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)

Our laboratory has demonstrated that insulin rapidly stimulates myosin-bound phosphatase (MBP) activity in vascular smooth muscle cells (VSMCs). In this study, we examined whether diabetes is accompanied by alterations in MBP activation and elucidated the components of the signaling pathway that mediate the effects of diabetes. VSMCs isolated from Goto-Kakizaki (GK) diabetic rats (a model for type 2 diabetes) exhibited marked impairment in MBP activation by insulin that was accompanied by failure of insulin to decrease the phosphorylation of a regulatory myosin-bound subunit (MBS) of MBP and inhibit Rho kinase activity resulting in increased myosin light-chain (MLC)20 phosphorylation and VSMC contraction. In VSMCs isolated from control rats, insulin inactivates Rho kinase and decreases MBS phosphorylation, leading to MBP activation. In addition to this pathway, insulin also appears to activate MBP by stimulating the phosphatidylinositol (PI) 3-kinase/nitric oxide (NO)/cGMP signaling pathway because treatment with the synthetic inhibitors of PI 3-kinase, NO synthase (NOS), and cGMP all blocked insulin's effect on MBP activation, whereas cGMP agonists and sodium nitroprusside (SNP) mimicked insulin's effect on MBP activation. VSMCs from diabetic GK rats exhibit reductions in insulin-mediated induction of inducible NOS protein expression and cGMP generation but normal MBP activation in response to SNP and cGMP agonist. This observation led us to examine the effect of diabetes on the activation status of the upstream insulin-signaling components. Although GK diabetes did not affect insulin-stimulated tyrosine phosphorylation of the insulin receptor or its content, insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation was severely impaired. This was accompanied by marked reductions in IRS-1-associated PI 3-kinase activity. We conclude that insulin stimulates MBP via its regulatory subunit, MBS, by inactivating Rho kinase and stimulating NO/cGMP signaling via PI 3-kinase as part of a complex signaling network that controls MLC20 phosphorylation and VSMC contraction. Defective signaling via Rho kinase and the IRS-1/PI 3-kinase/NOS/cGMP pathway may mediate the inhibitory effects of hyperglycemia and diabetes on MBP activation in this experimental model.
Diabetes 2000 Dec
PMID:Diabetes in the Goto-Kakizaki rat is accompanied by impaired insulin-mediated myosin-bound phosphatase activation and vascular smooth muscle cell relaxation. 1111 23

Available data suggest that hypertensive cardiopathy is principally determined by the phenoconversion that allows the myocyte to adapt to the new working conditions by re-expressing a fetal program. Nevertheless, in clinical conditions, the scheme is different. The above phenotype is modified by trophic factors, which originate from ischemia, senescence, diabetes, genetics, or neurohormonal reactions. This review only focuses on some of the most recent advances concerning the permanent changes in the myocyte. Changes in extracellular matrix have been excluded. Recently, emphasis has been on the kinetic basis of the myocardial dysfunction at the myosin level, the potential therapeutic utilization of transferring the adrenergic receptor gene, the participation of NO synthases in the adaptational process, the existence of an abnormal excitation-contraction coupling due to a redistribution of Ca2+ sparks, the role of the microtubule as a determinant of sarcomere motion, and the multifactorial origin of cell death by apoptosis.
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PMID:Biology of hypertensive cardiopathy. 1113 87

