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N Yano

Publications and source records attributed to N Yano.

At least 19 recordsLinked to original sources
PubMed2006

Effects of tetrabromobisphenol A, brominated flame retardant, in ICR mice after prenatal and postnatal exposure.

Tetrabromobisphenol A (TBBPA), brominated flame retardant, is produced in the largest amounts globally for use in plastics or building materials. TBBPA has been detected in sediment, air at the dismantling plant or human serum samples. In the present study, we examined the effects of prenatal and postnatal exposure to TBBPA in mice. TBBPA (99.1% pure) in diet was administered to pregnant ICR mice at doses of 0% (control), 0.01%, 0.1% or 1.0% from gestational day 0 to weaning at postnatal day 27. The average daily food intake and body weight of dams showed no significant differences between the control and treated groups. There were no dose-related effects on reproductive data. Serum concentrations of total-cholesterol and liver weights of treated dams and offspring were higher than those of the control mice. Histological findings in treated dams or offspring showed the increase of focal necrosis of hepatocytes and inflammatory cell infiltration in the liver, and increase of dilation or atrophy of renal tubules and cyst in the kidney. TBBPA was developed as a new, safe class of flame retardant and was not highly toxic. However, the present data suggested that TBBPA caused a lipid metabolic disorder and hepatic or kidney lesion, under these conditions.

Alanine Transaminase↗
PubMed2004

Expression of thyrotropin-releasing hormone receptor in immortalized beta-cell lines and rat pancreas.

Thyrotropin-releasing hormone (TRH), a hypothalamic tripeptide, is expressed in pancreatic islets at peak levels during the late gestation and early neonate period. TRH increases insulin production in cultured beta-cells, suggesting that it might play a role in regulating pancreatic beta-cell function. However, there is limited information on TRH receptor expression in the pancreas. The aim of the present study was to explore the distribution of the TRH receptor in the pancreas and its function in pancreatic beta-cells. TRH receptor type 1 (TRHR1) gene expression was detected by RT-PCR and verified by Northern blotting and immunoblotting in the beta-cell lines, INS-1 and betaTC-6, and the rat pancreatic organ. The absence of TRH receptor type 2 expression in the tissue and cells indicated the tissue specificity of TRH receptor expression in the pancreas. The TRHR1 signals (detected by in situ hybridization) were distributed not only in islets but also in the surrounding areas of the pancreatic ductal and vasal epithelia. The apparent dissociation constant value for the affinity of [(3)H]3-methyl-histidine TRH (MeTRH) is 4.19 in INS-1 and 3.09 nM in betaTC-6. In addition, TRH induced epidermal growth factor (EGF) receptor phosphorylation with a half-maximum concentration of approximately 50 nM, whereas the high affinity analogue of TRH, MeTRH, was 1 nM. This suggested that the affinity of TRH ligands for the TRH receptor influences the activation of EGF receptor phosphorylation in betaTC-6 cells. Our observations suggested that the biological role of TRH in pancreatic beta-cells is via the activation of TRHR1. Further research is required to identify the role of TRHR1 in the pancreas aside from the islets.

Animals↗
PubMed2001

Chronic toxicity of thiabendazole (TBZ) in CD-1 mice.

Male and female CD-1 mice (50 mice per group) were administered thiabendazole (TBZ) in diet at levels of 0 (control), 0.031, 0.125 and 0.5% for 78 weeks. A life time study was terminated after 78 weeks due to enhanced strain specific mortality. There were no significant differences in mortality between the control and treated groups. Mean body weights of high-dose groups showed significant decreases compared with the controls. The bladder weights of male and female mice of the 0.5% group were significantly higher than those of the control mice. Gross findings in treated mice included the renal atrophy, hydronephrosis, calculi in renal pelvis and/or bladder and ovarian atrophy. Microscopic findings in the kidneys of treated mice included the nephrosis, hydronephrosis or hyperplasia of transitional epithelium of renal pelvis or papilla. In the bladder of treated mice, hyperplasia or squamous metaplasia of transitional epithelium and one transitional cell papilloma were observed. Dose-dependent decreases in the incidence of spontaneous lesion in the male or female reproductive system were recognized. It is concluded that TBZ is not carcinogenic to CD-1 mice of both sexes. However, caution should be exercised in the long-term application of high TBZ doses.

