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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our previous investigations demonstrated that unsuppressed gluconeogenesis under hyperinsulinemia in newborn dogs may be a mechanism of neonatal hyperglycemia. In the present study, the transcription of the gene for fructose-1,6-bisphosphatase (fru-1,6-P2ase; E 3.1.3.11) of newborn dogs was studied under various metabolic perturbations (age, suckling, fasting, and hyperinsulinemia). Total RNAs isolated from livers and kidneys were hybridized with a rat fru-1,6-P2ase cDNA probe. We observed that (i) fru-1,6-P2ase mRNA was expressed in both kidney and liver at birth and was about 40 and 80% of those in kidney and liver of adult dog, respectively; (ii) suckling decreased the kidney fru-1,6-P2ase mRNA level to 77.8 +/- 1.7% (24 h) from 100.0 +/- 8.0% (4 h), but increased liver mRNA to 158.6 +/- 11.4% (24 h) from 100.0 +/- 2.3% (4 h); (iii) during a 24-h period of fasting, the kidney fru-1,6-P2ase mRNA level did not change in the first 10 h and then increased 18.5% at 24 h, whereas the liver fru-1,6-P2ase mRNA increased ca. 20% during the first 10 h and then up to 161.1 +/- 18.0% at 24 h compared to that at 100.0 +/- 11.4% (0 h); (iv) euglycemic hyperinsulinemia did not change the renal fru-1,6-P2ase mRNA level, but lowered the hepatic fru-1,6-P2ase mRNA level to 56.0 +/- 8.7 from 100.0 +/- 11.8% (fasted controls) in newborn dogs, which was identical to that in adult dogs. These data suggest that the fru-1,6-P2ase in liver may play a more important role in glucose homeostasis of newborn dogs than that in kidney during the first day of their lives and that the incomplete suppression of transcription of the hepatic fru-1,6-P2ase gene by insulin in newborn dogs may not contribute to neonatal hyperglycemia due to insulin resistance.
Biochem Mol Med 1997 Apr
PMID:Developmental aspects of transcription of fructose-1,6-bisphosphatase in newborn dogs. 916

Type 1 diabetes mellitus is caused by a lack of insulin that results from the autoimmune destruction of the pancreatic beta-cells. Severe diabetes, if not controlled by periodic insulin injections, can lead to ketoacidosis and death. We have previously shown that sustained low level production of insulin in the liver of diabetic rats prevented their death from complications of diabetes. To test the hypothesis that there is a window of serum insulin concentrations that can prevent ketoacidosis without significant risk of hypoglycemia secondary to hyperinsulinemia, rats were infused with various doses of a recombinant retrovirus encoding an engineered rat preproinsulin-1 gene. The gene was engineered to allow processing into mature insulin by the protease furin. At the lower doses tested, fatal ketoacidosis was prevented, but the rats exhibited nonfasting hyperglycemia. At intermediate doses, which resulted in serum insulin concentrations of 1.6 mg/ml, the rats achieved near-normoglycemia and no serum ketones. These rats did not exhibit hypoglycemia even during a 24-h fast. At high virus doses, the animals achieved nonfasting normoglycemia but exhibited hypoglycemia during the fast. In conclusion, we have defined a therapeutic window of hepatic insulin expression that provides protection against ketoacidosis without significant risk of hypoglycemia. This window of sustained hepatic insulin expression might permit its development into a novel treatment modality for the prevention of ketoacidosis in patients with severe insulin-dependent diabetes mellitus.
Mol Endocrinol 1997 Jun
PMID:Hepatic insulin gene expression as treatment for type 1 diabetes mellitus in rats. 917 Dec 46

