucokinase and muscle hexokinase activities increased rapidly after oral SMV was given, and that the blood glucose level was correlated closely with the activities of the two enzymes but not with the insulin level; which indicated that SMV could improve the altered glucose phosphorylation in diabetic mice independently of stimulating insulin secretion. This was probably one of the mechanisms of hypoglycemic effects of SMV.
文摘Non insulin dependent diabetes mellitus (NIDDM) as a most common form of diabetes is a major public health problem;there is a subgroup of NIDDM patients who develop the disease at an early age and show a dominant mode of inheritance. This type is nominates Maturity onset diabetes of the young (MODY). The prevalence of MODY is difficult to access, and patients with MODY genes mutations are often identified during routine screening for other purposes. MODY2 was linked to glucokinase gene (GCK) mutations, and accounted for 8% to 56% of MODY, with the highest prevalence found in the southern Europe. The aim of this study was to examine the prevalence and nature of mutations in GCK gene in Iranian paients. We have screened GCK mutations by polymerase chain reaction (PCR);single stranded conformation polymorphism (SSCP) technique in 12 Iranian families with clinical diagnosis of MODY, included 30 patients (8 males and 22 females) and their 21 family members. PCR products with abnormal mobility in denaturing gradient gel electrophoresis (DGGE) were directly sequenced. We identified 6 novel mutations in GCK gene in Iranian families (corresponding to 36.6% prevalence). Our findings and the last study on MODY1 highlight that in addition to GCK, other MODY genes such as MODY3 and MODYX may play a significant role in diabetes characterized by monogenic autosomal dominant transmission. There is an important point that the genetic recognation can be used to pre-symptomatically identify family members at risk for developing MODY.
文摘Objective:To examine the effects of Sapium ellipticum(SE) leaf extract on the hepatic activities of glucokinase and glucose-6-phosphatase in streptozotocin-induced diabetic Wistar rats.Methods:STZ-induced diabetic Wistar rats(four groups,n = 8) were used in this study.SE was assessed at two different doses,400 and 800 mg/kg BW,in comparison with metformin(METF)(12 mg/kg BW) as a reference antidiabetic drug.All treatments were done orally(p.o),twice daily at 8 h interval for a period of 21 days.Glucokinase and glucose-6-phosphatase activities were respectively determined using standard protocols.Hepatic and muscle glycogen contents were estimated as well.Results:STZ caused significant decrease in glucose-6-phosphatase activity and concomitant increase in glucokinase activity.SE extract especially at 400 mg dosage significantly reversed the alterations by increasing glucokinase activity by 40.31% and inhibiting glucose-6-phosphatase activity by 37.29% compared to diabetic control animals.However,the effects were significantly lower than that of METF which enhanced glucokinase activity by94.76% and simultaneously inhibited glucose-6-phosphatase activity by 49.15%.The extract also improved hepatic glycogen level by 32.37 and 27.06% at 400 and 800 mg dosage respectively.HPLC-MS analysis of some SE fractions in dynamic MRM mode(using the optimized compound-specific parameters) revealed among other active compounds,the presence of amentoflavone,which has been associated with antidiabetic function.Conclusions:The ability of SE extract to concurrently inhibit glucose-6-phosphatase and activate glucokinase in this study suggests that it may be a treatment option for type 2 diabetes patients,and the presence of amentoflavone in the plant extract may account for its anti-diabetic potential.
基金the Key R&D Project of the Ministry of Science and Technology,No.2016YFC0901200 and 2016YFC0901205.
文摘BACKGROUND Diabetic kidney disease is one of the common complications of type 2 diabetes(T2D).There are no typical symptoms in the early stage,and the disease will progress to moderate and late stage when albuminuria reaches a high level.Treatment is difficult and the prognosis is poor.At present,the pathogenesis of diabetic kidney disease is still unclear,and it is believed that it is associated with genetic and environmental factors.AIM To explore the relationship between the glucokinase regulatory protein(GCKR)gene rs780094 polymorphism and T2D with albuminuria.METHODS We selected 252 patients(126 males and 126 females)with T2D admitted to our hospital from January 2020 to October 2020,and 66 healthy people(44 females and 22 males).According to the urinary albumin/creatinine ratio,the subjects were divided into group I(control),group II(T2D with normoalbuminuria),group III(T2D with microalbuminuria),and group IV(T2D with macroalbuminuria).Additionly,the subjects were divided into group M(normal group)or group N(albuminuria group)according to whether they developed albuminuria.We detected the GCKR gene rs780094 polymorphism(C/T)of all subjects,and measured the correlation between GCKR gene rs780094 polymorphism(C/T)and T2D with albuminuria.RESULTS Gene distribution and genotype distribution among groups I-IV accorded with the Hardy-Weinberg equilibrium.Genotype frequency was significantly different among the four groups (P = 0.048, χ^(2)= 7.906). T allele frequency in groups II, III, and IV was significantly higherthan that in group I. Logistic regression analysis of the risk factors for T2D with albuminuria showed that the CT +TT genotype (odds ratio = 1.710, 95% confidence interval: 1.172-2.493) was a risk factor.CONCLUSION CT + TT genotype is a risk factor for T2D with albuminuria. In the future, we can assess the risk of individualscarrying susceptible genes to delay the onset of T2D.
