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1.
China Pharmacy ; (12): 2695-2700, 2023.
Artigo em Chinês | WPRIM | ID: wpr-998551

RESUMO

OBJECTIVE To analyze the patents of new target oral drugs for type 2 diabetes mellitus (T2DM), and to provide references for the research and development direction and patent layout of new domestic diabetes drugs. METHODS Based on global patent data in the HimmPat database, from multiple perspectives such as the number of patent applications and authorization, development trend, regional distribution and main applicants, statistics and analysis were performed for the patents related to 3 types of new target oral drugs for T2DM, such as glucokinase activator (GKA), protein tyrosine phosphatase 1B inhibitor (PTP-1B-IN), and 11β-hydroxysteroid dehydrogenase 1 inhibitor (11β-HSD1-IN). RESULTS & CONCLUSIONS A total of 1 649 patents of GKA, 709 patents of PTP-1B-IN, 592 patents of 11β-HSD1-IN were obtained, the main applicants were well-known pharmaceutical companies, which possessed the core patents of pharmaceutical compounds. The research on GKA drugs was more mature, with a larger number of patent applications and a more comprehensive enterprise layout. Domestic enterprises, universities and research institutions had advantages in the field of PTP-1B-IN. Domestic enterprises and research institutions can leverage the advantages of traditional Chinese medicine and resources to enhance their research capabilities and improve technological competitiveness through core technology exploration, the exploration of process route, patent layout, industry- university-research cooperation and the establishment of patent pool.

2.
Chinese Journal of Endocrinology and Metabolism ; (12): 256-260, 2023.
Artigo em Chinês | WPRIM | ID: wpr-994318

RESUMO

We report a case of a female teenage with monogenic diabetes mellitus caused by glucokinase regulator (GCKR) gene mutation who presented with diabetic ketosis and misdiagnosed as type 1 diabetes. The patient was treated with insulin for 3 years since diagnosis. The islet function was well preserved, but polycystic ovary syndrome was developed. Whole-exome gene sequencing revealed a GCKR gene c. 69delG heterozygous mutation. After molecular diagnosis, the insulin dosage was gradually reduced to full cessation, and only metformin sustained-release tablets were taken to control blood glucose. It is necessary to regular evaluate islet function of patient with type 1 diabetes, and genetic test is of significance for accurate diagnosis and treatment.

3.
Chinese Journal of Endocrinology and Metabolism ; (12): 118-124, 2023.
Artigo em Chinês | WPRIM | ID: wpr-994305

RESUMO

Objective:To explore the clinical and molecular genetic characteristics of patients with maturity-onset diabetes of the young type 2(MODY2).Methods:Clinical data and laboratory results were collected from five MODY2 patients and their family members diagnosed in the Department of Endocrinology, Genetics, and Metabolism of Xi ′an Children′s Hospital in the recent two years. Whole exome sequencing was carried out on every proband to identify potential variants, then the suspected variants were verified with Sanger sequencing in family numbers.Results:Among the 5 probands, except for proband 4 who presented with polydipsia and polyuria, hyperglycemia in the rest of the children was accidentally identified. Urine routine, urinary protein, and blood lipid of the five probands were all normal, and HbA 1C was between 5.96% and 8.15%. Moreover, an important discovery in this study was that proband 5 had insulin resistance(IRS), which was different from previous studies. It was confirmed by genetic analysis that a glucokinase(GCK) gene variant existed in every MODY2 pedigree. There were four GCK variants in this study, including c. 146C>T(p.T49I), c. 1237T>G(p.Y413D), c. 683C>T(p.T228M) and c. 952G>T(p.G318W), among which the C. 1237T>G(P.y413d) and C. 952G>T(P.G318W) had not been reported till now. All probands received lifestyle intervention, and the blood glucose control was relatively stable. Conclusion:There is MODY2 patient complicated with IRS. MODY2 patients can be controlled well by lifestyle interventions. In addition, we discovered two novel variants of GCK, which extend the mutation spectrum of this gene.

