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)

The effects of an overexpressed, non-insulin-responsive gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (GTP) (PEPCK; EC 4.1.1.32), on glucose homeostasis were investigated. Transgenic rats harboring a metallothionein-driven PEPCK gene (lacking the entire PEPCK upstream-regulatory region) expressed transgene PEPCK mRNA in the key gluconeogenic tissues, liver and kidney. Female transgenic rats, studied at 10 weeks of age, showed mild fasting hyperglycemia (6.9 +/- 0.2 vs. 5.9 +/- 0.1 mM P = 0.002 n = 6), hyperinsulinemia (92.2 +/- 4.0 vs. 54.0 +/- 6.6 pM, P = 0.001, n = 6), impaired glucose tolerance and increased weight gain (178.3 +/- 3.2 vs. 153.4 +/- 2.5 g, P = 0.001, n = 16 and n = 13 transgenic and control rats, respectively). Despite hyperinsulinemia at this age, kidneys of transgenic rats maintained a significant 20% elevation of total PEPCK enzyme activity, while total liver PEPCK activity was not reduced. This study suggests that an insulin-resistant step in the gluconeogenic pathway can lead to glucose intolerance and an increase in weight. These rats offer the unique opportunity to study the metabolic consequences of chronic, mild excess glucose supply, as seen in non-insulin-dependent diabetes.
Mol Endocrinol 1995 Oct
PMID:Impaired glucose tolerance and increased weight gain in transgenic rats overexpressing a non-insulin-responsive phosphoenolpyruvate carboxykinase gene. 854 47

Our previous investigation showed that hyperinsulinemia incompletely suppressed the transcription of the gene encoding L-serine dehydratase (SDH) (EC 4.2.1.13), a gluconeogenic enzyme, in newborn dogs. To test another hypothesis that insulin resistance in newborn mammals may be partially due to counterregulatory factors, such as epinephrine, euglycemic hyperinsulinemic clamps, hyperglycemic hyperinsulinemic clamps, and hyperglycemic hyperinsulinemic hyperepinephrinemic clamps were performed in newborn dogs in the present study. The infusion rates of insulin and epinephrine were 30 m U/kg/min and 150 ng/kg/min, respectively; the glucose infusion rate was adjustable. The SDH mRNA levels in kidney and liver of newborn dogs were quantitatively analyzed by using rat SDH cDNA probe and by a personal densitometer. The results showed that insulins, glucose, and epinephrine did not change the kidney SDH mRNA level; hyperinsulinemia and hyperglycemia reduced the liver SDH mRNA level by 8.5 and 29.2%, respectively; in the presence of hyperglycemia and hyperinsulinemia, epinephrine was able to increase the liver SDH mRNA by 27.8%, almost offsetting the reduction of the liver SDH mRNA level induced by the combination of insulin and glucose. We conclude that the enhanced regulatory effect of epinephrine counteracting insulin on SDH gene transcription in liver of newborn dogs may be one of the mechanisms responsible for the neonatal insulin resistance which contributes to neonatal hyperglycemia.
Biochem Mol Med 1996 Apr
PMID:Effects of insulin, epinephrine, and glucose on regulation of transcription of the serine dehydratase gene in newborn dogs. 873 86

The prevalence of hypertension and atherosclerosis among subjects with hyperinsulinemia supports the premise of a direct metabolic link between insulin and angiotensin II at the cellular level. In the present study, the effect of insulin on the angiotensin II-induced growth of A10 smooth muscle cells (SMC) was investigated. Treatment of quiescent A10 cells with angiotensin II caused an increase in RNA synthesis, proto-oncogene c-fos mRNA levels and cell size dependent upon pretreatment with insulin. The insulin requirement was independent of its actions as a growth factor, since a pre-treatment of at least 24 h with insulin was essential for growth stimulation by angiotensin II. Using RT-PCR, insulin was shown to regulate AT2 receptor expression in both quiescent and differentiating cells. These data suggest the AT2 receptor, which mediates the growth effects of angiotensin II in A10 cells, may be the critical target for the effect of insulin.
Mol Cell Endocrinol 1996 Aug 30
PMID:Insulin is required for angiotensin II-mediated hypertrophy of smooth muscle cells. 889 51

