肝细胞核因子-4α与糖尿病

肝细胞核因子(HNF)-4α是一种细胞特异性转录因子,为细胞核受体超家族成员之一.HNF-4α通过对靶基因的转录调节参与胰岛β细胞和肝脏的发育、分化和正常功能,并维持葡萄糖稳态.HNF-4α可与其他HNFs分子共同组成组织分化过程中所必需的转录因子调节网络.HNF-4α的突变型可诱发青少年发病的成年型糖尿病(MODY).近年来研究发现,HNF-4α基因可能与2型糖尿病易感性相关.深入研究HNF-4α对于解释和阐明2型糖尿病的遗传病理机制,指导糖尿病的预防和治疗具有重大意义.     

Hepatocyte nuclear factor-1a gene and non-insulin-dependent diabetes mellitus in the Japanese population

Recently, hepatocyte nuclear factor-1α (HNF-1α, which is encoded by the TCF1 gene) mutations were reported in a subset of patients with maturity onset diabetes of the young (MODY3). We studied the contribution of TCF1 to genetic susceptibility to common non-insulin-dependent diabetes mellitus (type 2) in Japanese subjects by investigating allelic association with type 2 diabetes use of three markers. We also studied the frequency of the G191D mutation, the only mutation of TCF1 reported so far in late-onset type 2 diabetes. A total of 356 subjects were studied. There were no significant differences in allele frequency of the three markers between patients with type 2 diabetes and control subjects. A G191D mutation was not found in the subjects studied, giving a frequency of less than 0.4% in common type 2 diabetes. The lack of association of type 2 diabetes with three markers in and near TCF1 suggests that mutations in TCF1 derived from a limited number of founders are not a major cause of common type 2 diabetes even in the genetically homogeneous Japanese population. The data also indicate that the G191D mutation in TCF1 plays little, if any, role in susceptibility to common type 2 diabetes in the Japanese. Received: 28 March 1998 / Accepted in revised form: 24 June 1998     

Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor-1alpha gene mutations: evidence for pharmacogenetics in diabetes.

INTRODUCTION: Maturity-onset diabetes of the young (MODY) is characterized by autosomal dominantly inherited, early-onset, non-insulin-dependent diabetes. Mutations in the hepatocyte nuclear factor (HNF)-1alpha gene are the commonest cause of MODY. Individual patients with HNF-1alpha mutations have been reported as being unusually sensitive to the hypoglycaemic effects of sulphonylurea therapy. We report three patients, attending a single clinic, with HNF-1alpha mutations that show marked hypersensitivity to sulphonylureas. CASE REPORTS: In cases 1 and 2 there were marked changes in HbA1c on cessation (4.4% and 5.8%, respectively) and reintroduction (5.0% and 2.6%) of sulphonylureas. Case 3 had severe hypoglycaemic symptoms on the introduction of sulphonylureas despite poor glycaemic control and was shown with a test dose of 2.5 mg glibenclamide to have symptomatic hypoglycaemia (blood glucose 2 mmol/l) after 4 h despite eating. CONCLUSIONS: HNF-1alpha MODY diabetic subjects are more sensitive to sulphonylureas than Type 2 diabetic subjects and this is seen in different families, with different mutations and may continue up to 13 years from diagnosis. This is an example of pharmacogenetics, with the underlying aetiological genetic defect altering the pharmacological response to treatment. The present cases suggest that in HNF-1alpha MODY patients: (i) sulphonylureas can dramatically improve glycaemic control and should be considered as initial treatment for patients with poor glycaemic control on an appropriate diet; (ii) hypoglycaemia may complicate the introduction of sulphonylureas and therefore very low doses of short acting sulphonylureas should be used initially; and (iii) cessation of sulphonylureas should be undertaken cautiously as there may be marked deterioration in glycaemic control.     

Serum amino acids in patients with mutations in the hepatocyte nuclear factor-1 alpha gene.

AIMS: Knockout mice lacking both copies of the hepatocyte nuclear factor 1 (HNF1) gene have altered serum levels of amino acids and generalized aminoaciduria. The aim of our study was to test whether alterations in serum amino acid levels were found in patients with mutations in the hepatocyte nuclear factor-1 alpha (HNF-1alpha) gene compared with controls. METHODS: Fasting serum from 20 patients with HNF-1alpha mutations and 20 age, sex and body mass index-matched controls was analysed for 16 amino acids. Means were compared between the two groups and Z scores calculated. RESULTS: There was no significant difference between patients with HNF-1alpha mutations and controls in serum levels of phenylalanine, arginine, citrulline or lysine as suggested by knockout mice models. Although serum levels of eight amino acids were different in the two groups, these were not significant after Bonferroni correction. CONCLUSIONS: The alterations in serum amino acid levels seen in mice models are not seen in patients with mutations in the HNF-1alpha gene. This suggests differences in mouse and man in the regulation of amino acid transport and has not provided us with a phenotypic marker to use before confirmatory genetic testing.     

