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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin resistance may be due directly to genetically programmed disorders of insulin action or acquired defects in which environmental factors influence insulin action. To address the issue of this distinction, we studied the ability of insulin to stimulate colony formation in primary cultures of erythroid progenitors (assumed to retain environmental influences) and immortalized T lymphocytes (presumed to reflect only genetic influences). Four patients with hyperinsulinemia and disturbed glucose metabolism were studied (2 patients with acanthosis nigricans, 1 of whom had circulating anti-insulin-receptor antibodies, 1 with partial lipodystrophy, and 1 with Cushing's syndrome). The mean colony-forming ability of their erythroid progenitor cells in response to insulin stimulation (less than or equal to 1.6 pM) was significantly blunted compared with control cells (P less than 0.05). The mean responsiveness of their immortalized T-lymphoblast cell lines to similar insulin concentrations was no different than that of control T-lymphocyte lines, consistent with an acquired cause for the observed insulin resistance in each case. A T-lymphocyte line from a patient with leprechaunism, however, showed no stimulation in response to physiological concentrations of insulin. With these same in vitro methodologies, there was normal T-lymphocyte line responsiveness to insulinlike growth factor I (IGF-I) or insulin concentrations greater than 8.6 pM; both of these responses could be completely blocked by preincubation with an antibody to the IGF-I receptor. These findings suggest that, despite resistance to physiological levels of insulin, the high circulating insulin concentrations present in the serum of these patients could mediate unwanted tissue-specific growth through an intact IGF-I receptor-effector mechanism.
Diabetes 1991 Jan
PMID:Use of in vitro clonogenic assays to differentiate acquired from genetic causes of insulin resistance. 184 48

Two species of glucose transporter (GT) are present in the liver: the erythroid/brain GT and the newly characterized liver GT. No information is available regarding the functional role of these two species or whether their expression is regulated concordantly in states in which hepatic glucose uptake or output are markedly altered. In this study, we analyzed the effect of fasting and refeeding and streptozocin-induced diabetes and subsequent insulin treatment on the expression of the erythroid/brain and liver GT polypeptides and their mRNAs in rat liver. The erythroid/brain GT mRNA in livers of control rats corresponded to 1-3% of the amount of liver GT mRNA. After a 4-day fast, its level increased approximately 3-fold and represented 8-10% of the liver GT mRNA, whereas the corresponding protein increased 4-fold. In livers from diabetic rats, levels of the erythroid/brain GT mRNA increased up to 2.4-fold and gradually returned to normal with chronic insulin treatment. Levels of the corresponding protein were minimally altered. Levels of immunoreactive liver GTs were not significantly changed by 2 days of fasting, 7 or 14 days of diabetes, or subsequent insulin treatment for 3, 5, or 7 days but increased up to 75% with refeeding for 3-48 h. Liver GT mRNA levels minimally decreased in diabetic or insulin-treated rats, decreased 45% after a 2-day fast, and increased up to 5-fold on refeeding for 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1990 Jun
PMID:Differential regulation of two glucose transporters in rat liver by fasting and refeeding and by diabetes and insulin treatment. 214 Aug 4

Growth factors, including insulin, are known to stimulate erythroid cell formation in vitro. This somatotrophic effect of insulin might be involved in blood abnormalities in diabetes mellitus. We therefore investigated whether growth hormone (GH) affects the morphology or filterability of circulating red blood cells (RBCs) in hypophysectomized rats. After hypophysectomy, rats became anemic with a decrease in hematocrit, hemoglobin concentration, RBC count, and reticulocytes. The RBC membrane area was enlarged, giving an increased area-to-volume ratio compared with the control RBCs. The calculated minimum cylindrical diameter (MCD) and resistance to initial folding of the RBC decreased after hypophysectomy, and was confirmed by an enhanced filtration of RBCs through 3 microns Nucleopore membranes. The number of filter clogging particles was also lower in hypophysectomized rats than in control rats. Substitution for 21 days with bovine GH (via subcutaneously implanted osmotic minipumps) normalized RBC morphology and filterability. After withdrawal of GH, all parameters returned toward the presubstitutional levels. Neither cortisone nor thyroxine had any measurable effect on RBC morphology or deformability, indicating that GH deficiency contributes to the abnormal RBC morphology and rheology seen after hypophysectomy.
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PMID:Effect of hypophysectomy and growth hormone substitution on red blood cell morphology and filterability in rats. 239 37

