Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutamic acid decarboxylase (GAD) catalyzes synthesis of the inhibitory neurotransmitter gamma-amino butyric acid. Two homologous forms of GAD encoded by separate genes have been cloned from rat brain, with predicted protein sizes of 67 and 65 kilodaltons. GAD is present outside the brain, and pancreatic islet GAD is believed to be a target of autoimmunity in insulin-dependent diabetes mellitus. However, peripheral expression of the two GAD genes is incompletely characterized. We, therefore, investigated GAD expression in peripheral tissues, including pancreas, of mouse and rat. cDNAs encoding GAD 67 and GAD 65 were cloned from mouse brain and shown to be 95% homologous with the rat sequences. RNase protection assay using specific cRNA probes demonstrated expression of both GAD forms in freshly harvested pancreas and testis. Levels of both GAD mRNAs were greater in rat than mouse pancreas. GAD 67 mRNA was more abundant than GAD 65, and both were localized to islet beta-cells by in situ hybridization. In testis, both GAD mRNAs were localized to spermatocytes. Additionally, GAD 67, but not GAD 65, mRNA was detected in mouse and rat spleen and mouse liver. Thus, both GAD genes are expressed in peripheral tissues, with GAD 67 mRNA being more abundant under physiological conditions. The expression of both GAD 67 and GAD 65 genes specifically in islet beta-cells indicates that both GAD forms are candidate autoantigens in rodent models of insulin-dependent diabetes mellitus.
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PMID:Localization and quantitation of expression of two glutamate decarboxylase genes in pancreatic beta-cells and other peripheral tissues of mouse and rat. 824 24

Linear growth retardation is common in uncontrolled insulin-deficient diabetes, but individual organs such as kidney may hypertrophy. To explore whether this heterogeneity of response might be mediated by differential local insulin-like growth factor-I (IGF-I) gene regulation, we injected rats with ip saline, 65, 120, or 175 mg/kg streptozotocin (STZ). Diabetics were untreated or received daily insulin. Animals were killed 24, 48, or 72 h after documentation of diabetes, and liver, kidney, and lung messenger RNA (mRNA) content analyzed by solution hybridization/RNase protection assay. Untreated diabetics had 10- to 100-fold reductions in hepatic IGF-I mRNA apparent as early as 24 h, and the magnitude of these changes varied directly with the severity of diabetes. In contrast, kidney IGF-I mRNA content increased by 400-500% at 24 h in untreated diabetics given 175 mg/kg STZ, and by 100-200% at 48 h in those given 120 mg/kg STZ, with return to control levels by 72 h. Renal IGF-I mRNA levels actually decreased by 250-350% at 24 h in rats injected with 65 mg/kg STZ, returning to supranormal values by 72 h. These results suggest that severity and/or duration of the metabolic abnormality qualitatively and quantitatively affect this response in the kidney. Liver and kidney IGF-I mRNA levels approached normal with insulin therapy and were similar to controls in rats which received STZ but did not develop diabetes. Lung IGF-I mRNA levels were minimally altered in all experimental groups. At the time point and STZ dosage at which liver IGF-I mRNA changes were most dramatic, little change in liver alpha-tubulin mRNA was noted. At the time point and STZ dosages at which kidney IGF-I mRNA induction was most dramatic, renal IGF-I receptor mRNA was only minimally changed, and renal alpha-tubulin mRNA was modestly reduced. In summary: 1) hepatic IGF-I mRNAs are dramatically reduced, and renal IGF-I mRNAs are significantly increased soon after the onset of insulin-deficient diabetes in STZ-treated rats; 2) insulin therapy restores IGF-I mRNA levels toward normal; and 3) these changes in IGF-I mRNA content are specific and are not the result of hepatic or renal STZ toxicity. These data suggest that IGF-I gene expression is regulated in a discordant, organ-specific manner in diabetes, and that metabolic factors in addition to GH may differentially modulate the endocrine and paracrine effects of IGF-I on growth.
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PMID:Discordant, organ-specific regulation of insulin-like growth factor-I messenger ribonucleic acid in insulin-deficient diabetes in rats. 842 71