Gender-related differences in the rate of coronary heart disease (CHD) between premenopausal women and men are greatly diminished in women with diabetes mellitus (DM). This may be related, in part, to altered platelet function in premenopausal diabetic women. Hyperglycemia may contribute to increase platelet aggregation through enhancement of oxidative stress, increased nitric oxide (NO) destruction, and increased myosin light-chain (MLC) phosphorylation (MLC-P). Accordingly, we investigated functional and biochemical parameters of platelet function in 32 women (14 premenopausal and postmenopausal controls and 18 age-matched patients with DM); platelet MLC-P and cyclic guanosine monophosphate ([cGMP] reflecting NO) were assessed. Other parameters including age, body mass index (BMI), waist to hip ratio, total cholesterol, and platelet count were not different in the control and diabetic groups. In the premenopausal women, baseline MLC-P was lower in women with DM versus the control group (P = .02). GMP levels were similar in the two groups at baseline (22.7 +/- 3 fmol/mL in controls v 23.1 +/- 3 fmol/mL in diabetic subjects) and 3 minutes after insulin exposure. The platelet content of ascorbic acid (AA), an endogenous antioxidant compound, was elevated in premenopausal women with DM (P = .02) compared with the controls. Despite similar estradiol (beta,E2) levels, platelets of premenopausal women with DM exhibited reduced MLC-P. This paradoxic difference may be accounted for by an increase in platelet AA, as this suggests decreased platelet oxidative stress in this patient population. These observations indicate that an altered redox state and associated MLC-P of platelets does not contribute to enhanced platelet aggregation and CHD in premenopausal women with DM.
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PMID:Altered myosin light-chain phosphorylation in resting platelets from premenopausal women with diabetes. 1122 21

Skeletal muscle is composed of different fibre types, which differ in contractile as well as in metabolic properties. The myosin molecule, which exists in several different isoforms, is of major importance in determining the contractile properties of the muscle cell. The plasticity of skeletal muscle is reflected in this tissue's adaptability to changes in the functional demand. In both rats and humans, a decrease in activity level will in most cases change the muscle fibre composition towards faster myosin isoforms and an increase in activity level (such as seen with exercise training) will induce an increase in slower myosin isoforms. The glucose transporter protein 4 (GLUT4), which is the major insulin regulatable glucose transporter in mammalian skeletal muscle, is found in larger amounts in slow muscle fibres compared with fast muscle fibres. An increase in activity level will increase the GLUT4 protein expression and a decrease in activity level will in most cases decrease GLUT4. Thus, there seems to be some kind of relationship between the muscle fibre type and GLUT4. However, the main factor regulating both the GLUT4 protein expression and the muscle fibre composition seems to be the activity level of the muscle fibre. Patients suffering from non-insulin-dependent diabetes mellitus (NIDDM) are insulin resistant in their skeletal muscles but are generally normal when it comes to skeletal muscle fibre composition and the GLUT4 protein expression. There is good evidence that exercise training beneficially impacts on insulin sensitivity in healthy individuals and in patients with type II diabetes. An increase in the GLUT4 protein expression in skeletal muscle may at least partly explain this effect of training.
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PMID:Relationship between muscle fibre composition, glucose transporter protein 4 and exercise training: possible consequences in non-insulin-dependent diabetes mellitus. 1141 39

Nonenzymatic glycosylation (glycation) is recognized as an important post-translational modification underlying alterations of structure and function of extracellular proteins. The effect of glycation on intracellular proteins is, on the other hand, less well known despite the vital importance of intracellular proteins for cell, tissue, and organ function. The aim of this study was to explore the effects of glycation on the structure and function of skeletal muscle myosin. Myosin was incubated for up to 30 min with glucose and subsequently tested for structural and functional modifications by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry and a single-fiber in vitro motility assay, respectively. MALDI spectra revealed glycation-related structural alterations as evidenced by the disappearance of specific Lys-C proteolysis products and the appearance of higher mass peaks that are attributed to cross-linking by glucose. This change was paralleled by a significant reduction in the in vitro motility speed, suggesting a structure-related decline in myosin mechanics in response to glucose exposure. Further evidence that early glycation products form in the regulatory regions of the myosin molecule is derived from the fact that there is complete reversal of motility speed after reaction with the Schiff base-cleaving agent hydroxylamine hydrochloride. Thus, glycation of skeletal muscle myosin has a significant effect on both the structural and functional properties of the protein, a finding that is important in understanding the mechanisms underlying the impairment in muscle function associated with aging and diabetes.
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PMID:Changes in myosin structure and function in response to glycation. 1168 66