4.
Chinese Journal of Clinical Pharmacology and Therapeutics ; (12): 1177-1183, 2023.
Artigo em Chinês | WPRIM | ID: wpr-1014599

RESUMO

Dorzagliatin is a new dual action allosteric systemic glucokinase agonist (GKA), which can simultaneously activate the glucokinase (GK) in the pancreas and liver, promote insulin secretion and liver glycogen conversion in patients with type 2 diabetes, and improve pancreatic islets β - Cell function and insulin resistance simultaneously stimulate intestinal GK to regulate the secretion of Glucagon-like peptide-1 to play multiple hypoglycemic effects. As the first marketed GKA drug, it provides a new therapeutic approach for patients with type 2 diabetes. This article reviews the mechanism of action, pharmacokinetics, Drug interaction, clinical research and safety of Dorzagliatin.

5.
China Pharmacy ; (12): 102-106, 2023.
Artigo em Chinês | WPRIM | ID: wpr-953727

RESUMO

OBJECTIVE To systematically evaluate the efficacy and safety of glucokinase activators in the treatment of type 2 diabetes mellitus. METHODS PubMed, Cochrane Library, Web of Science, Embase and CNKI databases were searched from the inception to March 2022. Randomized controlled trials about glucokinase activators versus placebo (or other oral hypoglycemic agents) in the treatment of type 2 diabetes were included, data were extracted and meta-analysis was analyzed using RevMan 5.4 software. RESULTS A total of 9 studies with 215 0 patients were included. In terms of hypoglycemic effect, compared with control group, glucokinase activators significantly reduced glycosylated hemoglobin (HbA1c) [MD=-0.40, 95%CI(-0.53, -0.26), P<0.000 01], fasting blood glucose[MD=-0.53, 95%CI(-0.85, -0.20), P=0.001] and 2 h postprandial blood glucose [MD=-2.28, 95%CI(-2.68, -1.88), P<0.000 01] in diabetic patients. In terms of safety, the incidence of hypoglycemia caused by glucokinase activators was higher than control group on the whole [RR=1.55, 95%CI(1.20,2.01), P= 0.000 8]. According to the subgroup analysis of organs activated by glucokinase activator, the incidence of hypoglycemia in the pancreas-liver dual activator group [RR=1.44, 95%CI(1.11,1.89), P=0.007] and liver-selective activator group [RR=2.26, 95%CI(1.02,5.03), P=0.05] was higher than that in the control group, the difference was statistically significant. CONCLUSIONS Glucokinase activators can effectively reduce HbA1c, fasting blood glucose and 2 h postprandial blood glucose in patients with type 2 diabetes, but the risk of hypoglycemia remains to be addressed.

6.
Chinese Journal of Endocrinology and Metabolism ; (12): 645-650, 2022.
Artigo em Chinês | WPRIM | ID: wpr-957601

RESUMO

Objective:To summarize the clinical manifestations and molecular genetic characteristics of 5 families with maturity-onset diabetes mellitus of the young 2 (MODY2) caused by glucokinase (GCK) gene mutations.Methods:Clinical data and biochemical results of probands were collected. Peripheral blood samples of probands and first-degree family members were collected and whole exome gene was detected using second-generation sequencing. After comparing against the database, the suspected pathogenic sites were selected for Sanger sequencing verification.Results:All the 5 probands presented with mild fasting hyperglycemia, HbA 1C<7.5%, and no symptoms of thirst, polydipsia or polyuria. There were 6 mutants in 5 families, including M1: c.555delT (P.leu186CysFS Ter19) and M3: c. 263T>A (p.Met88Lys) which haven′t been reported before. During the follow-up, all probands received life-style intervention, except 2 pregnant women who should consider insulin treatment if necessary according to fetal genotypes. Conclusion:Among patients who meet the diagnostic criteria for MODY, MODY2 screening should be performed for children or pregnant women with mild hyperglycemia and family history. GCK gene detection is the gold standard for diagnosis, and accurate diagnosis will be conducive to the selection of appropriate treatment.

