Biomedical subjects

A Matsutani

Publications and source records attributed to A Matsutani.

At least 37 records · Page 2Linked to original sources

PubMed1995

Sequence variations of the pancreatic islet/liver glucose transporter (GLUT2) gene in Japanese subjects with noninsulin dependent diabetes mellitus.

To assess the genetic susceptibility to noninsulin-dependent diabetes mellitus (NIDDM) in Japanese subjects, we investigated the role of GLUT2 gene defects in patients with NIDDM. When the allelic frequency of a simple tandem repeat polymorphism in the GLUT2 gene was compared, the allele with 155 base pairs was more common in NIDDM patients (n = 99) than in controls (n = 89; 5.1% vs. 0.6%; P = 0.0118, by Fisher's exact test), whereas this was not significant after the correction for multiple comparisons. To directly identify mutations, we then analyzed each of 11 exons by the polymerase chain reaction-single strand conformation polymorphism analysis in 60 NIDDM patients. We found 2 missense mutations in exon 3: CCC-->CTC (Pro68-->Leu) in 1 patient and ACT-->ATT (Thr110-->Ile) in 3 patients, all in the heterozygous state. These mutations were not found in 60 control subjects. To evaluate the significance of the Pro68-->Leu mutation, the family members of the proband were studied. The mutation did not appear to be associated with the disease or other clinical parameters including change in immunoreactive insulin/change in plasma glucose or oral glucose load. The other mutation (Thr110-->Ile) is known to be functionally insignificant. We identified 4 additional nucleotide changes, all of which appeared to be silent. We concluded that the mutations in the GLUT2 gene were not major determinants of genetic susceptibility to NIDDM in Japanese.

Adult↗

PubMed1994

Insulin-like effects of vanadate on rat liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase mRNA and protein inductions in diabetic rats.

Effects of vanadate on liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (6PF-2-K/F-2,6-P2ase) mRNA and protein inductions were examined in streptozotocin (STZ)-induced diabetic rats. In diabetic rats at one week after STZ (60 mg/kg body weight), the liver 6PF-2-K activity was decreased to 22% of the control. The enzyme protein was also decreased to 31% of the control, but the reduction in mRNA was not significant. Treatment of diabetes with vanadate (10 mg/kg BW, i.v., every 8 h), as well as insulin (10 u/kg BW, s.c., every 8 h), increased the 6PF-2-K activity and the enzyme protein content, though it was not completely restored to the control level. 68% of the control was the figure for enzyme activity and 65% of the control for protein content after 24-h of treatment. On the other hand, vanadate, like insulin, increased enzyme mRNA content to a higher level than the control (140% of the control). The present results indicate that vanadate, like insulin, modulates the liver 6PF-2-K/Fru-2,6-P2ase gene expression, and stimulated protein induction contributes to the regulation of its enzyme activity, resulting in amelioration of the deranged carbohydrate metabolism in the diabetic state.

Animals↗

PubMed1994

[Defects of candidate genes in Japanese NIDDM--glucose transporter gene(GLUT1 gene, GLUT4 gene)].

To assess the contribution of GLUT1 and GLUT4 genes to NIDDM susceptibility in Japanese population, we performed population studies using RFLP markers. We found the strong association between XbaI polymorphism at GLUT1 gene and NIDDM, but no association between KpnI polymorphism at GLUT4 gene and NIDDM. Based on these results, molecular scanning of GLUT1 gene was performed using SSCP and direct sequencing in Japanese population, to substantiate the gene defect predisposing to NDDM. Although silent mutations were found, the meaningful mutations within the coding regions were not demonstrated. Thus the positive association observed in population study may be spurious or due to the abnormalities in non-coding regions such as promoter or other regulatory elements at GLUT1 gene.

Asian People↗

PubMed1993

Polymorphic microsatellite repeat markers at the glucokinase gene locus are positively associated with NIDDM in Japanese.