Etomoxir, an inhibitor of mitochondrial carnitine palmitoyltransferase-1, is known to attenuate the changes in myosin isoforms and sarcoplasmic reticular function that occur in diabetic rat hearts. In the present study, we tested the hypothesis that etomoxir also prevents the diabetes-induced depression of sarcolemmal (SL) Na+-K+ATPase activity by differentially affecting its alpha and beta-subunit levels. Streptozotocin-induced diabetes was associated with a decreased in alpha2-, alpha3-subunit levels, whereas the alpha1-and beta1-subunits were unchanged. Treatment of diabetic rats for 4 weeks with etomoxir (8 mg/kg/day) increased the alpha1-subunit levels, but failed to prevent the decrease in alpha2- and alpha3-subunit levels. In euglycemic control rats, etomoxir increased the alpha1-subunit protein level per g heart weight, but did not alter the alpha2-, alpha3- and beta1-subunit levels. The large decrease in Na+-K+ ATPase activity per g heart weight in diabetic rats was prevented by etomoxir, which suggests that the increased alpha1-subunit levels seen with this drug compensated for the decreased alpha2- and alpha3-subunit levels. The SL yield was also increased by etomoxir in euglycemic rats in proportion to the higher alpha1-subunit level, which resulted in an unchanged alpha1-content when expressed per mg SL protein; however, the alpha2- and beta1-subunit levels were reduced (p < 0.05). The depressed alpha2- and beta3 subunit levels of diabetic rats were associated with reduced mRNA abundance. However, no increase in alpha1-subunit mRNA abundance was seen in the etomoxir treated rats, which suggests that possibly post-transcriptional mechanisms are occurring in these hearts.
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PMID:Differential effects of etomoxir treatment on cardiac Na+-K+ ATPase subunits in diabetic rats. 1203 Mar 80

This review focuses on what we consider to be the most important findings of the last year relating to the smooth muscle of the lower urogenital system and the different levels of regulation that control its contraction and relaxation. One level is through modulation of the smooth muscle itself or its environment. Recent findings examining myosin isoform composition and collagen content as well as mechanisms that appear to be involved in inducing hyperplasia/hypertrophy of smooth muscle are described. Another method of regulation is via calcium-dependent phosphorylation of the regulatory light chain of myosin, which increases its activity. Interesting results indicating an uncoupling of force from calcium in the bladder are discussed. A third level of regulation is pharmacologic. Thus, the most recent findings related to receptor subtypes, including muscarinic, endothelin, alpha-adrenergic and nicotinic receptors, are presented. In addition, the effects of diabetes, incontinence, and partial bladder outlet obstruction on these modes of contractile regulation are also discussed.
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PMID:Lower urinary tract physiology and pharmacology. 1208 18

Recent studies from our laboratory have shown that insulin induces relaxation of vascular smooth muscle cells (VSMCs) via stimulation of myosin phosphatase and inhibition of Rho kinase activity. In this study, we examined the mechanism whereby insulin inhibits Rho signaling and its impact on actin cytoskeleton organization. Incubation of confluent serum-starved VSMCs with thrombin or phenylephrine (PE) caused a rapid increase in glutathione S-transferase-Rhotekin-Rho binding domain-associated RhoA, Rho kinase activation, and actin cytoskeleton organization, which was blocked by preincubation with insulin. Preexposure to N(G)-monomethyl L-arginine acetate (L-NMMA), a nitric oxide synthase inhibitor, and Rp-8 CPT-cyclic guanosine monophosphate (RpcGMP), a cyclic guanosine monophosphate (cGMP) antagonist, attenuated the inhibitory effect of insulin on RhoA activation and restored thrombin-induced Rho kinase activation, and site-specific phosphorylation of the myosin-bound regulatory subunit (MBS(Thr695)) of myosin-bound phosphatase (MBP), and caused actin fiber reorganization. In contrast, 8-bromo-cGMP, a cGMP agonist, mimicked the inhibitory effects of insulin and abolished thrombin-mediated Rho activation. Insulin inactivation of RhoA was accompanied by inhibition of isoprenylation via reductions in geranylgeranyl transferase-1 activity as well as increased RhoA phosphorylation, which was reversed by pretreatment with RpcGMP and L-NMMA. We conclude that insulin may inhibit Rho signaling by affecting posttranslational modification of RhoA via nitric oxide/cGMP signaling pathway to cause MBP activation, actin cytoskeletal disorganization, and vasodilation.
Diabetes 2002 Jul
PMID:Negative regulation of rho signaling by insulin and its impact on actin cytoskeleton organization in vascular smooth muscle cells: role of nitric oxide and cyclic guanosine monophosphate signaling pathways. 1208 58