Hepatocyte nuclear factor-1 alpha gene inactivation: cosegregation between liver adenomatosis and diabetes phenotypes in two maturity-onset diabetes of the young (MODY)3 families

Heterozygous germline mutations of the hepatocyte nuclear factor (HNF)-1 alpha are associated with maturity-onset diabetes of the young (MODY)3. Recently, the biallelic inactivation of the HNF-1 alpha gene was reported in liver adenomas. We show the occurrence of liver adenomatosis in six MODY3-affected patients from two unrelated and large families. Liver adenomatosis was characterized by the presence of numerous adenomas within a normal hepatic parenchyma. The HNF-1 alpha hot-spot germline mutation P291fs was identified in the two probands and in 16 relatives from the two families. The six patients affected by liver adenomatosis and diabetes exhibited the mutation. The analysis of liver-cell tumors from two affected patients evidenced the biallelic inactivation of HNF-1 alpha. The familial screening confirmed the clinical heterogeneity of the liver phenotype, from silent liver adenomatosis to fatal hemorrhage. These observations warrant the systematic screening for liver adenomatosis in MODY3 families to prevent its potentially deadly complications. Moreover, such screening may help to determine if a particular mutational spectrum of HNF-1 alpha is associated with liver adenomatosis and to establish its prevalence in this frequent form of diabetes in the young adult.     

Impaired maximum microvascular hyperaemia in patients with MODY 3 (hepatocyte nuclear factor-1alpha gene mutations).

AIMS: Functional abnormalities of blood flow and capillary pressure may be involved in the pathogenesis of diabetic microangiopathy. Important differences in microvascular behaviour are observed between Type 1 and Type 2 diabetes mellitus, raising the possibility that the pathogenesis of microangiopathy may differ between these. MODY3 patients have hyperglycaemia as a result of genetic defect of beta-cell function rather than increased insulin resistance and are susceptible to microvascular complications and offer an opportunity to examine microvascular behaviour in this setting. METHODS: The maximum microvascular hyperaemic response to local heating of the skin was studied in 12 MODY3 patients and age and sex-matched control subjects using laser Doppler fluximetry. RESULTS: Maximum hyperaemia was reduced in MODY3 patients (median 1.17 (range 0.88-1.92)V vs. 1.70 (1.07-2.19)V normal control subjects; P=0.03) and thus was negatively associated with duration of diabetes (r(s)=-0.79; P = 0.002). CONCLUSIONS: The results suggest that the duration of diabetes is a determinant of impaired microvascular hyperaemia in MODY3 patients. The pattern of vasodilatory impairment is similar to that observed in Type 1 diabetes mellitus and differs from that seen in Type 2 diabetes. This provides support for the concept that beta cell dysfunction and insulin resistance may have differing effects on microvascular behaviour.     

Insulin secretion and insulin sensitivity in diabetic and non-diabetic subjects with hepatic nuclear factor-1alpha (maturity-onset diabetes of the young-3) mutations

OBJECTIVE: To evaluate insulin secretion and sensitivity in affected (diabetes mellitus or impaired glucose tolerance; n=7) and in unaffected (normal glucose tolerance; n=3) carriers of hepatocyte nuclear factor-1alpha (maturity-onset diabetes of the young-3 (MODY3)) gene mutations. METHODS: Insulin secretion was assessed by an i.v. glucose tolerance test (IVGTT), hyperglycemic clamp and arginine test, and insulin sensitivity by an euglycemic hyperinsulinemic clamp. Results were compared with those of diabetic MODY2 (glucokinase-deficient) and control subjects. RESULTS: The amount of insulin secreted during an IVGTT was decreased in affected MODY3 subjects (46+/-24 (s.d.) pmol/kg body weight (BW)) as compared with values in MODY2 (120+/-49pmol/kg BW) and control (173+/-37pmol/kg BW; P=0.0004) subjects. The amount of insulin secreted during a 10mmol/l glucose clamp was decreased in affected MODY3 subjects (171+/-78pmol/kg BW) and MODY2 subjects (302+/-104pmol/kg BW) as compared with control subjects (770+/-199pmol/kg BW; P=0.0001). Insulin secretion in response to arginine was decreased in affected MODY3 subjects. Milder and heterogeneous defects were observed in the unaffected MODY3 subjects; the amount of insulin secreted during the hyperglycemic clamp was 40-79% of that of controls. The response to arginine was abnormally delayed. Insulin sensitivity was decreased in diabetic but not in non-diabetic MODY3 subjects. CONCLUSIONS: Beta-cell dysfunction in response to glucose and arginine is observed in affected and unaffected MODY3 subjects. The MODY3 and MODY2 subtypes present different insulin secretion profiles. Secondary insulin resistance might contribute to the chronic hyperglycemia of MODY3 patients and modulate their glucose tolerance.     

