Maturity-onset diabetes of the young (MODY) is a heterogenous form of diabetes characterized by the early onset of diabetes, autosomal dominant inheritance, and impaired insulin secretion. MODY is mostly caused by mutations of the hepatocyte nuclear factor 1-alpha (HNF1-alpha) and glucokinase genes in Caucasians. However most Korean, Japanese, and Chinese patients with MODY do not express known MODY genes. The cause of MODY in Asians has not yet been elucidated clearly. This review focuses on studies on Asian patients with MODY.
Asian Continental Ancestry Group ; Diabetes Mellitus, Type 2 ; Glucokinase ; Hepatocyte Nuclear Factor 1-alpha ; Humans ; Insulin ; Wills

BACKGROUND/AIMS: Loss of liver fatty acid binding protein (LFABP) expression by immunohis-tochemistry is a useful marker for the identification of hepatocyte nuclear factor 1alpha (HNF1alpha)-inactivated hepatocellular adenomas; however, the expression status of LFABP in hepatocel-lular carcinomas (HCCs) is still unclear. We aimed to investigate the expression status of LFABP in HCCs and examine the clinicopathological characteristics of LFABP-negative HCCs. METHODS: Immunohistochemical stains LFABP, K19 (mouse monoclonal, Dako, Glostrup, Den-mark) and EpCAM (mouse monoclonal, Calbiochem, Darmstadt, Germany) were performed on tissue microarray sections from 188 surgically resected HCCs, and the association between LFABP expression status and the clinicopathological features, survival and "stemness"-related marker expression status were analyzed. RESULTS: Loss of LFABP expression was noted in 30 (16%) out of 188 HCCs. LFABP-negative HCCs were associated with a decreased recurrence-free survival (LFABP-negative: 17.0 +/- 4.84 months [95% confidence interval [CI]: 7.5-26.5 months] versus LFABP-positive: 51.0 +/- 8.7 months [95% CI: 34.0-68.0 months]; P=0.004). HCCs with LFABP expression loss were more frequently larger and showed more frequent vascular invasion, although not statistically sig-nificant; and an inverse correlation was seen between LFABP expression and K19 expression status (P=0.001). CONCLUSIONS: Loss of LFABP expression is seen in HCCs, and is associated with a decreased recurrence-free survival.
Adenoma, Liver Cell ; Carcinoma, Hepatocellular* ; Coloring Agents ; Fatty Acid-Binding Proteins* ; Hepatocyte Nuclear Factor 1-alpha ; Liver* ; Prognosis

PURPOSE: Previous studies have shown that treatment with Smilax china L. leaf extract (SCLE) produces antidiabetic effects due to alpha-glucosidase inhibition. In this study, we examined the mechanism underlying these antidiabetic effects by examining glucose uptake in HepG2 cells cultured with SCLE. METHODS: Glucose uptake and glucokinase activity were examined using an assay kit. Expression of glucose transporter (GLUT)-2, GLUT-4, and HNF-1alpha was measured by RT-PCR or western blot. RESULTS: Treatment with SCLE resulted in enhanced glucose uptake in HepG2 cells, and this effect was especially pronounced when cells were cultured in an insulin-free medium. SCLE induced an increase in expression of GLUT-2 but not GLUT-4. The increase in the levels of HNF-1alpha, a GLUT-2 transcription factor, in total protein extract and nuclear fraction suggest that the effects of SCLE may occur at the level of GLUT-2 transcription. In addition, by measuring the change in glucokinase activity following SCLE treatment, we confirmed that SCLE stimulates glucose utilization by direct activation of this enzyme. CONCLUSION: These results demonstrate that the potential antidiabetic activity of SCLE is due at least in part to stimulation of glucose uptake and an increase in glucokinase activity, and that SCLE-stimulated glucose uptake is mediated through enhancement of GLUT-2 expression by inducing expression of its transcription factor, HNF-1alpha.
Absorption* ; alpha-Glucosidases ; Blotting, Western ; China* ; Glucokinase ; Glucose Transport Proteins, Facilitative ; Glucose* ; Hep G2 Cells* ; Hepatocyte Nuclear Factor 1-alpha ; Smilax* ; Transcription Factors