In SHHF/Mcc-FAcp rats (formerly SHR/Mcc-cp), obesity and male gender synergistically modulate hyperinsulinemia, insulin resistance and predisposition to diabetes. Our previous studies showed gender and obesity modulate hepatic cell surface insulin binding and insulin clearance additively. Hepatic insulin receptors (IR) bind insulin as a first step in insulin clearance through internalization and degradation. We hypothesize that the synergistic effects of obesity and gender on hepatic insulin binding and clearance result from interaction of these two factors on hepatic IR expression. To address IR expression in SHHF/Mcc-FAcp rats, we quantitated IR protein levels in detergent-solubilized liver homogenates by Western blotting and IR mRNA levels by a solution hybridization/RNase protection assay. Obesity reduced total hepatic IR content in males and females, 50% and 68% respectively. Male gender reduced IR protein content 24% in lean, but had no effect on IR protein content in obese rats. Neither gender nor obesity affected hepatic IR mRNA content. Thus, obesity appears to affect hepatic IR protein content and cell surface binding through post-transcriptional mechanisms; similarly, male gender in lean rats reduces IR protein levels and cell surface binding through mechanisms not involving changes in mRNA levels. In obese rats, the synergistic effects of male gender appears to involve changes in IR trafficking and consequently cell surface insulin binding and processing.
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PMID:Effects of obesity and gender on insulin receptor expression in liver of SHHF/Mcc-FAcp rats. 852 Nov 66

The classical mouse fancy Agouti gene is responsible for the wild-type coat color where hairs are banded black and yellow. The Agouti gene encodes a 131-amino-acid secreted protein product that regulates phaeomelanin synthesis by melanocytes in mice. Mice with a dominant mutation at this locus, Ay, develop a yellow coat color, obesity, and diabetes, as the result of a deletion that results in ectopic overexpression of the Agouti gene mRNA in all tissues examined. Obesity and diabetes in Ay mutant mice could be caused by circulation of the protein, or localized action in specific tissues as a paracrine factor acting in cell-cell communication. To test these two possibilities, the Agouti cDNA was overexpressed in the skin of transgenic mice using either the Tyrosinase-Related Protein-1 or the keratin-14 (K14) promoter, the latter with and without an intron. The K14 promoter directed high constitutive levels of expression of Agouti mRNA in the skin, and several lines of transgenic mice exhibited coat colors resembling dominant Agouti allele phenotypes. Two highly expressing K14-Agouti transgenic lines, with light-yellow pelage, were analyzed for obesity and hyperglycemia. The transgenic mice were not significantly different from the controls (P > 0.05), indicating that the Agouti product does not act as an endocrine factor. RNase protection assays revealed a correlation between the levels of dorsal and ventral skin expression with pigmentation/phaeomelanin phenotypes. Co-injection experiments with the Agouti transgenes and other transgenes demonstrated co-integration of the two constructs at the same chromosomal site in approximately 95% of F1 progeny, allowing transgene inheritance to be visibly detected.
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PMID:Overexpression of an Agouti cDNA in the skin of transgenic mice recapitulates dominant coat color phenotypes of spontaneous mutants. 857 18

To determine whether defects of muscle glycogen synthase (GS) activity can be acquired by exposure to elevated glucose or insulin levels, human skeletal muscle cells obtained by needle biopsy from normal control subjects were grown in culture for 4-6 weeks followed by 4 days of fusion and differentiation in media containing either normal (5.5 mmol/l glucose and 22 pmol/l insulin) or increased concentrations of glucose (20 mmol/l), insulin (30 micromol/l), or both. After fusion in normal media, acute stimulation by 33 nmol/l insulin for 1 h increased GS fractional velocity (FV) approximately twofold (from 9.01 +/- 1.26 to 16.31 +/- 2.40, P < 0.05). Increasing the media glucose concentration alone to 20 mmol/l during fusion had no effect on basal FV but caused a marginal impairment of the insulin-stimulated GS response (from 8.51 +/- 1.33 to 12.99 +/- 1.90, P = 0.08). Increasing the media insulin concentration to 30 micromol/l during fusion at 5.5 mmol/l glucose also did not alter basal GS FV (10.61 +/- 1.69%) but completely abolished the normal insulin-stimulated increase in GS activity (to 11.63 +/- 1.55%, NS). The combination of high insulin (30 micromol/l) and high glucose (20 mmol/l) during fusion had no greater effect on the FV of either basal (11.66 +/- 2.16%, NS) or insulin-stimulated (9.20 +/- 1.80%, NS) GS activity than high insulin alone. Fusion in hyperinsulinemic media altered the kinetic parameters of GS with a near doubling of the basal Km0.1 and Vmax0.1 for uridinediphospho-glucose. Hyperinsulinemia also totally prevented the normal insulin-stimulated threefold increase in the Vmax0.1 and the 65% decrease in the A0.5 for glucose-6-phosphate. GS mRNA and protein expression, determined by RNase protection assay and immunoblotting, respectively, were unaffected by changes in media conditions. We conclude that exposure of human skeletal muscle cells primarily to high insulin induces severe insulin resistance through multiple acquired posttranslational defects, which affect both the kinetic characteristics and absolute activity of the GS enzyme.
Diabetes 1996 Apr
PMID:Acquired defects of glycogen synthase activity in cultured human skeletal muscle cells: influence of high glucose and insulin levels. 860 59