Current amino acid and monosaccharide transport models are based on an assumption which equates the intracellular chemical activity of a solute with its concentration. This assumption was tested for alpha-aminoisobutyric acid and 3-O-methylglucose in a giant cell, the amphibian oocyte, by using recently developed cryomicrodissection and internal reference phase techniques. We found the following. (i) alpha-Aminoisobutyric acid and 3-O-methylglucose activities were much greater in cytoplasm than was suggested by concentration data; i.e., activity coefficients were higher than in ordinary water solutions. This is attributable to the inaccessibility of considerable water as solvent (solute exclusion). (ii) Solute concentrations varied regionally as follows: nucleus > > animal cytoplasm > vegetal cytoplasm. Insulin increased the nucleus/cytoplasm concentration asymmetry, apparently by increasing cytoplasmic solute exclusion. (iii) Nuclear activity coefficients more closely resembled those of ordinary saline solutions so that nucleus/ extracellular concentration ratios reflected transmembrane activity gradients better than did cytoplasm (or whole cell)/extracellular ratios. (iv) Mediated passive alpha-aminoisobutyric acid and 3-O-methylglucose transport were constituent oocyte membrane properties. Membrane active transport was initiated with time (in the presence of substrate) and by insulin. (v) Increased temperature mimicked insulin in enhancing transmembrane alpha-aminoisobutyric acid activity gradients and increasing the nucleus/cytoplasm concentration asymmetry. These results indicated that concentration data are a misleading measure of cellular amino acid and monosaccharide activity; some consequences of this observation were explored. A model is proposed in which cell water has reduced solvent capacity or is compartmentalized (considered less likely) and is susceptible to physiological modulation. The model accounts for many observations in small cells, suggesting generality of the exclusion phenomenon and a previously unrecognized metabolic control mechanism.
Mol Cell Biol 1981 Sep
PMID:Intracellular monosaccharide and amino acid concentrations and activities and the mechanisms of insulin action. 927 90

Members of the ATP-binding cassette (ABC) transporter superfamily are mutated to cause diseases that include cystic fibrosis, hyperinsulinemia, adrenoleukodystrophy, Stargardt disease and multidrug resistance. We recently isolated a novel human member of ABC transporter superfamily as the candidate transporter for the glucuronide and glutathione-conjugated antitumor agents, and found it highly homologous to the rat cmoat gene. consistent with recent findings of defects in the homologous cmoat gene in two rat models of hyperbilirubinemia (TR- and Eisai), we report two deletions and a missense mutation in the active transport family signature region in the gene in patients with hyperbilirubinemia II/Dubin-Johnson syndrome (DJS; MIM 237500), respectively. These results strongly implicate the cMOAT gene as responsible for the defects in DJS patients.
Hum Mol Genet 1998 Feb
PMID:Mutations in the canilicular multispecific organic anion transporter (cMOAT) gene, a novel ABC transporter, in patients with hyperbilirubinemia II/Dubin-Johnson syndrome. 942 27

Many previous studies of obese rodents documented biochemical changes in pancreatic islets that contribute to hyperinsulinemia in vivo. Those studies used heterogeneous populations of islets, although the size of islets from obese rats ranges from < 100 to > 500 microm. Here, functional and morphological changes in size-sorted (< 125 and > 250 microm diameter) islets from obese Zucker (fa/fa) rats were correlated. Ultrastructural examination revealed that > 250 microm cultured islets had an increased number of immature secretory granules in the beta cells. The number of degranulated beta cells in > 250 and < 125 microm cultured islets from fa/fa rats was higher than in lean rat islets (33 vs 25%). The glucose EC50 values for cultured islets were 4.64 +/- 0.43, 7.9 +/- 0.70 and 7.29 +/- 1.64 mmol.l(-1) for > 250 microm, < 125 microm, and lean groups, respectively. Inhibition of insulin secretion by 10 mmol.l(-1) mannoheptulose was reduced by 50% in > 250 microm islets compared with small islets. Studies of individual beta cells by reverse hemolytic plaque assay revealed 3-fold more cells from > 250 microm islets were stimulated by 1.4 mmol.l(-1) glucose than cells from < 125 microm islets. We conclude that functional defects in mixed size populations of islets from fa/fa rats are mainly due to alterations in the large islets, whereas smaller islets have relatively normal function. Exposure to high glucose exacerbates morphological and functional differences of large islets, which could have important implications in the transition to noninsulin-dependent diabetes when beta cell insulin production is unable to compensate for hyperglycemia.
Mol Cell Endocrinol 1998 Jan 15
PMID:Ultrastructural and secretory heterogeneity of fa/fa (Zucker) rat islets. 954 15