7.
Rev. chil. endocrinol. diabetes ; 14(3): 121-126, 2021. tab, ilus
Artigo em Espanhol | LILACS | ID: biblio-1293387

RESUMO

La diabetes MODY 2 es un tipo de diabetes monogénica producida por una mutación en la enzima glucoquinasa, generando un fenotipo hiperglicémico. Para posibles fines terapéuticos o de diagnóstico, se debe conocer esta proteína, una enzima monomérica de la familia de las hexoquinasas, encargadas de convertir glucosa en glucosa-6-fosfato, el primer paso de la glicolisis. La glucoquinasa se caracteriza por sus propiedades cinéticas únicas: tiene una afinidad mucho menor por el sustrato que las demás hexoquinasas y no es inhibida por su producto. Se encuentra principalmente en páncreas e hígado (ßGK y LGK, respectivamente), donde como sensor regula los distintos estados metabólicos de estos tejidos, y controla la glicemia a nivel sistémico. Las formas ßGK y LGK se diferencian a nivel transcripcional, pues el gen posee dos promotores distintos, específicos para cada tejido. A nivel hormonal, la actividad de esta enzima es regulada selectivamente de manera tejido-específica por glucosa, insulina y otras proteínas reguladoras. La isoforma hepática puede ser secuestrada hacia el núcleo por la proteína reguladora de glucoquinasa (GKRP, por su sigla en inglés). La principal característica de la enzima glucoquinasa es su inusual regulación alostérica, propiedad que le permite adoptar dos conformaciones principales, una cerrada (activa) y otra súper-abierta (inactiva). Se han desarrollado distintas drogas activadoras de glucoquinasa, las cuales se unen al sitio alostérico de la enzima y estabilizan a la proteína en su estado cerrado. En esta revisión se describen las características estructurales y propiedades regulatorias que posee la enzima glucoquinasa, relacionándolas con su rol en el desarrollo de la diabetes MODY 2. También se profundiza en las implicancias moleculares de algunas mutaciones descritas que originan MODY 2, y se abordan los efectos de moléculas activadoras de glucoquinasa.


Diabetes MODY 2 or GCK-MODY is a type of monogenic diabetes produced by a mutation in the glucokinase enzyme, generating a hyperglycemic phenotype. This protein, a monomeric enzyme of the hexokinase family, is responsible for converting glucose into glucose-6-phosphate, the first step of glycolysis. Glucokinase is characterized by its unique kinetic properties: it has a much lower affinity for its substrate than other hexokinases and is not inhibited by its product. It is found mainly in pancreas (ßGK) and liver (LGK), where it acts as a sensor regulating the different metabolic states of these tissues, and ultimately, controlling systemic glycemia. The two forms ßGK and LGK differ at a transcriptional level, because the gene presents two different tissue-specific promoters. The activity of glucokinase in liver and pancreas is regulated by glucose, insulin and other regulatory proteins. The liver isoform can be sequestered to the nucleus by the glucokinase regulatory protein (GKRP). The main characteristic of the enzyme is its unusual allosteric regulation, a property that allows the protein to adopt a closed (active) conformation, and a super-open (inactive) conformation. Different glucokinase activating drugs have been developed, which bind to the allosteric site of the enzyme and stabilize glucokinase in its closed state. This review describes the structural and regulatory properties of the glucokinase enzyme, and its role in the development of MODY 2 diabetes. The molecular implications of some mutations that originate MODY 2 are also described, and the effects of glucokinase activating molecules are addressed.


Assuntos
Humanos , Diabetes Mellitus Tipo 2/genética , Glucoquinase/genética , Hiperglicemia/genética , Mutação
8.
Annals of Pediatric Endocrinology & Metabolism ; : 262-266, 2019.
Artigo | WPRIM | ID: wpr-785402

RESUMO

Maturity Onset Diabetes of the Young (MODY) includes a clinically and genetically heterogeneous group of diabetes subtypes with MODY-2 being the second most prevalent form. We report 2 cases of MODY-2 identified during the investigation of asymptomatic hyperglycemia. A 12-year-old girl with a familiar history of diabetes (mother, maternal aunt, and maternal grandfather) was referred due to hypercholesterolemia, abnormal fasting glucose (114 mg/dL), and increased levels of glycated haemoglobin (HbA(1c)) (6%) presenting with negative β-cell antibodies. A glucokinase (GCK) heterozygous missense mutation c.364C>T (p.Leu122Phe) in exon 4 was identified in the index patient and in the 3 family members. An obese 9-year-old boy was investigated for elevated fasting glycemic levels (99–126 mg/dL), HbA(1c) rise (6.6%–7.6%), and negative β-cell antibodies. The patient's father, paternal aunt, and paternal grandfather had a history of diabetes during their childhood. A GCK heterozygous missense mutation c.698G>A (p.Cys233Tyr) in exon 7 was identified in the index patient. This variant was only described in another family strongly affected by both MODY and classic autoimmune mediated diabetes, contrary to our case. MODY-2 should be suspected in the presence of early onset of persistent mild fasting hyperglycemia and negative β-cell antibodies associated with a positive family history of diabetes. These cases illustrate the challenging aspects of MODY diagnosis due to possible phenotypic overlap with other types of diabetes. The diagnosis requires a high level of suspicion and GCK genetic screening should be performed in the presence of compatible features. An early diagnosis allows for appropriate management, genetic counselling, and the identification of affected family members.