Administration, Oral↗
PubMed2001

Thiabendazole induces urinary tract toxicity in male ICR mice.

Male ICR mice were administered thiabendazole (TBZ) in the diet at concentration of 0 (control), 0.8, 1.2 and 1.6% for 44 weeks. The mortality was 10, 6, 40 or 90% in control, 0.8, 1.2 or 1.6% TBZ group, respectively. In dead mice, the gross findings included the abnormalities of kidney such as atrophy, hydronephrosis or swelling in 2, 67, 95 or 96% of the 0, 0.8, 1.2 or 1.6% TBZ group, respectively. In surviving mice at the end of study, the right kidney weight of treated groups was significantly lower than that of control group. The urinary bladder weight of treated groups was significantly higher than that of control group. Gross findings in treated mice included the renal atrophy, hydronephrosis, calculi in renal pelvis or urinary bladder and thickening of the bladder wall. Microscopic findings in the kidneys of treated mice included nephrosis, hydronephrosis and hyperplasia of transitional epithelium of renal pelvis and/or papilla. In the urinary bladder, hyperplasia or squamous metaplasia of transitional epithelium were found in treated mice. Administration of TBZ in the diet for 44 weeks results in nephrosis and calculus formation in the renal pelvis and urinary bladder of male ICR mice, and is associated with hyperplasia of transitional epithelium of renal pelvis or urinary bladder.

Animals↗
PubMed2001

Goitrogenic effects of green tea extract catechins by dietary administration in rats.

The effects of green tea extract catechins on the rat thyroid were examined in a 13-week feeding study and subsequent 2-,4- and 8-week studies. Commercially available polyphenon-60 (P-60) which contains green tea extract catechins at 66.2% was used as a source of catechins. A basic diet containing different concentrations of P-60 was used for experiments. In the 13-week study, 10 rats of each sex were administered diets containing P-60 at 0 (control), 0.625, 1.25, 2.5 and 5.0%. Goiters were observed in the 13-week test. The mean thyroid weight of rats fed a diet containing 5.0% of P-60 (5.0% group) significantly increased to 444% of the control in males and to 304% of the control in females. Histological examinations of the thyroid of the 5.0% group revealed marked hypertrophy and/or hyperplasia of the follicles, some with depletion of colloid and some with rich colloid, and formation of a fibrous capsule. Slight hypertrophy of follicular cells was observed in male rats fed a diet containing 1.25% of P-60 (1.25% group) and female rats fed a diet containing 2.5% of P-60 (2.5% group). Degree and incidence of thyroid lesions were higher in males than in females in the 1.25, 2.5 and 5.0% groups. In the 2-8-week studies, five rats of each sex were given diets containing 0 (control) and 5.0% of P-60. In the 5.0% group, the mean thyroid weight in males significantly increased to 161% of the control as early as 2 weeks and increased to 357% of the control at 8 weeks. Histologically, these goiters were also associated with follicular cell hypertrophy/hyperplasia as in the 13-week study. The degree and incidence of thyroid lesions were higher in males than in females. These results indicate that dietary administration of the green tea extract catechins at high doses induced goiters in rats, and this may be due to antithyroid effects of catechins. In the 13-week study, the no-observed effect level (NOEL) of green tea extract catechins for F344 rats based on histological changes of the thyroid was considered to be 0.625% in males and 1.25% in females in the diet, respectively.

Administration, Oral↗
PubMed2001

Profiling the adult human liver transcriptome: analysis by cDNA array hybridization.