Defects in glucose uptake are among the primary defects associated with peripheral insulin resistance, but fundamental mechanisms leading to this state are poorly understood. In order to elucidate mechanisms leading toward defects in glucose transport, we have used a partially pancreatectomized infusion (PxI) animal model with infusions of saline, glucose, or insulin to examine individual and combined effects of hyperglycemia and hyperinsulinemia on skeletal muscle glucose utilization. Moderate hyperglycemia induced by pancreatectomy reduced basal hindlimb muscle glucose utilization by 57% without affecting maximal insulin-stimulated glucose utilization; insulin administered in an amount sufficient to correct this hyperglycemia did not alter basal glucose utilization, but maximal insulin-stimulated glucose utilization was sharply diminished (75%); hyperglycemia with hyperinsulinemia similarly reduced basal and maximal insulin-stimulated glucose utilization. In order to establish the role of the glucose transporter protein in these insulin-resistant states, we quantified GLUT 4 content by immunoblotting and GLUT 4 mRNA by solution hybridization/RNAse protection assays. Hyperglycemia (2 weeks) reduced total muscle GLUT 4 protein content (53%) and mRNA (46%), while subsequent hyperinsulinemia (72 h) with either normo- or hyperglycemia partially restored both total GLUT 4 protein and mRNA levels. As insulin-stimulated GLUT 4 content in plasma membranes was not diminished by combined hyperglycemia/hyperinsulinemia, these results indicate functional GLUT 4 translocation in this model and suggest suppression of GLUT 4 transporter activity.
Mol Genet Metab 1998 Feb
PMID:Mechanisms of insulin-resistant glucose utilization in rat skeletal muscle. 956 66

Type III hyperlipoproteinemia (HLP) is a multifactorial disorder associated with homozygosity for the apolipoprotein (apo) E-2 allele. Factors which may promote the development of HLP include lipoprotein lipase (LPL) and hyperinsulinemia. These factors were investigated in eight patients with type III HLP and in nine normolipidemic controls. In vitro the interaction of apoE with LPL was analyzed in cell binding assays. All type III HLP patients showed delayed triglyceride (TG) clearance and remnant lipoprotein accumulation in an oral fat tolerance test. Normolipidemic apoE-2/2 controls revealed normal TG clearance comparable to apoE3/3 controls. HLP patients showed lower LPL activity and mass than controls. Analysis of the LPL gene revealed an Asn 291-->Ser mutation in three patients and a -93 T-G substitution combined with an Asp 9-->Asn mutation in one control subject. In addition to LPL abnormalities, postprandial hyperinsulinemia was observed in five out of eight patients. In vitro LPL compensated the defective function of apoE-2 in mediating remnant lipoprotein binding to cells. In summary, seven out of eight patients with type III HLP showed LPL abnormalities and/or postprandial hyperinsulinemia. Together with the in vitro data these findings support a coordinate effect of apoE and LPL for the manifestation of type III HLP. Hyperinsulinemia appears to be an additional factor important for disease expression.
J Mol Med (Berl) 1998 Apr
PMID:Expression of type III hyperlipoproteinemia in patients homozygous for apolipoprotein E-2 is modulated by lipoprotein lipase and postprandial hyperinsulinemia. 958 70