To assess the possible role of glucokinase defects contributing to a genetic susceptibility to NIDDM in Japanese, allelic frequencies of two microsatellite repeat polymorphisms, one in the 3'-flanking region (GCK1) and the other in the 5'-flanking region (GCK2) of the human glucokinase gene, were analyzed in subjects with NIDDM and in nondiabetic control subjects. After typing 107 diabetic and 74 nondiabetic subjects, we found four GCK1 alleles (Z, Z2, Z4, Z6) and six GCK2 alleles (0, -4, -2, 2, 4, 8). The frequency distribution of GCK1 alleles was different between the two groups (P = 0.005), although not significant after correction for multiple comparisons. The Z4 allele was found more frequently in diabetic than in nondiabetic subjects (23 vs. 10%, P = 0.002). This was still significant after correction for multiple comparisons (P < 0.05). The frequency distribution of GCK2 alleles was not different between the two groups. However, the -2 allele was more common in diabetic than in nondiabetic subjects (P = 0.044), although not significant after adjusting for multiple comparisons. Clinical characteristics were compared between the diabetic subjects with Z4 and/or -2 allele and those without either of these two alleles. No differences were found in the age of diagnosis, positive family history, mode of therapy, current HbA1c, or daily urinary C-peptide immunoreactivity excretion between the two groups. We demonstrated a significant association between GCK1 and GCK2 alleles and NIDDM. The results indicate that the polymorphic alleles GCK1 and GCK2 could be genetic markers in NIDDM in Japanese, suggesting a relationship between glucokinase defects and the susceptibility to NIDDM in this population.

Adult↗

PubMed1992

Effects of tolbutamide on fructose-2,6-bisphosphate formation and ketogenesis in hepatocytes from diabetic rats.

To assess the extrapancreatic action of sulfonylurea directly in the diabetic, effects of tolbutamide on hepatocyte fructose-2,6-bisphosphate (F-2,6-P2) formation and ketone production were investigated using isolated hepatocytes from streptozotocin (STZ)-induced diabetic rats. The basal level of hepatocyte F-2,6-P2 was significantly higher in diabetic rats within 2 weeks after STZ (40 mg/kg body weight) injection compared with that in the nondiabetic control group. Ultimately, a marked decrease in the F-2,6-P2 level was observed at 4 weeks after STZ administration (10% of the control). Although the addition of tolbutamide further increased the hepatocyte F-2,6-P2 level during the first week after STZ injection, no significant effect was observed after the second week and on from the initial STZ. Treatment of diabetes with insulin restored the stimulatory effect of tolbutamide on the hepatocyte F-2,6-P2 formation. Tolbutamide, independently of insulin treatment, lowered the ketone production of hepatocytes from diabetic rats. The present results indicate that insulin is necessary, in advance, for sulfonylurea to stimulate the liver F-2,6-P2 formation, while tolbutamide inhibition of hepatocyte ketone production is independent of insulin. These results provide further support for the role of sulfonylurea in regulating hepatic energy metabolism in the diabetic.

3-Hydroxybutyric Acid↗

PubMed1992

Mapping the human liver/islet glucose transporter (GLUT2) gene within a genetic linkage map of chromosome 3q using a (CA)n dinucleotide repeat polymorphism and characterization of the polymorphism in three racial groups.