BACKGROUND/AIMS: A comprehensive profile of genes expressed at the mRNA level (transcriptome) in human liver tissue is important for elucidating the pathogenesis and treatment of hepatic diseases. The recent development of cDNA array hybridization allows the parallel monitoring of thousands of genes expressed in a single organ. METHODS: High-density microarrays containing 4043 known and unique human cDNA gene targets were used to quantitatively analyze the expression of genes in human livers. Expressed gene transcripts were classified by function and listed with information of their chromosomal positions. Computational analysis was used to cluster genes according to similarity in pattern of gene expression. RESULTS: A total of 2418 unique gene transcripts were detected in five liver specimens. Through relational database analysis, we determined 1212 genes that were commonly expressed in 4 of the five liver specimens. Furthermore, analysis of the total 2418 expressed genes by self-organizing maps and hierarchical clustering unexpectedly revealed a genomic acute phase response in two of the liver specimens. CONCLUSIONS: These findings represent a comprehensive preliminary molecular index of genes transcribed in the adult human liver. The information may serve as a resource for speeding up the discovery of genes underlying human hepatic diseases.

Adult↗
PubMed2001

Enhanced interferon-gamma by CD8+ CD28- lymphocytes from HIV+ patients.

Flow cytometric analysis of T cells from HIV+ and normal individuals activated for 15 hr showed that the percentage of cells producing interferon-gamma (INFgamma) was enhanced approximately threefold (39 compared to 14%) in the HIV+ CD8+ population. Activation modes, other than anti-CD3 with PMA, were ineffective, and in no case did the percentage of HIV+ CD4+ T cells show increased INFgamma production over controls. Enhanced INFgamma production was not induced by either anti-CD3 or PMA alone, or anti-CD3 or ConA with anti-CD28, or enhanced by N-acetylcysteine. In contrast to INFgamma production, the percentage of CD4+ T cells producing interleukin-2 (Il-2) greatly exceeded that of the CD8+ T cells. The results from flow cytometry analyses of HIV+ CD8+ T cells was supported by quantitative analysis of INFgamma mRNA (by PCR) and INFgamma secretion by ELISA. These methods showed a sixfold and three- to fivefold increase, respectively, on a per cell basis. As HIV infection progresses, as shown by loss of CD4+ T cells, the proportion of CD8+ CD28- T cells increases, and it is this T cell subset that is responsible for 80% or more of the enhanced INFgamma production. The enhanced INFgamma in HIV+ patients derives from two factors: the increase in CD8+ CD28- cells to 70% and the percentage producing INFgamma (60%, compared to 21% for CD8+ CD28+ cells). Our findings of a substantial increase in INFgamma production in HIV infection arising from the increased number of CD8+ CD28- T cells are compatible with clinical studies which show elevated INFgamma in HIV+ serum and INFgamma producing CD8+ T cells dominating HIV+ lymph nodes. We also found a significantly decreased proliferative response of the HIV+-derived CD8+ T cell fraction with coactivator anti-CD-28, in contrast to PMA (with anti-CD3), which is probably a reflection of the diminished population of CD8+ CD28+ T cells in HIV+ donors compared to normal donors (30.7 compared to 67.9%).

Adult↗
PubMed2000

Immediate contact hypersensitivity induced by repeated hapten challenge in mice.

An immediate reaction was investigated during repeated challenge testing for contact hypersensitivity to dinitrofluorobenzene (DNFB) in BALB/c mice. The mice were sensitized to DNFB on back skin and repeatedly challenged with the same hapten on the left ear at 1 week intervals. The ear after the 5th challenge showed biphasic responses which consisted of an immediate and a delayed-type reaction. The reactions were hapten specific. Mast cell-deficient WBB6F1 W/WV mice did not show any immediate reaction, while congenic normal mice showed both immediate and delayed-type reactions. Histologically, numerous dermal mast cells were found in the left ear of repeatedly challenged BALB/c and WBB6F1 normal mice, while there were few mast cells in the ear of WBB6F1 W/WV mice. Anti-DNP IgE antibodies were detected in BALB/c, WBB6F1 normal and W/WV mice after repeated challenge with DNFB. Intradermal injection of anti-IgE antibodies in the repeatedly DNFB-challenged ear elicited an immediate reaction. These results suggest that immediate contact hypersensitivity develops through the production of anti-DNP IgE antibodies and an increase in dermal mast cells after repeated challenge with DNFB.