Nepsilon-(Carboxymethyl)lysine (CML) is an advanced glycation end product formed on protein by combined nonenzymatic glycation and oxidation (glycoxidation) reactions. We now report that CML is also formed during metal-catalyzed oxidation of polyunsaturated fatty acids in the presence of protein. During copper-catalyzed oxidation in vitro, the CML content of low density lipoprotein increased in concert with conjugated dienes but was independent of the presence of the Amadori compound, fructoselysine, on the protein. CML was also formed in a time-dependent manner in RNase incubated under aerobic conditions in phosphate buffer containing arachidonate or linoleate; only trace amounts of CML were formed from oleate. After 6 days of incubation the yield of CML in RNase from arachidonate was approximately 0.7 mmol/mol lysine compared with only 0.03 mmol/mol lysine for protein incubated under the same conditions with glucose. Glyoxal, a known precursor of CML, was also formed during incubation of RNase with arachidonate. These results suggest that lipid peroxidation, as well as glycoxidation, may be an important source of CML in tissue proteins in vivo and that CML may be a general marker of oxidative stress and long term damage to protein in aging, atherosclerosis, and diabetes.
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PMID:The advanced glycation end product, Nepsilon-(carboxymethyl)lysine, is a product of both lipid peroxidation and glycoxidation reactions. 862 37

The orphan nuclear receptor, peroxisome proliferator-activated receptor (PPAR) gamma, is implicated in mediating expression of fat-specific genes and in activating the program of adipocyte differentiation. The potential for regulation of PPAR gamma gene expression in vivo is unknown. We cloned a partial mouse PPAR gamma cDNA and developed an RNase protection assay that permits simultaneous quantitation of mRNAs for both gamma l and gamma 2 isoforms encoded by the PPAR gamma gene. Probes for detection of adipocyte P2, the obese gene product, leptin, and 18S mRNAs were also employed. Both gamma l and gamma 2 mRNAs were abundantly expressed in adipose tissue. PPAR gamma 1 expression was also detected at lower levels in liver, spleen, and heart; whereas, gamma l and gamma 2 mRNA were expressed at low levels in skeletal muscle. Adipose tissue levels of gamma l and gamma 2 were not altered in two murine models of obesity (gold thioglucose and ob/ob), but were modestly increased in mice with toxigene-induced brown fat ablation uncoupling protein diphtheria toxin A mice. Fasting (12-48 h) was associated with an 80% fall in PPAR gamma 2 and a 50% fall in PPAR gamma mRNA levels in adipose tissue. Western blot analysis demonstrated a marked effect of fasting to reduce PPAR gamma protein levels in adipose tissue. Similar effects of fasting on PPAR gamma mRNAs were noted in all three models of obesity. Insulin-deficient (streptozotocin) diabetes suppressed adipose tissue gamma l and gamma 2 expression by 75% in normal mice with partial restoration during insulin treatment. Levels of adipose tissue PPAR gamma 2 mRNA were increased by 50% in normal mice exposed to a high fat diet. In obese uncoupling protein diphtheria toxin A mice, high fat feeding resulted in de novo induction of PPAR gamma 2 expression in liver. We conclude (a) PPAR gamma 2 mRNA expression is most abundant in adipocytes in normal mice, but lower level expression is seen in skeletal muscle; (b) expression of adipose tissue gamma1 or gamma2 mRNAs is increased in only one of the three models of obesity; (c) PPAR gamma 1 and gamma 2 expression is downregulated by fasting and insulin-deficient diabetes; and (d) exposure of mice to a high fat diet increases adipose tissue expression of PPAR gamma (in normal mice) and induces PPAR gamma 2 mRNA expression in liver (in obese mice). These findings demonstrate in vivo modulation of PPAR gamma mRNA levels over a fourfold range and provide an additional level of regulation for the control of adipocyte development and function.
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PMID:Regulation of PPAR gamma gene expression by nutrition and obesity in rodents. 864 48

