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)

Insulin-like growth factor-I (IGF-I) and IGF-binding protein-1 (BP-1) are critical cell regulators, with regulation and action in endocrine, paracrine, and autocrine modes. Although IGF-I and BP-1 are thought to be modulated mainly at the level of synthesis, underlying molecular mechanisms are poorly understood. To examine regulation by insulin, we used run-on assays to measure IGF-I and BP-1 gene transcription rates in nuclei isolated from the livers of normal and diabetic rats. Streptozotocin (STZ)-treated rats exhibited 20-25% weight loss, a 2.5- to 3-fold increase in serum glucose, and a 50-60% fall in circulating IGF-I levels (all P less than 0.001). Diabetic animals also had a 45% reduction in hepatic IGF-I mRNA and over 400% increases in BP-1 mRNA (both P less than 0.005); all parameters were restored toward normal after treatment with insulin. Metabolically responsive IGF-I gene transcription was evaluated effectively with a 3.2-kilobase BglII/EcoRI genomic probe located down-stream from all initiation sites in exon 1, while BP-1 gene transcription was studied with a cDNA probe. Animals treated with 144 mg/kg STZ exhibited 50-97% decreases in IGF-I gene transcription (P less than 0.05), while insulin treatment raised IGF-I gene transcription to control levels (P less than 0.02). IGF-I gene transcription appeared to be more sensitive to metabolic status than IGF-I mRNA levels, resulting in a modest correlation between transcription rates and mRNA levels (r = 0.68; P less than 0.001). In contrast, changes in BP-1 mRNA and gene transcription appeared to be exquisitely sensitive to metabolic status.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1992 Jun
PMID:Expression of hepatic insulin-like growth factor-I and insulin-like growth factor-binding protein-1 genes is transcriptionally regulated in streptozotocin-diabetic rats. 137 75

This work explored the role of the cholinergic pathway, assessed at a post-synaptic level by the use of isolated smooth muscle cells, in the impairment of antral motility associated with diabetic gastroparesis. Contractile response to carbachol--but not to erythromycin, a motilin receptor agonist--was abolished in antral smooth muscle cells isolated from (i) rats previously rendered diabetic by a single i.v. dose of streptozotocin (STZ, 60 mg/kg) and (ii) db/db spontaneously diabetic mice. Insulin treatment of STZ-rats was able to prevent the impairment of the carbachol contractile response, but not to reverse it once established. In STZ-rats, impairment of contractile response was not associated with a change in density of [3H]-N-methyl-scopolamine ([3H]-NMS) binding sites (approximately 1.5 fmol/mg protein). Displacement curve of the [3H]-NMS binding by carbachol was shifted to the right in diabetic rats as compared to controls. The addition of GTP-gamma-S induced a shift to the right of the displacement curve in control but not in diabetic animals. These results strongly suggest that diabetes is associated with an early and specific alteration of the muscarinic control of contraction of antral smooth muscles at a post-synaptic level, associated with an alteration of the GTP-binding proteins coupled to muscarinic receptors.
Mol Cell Biochem 1992 Feb 12
PMID:Impairment of contractile response to carbachol and muscarinic receptor coupling in gastric antral smooth muscle cells isolated from diabetic streptozotocin-treated rats and db/db mice. 138 42

Considering the important role of the phosphocreatine energy shuttle in contractile function of the heart we decided to study the different components of this shuttle in STZ-induced diabetic rat heart with a known diabetic related cardiomyopathy. Diabetes produced a gradual decline in total CK activity, reaching a maximum of 35-40% decrease after 4 weeks of diabetes, in both atria and ventricles. All of the CK isoenzymes including the mitochondrial CK (CKm) were reduced but to a different extent in these two tissues. The percentage reduction in diabetic ventricles was BB greater than MB greater than CKm greater than MM and in atria was CKm greater than BB greater than MB greater than MM. A major difference between atrium and ventricle was the greater loss of CKm in diabetic atria than diabetic ventricle (75% in atria vs 32% in ventricle). The B subunit seemed to be the one that was affected the most followed by CKm isoenzyme and then the M subunit. The bound myofibrillar CK isoenzyme, expressed as units of activity/mg of myofibrillar protein, was not affected by 4 weeks of diabetes. The high energy phosphates were also reduced in diabetic heart with a greater reduction in phosphocreatine (43-45%) and a smaller change in ATP (27%). Mitochondrial oxidative phosphorylation with alpha-ketoglutarate was reduced (55%) in diabetic heart, whereas, there was no difference when succinate was used as substrate. These changes were reversible by 4 weeks of insulin treatment. The loss of CKm, phosphocreatine and the reduction in mitochondrial oxidative phosphorylation, could result in an inefficient phosphocreatine energy shuttle which could contribute to the cardiac functional defects associated with diabetes.
J Mol Cell Cardiol 1991 Nov
PMID:Alteration of the phosphocreatine energy shuttle components in diabetic rat heart. 180 23