Animals↗
PubMed2000

Comprehensive gene expression profile of the adult human renal cortex: analysis by cDNA array hybridization.

BACKGROUND: Profiling of gene expression in healthy and diseased renal tissue is important for elucidating the pathogenesis of renal diseases. Comprehensive information about the genes expressed in renal tissue is unavailable. The recently developed cDNA array hybridization methodology allows simultaneous monitoring of thousands of genes expressed renal tissue. METHODS: Complex [alpha-33P]-labeled cDNA probes were prepared from histopathologically uninvolved remnants of nine renal tissues obtained by nephrectomy. Each probe was hybridized to a high-density array of 18,326 paired target genes. The radioactive hybridization signals by phosphorimager screens were quantitated by special software. Bioinformatics from public genomic databases were used to assign a chromosomal location of each expressed transcript and gene function. Cluster analysis was used to arrange genes according to the similarity in pattern of gene expression. RESULTS: A total of 7563 different gene transcripts was detected in the nine tissue samples. Approximately 870 of these genes were full-length mRNA human transcripts (HT), and the remaining 6693 were expressed sequence tags (ESTs). The full-length transcripts were classified by function of the gene product and were listed with information of their chromosomal positions. To allow a comparison between gene expression in clinical and experimental studies, the mouse genes with known similar function to the human counterpart were included in the bioinformatics analysis. Cluster analysis of 502 full-length genes that are expressed in four or more renal tissues revealed more than 110 genes that are highly expressed in all the renal specimens. CONCLUSIONS: The presented data constitute a comprehensive preliminary transcriptional map of the adult human renal cortex. The information may serve as a resource for speeding up the discovery of genes underlying human renal disease. The integrated listing of the full-length expressed human and mouse genes is available through e-mail (Abdalla_Rifai@Brown.edu).

Adult↗
PubMed2000

Regulation of nitric oxide synthase to promote cytostasis in ovarian follicular development.

Our own recent studies have demonstrated that inducible nitric oxide synthase (iNOS) is predominantly localized in granulosa cells of healthy immature follicles in the rat ovary, whereas granulosa cells of either healthy mature follicles or follicles destined to be atretic are devoid of iNOS. These findings suggest that iNOS is pivotal for immature follicles to remain dormant. To test this hypothesis, we examined the effects of a GnRH agonist (buserelin), a proapoptotic substance, and epidermal growth factor (EGF), a mitogenic and, consequently, antiapoptotic factor, on the amount of iNOS mRNA in rat granulosa cells. Administration of buserelin in immature female rats transiently diminished iNOS mRNA levels in the ovaries as determined by Northern blot analysis. In cultured rat granulosa cells, buserelin and EGF increased the incidence of apoptosis and DNA synthesis, respectively, whereas both reduced iNOS mRNA levels as determined by reverse transcription-coupled polymerase chain reaction. The concomitant addition of S-nitroso-N-acetyl-DL-penicillamine, an NO donor, together with buserelin or EGF eliminated the observed effects of these substances (i.e., induction of apoptosis and stimulation of DNA synthesis, respectively). These results suggest that the changes in developmental status of immature follicles either into development or atresia are associated with reduced iNOS levels in granulosa cells, thus reinforcing the notion of NO as a cytostatic factor in ovarian follicles.

Animals↗
PubMed2000

Comparison of the effects of add-back therapy with various natural oestrogens on bone metabolism in rats administered a long-acting gonadotrophin-releasing hormone agonist.