Molecular cloning of cDNA encoding the human erythrocyte facilitated-diffusion glucose transporter (GT) has elucidated its structure and has permitted a careful study of its tissue distribution and of its involvement in processes such as insulin-stimulated glucose uptake by adipose cells or transformation-induced increase in glucose metabolism. An important outcome of these studies was the discovery that additional isoforms of this transporter were expressed in a tissue-specific manner; these comprise a family of structurally and functionally related molecules. Their tissue distribution, differences in kinetic properties, and differential regulation by ambient glucose and insulin levels suggest that they play specific roles in the control of glucose homeostasis. Herein, we will discuss the structure of three members of the GT family: erythroid/brain GT, liver GT, and adipose cell/muscle GT. In the light of their tissue-specific expression, kinetic parameters, and susceptibility to insulin action, we discuss their possible specific functions.
Diabetes Care 1990 Mar
PMID:Molecular physiology of glucose transporters. 240 76

Glucose transport in mammals is mediated by a multigene family whose expression can be highly tissue specific. All cells express at least one transporter isoform in a constitutive fashion, because a certain level of glucose uptake is an absolute necessity, regardless of influences by various regulatory factors. The level of the constitutive transporter, usually the erythroid glucose-transporter isoform, can be regulated by environmental factors, e.g., nutrition and transformation. Certain cells express unique transporter isoforms, the quantitatively most important of which is the muscle-adipocyte glucose-transporter isoform that functions in response to insulin to clear most of the blood glucose after a meal. The available data suggest that the major insulin target tissues are uniquely able to produce this transporter isoform, sequester it in a unique organelle, and bring it to the cell surface in response to insulin. This insulin response is dramatically different from that seen in various fibroblastic cells, quantitatively and qualitatively, and suggests the expression in adipose tissue and muscle of a multigene program that defines the insulin-stimulated glucose transport of relevance to organismal glucose homeostasis.
Diabetes Care 1990 Mar
PMID:Regulation of glucose-transporter function. 240 77

The developmental switch from production of fetal (gamma) to adult (beta) globin occurs on a normally set biologic clock which proceeds even if the adult (beta) globin genes are defective. Preventing or reversing the globin gene switch would be beneficial for subjects with abnormal beta globin genes. We have now identified a class of agents which, when present in elevated plasma concentrations during gestation, appears to inhibit the gamma beta globin gene switch in developing humans. Further investigation has shown that butyric acid and related compounds can increase gamma globin and decrease beta globin expression in erythroid cells cultured from subjects with diseases of abnormal beta globin. Butyrate compounds were therefore infused in an in vivo fetal animal model, and the globin switch was inhibited in most and reversed in some fetal lambs. These data suggest that inhibiting expression of abnormal beta globin genes may be possible in future generations. Histone modification may be a mechanism of action involved. The developmental switch from production of gamma globin to beta globin results in significant morbidity when the beta globin genes are defective. The globin switch has therefore been extensively studied, appearing to be set on a biologic clock and proceeding despite the site of blood production and solely on the basis of gestational age. We previously found that this developmental gene switch is delayed in human fetuses developing in the presence of maternal diabetes. A number of metabolites present in abnormal concentrations in these infants were therefore tested for effects on globin expression.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Butyric acid modulates developmental globin gene switching in man and sheep. 248 61