Chronic hypoinsulinemic states in rodents are known to cause an increase in the number of insulin receptors at the hepatocyte surface. To assess whether this change results from a reduced endocytosis of the receptors, the effects of streptozotocin treatment and fasting on the number and the subcellular distribution of hepatic insulin receptors have been evaluated in the rat. In streptozotocin-treated rats, insulin receptor number was increased by 25-40% in plasma membrane and total cellular membrane fractions, and by 60-130% in the light Golgi-endosomal (GE) fraction. In contrast, receptor number was unaffected in the intermediate GE fraction and decreased by 25-35% in the heavy GE fraction. Such changes were detectable at 12 h in GE fractions and at 2 days in other subcellular fractions, and lasted for at least 8 days. Streptozotocin treatment also led to a 3- to 4-fold decrease in the insulin content of GE fractions, indicating reduced hormone endocytosis. Fasting for 16 h elicited changes in receptor and ligand concentration in cell fractions comparable to those induced by streptozotocin. It is concluded that, although endocytosis of hepatic insulin receptors is reduced in chronic hypoinsulinemic states, changes in receptor synthesis and/or degradation also occur in these states.
Mol Cell Endocrinol 1991 Dec
PMID:Mechanisms of up-regulation of the liver insulin receptor in chronically hypoinsulinemic rats: assessment of receptor endocytosis. 183 92

Biochemical and morphological modifications occurring in the pancreas of multiple low dose streptozocin treated rats, subjected to a preventive or concomitant immunosuppressive administration of Cyclosporin A (CyA 8mg/Kg b. wt./45 days), were observed. Biochemical assays showed that CyA significantly enhances glycaemia (p less than 0.0001) and decreases serum insulin levels (p less than 0.0001), while serum creatinine was slightly increased (p less than 0.05). Morphological findings (L.M. and T.E.M.) of rats, diabetized during the CyA administration, demonstrated a variable degree of survival of B- cells (damaged and undamaged cells were noted) and areas of modified exocrine cells (extended vacuolation). Pancreases of rats, first immunosuppressed then diabetized, showed similar ultrastructural features to those of the previous group but presented a greater B-cell loss. It is evident that CyA is only moderately effective against direct cytotoxic effects of STZ, when given concomitantly, and completely fails to protect B cells when given prior to the diabetogenic drug.
Cell Mol Biol 1989
PMID:Multiple low dose streptozocin-treated rats: biochemical and morphological effects of cyclosporin A administration. 253 61

Eighteen timed-pregnant Syrian golden hamsters were injected subcutaneously with streptozotocin (STZ, 60 mg/kg bw) early on gestational day 10. The response varied widely, and based on changes in blood glucose levels during gestational days 11 to 15, the hamsters were categorized into four groups: 1) no change; 2) mild diabetes (200-250 mg/dl), which reverted; 3) moderate diabetes (greater than 300 mg/dl), which reverted; and 4) moderate to severe diabetes (300-500 mg/dl), which was sustained. Two hours before sacrifice, a 25 mg tablet of bromodeoxyuridine (BrdU) was implanted subcutaneously into each experimental hamster and into 17 control pregnant hamsters that had not received STZ. BrdU-labelling was demonstrated immunochemically in the pancreatic islet cells. In control hamsters, the mean labelling index (LI) of the islet cells was 0.07% and did not exceed 0.2% in any hamster. Following injection of STZ, islet cell LI's remained low (0.13%) if the blood glucose levels were not altered by the diabetogenic drug. However, LI's were increased in islet cells of hamsters which showed a mild to moderate diabetes which rapidly reverted; the highest LI's (5% +/- 2.1) occurred in four hamsters that were killed 2 days after receiving STZ. The LI's were moderately increased (1.4% +/- 0.42) in two hamsters with moderate diabetes killed 2 days after STZ, but LI's were low (0.12% +/- 0.04) in six hamsters with moderate to severe diabetes killed 3, 4, and 5 days after STZ. Reversion of hyperglycemia to normoglycemia correlated closely with increased DNA synthesis in the islet cells of the pregnant hamsters. These observations strongly suggest that following mild cytotoxic injury induced by STZ, the B cells regenerated and insulin production was restored sufficiently to maintain normoglycemia.
Virchows Arch B Cell Pathol Incl Mol Pathol 1989
PMID:Correlations between blood glucose levels and bromodeoxyuridine labelling indices of pancreatic islet cells following streptozotocin administration to pregnant Syrian golden hamsters. 256 82

The role of cytoplasmic activator of adenylate cyclase in rat lung metabolism was investigated. Mouse adrenal tumor (MAT) cells undergo differentiation in response to choleratoxin which acts through cyclic AMP. The activator of adenylate cyclase from rat lung also produced cyclic AMP in a disrupted MAT cell preparation. However, unlike choleratoxin, it did not induce MAT cell differentiation in whole cells. These results suggest impermeability of MAT cells, and possibly other cells, to the activator. Thus, means of altering activator activity in lung cytoplasm were sought, and changes in activator activity were related to lung glycogen. Adrenalectomy (ADX) in rats led to a reduction in activator activity that was accompanied by an elevation in lung glycogen. Dexamethasone treatment of adrenalectomized rats reversed both of these effects. Streptozotocin-induced diabetes in rats elevated activator activity and lowered lung glycogen. Insulin treatment of the diabetic rats restored activator activity to the normal control values. Preweaning of rats on day 16 instead of day 22 increased activator activity on the 19th day over the controls and there was a concomitant decrease in lung glycogen. Feeding the separated pups with homogenized milk restored glycogen and activator activity to the control values. These results indicate that activator activity in rat lung cytoplasm was dependent on the circulating levels of cortisol and insulin, and that there appeared to be an inverse relationship between activator activity and glycogen level in rat lungs.
Mol Cell Biochem 1988 Sep
PMID:Relationship between the cytoplasmic activator of adenylate cyclase and glycogen metabolism in rat lung. 285 15