The hypoestrogenic state induced by gonadotrophin-releasing hormone agonist (GnRHa) has been shown to be effective in the treatment of oestrogen-dependent disorders but to induce bone loss. Adding back low doses of oestrogen in GnRHa therapy has been proposed to prevent bone loss. The purpose of this study is to assess the efficacy of add-back therapy with different natural oestrogens such as oestrone (OE(1)), oestradiol (OE(2)) and oestriol (OE(3)). Three-month-old female rats (250 g) were subcutaneously administered microcapsules of leuprorelin acetate in doses of 1 mg/kg of body weight every 4 weeks. GnRHa therapy lasted 16 weeks, and pellets of OE(1), OE(2) or OE(3) (0.5 mg/pellet, 60 day release), as an add-back agent, were implanted at 8 weeks of treatment. At the end of treatment, GnRHa alone decreased bone mineral density of the femur and lumbar vertebrae, and increased serum levels of bone metabolic markers such as alkaline phosphatase and osteocalcin levels. As for cancellous bone histomorphometry, GnRHa decreased bone volume while it increased osteoid volume, osteoid surface, eroded surface, mineral apposition rate and bone formation rate. All the oestrogens tested prevented these changes caused by GnRHa therapy. GnRHa induced a significant increase in body weight and a marked reduction in uterine weight, which was not observed in OE(1) or OE(2) add-back group. Body weight and uterine weight of the OE(3) add-back group were the same as those of the GnRHa group. These findings indicate that GnRHa induces high turnover bone loss which can be prevented by concomitant administration of natural oestrogens such as OE(1), OE(2) and OE(3) to the same extent. In addition, OE(3) is unique in that it is much less effective than OE(1) and OE(2) in blocking body weight gain and in promoting growth of uterine tissues. Because of its tissue-selective actions, OE(3) could be considered as one of the most appropriate oestrogens used for GnRHa add-back therapy.

Alkaline Phosphatase↗
PubMed1999

Inhibition of human endometrial cancer cell growth in vitro and in vivo by somatostatin analog RC-160.

OBJECTIVE: Our purpose was to investigate the effect of the somatostatin analog RC-160 on the growth of the HEC-1 human endometrial cancer cell line in vivo and in vitro. STUDY DESIGN: Nude mice bearing subcutaneous implanted HEC-1 tumors were treated for 25 days with RC-160 (100 microgram/d) delivered by osmotic minipumps. In cultured HEC-1 cells radioreceptor assay of somatostatin was performed, and the expression of messenger ribonucleic acid for somatostatin receptor subtypes (somatostatin receptors 1-5) was analyzed by reverse transcription-polymerase chain reaction. The effects of RC-160 on epidermal growth factor-stimulated cell proliferation and tyrosine phosphorylation of epidermal growth factor receptor were examined by colorimetric assay and Western blotting, respectively. RESULTS: The treatment with RC-160 resulted in a significant decrease in tumor volume, tumor weight, and serum insulin-like growth factor I levels compared with those values in control animals. The presence of high-affinity somatostatin binding sites and the expression of somatostatin receptor 2 and somatostatin receptor 3 messenger ribonucleic acid were demonstrated in HEC-1 cells by radioreceptor assay and reverse transcription-polymerase chain reaction, respectively. Epidermal growth factor-stimulated proliferation of HEC-1 cells was inhibited by RC-160 in a dose-dependent manner. Western blotting revealed that epidermal growth factor-induced tyrosine phosphorylation of epidermal growth factor receptor was inhibited by RC-160, which suggests that the direct inhibitory effect of RC-160 on HEC-1 cell growth might be mediated in part by interference with epidermal growth factor receptor phosphorylation. CONCLUSION: These results indicate that somatostatin analog RC-160 inhibits the growth of HEC-1 human endometrial cancer cells, thus implying its potential clinical utility in treating endometrial cancer.

Animals↗
PubMed1999

A case of ovarian hyperstimulation syndrome in which antithrombin III deficiency occurred because of its loss into ascites.