The effect of streptozocin (STZ)-induced maternal diabetes in rats on fetal erythropoiesis was studied in short-term cultures of fetal liver cells at the time of switch from embryonic to adult hemoglobins. Liver erythroid cell functions were monitored by measuring the incorporation of [3H]-uridine in trichloroacetic acid (TCA)-soluble and -insoluble cell fractions and of [3H]-leucine in hemoglobin chains. Fetal liver cells of diabetic rats showed a higher incorporation of [3H]-uridine compared with controls when the cells were obtained from 14-day-old fetuses. However, there were no significant differences in the uptake of uridine when cells were obtained from 16-day-old fetuses. In parallel cell cultures, incorporation of [3H]-leucine into adult and embryonic globin chains was studied by separation of the globin chains by high-performance liquid chromatography (HPLC). The overall globin chain synthesis was higher in the fetuses of diabetic mothers compared with controls on day 14 of gestation. Erythropoietin had similar effects on the stimulation of globin chains in the two groups of fetuses. However, in the fetuses of diabetic mothers, erythropoietin had a specific stimulatory effect on embryonic-type globins that was significantly higher in the fetuses of diabetic mothers compared with controls. Differences between fetuses of control and diabetic mothers completely disappeared at 16 days of gestation. It is concluded that maternal diabetes has an effect on the cells synthesizing embryonic hemoglobins on day 14 of gestation, but by the time the switch from embryonic to adult-type hemoglobins is complete, these differences are abolished.
Diabetes 1985 Mar
PMID:Influence of maternal diabetes in rats on hemoglobin synthesis and uridine uptake by fetal liver cells. 388 87

A previously healthy 39-year-old woman presented with severe iron-deficiency anaemia, but she had lost no blood and her serum iron level was high. Her bone marrow was hypercellular with a predominance of erythroid elements and had no stainable iron deposits, but it also showed dyserythropoiesis and an excess of apparently normal plasma cells. IgM was demonstrated on her bone-marrow erythrocytes and their precursors. On azathioprine and prednisone therapy she had a complete clinical and haematological remission. The impaired iron transport and the associated dyserythropoiesis were probably due to an IgM-mediated autoimmune process. Diabetes mellitus, which first appeared during her anaemic illness, could also have been due to an autoimmune process. This is the first report of an iron-deficiency anaemia caused by a naturally acquired impairment of iron transport.
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PMID:Acquired iron-deficiency anaemia due to impaired iron transport. 612 57

Normal rabbit bone marrow erythroid cells have been found to possess insulin receptors. Their number shows an inverse relationship with the stage of differentiation, ranging from 20,000 sites/cell in the less mature to 8,000 sites/cell in the more mature cells. In addition, insulin rapidly stimulates the incorporation of leucine into protein in these cells and in rabbit, human, and rat peripheral blood reticulocytes. In rat reticulocytes, the concentration range of the hormone required for this phenomenon is from 25 to 625 microU/ml.
Diabetes 1980 Oct
PMID:Insulin receptors and protein synthesis in bone marrow cells and reticulocytes. 700 63

The obese gene product, leptin, regulates adiposity. Mice homozygous for a nonfunctional obese gene become massively obese and develop diabetes mellitus due to overeating and increased metabolic efficiency. The cDNA sequence of obese was recently reported (Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., and Friedman, J. L. (1994) Nature 372, 425-432; Correction: (1995 Nature 374, 479). We have determined the genomic organization of the 5' end of the mouse obese gene. The coding sequence is in exons 2 and 3. A single TATA-containing promoter was found upstream of exon 1. A minority (probably approximately 5%) of the obese mRNA contained an extra, untranslated exon between exons 1 and 2. Transcription of the obese gene was detected only in adipose cells. A 762-base pair obese gene promoter driving a luciferase gene yielded abundant activity in transiently transfected rat adipose cells in primary culture. The obese promoter was inactive in erythroid K562 cells. Deletion of bases from -762 downstream to -161 did not affect promoter activity in transfected adipose cells. The -161 minimal promoter contained consensus Sp1 and CCAAT/enhancer-binding protein (C/EBP) motifs. Cotransfection with C/EBP alpha (a transcription factor important in adipose cell differentiation) caused 23-fold activation. These data suggest that the obese promoter is a natural target of C/EBP alpha.
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PMID:The mouse obese gene. Genomic organization, promoter activity, and activation by CCAAT/enhancer-binding protein alpha. 749 16


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