BACKGROUND: Hepatocellular adenoma (HCA) is a rare benign tumor of the liver. A subtype classification of HCA (hepatocyte nuclear factor 1alpha [HNF1alpha]-mutated, beta-catenin-mutated HCA, inflammatory HCA, and unclassified HCA) has recently been established based on a single institutional review of a HCA series by the Bordeaux group. METHODS: We used histologic and immunohistochemical parameters to classify and evaluate eight cases from our institution. We evaluated the new classification method and analyzed correlations between our results and those of other reports. RESULTS: Seven of our eight cases showed histologic and immunohistochemical results consistent with previous reports. However, one case showed overlapping histologic features, as previously described by the Bordeaux group. Four cases showed glutamine synthetase immunohistochemical staining inconsistent with their classification, indicating that glutamine synthetase staining may not be diagnostic for beta-catenin-mutated HCA. HNF1alpha-mutated HCA may be indicated by the absence of liver fatty acid binding protein expression. Detection of amyloid A may indicate inflammatory HCA. HCA with no mutation in the HNF1alpha or beta-catenin genes and no inflammatory protein expression is categorized as unclassified HCA. CONCLUSIONS: Although the new classification is now generally accepted, validation through follow-up studies is necessary.
Adenoma, Liver Cell* ; Amyloid ; beta Catenin ; Fatty Acid-Binding Proteins ; Glutamate-Ammonia Ligase ; Hepatocyte Nuclear Factor 1-alpha ; Liver ; Serum Amyloid A Protein

OBJECTIVETo study the expressions of β-catenin in hepatocellular carcinoma (HCC) tissue, adjacent cirrhotic liver tissue and hemangioma-surrounding liver tissue to understand whether their difference in expression will influence on the prognosis and to study the relationship between Wnt/β-catenin signaling pathway and HNF-1α expression.

METHODS50 specimens of HCC, 50 specimens of adjacent cirrhotic liver tissue and 7 specimens of hemangioma-surrounding liver tissue were used to detect the differences in the expression of β-catenin and HNF-1α in them by immunohistochemistry.

RESULTSThe expression rate of β-catenin was 74.0% (37/50) in the HCC tissue, 18.0% (9/50) in cirrhotic liver tissue, and 14.3% (1/7) in hemangioma-surrounding liver tissue. The expression rate of β-catenin in HCC tissue was significantly higher than that in the hemangioma-surrounding liver tissue (P = 0.002) and cirrhotic liver tissue (P < 0.001). The patients with abnormal expression had worse prognosis. Among the 50 HCC cases, the expression of HNF-1&alpha; was negative in 20.0% (10/50), weak positive in 40.0% (20/50), moderately positive in 26.0% (13/50), and strong positive in 14.0% (7/50). Among the 50 adjacent cirrhotic liver tissues, the expression of HNF-1&alpha; was negative in 12.0% (6/50), weak positive in 20.0% (10/50), moderately positive in 52.0% (26/50) and strong positive in 16.0% (8/50). In the 7 cases of hemangioma-surrounding liver tissue, the expression of HNF-1&alpha; was negative in 0(0/7), weak positive in 14.3% (1/7), moderately positive in 28.6% (2/7) and strong positive in 57.1% (4/7). The positive expression rate of HNF-1&alpha; in the HCC tissue was significantly lower than that in the hemangioma-surrounding liver tissues (P = 0.029) and adjacent cirrhotic liver tissues (P = 0.008). The patients with positive HNF-1&alpha; expression had a better prognosis. The abnormal expression of β-catenin was negatively correlated with positive HNF-1&alpha; expression (r = -0.673, P < 0.001).

CONCLUSIONSThe occurrence and development of HCC is related to the abnormal β-catenin expression. There is a negative correlation between Wnt/β-catenin signaling pathway and HNF-1&alpha; expression.

Carcinoma, Hepatocellular ; diagnosis ; metabolism ; Hemangioma ; Hepatocyte Nuclear Factor 1-alpha ; genetics ; metabolism ; Humans ; Immunohistochemistry ; Liver Neoplasms ; diagnosis ; metabolism ; Prognosis ; beta Catenin ; genetics ; metabolism

OBJECTIVETo investigate the genetic and clinical features of mutations and sequence variations of the transcription factor 1 gene (TCF1, HNF-1A) in Chinese with familial early-onset and/or multiplex diabetes mellitus.