OBJECTIVE: To present a case of ovarian hyperstimulation syndrome in which antithrombin III activity in plasma was decreased and in ascites was increased. DESIGN: Case report. SETTING: Hospital-based clinic for reproductive medicine. PATIENT(S): A 27-year-old woman who was transferred to our hospital because of ovarian hyperstimulation syndrome. INTERVENTION(S): Induced abortion. MAIN OUTCOME MEASURE(S): Antithrombin III activity in plasma and ascites. RESULT(S): Antithrombin III activity in ascites was slightly lower than that in plasma. CONCLUSION(S): The loss of antithrombin III into ascites probably caused its deficiency in this case.

Adult↗
PubMed1998

Polymorphism in the Ialpha1 germ-line transcript regulatory region and IgA productivity in patients with IgA nephropathy.

Enhanced in vivo and in vitro production of IgA has been reported in patients with IgA nephropathy (IgAN) and their family members. It is generally considered that IgA1 is a prominent subclass of IgA in IgAN. Although genetic mechanisms of IgA class switch recombination in IgAN have been studied enthusiastically, the critical factors that induce IgA1-specific class switching in IgAN have yet to be elucidated. A large body of data indicates that the germ-line transcript of Ig constant region (C(H)) genes that precedes actual class switching has regulatory effects on class switch recombination. To analyze structural abnormalities in the Ialpha1 germ-line transcript regulatory gene, a region about 1000 bp long located upstream of Ialpha1 exons was surveyed by the PCR-single strand conformation polymorphism method, and the polymorphism detected was confirmed by subsequent DNA sequencing. Three hot spots for point mutation were detected upstream of the promoter region of the Ialpha1 germ-line transcript, and the mutations were observed more frequently in patients than in controls. Patients with the mutations showed higher levels of serum IgA and higher in vitro IgA synthesis. In the luciferase assay, the regulatory gene with the mutations showed a potent effect for induction of the Ialpha1 germ-line transcript. The polymorphism in the Ialpha1 regulatory region possibly causes enhanced IgA production in some patients with IgAN.

Base Sequence↗
PubMed1998

Suppression of intracellular hydrogen peroxide generation and catalase levels in CD8+ T-lymphocytes from HIV+ individuals.

CD8+ T-lymphocytes from HIV+ individuals contain short telomeres, a sign of cell senescence. To test our hypothesis that the cell type is functionally defective in the biochemical indices related to cell proliferation, we investigated the profiles of intracellularly generated H2O2 levels with or without PMA as well as immunoreactive catalase levels using flow cytometric method. We observed that, in HIV+ but not in HIV- individuals, the constitutively generated H2O2 level was significantly lower in CD8+ T-cells compared with CD4+ T-cells. Importantly, activated effector CD8+CD28- cells showed remarkably low H2O2 levels compared with CD8+CD28+ cells, and the latter in HIV+ individuals also showed low levels. A similar defect of CD8+ cells of HIV+ individuals was also seen with H2O2 levels stimulated with PMA in the presence of a catalase inhibitor. Furthermore, the immunoreactive catalase content was lower in CD8+ cells compared with CD4+ cells only in HIV+ individuals. These results suggest that CD8+ T-lymphocytes are functionally defective with the constitutively generated and PMA-elicited levels of H2O2 and the corresponding scavenger. Diminished immunocompetence of HIV+ individuals may be caused, in part, by the functional defect of CD8+ T-cells.

Adult↗
PubMed1998

Evidence for an inverse relationship between apoptosis and inducible nitric oxide synthase expression in rat granulosa cells: a possible role of nitric oxide in ovarian follicle atresia.