Physiological studies hypothesized that unsuppressed gluconeogenesis by insulin in newborn dogs may be a mechanism responsible for neonatal hyperglycemia. In the present study, we determined the effects of fasting and the infusion of insulin, glucose, and/or epinephrine on the liver cytosolic mRNA levels of the gene for the key regulatory enzyme of gluconeogenesis, phosphoenolpyruvate carboxykinase PEPCK (PEPCK; EC 4.1.1.32), in newborn dogs in vivo to further test the hypothesis. We observed the following: (i) Fasting increased the hepatic PEPCK mRNA level in newborn dogs. The hepatic PEPCK mRNA level was not detectable at birth; the PEPCK mRNA level at 4 h was arbitrarily determined as 100.0 +/- 27.8%, was 108.1 +/- 18.4% at 10 h, and stayed at the same level at 24 h (109.1 +/- 8.2). (ii) Euglycemic hyperinsulinemia did not significantly reduce the hepatic PEPCK mRNA levels in newborn dogs; however, the same treatment resulted in the repression of the liver PEPCK mRNA to undetectable levels in adult dogs. (iii) Under hyperinsulinemia, a moderate hyperglycemia lowered the liver PEPCK mRNA in newborn dogs to undetectable levels. (iv) In newborn dogs, despite the presence of hyperinsulinemia and hyperglycemia, the infused epinephrine was still able to elevate the liver PEPCK mRNA from undetectable levels to 79% of the control levels. We suggest that unsuppressed neonatal gluconeogenesis in the presence of hyperinsulinemia may be evidence of insulin resistance in newborn dogs and that the stimulatory effect of epinephrine on gluconeogenesis overriding insulin and glucose in the liver of the newborn dogs may be a mechanism for inducing neonatal hyperglycemia.
Biochem Mol Med 1996 Oct
PMID:Transcription of hepatic cytosolic phosphoenolpyruvate carboxykinase gene in newborn dogs. 890 88

Familial hyperinsulinism (HI) is a disorder of pancreatic beta-cell function characterized by persistent hyperinsulinism despite severe hypoglycemia. To define the molecular genetic basis of HI in Ashkenazi Jews, 25 probands were screened for mutations in the sulfonylurea receptor (SUR1) gene by single-strand conformation polymorphism (SSCP) analysis of genomic DNA and subsequent nucleotide sequence analyses. Two common mutations were identified: (I) a novel in-frame deletion of three nucleotides (nt) in exon 34, resulting in deletion of the codon for F1388 (delta F1388) and (II) a previously described g-->a transition at position-9 of the 3' splice site of intron 32 (designated 3992-9g-->a). Together, these mutations are associated with 88% of the HI chromosomes of the patients studied. 86Rb+ efflux measurements of COSm6 cells co-expressing Kir6.2 and either wild-type or delta F1388 SUR1 revealed that the F1388 mutation abolished ATP-sensitive potassium channel (KATP) activity in intact cells. Extended haplotype analyses indicated that the delta F1388 mutation was associated with a single specific haplotype whereas the 3992-9g-->a mutation was primarily associated with a single haplotype but also occurred in the context of several other different haplotypes. These data suggest that HI in Ashkenazi Jews is predominantly associated with mutations in the SUR1 gene and provide evidence for the existence of at least two founder HI chromosomes in this population.
Hum Mol Genet 1996 Nov
PMID:Mutations in the sulonylurea receptor gene are associated with familial hyperinsulinism in Ashkenazi Jews. 892 11

The inhibitory action of vanadate towards protein tyrosine phosphatase (PTPase) has been considered as a probable mechanism by which it exerts insulin-like effects. In this study, we have examined the in vivo effects of vanadate on PTPases in the liver of obese Zucker rats, a genetic animal model for obesity and type II diabetes. These animals were characterized by hyperinsulinemia and mild hyperglycemia. The number of insulin receptors were significantly (p < 0.01) decreased in liver. After chronic administration of vanadate in obese rats, 80% decrease in the plasma levels of insulin was observed. The insulin receptor numbers were significantly (p < 0.01) higher in vanadate-treated obese rats as compared to the untreated ones. The hepatic PTPase activities in cytosolic and particulate fractions, with phosphorylated poly glu:tyr (4:1) and the insulin receptor peptide (residues 1142-1153) as substrates, increased in obese rats. In vanadate-treated obese rat livers, the PTPase activities in both subcellular fractions with these substrates decreased significantly (p < 0.001). The decreases in PTPase activities from these groups of rats were further supported by chromatography on a Mono Q column. These data support the view that inhibition of PTPases plays a role in the insulin-mimetic action of vanadate.
Mol Cell Biochem
PMID:Decrease in protein tyrosine phosphatase activities in vanadate-treated obese Zucker (fa/fa) rat liver. 892 27

Although considerable evidence lends credence to the association between insulin resistance, hyperinsulinemia and essential hypertension, the precise nature of this relationship remains unexplained. In the present investigation, we examined the proposition that these metabolic defects contribute causally to the development of high blood pressure. If these metabolic abnormalities were responsible for the development of hypertension, then drug interventions that improve these defects should also decrease high blood pressure. Since previous studies have demonstrated that vanadium compounds enhance insulin action and lower plasma insulin levels in nondiabetic rats, we examined the effects of these compounds on insulin sensitivity, plasma insulin concentration and blood pressure in two hyperinsulinemic models of experimental hypertension. The animal models studied were the genetically predisposed spontaneously hypertensive rat and the fructose-hypertensive rat, where hypertension is induced in normotensive rats by feeding them a high fructose diet. Vanadium compounds caused marked and sustained decreases in plasma insulin concentration and blood pressure in both the animal models studied. Furthermore, the effect of the drugs on blood pressure was reversed by restoring plasma insulin levels in the drug-treated rats to those observed in their untreated counterparts. These data suggest that either hyperinsulinemia contributes to the development of hypertension in both the spontaneously hypertensive and the fructose-hypertensive rats or that the underlying mechanism is closely related to the expression of both these disorders.
Mol Cell Biochem
PMID:Antihypertensive effects of vanadium compounds in hyperinsulinemic, hypertensive rats. 892 40