The human liver/islet glucose transporter (GLUT2), a candidate gene for diabetes, has been incorporated into a genetic linkage map for chromosome 3q using a (CA)n dinucleotide repeat polymorphism adjacent to the 3'-end of exon 4a. We have found a total of nine alleles ranging in length from 153 to 169 nucleotides in three racial groups and have determined the precise structure of the variable region for four of the alleles by DNA sequencing. Five alleles were found to be common to the American Black, Caucasian, and Pima Indian racial groups studied. One allele (169 bp) was unique to American Blacks, and another rare allele (153 bp) was found only in the Caucasian population studied. Observed heterozygosity of the polymorphism in the Caucasian (CEPH) reference pedigree collection is 60%, for American Blacks 71%, and for Pima Indians 53%. An independent study recently identified the same dinucleotide repeat and found six alleles in a Caucasian population (Froguel et al., 1991), a result that we confirm; however, our sequencing data indicate a different molecular structure for the polymorphism for some of the alleles. We have constructed a new genetic linkage map of chromosome 3q uniquely placing the GLUT2 gene between flanking markers D3S26 and D3S43. The genetic map consists of 23 loci (25 RFLPs and 2 (CA)n dinucleotide repeat markers) with 14 markers uniquely localized with odds of at least 1000:1. Three genes (FTHL4, TF, GLUT2) are integrated into the map, which spans a sex-average distance of 147.3 cM, 103.8 cM in males and 227.0 cM in females.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗

PubMed1992

A polymorphic (CA)n repeat element maps the human glucokinase gene (GCK) to chromosome 7p.

A compound imperfect dinucleotide repeat element, [CA]4TTTGT[CT]7[CA]9AA[CA]4CCACATA[CA]3, was found approximately 10 kb 3' to the human glucokinase gene (GCK) from analysis of contiguous genomic DNA obtained from a bacteriophage lambda chromosome walk. Direct human genomic sequencing revealed the source of polymorphism to be variable numbers of CT and CA repeats. Altogether six alleles that range in length from +10 to -15 nucleotides compared to the most common (Z) allele have been identified. Alleles Z, Z + 2, and Z + 4 were present in American Blacks, Pima Indians, and Caucasians, with somewhat varied frequencies among the groups. Two alleles, Z + 10 and Z - 15, appear to be unique to American Blacks, while a Z + 6 allele was observed only in the Caucasian population studied. Observed heterozygosity of the polymorphism in the CEPH reference pedigree collection is 44% and the PIC 0.44. The polymorphism is assayed by PCR amplification and resolution of 32P-end-labeled products (ranging in length from 180 to 205 bp) on denaturing polyacrylamide sequencing gels. Using the PCR assay, the human glucokinase gene was physically localized to chromosome 7 in a panel of rodent/human somatic cell lines. Genetic analysis in CEPH pedigrees placed the dinucleotide repeat element, and thereby the human glucokinase gene, on chromosome 7p between TCRG and a RFLP locus D7S57. The glucokinase dinucleotide repeat genetic marker can now be used to assess the role of the glucokinase gene in diabetes by population association studies. In addition, this repeat marker and others flanking it on chromosome 7 can be used in linkage studies with families segregating the disorder.

Alleles↗

PubMed1992

Human glucokinase gene: isolation, structural characterization, and identification of a microsatellite repeat polymorphism.

The gene encoding human glucokinase (ATP:D-hexose 6-phosphotransferase, EC 2.7.1.1), a major component of glucose sensing in pancreatic islet beta-cells, was isolated and characterized. The gene was shown by Southern blotting to exist as a single copy in the genome which mapped to chromosome 7p. It contained 12 exons including two tissue-specific first exons, one active in islet beta-cells (1B), and the other active in liver (1H), and one optional cassette exon which was expressed as a minor form in the liver. Thus the three previously reported isoforms of glucokinase mRNA were the result of tissue-specific activation of separate liver and islet promoters and subsequent alternative splicing events. Eleven exons, including 1H and the optional cassette exon 2A, were scattered over 16 kilobase (kb) in the genome, while exon 1B was separated from the rest by at least 20 kb. Although the islet promoter was found to lack a TATA box, a major transcript from the islet promoter was mapped 486 nucleotides upstream of the translation initiation site. The presence in the islet glucokinase promoter of the potential control element GCCACCAG, a homology of the regulatory element present in both human insulin (GCCACCGG) and rat insulin (GCCATCTG) genes, implied a possible tissue-specific regulatory role of this element. The liver promoter was found to contain a TATA box-like sequence, and transcription was initiated predominantly at 168 nucleotides upstream of the translation initiation site of the major isoform. A new highly polymorphic microsatellite, composed of a compound imperfect dinucleotide repeat [GT]15[GA]8CA[GA]7CA[GA]3AA[GA]2, was mapped 6 kb upstream of islet exon 1. A polymerase chain reaction-based assay was developed, and seven different sized alleles were identified in American Blacks. The sequence information reported here, along with the new polymorphic marker, will make it possible to clarify the molecular basis of potential glucokinase defects in noninsulin-dependent diabetes mellitus patients and may further elucidate the nature of genetic susceptibility to the development of this common metabolic disease.