METHODSAll ten exons of the TCF1 gene were screened, including exon and intron junctions, by direct sequencing method in 341 unrelated Chinese subjects, including 80 healthy controls and 261 probands of early-onset and/or multiplex diabetes pedigrees.

RESULTSFive mutations were found in all. Four of the 5 different TCF1 mutations were newly identified novel mutations(T82M, Q130H, G253G, P353fsdelACGGGCCTGGAGC), mean body mass index of mutation carriers was 21.9 kg/m (2), and insulin secretion was impaired in the mutation carriers. In this study, the maturity-onset diabetes of the young type III (MODY3) only accounted for 3% of Chinese early-onset diabetes. Moreover, eleven substitutions were identified in 261 probands. Of them, three variants IVS1-8 (G-->A), IVS1 -128 (T-->G ) and IVS2+21 (G-->A) were not observed in 80 healthy controls and one of them IVS1-8 (G-->A) was not reported previously and the two promoter variants co-segregated with diabetes.

CONCLUSIONTCF1 gene is not a common cause of early-onset and/or multiplex diabetes among Chinese patients.

Adult ; Asian Continental Ancestry Group ; genetics ; China ; Diabetes Mellitus ; ethnology ; genetics ; pathology ; Female ; Gene Frequency ; Genotype ; Hepatocyte Nuclear Factor 1-alpha ; genetics ; Humans ; Male ; Mutation ; Polymerase Chain Reaction

BACKGROUNDMutations in the hepatocyte nuclear factor-1A 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.

METHODSWe screened all ten exons of the HNF-1A gene, including exon/intron junctions, by direct sequencing in 272 unrelated Chinese, including 80 healthy controls and 192 probands of early-onset and/or multiplex diabetes pedigrees.

RESULTSIn addition to one silent mutation of c.864 G > C [p.G288G] in exon4 at codon 288, which had been reported previously, a total of four novel mutations including two missense mutations (c.245C > T [p.T82M] and c. 390 G > T [p.Q130H]) and one frameshift mutation P353fsdelACGGGCCTGGAGC and one silent mutation c.759 G > T [p.G253G] were identified. Moreover, eleven substitutions were identified in 192 probands. Of these, three variants (-8 G > A, -128 T > G and IVS2 + 21 G > A) were not observed in 80 healthy controls and one of them (-8 G > A) was not reported previously and the two promoter variants co-segregated with diabetes. The genotype and allele frequencies of the other eight variants in the diabetic patients were not significantly different from those in the healthy controls. No significant relationships were observed between the eight variants of the HNF-1A gene and clinical variables (plasma glucose, insulin, C-peptide and fasting lipid profile).

CONCLUSIONThe prevalence of structural mutations in the HNF-1A gene responsible for familial early-onset and/or multiplex diabetes appears to be rare among Chinese patients.

Adult ; Aged ; Diabetes Mellitus, Type 2 ; genetics ; Female ; Hepatocyte Nuclear Factor 1-alpha ; genetics ; Humans ; Male ; Middle Aged ; Mutation ; Pedigree ; Polymorphism, Genetic

BACKGROUNDS: Gestational diabetes mellitus (GDM) is defined as glucose intolerance with onset or first detection during pregnancy and mostly caused by insulin resistance and beta-cell dysfunction like type 2 diabetes. However, autoimmune or monogenic diabetes can contribute to GDM. Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes characterized by an early age of onset and an autosomal dominant pattern of inheritance. Most MODY cases are attributable to mutations in HNF-1alpha gene, also known as MODY3. We investigated whether mutations in HNF-1alpha gene are present in Korean women with GDM. METHODS: A total of 96 Korean women with GDM who have a family history of DM were screened for mutations in the HNF-1alpha gene. We evaluated the clinical characteristics of GDM women with HNF-1alpha gene mutations. RESULTS: Five of 96 patients (5.2%) were found to have a mutation in HNF-1alpha gene. Four of those (-23C > G, 833G > A (Arg278Gln), 923C > T, IVS5 + 106A > G) were novel and one (-124G > C) in promoter region was reported in previous study. The mean age of GDM women with mutations of HNF-1alpha gene was 34 years. Four women with MODY3 gene mutations required insulin therapy during pregnancy. GDM women with MODY3 gene mutations appeared to be decreased insulin secretion (HOMA-%B) than those without mutations. CONCLUSIONS: We have found the existence of MODY3 as well as novel HNF-1alpha gene mutations in Korean women with GDM.
Age of Onset ; Diabetes Mellitus, Type 2 ; Diabetes, Gestational ; Female ; Glucose Intolerance ; Hepatocyte Nuclear Factor 1-alpha ; Humans ; Insulin ; Insulin Resistance ; Mass Screening ; Pregnancy ; Promoter Regions, Genetic ; Wills