The insulin-mimetic action of vanadate is well established but the exact mechanism by which it exerts this effect is still not clearly understood. The role of insulin in the regulation of hepatic glycogen metabolizing and lipogenic enzymes is well known. In our study, we have, therefore, examined the effects of vanadate on these hepatic enzymes using four different models of diabetic and insulin-resistant animals. Vanadate normalized the blood glucose levels in all animal models. In streptozotocin-induced diabetic rats, the amount of liver glycogen and the activities of the active-form of glycogen synthase, both active and inactive-forms of phosphorylase, and lipogenic enzymes like glucose 6-phosphate dehydrogenase and malic enzyme were decreased and vanadate treatment normalized all of these to near normal levels. The other three animal models (db/db mouse, sucrose-fed rats and fa/fa obese Zucker rats) were characterized by hyperinsulinemia, hypertriglyceridemia, increases in activities of lipogenic enzymes, and marginal changes in glycogen metabolizing enzymes. Vanadate treatment brought all of these values towards normal levels. It should be noted that vanadate shows differential effects in the modulation of lipogenic enzymes activities in type I and type II diabetic animals. It increases the activities of lipogenic enzymes in streptozotocin-induced diabetic animals and prevents the evaluation of activities of these enzymes in hyperinsulinemic animals. The insulin-stimulated phosphorylation of insulin receptor beta subunit and its tyrosine kinase activity was increased in streptozotocin-induced diabetic rats after treatment with vanadate. Our results support the view that insulin receptor is one of the sites involved in the insulin-mimetic actions of vanadate.
Mol Cell Biochem
PMID:In vivo effects of vanadate on hepatic glycogen metabolizing and lipogenic enzymes in insulin-dependent and insulin-resistant diabetic animals. 892 52

Lean and obese male Zucker rats were fed high fat (72% of energy as fat), high carbohydrate (66% of energy as carbohydrate) or intermediate diets for 4 weeks commencing 1 week after weaning. We examined the effects of these diets on growth rates, plasma insulin and corticosterone titres, and hypothalamic gene expression of 3 appetite-related neuropeptides. Messenger RNA levels for neuropeptide Y (NPY), galanin (GAL) and corticotropin-releasing factor (CRF) in critical hypothalamic locations were measured by in situ hybridization in each brain. Obese rats grew more rapidly and had elevated plasma insulin and corticosterone concentrations relative to their lean littermates. The obese phenotype was also associated with elevated NPY gene expression in the arcuate nucleus of the hypothalamus and increased GAL gene expression in the hypothalamic paraventricular nucleus. There was no effect of diet on NPY or CRF gene expression in either lean or obese rats. However, maintenance on the high fat diet had a significant effect on GAL gene expression in obese but not lean rats: high fat diet significantly reduced mRNA levels in the obese rats. This reduction in GAL mRNA was accompanied by attenuation of the hyperinsulinemia that is characteristic of this genetic obesity.
Brain Res Mol Brain Res 1996 Dec 31
PMID:Regulation of galanin gene expression in the hypothalamic paraventricular nucleus of the obese Zucker rat by manipulation of dietary macronutrients. 903 34

In the present report changes in the mRNA level of glucose-6-phosphatase (G6Pase; EC 3.1.39) in newborn and adult dogs in vivo were studied to further test the hypotheses that neonatal hyperglycemia may be due to unsuppressed gluconeogenesis by insulin and that the antidiabetic role of insulin-like growth factor-1 (IGF-1) may be intact in newborn dogs who have consistently demonstrated insulin resistance. Our results were the following: (i) Both renal and hepatic G6Pase mRNA were expressed at birth and increased with time during a 24-h period of fasting after birth. (ii) The renal G6Pase mRNA levels in newborn dogs did not respond to either insulin or epinephrine. (iii) Hyperinsulinemia lowered the liver G6Pase mRNA by only 16.3% in newborn dogs, but reduced the liver G6Pase mRNA to an undetectable level in adult dogs. (iv) Hyperglycemia decreased the hepatic G6Pase mRNA by 14.3% in newborn dogs under hyperinsulinemia. (v) Infused epinephrine did not elevate the hepatic G6Pase mRNA level in newborn dogs in the presence of hyperglycemia and hyperinsulinemia. (vi) In newborn dogs, hyper-IGF-1 rapidly reduced the hepatic G6Pase mRNA level by 50%, and hypoglycemia was unable to elevate the hepatic G6Pase mRNA level under the hyper-IGF-1. We concluded that the reduced rate of suppression of transcription of the liver G6Pase gene by insulin in newborn dogs may reflect the unsuppressed neonatal hepatic gluconeogenesis due to insulin resistance and that the physiological roles of IGF-1 seemed to be intact in newborn dogs and may be not responsible for neonatal hyperglycemia.
Biochem Mol Med 1997 Apr
PMID:Insulin resistance and the transcription of the glucose-6-phosphatase gene in newborn dogs. 916 94


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