Pancreatic islets, newly formed in vitro were incubated in the presence of streptozotocin (STZ; 0.4 mM) for up to 6 h. Ultrastructural changes first appeared between 2 and 4 h; heterochromatization, was followed by swelling of nuclear and reticular membranes, vesiculation of the Golgi apparatus, fragmentation of cell membranes and finally mitochondrial destruction. At the end of the experiment all the B cells were destroyed, whereas the other cell types remained intact. Exogenous ZnSO4 was added during preincubation periods to increase the intrainsular zinc content and to determine any protective effect against STZ-cytotoxicity. Since the addition of zinc had no obvious effect, it is suggested that STZ cytotoxicity on B cells cannot be attributed to competition for zinc between copper-zinc superoxide dismutase (Cu-Zn-SOD) and the crystallization of insulin.
Virchows Arch B Cell Pathol Incl Mol Pathol 1987
PMID:Ultrastructural aspects of streptozotocin cytotoxicity on rat pancreatic islets in vitro. Test of a protective effect of zinc. 288 57

Streptozotocin diabetes in rats is associated with reduced function of the hypothalamo-pituitary-thyroid axis. The structure and hormone secretion of the thyroid and pituitary glands were studied in adult male rats 1 month after streptozotocin injection. The thyroid of diabetic rats was characterized by decreased follicle area and epithelial thickness. By electron microscopy, thyroid epithelial cells were characterized by flattened and almost empty rough endoplasmic reticulum cisternae, scanty exocytotic apical and endocytotic vesicles as well as degenerate mitochondria and rough endoplasmic reticulum. By immunohistochemistry, intracolloidal thyroglobulin and T3 as well as intraepithelial thyroglobulin were reduced. Electron microscopic and immunohistochemical analysis of pituitary glands showed that in diabetic rats thyrotrophs were mostly of type II, and the number of thyrotrophs (type I + type II) was greater than in controls. By radioimmunoassay (RIA), plasma T3, T4, and TSH levels were markedly reduced, and the TSH response to TRH was deficient in diabetic animals. The pituitary TSH concentration was increased, as expected from the morphological data. This study demonstrates severe structural changes in the thyroid and pituitary glands of diabetic rats which are accompanied by marked alterations of their secretory activity.
Virchows Arch B Cell Pathol Incl Mol Pathol 1987
PMID:Thyroid and pituitary secretory disorders in streptozotocin-diabetic rats are associated with severe structural changes of these glands. 288 60

Poor growth in diabetes involves low circulating levels of somatomedins/insulin-like growth factors (IGFs), largely reflecting decreased growth factor release by the liver. To define regulatory mechanisms, circulating IGF-1 was compared with levels of a high mol wt putative hepatic IGF-1 precursor and hepatic IGF-1 mRNA in a model of progressive severity of diabetes in rats. Streptozotocin administered at 36, 72, 144, and 288 mg/kg produced graded metabolic decompensation 2 days later, from minimal hyperglycemia with continued weight gain at 36 mg/kg, to marked hyperglycemia, ketonemia, and weight loss at 288 mg/kg (all P less than 0.001). Total serum IGF-1 measured by RIA was unchanged with the 36 and 72 mg/kg doses of streptozotocin (471 +/- 19 and 439 +/- 27 ng/ml, respectively, vs. 517 +/- 27 ng/ml in controls) despite serum glucose greater than 400 mg/dl. With streptozotocin 144 and 288 mg/kg, serum IGF-1 fell to 131 +/- 27 and 142 +/- 10 ng/ml, respectively (both P less than 0.005 vs. controls). Serum IGF-1 was correlated strongly with serum beta-hydroxybutyrate and body weight (r = -0.88 and 0.91, respectively, P less than 0.0001), and less strongly with serum glucose (r = -0.59, P less than 0.0002). Extractable hepatic content of a high mol wt form of immunoreactive IGF-1 (a putative precursor) was unchanged at the two lowest doses of streptozotocin (68 +/- 4 and 83 +/- 9 ngeq/g vs. 67 +/- 4 in controls), but decreased to 16 +/- 3 and 29 +/- 4 ng/g at the two highest doses (both P less than 0.001 vs. controls).(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1988 Nov
PMID:Nutrition and somatomedin. XIX. Molecular regulation of insulin-like growth factor-1 in streptozotocin-diabetic rats. 297 56


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