Assuntos
Criança , Feminino , Humanos , Masculino , Anticorpos , Diabetes Mellitus Tipo 2 , Diagnóstico , Diagnóstico Precoce , Éxons , Jejum , Pai , Testes Genéticos , Glucoquinase , Glucose , Avós , Hipercolesterolemia , Hiperglicemia , Mutação de Sentido Incorreto
9.
Chinese Pharmacological Bulletin ; (12): 187-191, 2019.
Artigo em Chinês | WPRIM | ID: wpr-857280

RESUMO

Aim: To observe the effect of uc.48 + small interference RNA (siRNA) on liver glycogen abnormality in type 2 diabetic rats and its possible mechanism. Methods: The diabetes model was established by feeding high glucose and high fat diet combined with streptozotocin(STZ). After the success of the model, the long noncoding RNA uc. 48 + siRNA was injected into the rat body via tail vein. The changes of blood glucose and the content of liver glycogen were detected dynamically, and the liver glycogen was detected one week after injection. Glucokinase (GK) mRNA and protein expression in liver tissues of each group were detected by qPCR and Western blot. Results: It was observed that postprandial blood glucose and fasting blood glucose decreased in diabetic model rats after treated with uc. 48 + siRNA compared with those in model rats. The level of liver glycogen in diabetic model rats was significantly lower than that in control group. The synthesis of liver glycogen in diabetic model rats with uc. 48 + siRNA treatment increased compared with that in diabetic model group. The expressions of GK mRNA and protein in the diabetic model group were significantly lower than those in control group. The expression of GK mRNA and protein markedly increased after uc. 48 + siRNA treatment. Conclusions: uc. 48 + siRNA reduces blood glucose and increases glycogen synthesis in type 2 diabetic rats, and its mechanism may involve in increasing GK expression and Aktl phosphorylation.

10.
Journal of Medical Postgraduates ; (12): 1031-1036, 2019.
Artigo em Chinês | WPRIM | ID: wpr-818135

RESUMO

Objective The imbalance of glucagon secretion plays an important role in the development of diabetes. The newly discovered ACE2/Ang(1-7)/Mas pathway is an vital branch of the RAS system and has regulatory effects on islet function, but its effect on glucagon secretion is still unknown. The article aimed to investigate the effect and possible mechanisms of AVE0991, a Mas receptor agonist on glucagon secretion of diabetic db/db mice. Methods A tolal of 30 db/db mice were randomized to AVE group and model group (n=15), and their age-matched nondiabetic db/m mice were selected as the normal group (n=15). The mice in AVE group were treated with AVE0991 20mg/kg/d and those in model group were treated with placebo via gavage for 6 weeks. The metabolic indicators were measured every week. After 6 weeks of treatment, intraperitoneal glucose tolerance test (IPGTT) and islet perifusion were performed to evaluate glucagon release kinetics in vivo and vitro. Double-label immunofluoresence assay was adoppted to assess the content of α and β cells. Moreover, qRT-PCR and western blot were employed to detect the GCK expression in islets. Results The fasting blood sugar[(19.1±0.8)mmol/L] and glucose tolerance [(14.1±0.5) mU/L]of AVE group were significantly lower than those of the model group[(25.3±3.0)mmol/L,(17.3±1.8)mU/L](P<0.05) and still higher than those of normal group[(6.3±0.5)mmol/L,(5.7±0.3)mU/L](P<0.05). At the 30, 60, and 120 min after IPGTT, the blood glucose level and glucagon level in AVE group were lower than model group, but still higher than the normal group (P<0.05). During low glucose perfusion, the glucagon secretion level of the islets of normal group [(20.6±0.5 pmol/L)] was lower than that of model group [(29.1±0.7) pmol/L)] and AVE group [(27.6±0.8) Pmol/L], and the difference was statistically significant (P<0.05). During high glucose perfusion, there was a statistically significant difference in glucagon level between AVE group and model group at 30 and 60 min(P<0.05). Semi-quantitative analysis showed that the islet α-cell content of model group [(3.3±0.7) mg] was significantly higher than that of normal group [(1.2±0.3) mg] (P<0.05), and the β cell content [(2.4±0.6) mg] was significantly lower than that of normal group [(4.8±0.3) mg] (P<0.05); While compared with the model group, the islet α-cell content [(1.8±0.4) mg] decreased significantly (P<0.05) and the β-cell content [(4.2±0.5) mg] increased significantly in AVE group (P<0.05). The expression levels of GCK mRNA and protein in model group were lower than those in normal group (P<0.05). Conclusion Activation of Mas receptors can improve glucose metabolism by reducing the secretion of glucagon after glucose load in db/db diabetic mice. The mechanism may be related to the decrease of islet α cell content and the increase of islet GCK expression.

