Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To understand the role of amylin, the novel pancreatic hormone, in fuel metabolism of neonatal mammals, the transcription of the amylin gene in newborn dogs was studied under different conditions, such as fasting, hyperinsulinemia, and hyper IGF-1. Our results showed (1) The amylin mRNA level decreased during a 24-h fasting period after birth, 59.1 +/- 4.5% at 4 h, 80.1 +/- 7.9% at 10 h, and 44.5 +/- 3.0% at 24 h, compared to 0-h-fasted controls, respectively. In this period, the decreased mRNA level of the amylin gene and the increased mRNA levels of the gluconeogenic genes showed an inverse ratio relationship. (2) Euglycemic hyperinsulinemic clamp did not alter the amylin mRNA level, 39.6 +/- 1.2% (hyperinsulinemia) vs 41.4 +/- 3.1% (controls), in newborn dogs, but lowered the amylin mRNA by 35.3%, 64.7 +/- 12.5% vs 100.0 +/- 12.0%, in adult dogs. (3) Euglycemic hyper-IGF-1 clamp had no effect on the amylin mRNA levels of either newborn or adult dogs, 52.4 +/- 9.1% (hyper IGF-1) vs 47.9 +/- 4.3% (controls) in newborns and 95.2 +/- 12.6% (hyper IGF-1) vs 100.0 +/- 14.0% (controls) in adults. The data from the present study showed that amylin may be involved in carbohydrate homeostasis, but may not be able to stimulate gluconeogenesis in newborn dogs during a 24-h fasting period after birth. Whether amylin action may be another mechanism for neonatal hyperglycemia by inducing insulin resistance in peripheral tissues needs further investigation.
Biochem Mol Med 1997 Aug
PMID:Transcription of the amylin gene in newborn dogs. 925 84

As shown by ourselves and others, animals models closely resembling human complex diseases like IDDM in BB/OK and hypertension in SHR/Mol rats can be used to dissect a complex disease into discrete genetic factors as has been done for hypertension in (BB/OK x SHR/Mol) cross hybrids. Discrete genetic factors, so-called QTLs, were detected on chromosomes 1, 10, 18, 20, and X. To gain additional information about the physiologic effect of the mapped blood pressure QTLs, genetically defined regions of the SHR rat were transferred onto the genetic background of diabetes-prone BB/OK rats. Four new congenic BB.SHR rats named BB.Sa, BB.Bp2, BB.1K, and BB.Xs were generated and characterized telemetrically for blood pressure, heart rate, and motor activity. The data demonstrate clearly that each single blood pressure QTL of the SHR rat causes a significant increase of the systolic blood pressure and has a different influence on diastolic blood pressure, heart rate, and motor activity. The effects were modified differently by the diabetic state in BB.Sa, BB.Bp2, and BB.Xs rats carrying all diabetogenic genes of the BB/OK rats. The results demonstrate that these newly established congenic strains are a unique tool to study the physiological control of blood pressure by a single blood pressure QTL on the one hand and their interaction with hyperglycemia on the other. It is well within the bounds of possibility that diabetic congenics reflect the diabetic hypertension seen in diabetic patients. Because of the synteny conservation in gene order between different mammals, genes of the appropriate human region could therefore be candidate genes for hypertension in diabetics. Furthermore, these congenic strains can also be used to study interactions between a blood pressure QTL and various selected environmental conditions. In this way, one could learn which QTL can be influenced by environmental factors and to what extent. Another point is the study of gene interactions. Because congenics are genetically identical except for the defined transferred region, congenics can be crossed to investigate the interaction between two or three blood pressure QTLs selected by the investigator and not by nature. These QTL combinations can be studied in the nondiabetic as well as diabetic state. Although the advantage of congenic strains has been shown, the transferred chromosomal regions are too large to pinpoint the gene responsible for the phenotypic change. Therefore, regions on each chromosome must be systematically whittled down, which can be done by crossing the congenics with BB/OK rats and intercrossing their progeny to generate recombinants. These can then be used for the creation of new congenic lines carrying a much smaller region of the SHR/Mol rat. This has been started for the region on chromosome 1 spanning a 16-cM region from the Sa to the Igf2 gene. BB.Sa rats were therefore backcrossed onto BB/OK rats and the resulting progeny were intercrossed. The aim will be to create at least three new congenic BB.Sa rat strains homozygous for the SHR alleles of Sa, Lsn, or Igf2 genes. However, new problems will emerge with these new congenics. To genetically define small regions requires more dense polymorphic markers than are currently available. Dense polymorphic markers will also be necessary to split the other regions on chromosomes 10, 18, 20, and X. We expect that in the near future it will be possible using this approach to define small regions of < 0.5 cM. The recent progress in gene mapping in the rat gives hope that the use of such congenic lines will allow the identification and recovery of the blood pressure genes in the near future.
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PMID:Diabetes and hypertension in rodent models. 932 42