To characterize the phenotypic modulation of mesangial and glomerular epithelial cells, we investigated the expression of a nonmuscle type myosin heavy chain, SMemb, and alpha-smooth muscle actin (alpha-SM actin) in rat experimental glomerular diseases, which included anti-Thy 1 nephritis, 5/6 nephrectomy, diabetes, and anti-glomerular basement membrane nephritis. SMemb was only slightly expressed in normal glomerular epithelial cells but not in mesangial cells. In the anti-Thy 1 nephritis rats, both SMemb and alpha-SM actin were most conspicuously induced in mesangial cells. However, the expression profile was shifted from alpha-SM actin to SMemb dominant pattern over the course of glomerulonephritis. The expression of SMemb was also increased in epithelial cells in this model. In the other three models, glomerular cells did not express alpha-SM actin, but did so for SMemb. In the nephrectomized and the diabetic rats SMemb was newly expressed in mesangial cells at earlier stages, but at later stages was remarkably enhanced in epithelial cells when severe glomerular hypertrophy developed. In the anti-GBM nephritis rats, SMemb expression was increased in epithelial cells. In all models examined, mesangial and epithelial expression of SMemb was confirmed by immunoelectron microscopy, and enhanced expression of SMemb mRNA in glomeruli was verified by RNase protection assay. We conclude from these results that glomerular cells change their phenotypes differently depending on various types of glomerular diseases. These phenotypic changes in glomerular cells can be revealed by the combined immunostaining for SMemb and alpha-SM actin. SMemb is especially useful to detect both mesangial and glomerular epithelial cell activation in these glomerular disease models. Understanding the functional difference and regulatory mechanisms of these cytoskeletal proteins will provide insight into the pathogenesis and progression of glomerular diseases.
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PMID:Expression of a nonmuscle myosin heavy chain in glomerular cells differentiates various types of glomerular disease in rats. 873 Oct 86

We describe the cloning, characterization, and tissue distribution of the two human peroxisome proliferator activated receptor isoforms hPPARgamma2 and hPPARgamma1. In cotransfection assays the two isoforms were activated to approximately the same extent by known PPARgamma activators. Human PPARgamma binds to DNA as a heterodimer with the retinoid X receptor (RXR). This heterodimer was activated by both RXR agonists and antagonists and the addition of PPARgamma ligands with retinoids resulted in greater than additive activation. Such heterodimer-selective modulators may have a role in the treatment of PPARgamma/RXR-modulated diseases like diabetes. Northern blot analysis indicated the presence of PPARgamma in skeletal muscle, and a sensitive RNase protection assay confirmed the presence of only PPARgamma1 in muscle that was not solely due to fat contamination. However, both PPARgamma1 and PPARgamma2 RNA were detected in fat, and the ratio of PPARgamma1 to PPARgamma2 RNA varied in different individuals. The presence of tissue-specific distribution of isoforms and the variable ratio of PPARgamma1 to PPARgamma2 raised the possibility that isoform expression may be modulated in disease states like non-insulin-dependent diabetes mellitus. Interestingly, a third protected band was detected with fat RNA indicating the possible existence of a third human PPARgamma isoform.
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PMID:Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARgamma2 versus PPARgamma1 and activation with retinoid X receptor agonists and antagonists. 906 81

Advanced glycation end-products and glycoxidation products, such as Nepsilon-(carboxymethyl)lysine (CML) and pentosidine, accumulate in long-lived tissue proteins with age and are implicated in the aging of tissue proteins and in the development of pathology in diabetes, atherosclerosis and other diseases. In this paper we describe a new advanced glycation end-product, Nepsilon-(carboxyethyl)lysine (CEL), which is formed during the reaction of methylglyoxal with lysine residues in model compounds and in the proteins RNase and collagen. CEL was also detected in human lens proteins at a concentration similar to that of CML, and increased with age in parallel with the concentration of CML. Although CEL was formed in highest yields during the reaction of methylglyoxal and triose phosphates with lysine and protein, it was also formed in reactions of pentoses, ascorbate and other sugars with lysine and RNase. We propose that levels of CML and CEL and their ratio to one another in tissue proteins and in urine will provide an index of glyoxal and methylglyoxal concentrations in tissues, alterations in glutathione homoeostasis and dicarbonyl metabolism in disease, and sources of advanced glycation end-products in tissue proteins in aging and disease.
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PMID:N-epsilon-(carboxyethyl)lysine, a product of the chemical modification of proteins by methylglyoxal, increases with age in human lens proteins. 918 19


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