11.
Rev. méd. Chile ; 146(7): 929-932, jul. 2018. tab, graf
Artigo em Espanhol | LILACS | ID: biblio-961480

RESUMO

We report a 21 years old woman, without offspring, with diabetes mellitus diagnosed at 17 years of age, without ketosis or weight loss. Her body mass index was 18 kg/m2. Her C peptide was normal (2.3 ng/ml) and diabetes mellitus type 1 autoantibodies were negative. A monogenic diabetes Maturity Onset Diabetes of the Young (MODY) was proposed. Her family study disclosed a diabetic father and a brother with altered fasting glucose levels. The University of Exeter score for MODY yielded a 75.5% probability of MODY2. In the genetic-molecular study of the glucokinase gene (MODY2), the patient had a mutation at position 1343 of exon 10, corresponding to a heterozygous substitution of guanine by adenine (1343 G >A). The same mutation was found in her father and brother. This mutation is different from those previously described in the literature. The described change determines that a glycine is replaced by aspartic at amino acid 448 of the enzyme (non-synonymous substitution). The diagnosis of MODY2 was therefore confirmed in the patient and her father. The mutation was inherited by paternal line.


Assuntos
Humanos , Feminino , Adulto Jovem , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Chile , Glucoquinase , Mutação
12.
Diabetes & Metabolism Journal ; : 465-471, 2018.
Artigo em Inglês | WPRIM | ID: wpr-719116

RESUMO

My professional journey to understand the glucose homeostasis began in the 1990s, starting from cloning of the promoter region of glucose transporter type 2 (GLUT2) gene that led us to establish research foundation of my group. When I was a graduate student, I simply thought that hyperglycemia, a typical clinical manifestation of type 2 diabetes mellitus (T2DM), could be caused by a defect in the glucose transport system in the body. Thus, if a molecular mechanism controlling glucose transport system could be understood, treatment of T2DM could be possible. In the early 70s, hyperglycemia was thought to develop primarily due to a defect in the muscle and adipose tissue; thus, muscle/adipose tissue type glucose transporter (GLUT4) became a major research interest in the diabetology. However, glucose utilization occurs not only in muscle/adipose tissue but also in liver and brain. Thus, I was interested in the hepatic glucose transport system, where glucose storage and release are the most actively occurring.


Assuntos
Animais , Humanos , Ratos , Adipogenia , Tecido Adiposo , Encéfalo , Células Clonais , Clonagem de Organismos , Diabetes Mellitus Tipo 2 , Glucoquinase , Gluconeogênese , Proteínas Facilitadoras de Transporte de Glucose , Transportador de Glucose Tipo 2 , Glucose , Glicólise , Homeostase , Hiperglicemia , Fígado , Regiões Promotoras Genéticas , Fatores de Transcrição
13.
Chinese Journal of Rheumatology ; (12): 293-297, 2018.
Artigo em Chinês | WPRIM | ID: wpr-707856