To clearly understand the hyperglycemic action of glucocorticoids, we studied the action of glucagon on lactate gluconeogenesis in the liver of rats 7 days after adrenalectomy and after treatment with 1 mg/kg dexamethasone for 7 days. The liver was isolated and cyclically perfused at 20 ml/min with 25 ml of perfusion medium containing 5 mM lactate, [U-14C]lactate, and 0-100 ng/ml glucagon. In the absence of glucagon, incorporation of [14C]lactate into glucose carbon 1 did not change significantly in the adrenalectomized rat liver (1.66 +/- 0.12% of total radioactivity for 5 min) and increased in the dexamethasone-treated rat liver (3. 61 +/- 0.54%, P < 0.01) compared to the normal rat liver (1.99 +/- 0. 28%). The response of lactate gluconeogenesis to glucagon was extremely blunted in the adrenalectomized rat liver and was much larger in the dexamethasone-treated rat than in the normal rat liver (at a glucagon concentration of 100 ng/ml, 2.13 +/- 0.33, 8.55 +/- 1. 06, and 4.61 +/- 0.53% for 5 min, respectively). Glucagon binding to liver plasma membrane was not changed by adrenalectomy and was decreased by dexamethasone treatment. These results suggest that glucocorticoids induce hyperglycemia by increasing the response to glucagon, together with the high basal activity of hepatic gluconeogenesis. In addition, these effects do not occur through changes in glucagon binding to receptors.
Biochem Mol Med 1997 Oct
PMID:Increased glucagon action on lactate gluconeogenesis in perfused liver of dexamethasone-treated rats. 936

Insulin resistance is associated with diabetes. Hyperglycemia per se causes insulin resistance as well as increased flux of glucose through the hexosamine biosynthetic pathway. The rate-limiting enzyme for entry of glucose into this pathway is glutamine:fructose-6-phosphate amidotransferase (GFAT). To directly evaluate the role of GFAT in modulating insulin-stimulated glucose transport, we co-transfected primary cultures of rat adipose cells with expression vectors for human GFAT as well as an epitope-tagged GLUT4 and examined the effect of overexpressed GFAT on insulin-stimulated translocation of GLUT4. When we measured cell surface tagged GLUT4 in response to insulin, cells overexpressing GFAT and tagged GLUT4 had an insulin-dose response curve that was similar to that of control cells expressing only tagged GLUT4. As an alternative means of increasing flux through the hexosamine biosynthetic pathway, we incubated adipose cells with glucosamine (a substrate of the pathway downstream from GFAT) and insulin. Interestingly, for short incubation times (4 h) we observed a decrease in both basal and insulin-stimulated glucose transport without a detectable effect on insulin-stimulated translocation of GLUT4. However, for longer incubation times (16 h), we observed a significant decrease in the amount of GLUT4 in the plasma membrane. Our data suggest that products of the hexosamine biosynthetic pathway may cause insulin resistance, in part, by acutely decreasing intrinsic activity of GLUT4 as well as chronically altering the amount of GLUT4 at the cell surface.
Mol Cell Endocrinol 1997 Nov 30
PMID:Effects of overexpression of glutamine:fructose-6-phosphate amidotransferase (GFAT) and glucosamine treatment on translocation of GLUT4 in rat adipose cells. 945 42

Hyperglycemia is the major causal factor in the development of diabetic vascular complications and can mediate their adverse effects through multiple pathways. One of those mechanisms is the activation of protein kinase C (PKC) by hyperglycemia-induced increases in diacylglycerol (DAG) level, partly due to de novo synthesis. The activation of PKC regulates various vascular functions by modulating enzymatic activities such as cytosolic phospholipase A2 and Na+,K+-ATPase, and gene expressions including extracellular matrix components and contractile proteins. Some of the resulting vascular abnormalities include changes in retinal and renal blood flow, contractility, permeability, proliferation, and basement membrane. Among the various isoforms of PKC predominantly the beta isoforms are activated in cultured vascular cells exposed to high glucose and vascular tissues isolated from animal models of diabetes mellitus. Administration of vitamin E, which decreases DAG level possibly through the activation of DAG kinase, prevents hemodynamic changes in retina and renal glomeruli of diabetic rats. In addition, the inhibition of PKC beta isoforms by a specific inhibitor (LY333531) can normalize the changes in gene expression of cytokines, caldesmon, and hemodynamics. These results provide supportive evidence that the activation of PKC, especially the beta isoforms, is involved in the development of diabetic vascular complications, and that PKCbeta inhibitors can be used in the treatment of diabetic vascular complications.
J Mol Med (Berl) 1998 Jan
PMID:Protein kinase C activation and its role in the development of vascular complications in diabetes mellitus. 946 65

