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
BACKGROUND Maturity-onset diabetes of the young(MODY)is the most common form of monogenic diabetes.The disease is transmitted in autosomal dominant mode and diabetes is usually diagnosed before age 25 year.MODY 3 is c...BACKGROUND Maturity-onset diabetes of the young(MODY)is the most common form of monogenic diabetes.The disease is transmitted in autosomal dominant mode and diabetes is usually diagnosed before age 25 year.MODY 3 is caused by mutation of hepatocyte nuclear factor(HNF)1A genes and is the most common MODY subtype.Diagnosis of MODY 3 is crucial since glycemic control can be accomplished by very low dose of sulfonylurea.In this report we described a Thai MODY 3 patient who had excellence plasma glucose control by treating with glicazide 20 mg per day and insulin therapy can be discontinued.CASE SUMMARY A 31-year-old woman was diagnosed diabetes mellitus at 14 years old.The disease was transmitted from her grandmother and mother compatible with autosomal dominant inheritance.Sanger sequencing of proband’s DNA identified mutation of HNF1A at codon 203 which changed amino acid from arginine to cysteine(R203C).This mutation was carried only by family members who have diabetes.The patient has been treated effectively with a combination of oral hypoglycemic agents and must include a very low dose of glicazide(20 mg/d).Insulin therapy was successfully discontinued.CONCLUSION We demonstrated a first case of pharmacogenetics in Thai MODY 3 patient.Our findings underscore the essential role of molecular genetics in diagnosis and guidance of appropriate treatment of diabetes mellitus in particular patient.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
BACKGROUND The diagnosis of type 2 diabetes(T2D)in younger adults,an increasingly common public health issue,is associated with a higher risk of cardiovascular complications and mortality,which may be due to a more ad...BACKGROUND The diagnosis of type 2 diabetes(T2D)in younger adults,an increasingly common public health issue,is associated with a higher risk of cardiovascular complications and mortality,which may be due to a more adverse cardiovascular risk profile in individuals diagnosed at a younger age.AIM To investigate the association between age at diagnosis and the cardiovascular risk profile in adults with T2D.METHODS A pooled dataset was used,comprised of data from five previous studies of adults with T2D,including 1409 participants of whom 196 were diagnosed with T2D under the age of 40 years.Anthropometric and blood biomarker measurements included body weight,body mass index(BMI),waist circumference,body fat percentage,glycaemic control(HbA1c),lipid profile and blood pressure.Univariable and multivariable linear regression models,adjusted for diabetes duration,sex,ethnicity and smoking status,were used to investigate the association between age at diagnosis and each cardiovascular risk factor.RESULTS A higher proportion of participants diagnosed with T2D under the age of 40 were female,current smokers and treated with glucose-lowering medications,compared to participants diagnosed later in life.Participants diagnosed with T2D under the age of 40 also had higher body weight,BMI,waist circumference and body fat percentage,in addition to a more adverse lipid profile,compared to participants diagnosed at an older age.Modelling results showed that each one year reduction in age at diagnosis was significantly associated with 0.67 kg higher body weight[95%confidence interval(CI):0.52-0.82 kg],0.18 kg/m^(2) higher BMI(95%CI:0.10-0.25)and 0.32 cm higher waist circumference(95%CI:0.14-0.49),after adjustment for duration of diabetes and other confounders.Younger age at diagnosis was also significantly associated with higher HbA1c,total cholesterol,low-density lipoprotein cholesterol and triglycerides.CONCLUSION The diagnosis of T2D earlier in life is associated with a worse cardiovascular risk factor profile,compared to those diagnosed later in life.展开更多