Amino Acid Sequence↗

PubMed1992

Linkage analysis of GLUT1 (HepG2) and GLUT2 (liver/islet) genes in familial NIDDM.

Familial NIDDM probably results from combined inherited defects of insulin secretion and action. Members of the facilitative glucose transporter family are strong candidates for both defects, and RFLPs for both GLUT1 (erythrocyte) and GLUT2 (liver/islet) genes have been associated with NIDDM in some populations. To test the hypothesis that GLUT1 and GLUT2 mutations contribute to the inherited predisposition to NIDDM, we examined linkage of these loci with NIDDM in 18 large Utah white pedigrees (two and three generation) ascertained for > or = 2 NIDDM siblings. We used two RFLPs detected with Xba1 and Stu1 for the GLUT1 transporter. For the GLUT2 (liver/beta-cell) transporter gene, we used an RFLP detected with EcoR1 and a highly polymorphic (6-allele) dinucleotide (microsatellite) repeat. Analysis was performed with the MLINK program of the LINKAGE package. We tested four models for each locus: dominant and recessive, with IGT alternately considered as unknown affection status, or affected if IGT was diagnosed < or = 45 yr of age and unknown if > 45 yr. Disease gene frequencies were chosen to give approximate disease prevalence in American whites (q = 0.03, dominant; q = 0.25, recessive). Linkage of GLUT1 and NIDDM was strongly and significantly rejected under all models, with total (pooled) LOD scores of -5.7 to -8.9, indicating > 500,000:1 odds against linkage. Pooled LOD scores were significantly negative (< -2.0, or 100:1 odds against linkage) to a recombination fraction of > 5%. No heterogeneity was apparent. Analysis of GLUT2 gave similar results, with LOD scores of < -4.0 under each model, indicating at least 10,000:1 odds against linkage.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1992

Tolbutamide inhibits cAMP-dependent phosphorylation of liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase.

The activity of a bifunctional enzyme, liver 6-phosphofructo-2-kinase (PFK-2)/fructose-2,6-bisphosphatase (F-2,6-Pase), which regulates the level of liver fructose-2,6-bisphosphate (F-2,6-P2), the most potent activator of PFK, is modulated by its phosphorylation rate mainly catalyzed by cAMP-dependent protein kinase A (PKA). To elucidate the action mechanism of sulfonylurea on liver F-2,6-P2 production, effects of tolbutamide on PKA-dependent phosphorylation of purified liver PFK-2/F-2,6-Phase protein and on kinase and phosphatase activities of the purified enzyme were examined in vitro. The purified enzyme was phosphorylated in the presence of the catalytic subunit of PKA, and tolbutamide inhibited the enzyme phosphorylation catalyzed by PKA in a dose-dependent manner. By adding the same dosages of tolbutamide used in the phosphorylation experiment, reduced activity of PFK-2 and increased activity of F-2,6-Pase in the presence of PKA were restored to the levels observed in the absence of PKA. On the other hand, carboxytolbutamide, an inactive metabolite of tolbutamide, had little effect on enzyme phosphorylation and activity. Our results indicate that tolbutamide inhibits a phosphorylation of the liver PFK-2/F-2,6-Pase catalyzed by PKA along with an activation of PFK-2 and an inactivation of F-2,6-Pase, leading to liver F-2,6-P2 production.