We have reported that chronic exposure of HIT-T15 cells to supraphysiological concentrations of glucose over many months leads to decreased insulin gene transcription and decreased binding activities of two beta-cell-specific transcription factors, STF-1 and C1 activators, and have postulated that these events may provide a mechanism for glucose toxicity on beta-cell function. We now report that culturing the highly differentiated rat insulinoma cell line, INS-1, in glucose concentrations above 8.0 mM caused a marked decrease in insulin mRNA levels within 24 h. The decrease in insulin mRNA levels was reversed by further incubation of the cells in 4.0 mM glucose. Transient transfection of a chloramphenicol acetyltransferase reporter gene regulated by the 5'-regulatory sequences of the human insulin gene showed that elevated glucose concentrations caused a large decrease in insulin gene promoter activity. The decrease in insulin gene promoter activity was associated with reductions in the binding activities of both STF-1 and C1 activator, and these were partially reversed by lowering the glucose concentration. The decrease in STF-1 binding activity was associated with decreased STF-1 mRNA and occurred independently of changes in STF-1 promoter activity, suggesting a posttranscriptional regulatory mechanism. Furthermore, the decrease in insulin gene expression was found to occur independently of changes in cell proliferation. We conclude that physiologically relevent elevations in glucose can reversibly diminish insulin gene transcription by reducing the expression and/or binding activity of two critical beta-cell transcription factors.
Mol Endocrinol 1998 Feb
PMID:Glucose rapidly and reversibly decreases INS-1 cell insulin gene transcription via decrements in STF-1 and C1 activator transcription factor activity. 948 63

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

Hyperglycaemia in poorly controlled diabetic patients induces non-enzymatic glycosylation (glycation) of proteins, altering their structure and physiological bioactivity. Alkaline phosphatase (ALP) is a membrane-bound exoenzyme which faces the extracellular compartment. We have investigated the glycation of intestinal alkaline phosphatase in vitro and the consequences of such molecular modifications on certain structural and functional characteristics. The effect of glycation on alkaline phosphatase specific activity was determined after incubation of the enzyme with different sugars for various periods of time. The formation of early reversible glycation products was determined by the measurement of fructosamine levels, while the appearance of advanced glycation end products was estimated by spectrofluorometric analysis. A decrease in the specific activity of ALP was associated both with an increase in fructosamine levels and with the appearance of AGE-characteristic fluorescence. Changes in these parameters were found to depend on the incubation time, and on the concentration and glycating capability of the sugar employed. Co-incubation with aminoguanidine slowed down the appearance of protein-linked fluorescence, and additionally curbed the decrease in enzymatic specific activity. A significant correlation between the levels of ALP-fructosamine and ALP-advanced glycation end product was observed. Patterns of protein bands fractionated by SDS-PAGE were essentially identical for the nonglycated controls and the glycated samples. The electrophoretic mobility of the band of alkaline phosphatase on cellulose acetate gels increased as a function of the incubation time and the glycosylating power of the carbohydrate used. The present study provides evidence for the in vitro glycation of alkaline phosphatase, and for the consecutive alteration of its activity and structure.
Mol Cell Biochem 1998 Apr
PMID:Non-enzymatic glycosylation of alkaline phosphatase alters its biological properties. 956 42

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

It was recently reported that hyperglycemia provokes a rapid and sustained translocation of glucokinase in rat pancreatic B-cells, and it was speculated that this may be associated with enhancement of its catalytic activity, as possibly attributable to the mitochondrial binding of the enzyme. In the present work, the activities of both hexokinase and glucokinase were measured in particulated and cytosolic subcellular fractions prepared from islets first incubated for 60 min either in the absence of exogenous nutrient or in the presence of D-glucose, tested at both low (2.8 mmol/L) and high (16.7 mmol/L) concentrations. The relative contribution of the cytosolic domain to the total activity of glucokinase recovered in the two subcellular fractions was higher in islets deprived of exogenous nutrient than in islets first exposed to 2.8 or 16.7 mmol/L D-glucose, the results obtained at each of the latter two hexose concentrations being comparable to one another. The subcellular distribution of hexokinase, however, was not significantly different in islets deprived of D-glucose or exposed to the hexose. These findings are interpreted as indicative of an energy-dependent translocation of glucokinase in the B-cell, distinct from the redistribution of the enzyme occurring in response to a rise in D-glucose concentration above its physiological value.
Mol Genet Metab 1998 Mar
PMID:Energy-dependent intracellular translocation of glucokinase in rat pancreatic islets. 960 39


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