The disorder, Maturity Onset of Diabetes of the young (MODY) is a monogenic form of Non-Insulin dependent Diabetes Mellitus (NIDDM), characterized by autosomal dominant mode of inheritance and onset is usually before ...The disorder, Maturity Onset of Diabetes of the young (MODY) is a monogenic form of Non-Insulin dependent Diabetes Mellitus (NIDDM), characterized by autosomal dominant mode of inheritance and onset is usually before 25 years of age. Clinical studies of subjects with the different forms of MODY indicate that each is associated with a different defect in the normal pattern of glucose stimulated insulin secretion. MODY can result from mutations in any one of the six different genes, one of which encodes the glycolytic enzyme Glucokinase, associated with MO-DY2 and the other five encode transcription factors HNF4-alpha associated with MODY 1, HNF1-alpha associated with MODY 3, IPF with MODY 4, HNF1-Beta with MODY 5 and NeuroD1 with MO-DY6. Studies related to mutations in the MODY genes have led to a better understanding of the genetic causes of the Beta cell dysfunction as genetic factors plays a great role in this disorder. Objective: To investigate the mutation pattern in the different transcription factor genes with special reference to HNF1-alpha which are highly penetrant with 63% mutation carriers manifesting clinical diabetes by the age of 25 years. Hence study of mutation pattern in this gene is essential in our population i.e. Eastern Indian population. Our study is focused on HNF1-alpha related to MODY 3, which is the most common one. Methods: In our study enzyme amplification (PCR) of the 10 target exons of the said gene with simultaneous mutation detection in them by PCR-SSCP (Polymerase chain reaction-single strand conformational polymorphism) reaction analysis method was attempted by screening of exon 1 - 10 with respect to normal healthy controls without Diabetes Mellitus. The nature of the specific mutations was also determined by sequencing. Result: It was observed that maximum number of variations exist in exon 5 of HNF1-alpha gene which may be referred to as “Mutational Hotspot” in our Eastern Indian population. Conclusions: Since maximum number of variations exists in exon 5 of the said gene, hence one can initially go for exon5 followed by other exons, while screening for pathogenic MODY 3 mutations in the responsible gene by PCR-SSCP method.展开更多
Background Mutations in the hepatocyte nuclear factor-lA gene cause the type 3 form of maturity-onset diabetes of the young （MODY3）. This study was undertaken to determine mutations and sequence variations of the HN...Background Mutations in the hepatocyte nuclear factor-lA gene cause the type 3 form of maturity-onset diabetes of the young （MODY3）. This study was undertaken to determine mutations and sequence variations of the HNF-1A gene in Chinese with familial early-onset and/or multiplex diabetes mellitus.展开更多
BACKGROUND Risk factors such as hereditary, ecological, and metabolic are interrelated and contribute to the development of type 2 diabetes mellitus. Family history(FH) of diabetes mellitus, age, obesity, and physical...BACKGROUND Risk factors such as hereditary, ecological, and metabolic are interrelated and contribute to the development of type 2 diabetes mellitus. Family history(FH) of diabetes mellitus, age, obesity, and physical inactivity are some of the risk factors for the development of type 2 diabetes.AIM To study various aetiological determinants and risk factors for type 2 diabetes in Bangalore, India. This retrospective study examined questionnaire from patients attending the Diabetes Clinic.METHODS Data on various parameters were obtained through a questionnaire from 533 patients on the first visit to the diabetes clinic. Data regarding various aetiological determinants and risk