Etiology of early-onset type 2 diabetes in Indians: islet autoimmunity and mutations in hepatocyte nuclear factor 1alpha and mitochondrial gene

CONTEXT: Indians are at high risk of developing type 2 diabetes mellitus (T2DM) at an early age, despite their lower body mass index. Studies on the etiology of patients presenting as early-onset T2DM in this racial group are not available. OBJECTIVE: The objective was to delineate the clinical features in young Indian patients with T2DM and to determine the role of mutations in the hepatocyte nuclear factor 1alpha (HNF1alpha) gene [MODY3 (maturity-onset diabetes of the young, type 3)], mitochondrial A3243G mutation, and islet autoimmunity in its etiology. DESIGN: This was an observational cohort study. SETTING: The setting was an outpatient diabetes clinic in a teaching hospital. PATIENTS: Ninety-six consecutive young patients with T2DM (onset, 相似文献   

2型糖尿病家系肝细胞核因子1β基因1968A/G的多态性

糖尿病组中肝细胞核因子1β基因的G等位基因携带者的空腹C肽、△I10／△G30均明显低于AA基因型纯合子。一级亲属组中G等位基因携带者的空腹及餐后3h血糖，空腹、餐后2h及3h胰岛素明显高于AA基因型纯合子。     

Polymorphisms in the gene encoding hepatocyte nuclear factor-4alpha and susceptibility to type 2 diabetes in a Polish population

Recently, several association studies of type 2 diabetes mellitus (T2DM) and the hepatocyte nuclear factor (HNF)-4alpha gene were reported with conflicting results. Our aim was to search for association between two polymorphisms of HNF-4alpha and T2DM in Polish Caucasians. The study groups comprised of 461 T2DM cases and 366 controls. Genotype-quantitative trait analyses were based on the oral glucose tolerance test (OGTT), glucose and insulin results, and comprised 310 glucose-tolerant subjects. All individuals were genotyped for two HNF-4alpha polymorphisms. The frequencies of the minor alleles were as follows: 19.2% in T2DM vs. 17.6% in controls for rs2144908; and 20.6% vs. 20.1% for rs4810424, respectively. The distributions of alleles, genotypes, and haplotypes of the HNF-4alpha polymorphisms did not differ between the study groups (lowest P = 0.41). None of the examined SNPs showed an association in control subjects with quantitative traits of fasting plasma glucose, fasting insulin, as well as plasma glucose and insulin 2 hours after glucose load in OGTT. We conclude that both examined polymorphisms in HNF-4alpha are not associated with T2DM and prediabetic phenotypes in Polish Caucasian study groups of this size.     

Mutations in the hepatocyte nuclear factor-1alpha gene in Chinese MODY families: prevalence and functional analysis

AIMS/HYPOTHESIS: Maturity-onset diabetes of the young is an autosomal dominant form of diabetes characterised by an early age of onset (usually <25 years). We investigated the prevalence and trans-activating activity of hepatocyte nuclear factor (HNF) -1 alpha mutations in southern Chinese families with MODY. METHODS: We screened for mutations in the HNF-1 alpha gene in 50 unrelated southern Chinese families, which fulfilled the minimum criteria for MODY. Functional properties of the mutant proteins were investigated using site-directed mutagenesis and luciferase reporter assay. RESULTS: Five of the 50 (10%) families were found to have mutations in the coding region, including a new nonsense mutation Q176X and four reported mutations (frameshift mutation P379fsdelCT, nonsense mutation R171X, missense mutations G20R and P112L). These mutations had decreased trans-activating activity on the human insulin gene promoter. We also detected a new intronic sequence variation IVS7nt-6 G-->A, which co-segregated with diabetes. The intronic variation creates a potential splice acceptor site and might alter the splicing of the HNF-1 alpha mRNA. CONCLUSION/INTERPRETATION: Mutations in the HNF-1 alpha gene seem to be an important cause of MODY in southern Chinese. The mutations could affect normal islet function by altering the expression of target genes.