Animals↗

PubMed1991

Possible mechanism of proteolysis for the extrapancreatic action of tolbutamide.

In order to assess the mode of the extrapancreatic action of the sulfonylureas, we evaluated the contribution of a proteolytic mechanism for sulfonylurea action by analyzing the effects of a protease inhibitor on insulin- or tolbutamide-stimulated liver fructose-2,6-bisphosphate (F-2,6-P2) formation using isolated rat hepatocytes. The F-2,6-P2 level in hepatocytes was significantly increased by the addition of insulin or tolbutamide. The stimulatory effect of insulin on the F-2,6-P2 formation was most significant when its level was reduced by the addition of 2 microM of forskolin. Insulin action on F-2,6-P2 formation was inhibited by the addition of a protease inhibitor, p-tosyl-L-arginine methyl ester hydrochloride (TAME). Tolbutamide (2 mM) significantly increased hepatocyte F-2,6-P2 level (P less than 0.01 vs the control level). In the presence of TAME, the stimulatory effect of tolbutamide was also suppressed. The present data suggest that a proteolytic mechanism is important in both insulin and tolbutamide action on the F-2,6-P2 formation, and it may be hypothesized that, like insulin, the chemical mediator of tolbutamide action is formed proteolytically.

Animals↗

PubMed1990

Polymorphisms of GLUT2 and GLUT4 genes. Use in evaluation of genetic susceptibility to NIDDM in blacks.

The liver/islet (GLUT2) and muscle/adipose tissue (GLUT4) glucose-transporter gene products, membrane proteins that facilitate glucose uptake into cells, are important molecules for normal carbohydrate metabolism. Recent isolation of the genes encoding these proteins provides a means to assess the role of possible defects that might contribute to impaired glucose-stimulated insulin secretion or impaired insulin-mediated glucose uptake, both prominent phenotypic features of non-insulin-dependent diabetes (NIDDM). A GLUT2 cDNA clone was isolated from a human liver cDNA library to search for polymorphisms at this locus in American Blacks. Three highly polymorphic sites were identified, one of which (EcoRI-Hae III) appears to be due to an insertion and/or deletion of 200 base pairs of DNA. Significant linkage disequilibrium between these sites over approximately 30 kilobases of genomic DNA suggested that these polymorphisms could be in linkage disequilibrium with mutations at this locus if they exist. A GLUT4 cDNA clone was also utilized to search for polymorphisms at this locus, but only one previously described polymorphism was observed. GLUT2 and GLUT4 cDNA probes were used to evaluate DNA polymorphisms in genomic DNA from American Blacks with NIDDM. The allelic, genotypic, and haplotypic frequencies of the DNA polymorphisms at these loci did not differ from the frequencies in nondiabetic subjects. Because no associations with NIDDM were found, it appears unlikely that mutations at these loci contribute in a major way to the genetic susceptibility to NIDDM observed in American Blacks.

Alleles↗

PubMed1990

Polymorphisms of HepG2/erythrocyte glucose-transporter gene. Linkage relationships and implications for genetic analysis of NIDDM.