RESUMO

Objective To investigate the relationship between rs1260326 polymorphism of glucokinase regulatory protein gene and hyperuricemia and primary gout in Enshi area populations.Methods One hundred and fifty-eight primary gout,190 hyperuricemia and 104 healthy controls (normal group) in total were collected.Hi-single nucleotide polymorphism (SNP) combined with multiplex polymerase chain reaction (PCR) with next generation sequencing techniques were used for gene polymorphism analysis,and the relationship between different alleles or genotypes and susceptibility to primary gout and hyperuricemia were analyzed.The measurement data and numeration data were statistically analyzed with t test and x2 test respectively.Logistic regression analysis was used to assess the relative risk of gout and hyperuricemia.Results The frequency of rs1260326 genotype CC,TC,TT was 8.8%(14/158),60.8%(96/158),30.4%(48/158) respectively in gout patients,15.8% (30/190),54.7% (104/190),29.5% (56/190) in hyperuricemia patients,21.2% (22/104),45.1% (47/104),33.7%(35/104) in the normal group,the genotype distribution was significantly different in gout group and normal group (x2=9.895,P=0.007),and there was no difference between hyperuricemia group and normal group (x2=2.665,P=0.264).Allele C and T frequency was 39.2%(124/316) and 60.8%(192/316) in gout patients,43.2%(164/380) and 56.8%(216/380) in hyperuricemia patients,43.8%(91/208) and 56.2%(117/208) in the normal group.Allele T was the susceptible gene for gout.Logistic regression analysis showed that genotypes TC,TT,TC+TT increased the risk of gout.And Logistic regression analysis showed that rs1260326 single nucleotide polymorphism and hyperuricemia were no susceptibile.Conclusion Glucokinase regulatory protein (GCKR) rs1260326 sin-gle nucleotide polymorphism may be associated with primary gout risk in En Shi area,but has no significant correlation with hyperuricemia.

14.
Rev. méd. Chile ; 145(9): 1203-1207, set. 2017. tab, graf
Artigo em Espanhol | LILACS | ID: biblio-902608

RESUMO

Maturity-Onset Diabetes of the Young (MODY) refers to a heterogeneous group of monogenic diabetes. Unlike other types of MODY characterized by genetic defects in transcription factors, MODY 2 is triggered by metabolic alterations caused by mutations of glucokinase (GCK), the first enzyme of the glycolytic pathway. We report a three-generation Chilean family with multiple cases affected with this disease. The index case is a patient who presented severe neonatal hyperglycemia (831 mg/dl, without ketosis) requiring continuous infusion of insulin, which was suspended after 48 hours with normalization of blood glucose. Subsequently, continuous glucose monitoring at 4 months of age revealed 47% of tissue glucose levels above 140 mg/dl, with fasting glucose levels between 120 and 166 mg/dl. The genetic analysis revealed a previously reported mutation in heterozygous state of the GCK gene (c.148C>T; p.His50Tyr). This mutation was also identified in more than one affected relative in the last two generations, with a transmission pattern suggestive of dominant inheritance. GCK gene sequencing led to a correct molecular diagnosis of MODY 2 while bioinformatic analysis indicated the possible molecular causes of the enzyme dysfunction. The knowledge of the molecular diagnosis allowed an adequate medical treatment for this disease.


Assuntos
Humanos , Masculino , Recém-Nascido , Diabetes Mellitus Tipo 2/genética , Glucoquinase/genética , Mutação/genética , Linhagem , Glicemia/análise , Hemoglobinas Glicadas/análise , Seguimentos , Diabetes Mellitus Tipo 2/congênito
15.
Nutrition Research and Practice ; : 180-189, 2017.
Artigo em Inglês | WPRIM | ID: wpr-20676