Familial hyperinsulinism (HI) is a disorder characterized by dysregulation of insulin secretion and profound hypoglycemia. Mutations in both the Kir6.2 and sulfonylurea receptor (SUR1) genes have been associated with the autosomal recessive form of this disorder. In this study, the spectrum and frequency of SUR1 mutations in HI and their significance to clinical manifestations of the disease were investigated by screening 45 HI probands of various ethnic origins for mutations in the SUR1 gene. Single-strand conformation polymorphism (SSCP) and nucleotide sequence analyses of genomic DNA revealed a total of 17 novel and three previously described mutations in SUR1 . The novel mutations comprised one nonsense and 10 missense mutations, two deletions, three mutations in consensus splice-site sequences and an in-frame insertion of six nucleotides. One mutation occurred in the first nucleotide binding domain (NBF-1) of the SUR1 molecule and another eight mutations were located in the second nucleotide binding domain (NBF-2), including two at highly conserved amino acid residues within the Walker A sequence motif. The majority of the remaining mutations was distributed throughout the three putative transmembrane domains of the SUR1 protein. With the exception of the 3993-9G-->A mutation, which was detected on 4.5% (4/88) disease chromosomes, allelic frequencies for the identified mutations varied between 1.1 and 2.3% for HI chromosomes, indicating that each mutation was rare within the patient cohort. The clinical manifestations of HI in those patients homozygous for mutations in the SUR1 gene are described. In contrast with the allelic homogeneity of HI previously described in Ashkenazi Jewish patients, these findings suggest that a large degree of allelic heterogeneity at the SUR1 locus exists in non-Ashkenazi HI patients. These data have important implications for genetic counseling and prenatal diagnosis of HI, and also provide a basis to further elucidate the molecular mechanisms underlying the pathophysiology of this disease.
Hum Mol Genet 1998 Jul
PMID:Genetic heterogeneity in familial hyperinsulinism. 961 69

We have used the partially pancreatectomized infusion model in order to examine individual and combined effects of glucose and insulin on insulin resistance in rat skeletal muscles. Infusing glucose or insulin can produce animals which are hyperglycemic, hyperinsulinemic, or both. Individual and combined effects of chronic hyperglycemia and hyperinsulinemia on basal and insulin-mediated glucose utilization indices in glycolytic and oxidative muscle fibers were examined by 2-deoxyglucose uptake. Hyperglycemia reduced the basal glucose utilization index by 49% and hyperinsulinemia by 55%, while combined hyperglycemia + hyperinsulinemia diminished 2-deoxyglucose uptake by 69%. Maximally insulin-stimulated utilization was diminished only 28% under hyperglycemia but by 81% in the hyperinsulinemic state. In order to assess utilization in individual muscle fibers, uptake was examined in three tissues of differing fiber composition. The slow-twitch oxidative soleus muscle demonstrated greater basal uptake than the fast-twitch gastrocnemius (glycolytic) and quadriceps (oxidative) muscles. In addition basal (though not maximally insulin-stimulated) glucose utilization in the fast-twitch fibers was affected by chronic glucose and insulin to a greater extent than the slow-twitch soleus muscle, indicating that chronic hyperglycemia is more likely to precipitate insulin resistance in fast-twitch muscles. Significant differences in glucose metabolism among muscle fiber types suggests that results from insulin resistance studies in mixed muscles may be skewed according to their fiber composition.
Mol Genet Metab 1998 Sep
PMID:Glucose utilization in muscle fiber types: use of the partial pancreatectomized rat model to distinguish effects of glucose and insulin on insulin resistance. 978 94

The effect of insulin on GLUT-4 protein level in samples of adipose tissue and skeletal muscles from goats was studied in vivo using an euglycemic hyperinsulinemic clamp. The clamp was maintained in conscious goats for 6 h in the presence of amino acids to prevent insulin-induced hypoaminoacidemia. GLUT-4 protein was assessed in crude membrane preparations from adipose tissue and four skeletal muscles (longissimus dorsi, tensor fasciae latae, anconeus and diaphragm) by Western blot analysis. No changes of GLUT-4 protein content were detected after 6 h of hyperinsulinemia in either adipose tissue or skeletal muscles from goats. These results suggest that insulin is not the prime factor involved in the short-term regulation of GLUT-4 protein transporter content in insulin-sensitive tissues from goats.
Comp Biochem Physiol A Mol Integr Physiol 1998 Jul
PMID:Acute hyperinsulinemia fails to change GLUT-4 content in crude membranes from goat skeletal muscles and adipose tissue. 978 27


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