BACKGROUND/AIMS: The prevalence of diabetes in Korea is reported to be approximately 10%, but cases of maturity-onset diabetes of the young (MODY) are rare in Korea. A diagnostic technique for autosomal dominant MODY is being actively sought. In this regard, we used a DNA chip to investigate the frequency of mutations of the MODY3 gene (hepatocyte nuclear factor-1alpha) in Korean patients with early-onset type 2 diabetes. METHODS: The genomic DNA of 30 normal individuals [age, 24.9+/-8.6 years] and 25 patients with early-onset type 2 diabetes (age, 27+/-5.9 years) was extracted, and the MODY3 gene was amplified. The amplified DNA was hybridized onto a MODY3 chip, which has oligonucleotides of 15-25 bases, representing wild-type and mutant MODY3 sequences in both forward and reverse orientations, immobilized on its surface. RESULTS: Among the normal subjects, there was no mutation of MODY3. Among those with early-onset type 2 diabetes, there was one case of MODY3 mutation. CONCLUSIONS: Our results indicate that MODY3 mutations are not rare in Korean early-onset type 2 diabetes patients in Korea and suggest that MODY3 mutations in patients with early-onset type 2 diabetes need to be further evaluated.
Adolescent ; Adult ; Age of Onset ; Asian Continental Ancestry Group/genetics/*statistics & numerical data ; Case-Control Studies ; Cohort Studies ; Diabetes Mellitus, Type 2/*epidemiology/*genetics ; Female ; Hepatocyte Nuclear Factor 1-alpha/*genetics ; Humans ; Korea ; Male ; Mutation/*genetics ; Prevalence ; Young Adult

PURPOSE: Maturity-onset diabetes of the young(MODY) is a subtype of type 2 diabetes defined by autosomal dominant mode of inheritance, onset of diabetes usually before the age of 25 yrs, and a primary defect in the function of the beta cells of the pancreas. MODY3 is known as the most common form and is caused by mutations in hepatocyte nuclear factor(HNF)-1alpha. We examined the prevalence of MODY3 in children with type 2 diabetes mellitus(DM). METHODS: Children with type 2 DM(N=17) and their family members with type 2 DM(N=5) were enrolled. Inclusion criteria for the children were fasting C-peptide and postprandial C-peptide more than 1.0 ng/mL and 1.5 ng/mL respectively, familial type 2 DM in at least two generations, and body mass index(BMI)(kg/m(2)) less than 95th percentile. Genomic DNA was extracted from blood samples. We analyzed HNF-1alpha for mutation by DNA microarray method and direct sequencing. RESULTS: We found one case with a mutation of the promoter region of HNF-1alpha(5'-ctaGGCTAGTGGGGTTTTGCGGGGGCAGTGGGTGCAAGG-3') in one child's family member among 22 children and adult subjects with type 2 DM. CONCLUSION: Although we found a mutation of HNF-1alpha in an adult family member with type 2 DM, we did not find this mutation in a child with type 2 DM. The further investigation of MODY in children, including other types, is required.
Adult ; C-Peptide ; Child* ; Diabetes Mellitus, Type 2* ; DNA ; Family Characteristics ; Fasting ; Hepatocyte Nuclear Factor 1-alpha ; Hepatocytes ; Humans ; Oligonucleotide Array Sequence Analysis ; Pancreas ; Prevalence* ; Promoter Regions, Genetic ; Wills