factors viz.: Genetic risk factor and few modifiable risk factors were collected. Chi-squared test was used for statistical analysis.RESULTS A higher incidence of type 2 diabetes in males and younger population was observed in Bangalore, India. Obesity and FH were significant risk factors for not only type 2 diabetes but also early onset of diabetes. In addition, maternal history of type 2 diabetes and consanguinity increased incidence of early onset type 2 diabetes.CONCLUSION Risk factors such as obesity and FH(maternal history of type 2 diabetes) and consanguinity may play an important role in screening of family members of type 2 diabetes patients which may lead to early intervention and reduced risk of subsequent complications. Moreover, susceptible population can be counselled for the management of the type 2 diabetes including periodic investigation of blood glucose levels and lifestyle changes.展开更多
目的报道1例中国人葡萄糖激酶(glucokinase,GCK)新发基因突变导致青少年起病的成人型糖尿病2型(maturity-onset diabetes of the young,type 2,MODY2)家系,分析其遗传学特征及临床特点。方法对1例MODY2家系行基因测序、临床资料采集及...目的报道1例中国人葡萄糖激酶(glucokinase,GCK)新发基因突变导致青少年起病的成人型糖尿病2型(maturity-onset diabetes of the young,type 2,MODY2)家系,分析其遗传学特征及临床特点。方法对1例MODY2家系行基因测序、临床资料采集及分析。结果调查此家系成员共18人,其中先证者及其弟、父亲、叔父、堂弟等父系成员11人罹患糖尿病;先证者及其弟、父亲、叔父均存在GCK基因杂合同义突变(exon1:c.45G>A:p.K15K),生物信息学功能预测提示该突变可能影响mRNA剪接而致GCK功能受损,国内研究人群尚未见此突变报道;先证者及其弟糖化血红蛋白分别为6.49%、6.72%,空腹血糖分别为6.80、7.01 mmol/L,糖尿病自身抗体谱均为阴性,6~18个月随访示血糖水平保持稳定。结论此MODY2家系中GCK基因杂合同义突变(exon1:c.45G>A:p.K15K)为中国人新发突变位点,其临床表现为轻度、持续稳定的空腹高血糖及糖化血红蛋白升高,不应低估GCK基因同义突变的致病性。展开更多
报告1例青少年起病的成人型糖尿病(maturity-onset diabetes of the young,MODY)3型(MODY3)合并5型(MODY5)患者的临床特征、诊断及治疗,并复习相关文献。利用MODY(1~14型)基因外显子二代测序和Sanger测序验证MODY患者及其母亲,结合临床...报告1例青少年起病的成人型糖尿病(maturity-onset diabetes of the young,MODY)3型(MODY3)合并5型(MODY5)患者的临床特征、诊断及治疗,并复习相关文献。利用MODY(1~14型)基因外显子二代测序和Sanger测序验证MODY患者及其母亲,结合临床表型及基因检测结果,该患者诊断为MODY3合并MODY5,给予胰岛素及利格列汀治疗,观察血糖变化。临床医师应提高对MODY临床表型的认识,对于合并先天性胰腺和肾脏发育不全、高密度脂蛋白胆固醇升高,无自发酮症、胰岛素分泌缺陷,胰岛自身抗体阴性,无明显胰岛素抵抗,非肥胖的青少年糖尿病患者应行基因检测以筛查MODY,精准诊断并予以个体化治疗将有助于血糖水平达标及改善生活质量,并指导优化生育。展开更多
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.
基金Supported by Mahidol University Research Grant,Nos.R015810001and 016120003(to Nattachet Plengvidhya)Siriraj Research Grant for Research and Development,Faculty of Medicine Siriraj Hospital,Mahidol University,No.R015934015(to Tassanee Narkdontri and Watip Tangjittipokin)Thailand Research Fund grants,Nos.TRG5780113(to Watip Tangjittipokin),BRG5280008(to Nattachet Plengvidhya),and IRG5980006(to Pa-thai Yenchitsomanus)
文摘BACKGROUND Maturity-onset diabetes of the young(MODY)is the most common form of monogenic diabetes.The disease is transmitted in autosomal dominant mode and diabetes is usually diagnosed before age 25 year.MODY 3 is caused by mutation of hepatocyte nuclear factor(HNF)1A genes and is the most common MODY subtype.Diagnosis of MODY 3 is crucial since glycemic control can be accomplished by very low dose of sulfonylurea.In this report we described a Thai MODY 3 patient who had excellence plasma glucose control by treating with glicazide 20 mg per day and insulin therapy can be discontinued.CASE SUMMARY A 31-year-old woman was diagnosed diabetes mellitus at 14 years old.The disease was transmitted from her grandmother and mother compatible with autosomal dominant inheritance.Sanger sequencing of proband’s DNA identified mutation of HNF1A at codon 203 which changed amino acid from arginine to cysteine(R203C).This mutation was carried only by family members who have diabetes.The patient has been treated effectively with a combination of oral hypoglycemic agents and must include a very low dose of glicazide(20 mg/d).Insulin therapy was successfully discontinued.CONCLUSION We demonstrated a first case of pharmacogenetics in Thai MODY 3 patient.Our findings underscore the essential role of molecular genetics in diagnosis and guidance of appropriate treatment of diabetes mellitus in particular patient.