RESUMO

BACKGROUND/OBJECTIVES: Recent living condition improvements, changes in dietary habits, and reductions in physical activity are contributing to an increase in metabolic syndrome symptoms including diabetes and obesity. Through such societal developments, humankind is continuously exposed to metabolic diseases such as diabetes, and the number of the victims is increasing. This study investigated Cordyceps militaris water extract (CMW)-induced glucose uptake in HepG2 cells and the effect of CMW treatment on glucose metabolism. MATERIALS/METHODS: Colorimetric assay kits were used to determine the glucokinase (GK) and pyruvate dehydrogenase (PDH) activities, glucose uptake, and glycogen content. Either RT-PCR or western blot analysis was performed for quantitation of glucose transporter 2 (GLUT2), hepatocyte nuclear factor 1 alpha (HNF-1α), phosphatidylinositol 3-kinase (PI3k), protein kinase B (Akt), phosphorylated AMP-activated protein kinase (pAMPK), phosphoenolpyruvate carboxykinase, GK, PDH, and glycogen synthase kinase 3 beta (GSK-3β) expression levels. The α-glucosidase inhibitory activities of acarbose and CMW were evaluated by absorbance measurement. RESULTS: CMW induced glucose uptake in HepG2 cells by increasing GLUT2 through HNF-1α expression stimulation. Glucose in the cells increased the CMW-induced phosphorylation of AMPK. In turn, glycolysis was stimulated, and glyconeogenesis was inhibited. Furthermore, by studying the mechanism of action of PI3k, Akt, and GSK-3β, and measuring glycogen content, the study confirmed that the glucose was stored in the liver as glycogen. Finally, CMW resulted in a higher level of α-glucosidase inhibitory activity than that from acarbose. CONCLUSION: CMW induced the uptake of glucose into HepG2 cells, as well, it induced metabolism of the absorbed glucose. It is concluded that CMW is a candidate or potential use in diabetes prevention and treatment.


Assuntos
Acarbose , alfa-Glucosidases , Proteínas Quinases Ativadas por AMP , Western Blotting , Cordyceps , Comportamento Alimentar , Glucoquinase , Proteínas Facilitadoras de Transporte de Glucose , Glucose , Glicogênio , Quinase 3 da Glicogênio Sintase , Glicólise , Células Hep G2 , Fator 1-alfa Nuclear de Hepatócito , Hipoglicemiantes , Fígado , Doenças Metabólicas , Metabolismo , Atividade Motora , Obesidade , Oxirredutases , Fosfatidilinositol 3-Quinase , Fosfoenolpiruvato , Fosforilação , Proteínas Proto-Oncogênicas c-akt , Ácido Pirúvico , Condições Sociais , Água
16.
Asian Pacific Journal of Tropical Biomedicine ; (12): 544-548, 2017.
Artigo em Chinês | WPRIM | ID: wpr-950573

RESUMO

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 by 94.76% 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.

17.
Asian Pacific Journal of Tropical Biomedicine ; (12): 544-548, 2017.
Artigo em Chinês | WPRIM | ID: wpr-686718

RESUMO

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 concomi-tant 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 ef-fects were significantly lower than that of METF which enhanced glucokinase activity by 94.76%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.

18.
Endocrinology and Metabolism ; : 296-301, 2017.
Artigo em Inglês | WPRIM | ID: wpr-112716

RESUMO

Glucokinase maturity-onset diabetes of the young (GCK-MODY) represents a distinct subgroup of MODY that does not require hyperglycemia-lowering treatment and has very few diabetes-related complications. Three patients from two families who presented with clinical signs of GCK-MODY were evaluated. Whole-exome sequencing was performed and the effects of the identified mutations were assessed using bioinformatics tools, such as PolyPhen-2, SIFT, and in silico modeling. We identified two mutations: p.Leu30Pro and p.Ser383Leu. In silico analyses predicted that these mutations result in structural conformational changes, protein destabilization, and thermal instability. Our findings may inform future GCK-MODY diagnosis; furthermore, the two mutations detected in two Korean families with GCK-MODY improve our understanding of the genetic basis of the disease.


Assuntos
Humanos , Biologia Computacional , Simulação por Computador , Complicações do Diabetes , Diabetes Mellitus Tipo 2 , Diagnóstico , Glucoquinase
19.
International Journal of Laboratory Medicine ; (12): 2507-2510, 2016.
Artigo em Chinês | WPRIM | ID: wpr-504751