To assess the contribution of the HepG2/erythrocyte glucose-transporter (HepG2 GT) gene to the inherited susceptibility to non-insulin-dependent diabetes mellitus (NIDDM), cDNA and genomic probes were used to search for restriction-endonuclease polymorphisms at this locus. Analysis of DNA from 16 unrelated Black American individuals with 19 enzymes and as many as six different probes, defined four polymorphisms over a 45-kilobase region. Nucleotide diversity (pi = 0.006) was low relative to that at other loci, with an average of 1 in 1700 base pairs different between two chromosomes at this locus. The observed combined heterozygosity for these four sites was 0.69, which indicates that the markers at this locus could be useful for linkage analysis in families. Linkage-disequilibrium values between the four polymorphisms were evaluated by pairwise analysis and extended haplotypes. Calculating pairwise associations by the disequilibrium statistic delta or by another measure of disequilibrium, D' (the maximum likelihood of disequilibrium, which is less dependent on frequency), significant linkage disequilibrium could not be demonstrated. However, the frequencies of the observed extended haplotypes were shown to differ (chi 2 = 9.1, df = 2, P less than 0.025) from predicted frequencies if the sites were in linkage equilibrium in Blacks. The frequencies of these four polymorphisms were determined in Black nondiabetic (n = 44) and NIDDM (n = 63) subjects. Neither the allelic nor genotypic frequencies of the polymorphisms differed between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Black People↗

PubMed1989

[Clinical experience of chemotherapy with cefmetazole for severe infections accompanying malignant hematological disorders].

We made an attempt to treat with cefmetazole (CMZ) 25 patients who developed severe infectious diseases while suffering with granulocytopenia associated with the treatment of malignant hematological disorders. 1. Determination of bacteriological efficacy While 20 strains were isolated and identified from 15 patients, no significant bacteria were detected in 9 patients. Isolates obtained were: 5 strains of Enterococcus faecalis, 3 strains of Haemophilus influenzae, 2 strains of Staphylococcus epidermidis, 2 strains of Klebsiella oxytoca, 2 strains of Staphylococcus aureus, and 1 strain each of Neisseria sp., Pseudomonas maltophilia, Enterobacter sp., alpha-Streptococcus, beta-Streptococcus and Gram-positive cocci. Causative organisms were eradicated or markedly in 7 of the 15 patients from whom bacteria were isolated. Clinical findings, including fever, revealed that none of the patients, in whom bacteriological efficacy was determined to be poor, exhibited sufficient clinical response. E. faecalis was isolated from 4 of 6 patients bacteriologically determined to have no response. 2. As for 23 patients, who were found to be evaluable among the 25 patients, 8 (34.8%), 4 (17.4%), 4 (17.4%), and 7 (30.4%) demonstrated excellent, good, fair and poor responses, respectively, showing a 69.6% efficacy rate which indicates a sum of percentages of patients with excellent, good and fair responses. 3. While an efficacy rate of 100% was obtained for 3 patients with number of peripheral neutrophils less than 500/mm3 before the beginning of CMZ administration, only an efficacy rate of 66.7% was obtained for 15 patients with neutrophils more than 500/mm3.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1987

A clinical evaluation of transcatheter arterial embolization on hepatocellular carcinoma.

TAE was performed in 49 cases of HCC for clinical assessment of the usefulness. This procedure was aimed to subside intraperitoneal hemorrhage in 8 cases among them and to provide a possible antitumor effect in the remaining 41 cases. The prognosis in the 8 cases of intraperitoneal hemorrhage was 54.9 +/- 41.1 days including one case survived as long as 116 days. The prognosis in the remaining 41 cases was 12.6 +/- 8.3 months in group A, 7.8 +/- 6.1 months in group B and 1.6 +/- 1.3 months in group C according to Child's classification, while it was 2.8 +/- 2.5 months in 1st branch occluded, 9.4 +/- 6.1 months in IInd branch occluded and 19.2 +/- 6.7 months in IIIrd branch occluded group according to the portal vein occlusion due to tumor thrombi suggesting that a more prolonged survival was attained with more favorable degree of Child's classification and less affected portal embolization. The cumulative survival time (by Kaplan-Meier's methods) was 6 months in 89% of the cases examined, 1 year in 59%, 2 years in 34% and 3 years or more in 11%, indicating significantly higher survival as compared to our TAI group. Angiographic re-opening of tumor vessel within 3 months was observed in 46.7%. TAE on HCC was useful both for the purpose of antitumor effect and of hemostasis. The degree of Child's classification and severity of portal occlusion at the initial examination may closely relate to the prognosis. Thus, angiography should be repeated within 3 months following the first TAE at least.