Ovarian follicle atresia is thought to be induced through apoptosis of granulosa cells. This study was designed to investigate the possible involvement of nitric oxide (NO) in granulosa cell apoptosis. In immature rat ovaries obtained 48 h after pregnant mare serum gonadotropin administration, immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL), a method to detect apoptotic cells, revealed that inducible NO synthase (iNOS) was predominantly localized in granulosa cells in most healthy immature follicles with TUNEL-negative granulosa cells. In contrast, all atretic follicles with TUNEL-positive granulosa cells were iNOS-negative whatever the developmental stage of the follicle. In cultured granulosa cells, the addition of S-nitroso-N-acetyl-DL-penicillamine (SNAP), an NO generator, directly inhibited spontaneously occurring apoptosis. These results suggest that NO produced by iNOS in granulosa cells of immature follicles may prevent ovarian follicle atresia by inhibiting granulosa cell apoptosis in an autocrine/paracrine manner.

Animals↗
PubMed1998

Liver and kidney function in Japanese patients with maturity-onset diabetes of the young.

OBJECTIVE: Heterozygous mutations in the transcription factors hepatocyte nuclear factor (HNF)-1 alpha, HNF-1 beta, and HNF-4 alpha are associated with maturity-onset diabetes of the young (MODY) and are believed to cause this form of diabetes by impairing pancreatic beta-cell function. The HNFs also play a central role in the tissue-specific regulation of gene expression in liver and kidney, suggesting that patients with MODY due to a mutation in HNF-1 alpha, HNF-1 beta, or HNF-4 alpha may exhibit abnormal liver or kidney function. Here, we have examined liver and kidney function in a series of Japanese patients with HNF-4 alpha/MODY1, HNF-1 alpha/MODY3, and HNF-1 beta/MODY5 diabetes. RESEARCH DESIGN AND METHODS: Clinical and biochemical data were obtained from Japanese subjects with HNF-1 alpha, HNF-1 beta, and HNF-4 alpha diabetes. The clinical data included information on BMI, age at diagnosis, current treatment, and the presence and nature of any complications. The biochemical studies examined liver and kidney function and included measures of alanine and aspartate aminotransferase, gamma-glutamyl transpeptidase, blood urea nitrogen, creatinine, uric acid, total and HDL cholesterol, triglycerides, and 17 serum proteins. RESULTS: The present age and duration of diabetes were similar in patients with HNF-1 alpha, HNF-1 beta, or HNF-4 alpha diabetes, as was the age at diagnosis of diabetes in the youngest generation. All subjects were lean. Of the subjects with HNF-1 alpha and HNF-4 alpha diabetes, 50% were treated with insulin, as were all three subjects with HNF-1 beta diabetes. Retinopathy was present in patients with each form of diabetes. None of the subjects with HNF-4 alpha diabetes had evidence of nephropathy, whereas 36% of the patients with HNF-1 alpha diabetes and 100% of those with HNF-1 beta diabetes showed diminished kidney function. The three subjects with HNF-1 beta diabetes also had abnormally high serum creatinine, uric acid, and blood urea nitrogen levels, which are consistent with impaired kidney function, and one of seven subjects with HNF-1 alpha diabetes had a mild elevation in creatinine and blood urea nitrogen levels. These values were within the normal range in the three patients with HNF-4 alpha diabetes. Although the HNFs play a role in regulating the expression of the genes for most, if not all, serum proteins, there was no decrease in the levels of any of the 17 serum proteins examined, and most were within or slightly above the normal range. Lipoprotein(a) [Lp(a)] levels were elevated in the three patients with HNF-4 alpha diabetes and in one patient with HNF-1 beta diabetes, and in a second patient with HNF-1 beta diabetes, Lp(a) was at the upper limit of normal. CONCLUSIONS: The results indicate that as in white patients, MODY resulting from mutations in the HNF-1 alpha, HNF-1 beta, and HNF-4 alpha genes in Japanese patients may be a severe disease similar to classic type 2 diabetes. In addition, they suggest that patients with HNF-1 beta diabetes may be characterized by diminished kidney function and perhaps abnormal liver function. Further studies are needed to determine whether tests of liver and kidney function will be useful in the diagnosis and subclassification of MODY.

Adolescent↗