A considerable number of experimental, epidemiological and clinical studies are now available which point to an important role of Mg2+ in the etiology of cardiovascular pathology. In human subjects, hypomagnesemia is often associated with an imbalance of electrolytes such as Na+, K+ and Ca2+. Abnormal dietary deficiency of Mg2+ as well as abnormalities in Mg2+ metabolism play important roles in different types of heart diseases such as ischemic heart disease, congestive heart failure, sudden cardiac death, atheroscelerosis, a number of cardiac arrhythmias and ventricular complications in diabetes mellitus. Mg2+ deficiency results in progressive vasoconstriction of the coronary vessels leading to a marked reduction in oxygen and nutrient delivery to the cardiac myocytes. Numerous experimental and clinical data have suggested that Mg2+ deficiency can induce elevation of intracellular Ca2+ concentrations, formation of oxygen radicals, proinflammatory agents and growth factors and changes in membrane perrmeability and transport processes in cardiac cells. The opposing effects of Mg2+ and Ca2+ on myocardial contractility may be due to the competition between Mg2+ and Ca2+ for the same binding sites on key myocardial contractile proteins such as troponin C, myosin and actin. Stimulants, for example, catecholamines can evoke marked Mg2+ efflux which appears to be associated with a concomitant increase in the force of contraction of the heart. It has been suggested that Mg2+ efflux may be linked to the Ca2+ signalling pathway. Depletion of Mg2+ by alcohol in cardiac cells causes an increase in intracellular Ca2+, leading to coronary artery vasospasm, arrhythmias, ischemic damage and cardiac failure. Hypomagnesemia is commonly associated with hypokalemia and occurs in patients with hypertension or myocardial infarction as well as in chronic alcoholism. The inability of the senescent myocardium to respond to ischemic stress could be due to several reasons. Mg2+ supplemented K+ cardioplegia modulates Ca2+ accumulation and is directly involved in the mechanisms leading to enhanced post ischemic functional recovery in the aged myocardium following ischemia. While many of these mechanisms remain controversial and in some cases speculative, the beneficial effects related to consequences of Mg2+ supplementation are apparent. Further research are needed for the incorporation of these findings toward the development of novel myocardial protective role of Mg2+ to reduce morbidity and mortality of patients suffering from a variety of cardiac diseases.
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PMID:Protective role of magnesium in cardiovascular diseases: a review. 1234 4

Oxidative stress is implicated in a broad variety of chronic and acute diseases, including such age-related diseases as diabetes. To understand at the protein level cellular damage caused by the stress, we developed a proteomic method, in which protein carbonyls were derivatized with biotin hydrazide followed by two-dimensional gel electrophoresis. The method, being capable of analyzing high-molecular-mass proteins as large as myosin heavy chains (molecular mass approximately 200 kDa), was applied to detecting protein carbonyls in muscles of a diabetes model Otsuka Long-Evans Tokushima Fatty (OLETF) rat and a control Long-Evans Tokushima Otsuka (LETO) rat. A number of proteins, including mitochondrial ATP synthase beta-chain, desmin, actin, and myosin, were found carbonylated. Our method would provide a means toward clarifying a comprehensive view of oxidative modifications of proteins during a long progression of age-related diseases and understanding the mechanism of the onset, progression, and complication of the diseases.
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PMID:Proteomic method detects oxidatively induced protein carbonyls in muscles of a diabetes model Otsuka Long-Evans Tokushima Fatty (OLETF) rat. 1249 75


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