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.
基金Supported by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (NIHR201165)by the NIHR Leicester Biomedical Research Centrethe NIHR Applied Research Collaboration East Midlands
文摘BACKGROUND The diagnosis of type 2 diabetes(T2D)in younger adults,an increasingly common public health issue,is associated with a higher risk of cardiovascular complications and mortality,which may be due to a more adverse cardiovascular risk profile in individuals diagnosed at a younger age.AIM To investigate the association between age at diagnosis and the cardiovascular risk profile in adults with T2D.METHODS A pooled dataset was used,comprised of data from five previous studies of adults with T2D,including 1409 participants of whom 196 were diagnosed with T2D under the age of 40 years.Anthropometric and blood biomarker measurements included body weight,body mass index(BMI),waist circumference,body fat percentage,glycaemic control(HbA1c),lipid profile and blood pressure.Univariable and multivariable linear regression models,adjusted for diabetes duration,sex,ethnicity and smoking status,were used to investigate the association between age at diagnosis and each cardiovascular risk factor.RESULTS A higher proportion of participants diagnosed with T2D under the age of 40 were female,current smokers and treated with glucose-lowering medications,compared to participants diagnosed later in life.Participants diagnosed with T2D under the age of 40 also had higher body weight,BMI,waist circumference and body fat percentage,in addition to a more adverse lipid profile,compared to participants diagnosed at an older age.Modelling results showed that each one year reduction in age at diagnosis was significantly associated with 0.67 kg higher body weight[95%confidence interval(CI):0.52-0.82 kg],0.18 kg/m^(2) higher BMI(95%CI:0.10-0.25)and 0.32 cm higher waist circumference(95%CI:0.14-0.49),after adjustment for duration of diabetes and other confounders.Younger age at diagnosis was also significantly associated with higher HbA1c,total cholesterol,low-density lipoprotein cholesterol and triglycerides.CONCLUSION The diagnosis of T2D earlier in life is associated with a worse cardiovascular risk factor profile,compared to those diagnosed later in life.
文摘The disorder, Maturity Onset of Diabetes of the young (MODY) is a monogenic form of Non-Insulin dependent Diabetes Mellitus (NIDDM), characterized by autosomal dominant mode of inheritance and onset is usually before 25 years of age. Clinical studies of subjects with the different forms of MODY indicate that each is associated with a different defect in the normal pattern of glucose stimulated insulin secretion. MODY can result from mutations in any one of the six different genes, one of which encodes the glycolytic enzyme Glucokinase, associated with MO-DY2 and the other five encode transcription factors HNF4-alpha associated with MODY 1, HNF1-alpha associated with MODY 3, IPF with MODY 4, HNF1-Beta with MODY 5 and NeuroD1 with MO-DY6. Studies related to mutations in the MODY genes have led to a better understanding of the genetic causes of the Beta cell dysfunction as genetic factors plays a great role in this disorder. Objective: To investigate the mutation pattern in the different transcription factor genes with special reference to HNF1-alpha which are highly penetrant with 63% mutation carriers manifesting clinical diabetes by the age of 25 years. Hence study of mutation pattern in this gene is essential in our population i.e. Eastern Indian population. Our study is focused on HNF1-alpha related to MODY 3, which is the most common one. Methods: In our study enzyme amplification (PCR) of the 10 target exons of the said gene with simultaneous mutation detection in them by PCR-SSCP (Polymerase chain reaction-single strand conformational polymorphism) reaction analysis method was attempted by screening of exon 1 - 10 with respect to normal healthy controls without Diabetes Mellitus. The nature of the specific mutations was also determined by sequencing. Result: It was observed that maximum number of variations exist in exon 5 of HNF1-alpha gene which may be referred to as “Mutational Hotspot” in our Eastern Indian population. Conclusions: Since maximum number of variations exists in exon 5 of the said gene, hence one can initially go for exon5 followed by other exons, while screening for pathogenic MODY 3 mutations in the responsible gene by PCR-SSCP method.