Adult↗

PubMed1987

[Relationship between clinical efficiency of cefoperazone and the value of area under the time concentration curve in infectious diseases].

Clinical efficiency and side effects of cefoperazone (CPZ) against 40 infectious diseases in the field of internal medicine were studied. In addition, relationship between clinical efficiency and the value of area under the time concentration curve (AUC) was evaluated. It was possible to evaluate clinical responses in 36 cases of 40 infections; Responses were excellent in 15, good in 16, fair in 3 and poor in 2. An overall efficacy rate was 86.1%. A high dose of CPZ (2 g X 2/day) produced a higher efficacy rate than a low dose of the drug (1 g X 2/day) [95.8% (23/24 cases) vs. 66.7% (8/12 cases)] but the difference was not statistically significant. It was possible to evaluate bacteriological efficacy in 32 cases. Bacteria were eradicated in 29 (90.6%) and decreased in 3. The value of AUC in the high dose group was significantly higher than that in the low dose group. Values of AUC in cases of excellent or good clinical responses tended to be higher than values in cases of fair or poor responses. Side effects were noted in 4 cases, but they were not serious and improvements were observed without withdrawal of the drug except 1 case.

Adolescent↗

PubMed1986

Effect of tolbutamide on fructose-6-phosphate,2-kinase and fructose-2,6-bisphosphatase in rat liver.

The effects of tolbutamide on the activities of fructose-6-phosphate,2-kinase and fructose-2,6-bisphosphatase were examined using rat hepatocytes. Tolbutamide stimulated fructose-6-phosphate,2-kinase activity and inhibited fructose-2,6-bisphosphatase activity, resulting in an increase of fructose-2,6-bisphosphate level. Changes in the activities of the enzyme by tolbutamide were due to variation in the Km value, but not dependent on alteration of Vmax. Glucagon inhibition of fructose-2,6-bisphosphate formation resulting from an inactivation of fructose-6-phosphate,2-kinase and an activation of fructose-2,6-bisphosphatase was released by tolbutamide. Tolbutamide stimulation of fructose-2,6-bisphosphate formation through regulation of fructose-6-phosphate,2-kinase/fructose-2,6-bisphosphatase may produce enhancement of glycolysis and inhibition of gluconeogenesis in the liver.

Animals↗

PubMed1984

Tolbutamide stimulates fructose-2, 6-bisphosphate formation in perfused rat liver.

Effect of tolbutamide on liver fructose-2,6-bisphosphate (F-2,6-P2) was examined in isolated perfused rat liver in situ with a flow-through method. Tolbutamide (1 mM) gradually increased liver F-2,6-P2 level from 7.4 +/- 1.6 to 21.2 +/- 1.6 pmol/mg wet wt for 20 min perfusion. The increase of liver F-2,6-P2 induced by tolbutamide was dose dependent and was significantly observed at 10 min perfusion. The maximum plateau level of F-2,6-P2 induced by 16.7 mM glucose was further increased with 1 mM tolbutamide. Glucagon (10(-11) M) decreased the elevated level induced by 16.7 mM glucose, but this effect was completely inhibited with 2 mM tolbutamide. Cyclic AMP level of the liver throughout the perfusion with tolbutamide did not change. Carboxytolbutamide or gliclazide perfusion did not change significantly the liver F-2,6-P2 level; however, the results suggest that tolbutamide may increase the liver F-2,6-P2 level by affecting the phosphorylation state of fructose-6-phosphate, 2-kinase/fructose-2,6-bisphosphatase through cyclic AMP-dependent protein kinase, resulting in the stimulation of glycolysis and the inhibition of gluconeogenesis in the liver. Thus, the extrapancreatic action and the mechanism of action of different sulfonylureas may differ.

Animals↗