RESUMO

Objective To investigate the relationships between Glucokinase(GCK) gene 4 tag single‐nucleotide polymorphisms , tagSNPs)sites which named rs12702070 ,rs2268569 ,rs2268573 and rs1476891 polymorphisms and type 2 diabetes in Chinese South‐ern Han Population .Methods This study was designed as a case‐control .499 type 2 diabetes patients and 499 healthy controls were chosen .4 GCK tagSNPs sites were analyzed by improved multiple ligase detection reaction(iMLDR) ,and genotype and allele fre‐quency between T2D group and healthy controls could be determined by chi‐square test ,logistic regression analysis ,and tagSNPs were further analyzed under three genetic modes(dominant ,recessive and additive) .What′s more ,Haploview software was used to construct the haplotype of 4 GCK tagSNPs and the linkage disequilibrium(LD) and relationship between various GCK haplotype and T2D susceptibility could be analyzed .Results Genotype distribution of rs2268573 ,rs2268569 and rs1476891 and allele frequen‐cy in T2D group were no significant differences with health controls .Significant differences in genotype distribution of rs12702070 and allele frequency were observed between T2D group and health controls .Under dominant model and additive model ,genotype distribution of rs12702070 in T2D was significantly different from health controls .One LD domain was observed in 3 tagSNPs a‐mong those 4 sites of GCK gene .There are 4 main haplotypes(TAG ,TGG ,TAT ,CGG)in rs2268569 ,rs12702070 and rs1476891 , but all these haplotypes have no relevance to the individual risk of T2D(P>0 .05) .Conclusion The results indicated that the GCK gene tagSNPs site rs12702070 imparts susceptibility to T2D in Han Chinese ,but not rs2268573 ,rs2268569 and rs1476891 .Four main haplotypes in rs2268569 ,rs12702070 and rs1476891 have no relevance to T2D .

20.
Chinese Journal of Applied Clinical Pediatrics ; (24): 1546-1549, 2016.
Artigo em Chinês | WPRIM | ID: wpr-502172

RESUMO

Objective To analyze the genetic changes and detailed clinical presentations of 5 maturity-onset diabetes of the young (MODY) cases in order to enhance the knowledge about MODY in children.Methods Seventy-eight patients initially diagnosed as diabetes mellitus between January 1 and December 31,2015 in Capital Institute of Pediatrics were retrospectively studied.Nine of them were suspected of MODY,and 5 patients were diagnosed as MODY through gene test.Clinical informations were collected including age,gender,main complaint,family history,body mass index (BMI),fasting blood glucose,fasting blood insulin,2-hour blood glucose and insulin after oral glucose tolerance test and glycosylated hemoglobin.The blood glucose was monitored dynamically in 2 patients.Targeted capture panel was designed to capture the 16 genes related to MODY,including 12 genes from MODY1 to MODY13 type and 4 genes with weak evidence of MODY according to Human Gene Mutation Database Exome capture,and Next-Generation sequencing on a HiSeq2000 (Illumina) was performed.After bioinformatics analysis,all prioritized variants detected in patients were validated by Sanger sequencing,including the probands and their parents.Results Five patients were confirmed as MODY by molecular diagnosis,accounting for 6.4% of all the 78 patients in 2015.The ratio of male to female was 2 ∶ 3.The ages at diagnosis ranged from 2 to 11 years old,and the median age was 3 years old.Two cases were found to have abnormal blood glucose in physical examination.The rest 3 cases were discovered with abnormal blood glucose during hospitalization because of pneumonia (1 case)or diarrhea (2 cases).In 4 cases,their mothers had gestational diabetes history,in 1 case the father suffering from diabetes.BMI ranged 15.68-23.40 kg/m2.Fasting blood glucose was 6.3-7.2 mmol/L.Fasting blood insulin was 0.5-8.0 IU/L.Glucose tolerance test results showed that blood glucose of the patients was 8.6-10.8 mmol/L after 2 hours.The level of glycosylated hemoglobin was 5.5%-6.7%.Blood glucose was 3.9-13.0 mmol/L.All the 5 confirmed patients were caused by GCK gene mutation (MODY2 type).The mutations detected were located at Exon7 (2 cases),Exon4 (1 case),Exon5 (1 case),and Exon10 (1 case).Conclusions All the confirmed MODY patients were identified either through medical exam or infectious disease,and all had positive family history.Their BMI ranged widely.Fasting blood glucose was slightly elevated and glycosylated hemoglobin was normal or slightly elevated,but fasting blood insulin was normal in all the patients.Abnormal glucose tolerance test results were found in all 5 patients.Glycosylated hemoglobin was normal or slightly elevated.MODY2 was the only subtype detected in this group,which indicated that the common type in children was different from that in adults.

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