基金This work was supported by grants from the National Natural Science Foundation of China (No. 30470813) Shanghai Scientific Committee (No. 02DJ14052-I).
文摘Background Mutations in the hepatocyte nuclear factor-lA gene cause the type 3 form of maturity-onset diabetes of the young （MODY3）. This study was undertaken to determine mutations and sequence variations of the HNF-1A gene in Chinese with familial early-onset and/or multiplex diabetes mellitus.
文摘BACKGROUND Risk factors such as hereditary, ecological, and metabolic are interrelated and contribute to the development of type 2 diabetes mellitus. Family history(FH) of diabetes mellitus, age, obesity, and physical inactivity are some of the risk factors for the development of type 2 diabetes.AIM To study various aetiological determinants and risk factors for type 2 diabetes in Bangalore, India. This retrospective study examined questionnaire from patients attending the Diabetes Clinic.METHODS Data on various parameters were obtained through a questionnaire from 533 patients on the first visit to the diabetes clinic. Data regarding various aetiological determinants and risk factors viz.: Genetic risk factor and few modifiable risk factors were collected. Chi-squared test was used for statistical analysis.RESULTS A higher incidence of type 2 diabetes in males and younger population was observed in Bangalore, India. Obesity and FH were significant risk factors for not only type 2 diabetes but also early onset of diabetes. In addition, maternal history of type 2 diabetes and consanguinity increased incidence of early onset type 2 diabetes.CONCLUSION Risk factors such as obesity and FH(maternal history of type 2 diabetes) and consanguinity may play an important role in screening of family members of type 2 diabetes patients which may lead to early intervention and reduced risk of subsequent complications. Moreover, susceptible population can be counselled for the management of the type 2 diabetes including periodic investigation of blood glucose levels and lifestyle changes.
文摘目的报道1例中国人葡萄糖激酶(glucokinase,GCK)新发基因突变导致青少年起病的成人型糖尿病2型(maturity-onset diabetes of the young,type 2,MODY2)家系,分析其遗传学特征及临床特点。方法对1例MODY2家系行基因测序、临床资料采集及分析。结果调查此家系成员共18人,其中先证者及其弟、父亲、叔父、堂弟等父系成员11人罹患糖尿病;先证者及其弟、父亲、叔父均存在GCK基因杂合同义突变(exon1:c.45G>A:p.K15K),生物信息学功能预测提示该突变可能影响mRNA剪接而致GCK功能受损,国内研究人群尚未见此突变报道;先证者及其弟糖化血红蛋白分别为6.49%、6.72%,空腹血糖分别为6.80、7.01 mmol/L,糖尿病自身抗体谱均为阴性,6~18个月随访示血糖水平保持稳定。结论此MODY2家系中GCK基因杂合同义突变(exon1:c.45G>A:p.K15K)为中国人新发突变位点,其临床表现为轻度、持续稳定的空腹高血糖及糖化血红蛋白升高,不应低估GCK基因同义突变的致病性。
文摘报告1例青少年起病的成人型糖尿病(maturity-onset diabetes of the young,MODY)3型(MODY3)合并5型(MODY5)患者的临床特征、诊断及治疗,并复习相关文献。利用MODY(1~14型)基因外显子二代测序和Sanger测序验证MODY患者及其母亲,结合临床表型及基因检测结果,该患者诊断为MODY3合并MODY5,给予胰岛素及利格列汀治疗,观察血糖变化。临床医师应提高对MODY临床表型的认识,对于合并先天性胰腺和肾脏发育不全、高密度脂蛋白胆固醇升高,无自发酮症、胰岛素分泌缺陷,胰岛自身抗体阴性,无明显胰岛素抵抗,非肥胖的青少年糖尿病患者应行基因检测以筛查MODY,精准诊断并予以个体化治疗将有助于血糖水平达标及改善生活质量,并指导优化生育。
