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)

Chronic diabetes due to streptozotocin administration has been shown to induce heart dysfunction characterized by prolonged relaxation time as well as decreased Ca2+ transport and Ca(2+)-ATPase (SERCA2) activities of the cardiac sarcoplasmic reticulum (SR). Rats made diabetic with 65 mg/kg of streptozotocin for 3 and 5 weeks exhibited decreased SR Ca(2+)-pump activities; these were normalized upon treatment with insulin. Northern blot and slot blot analyses did not show statistically significant reduction in the relative level of SERCA2 mRNA expression in diabetic or insulin treated rats. Quantitation of SERCA2 protein by Western blot did not reveal any change in diabetic and insulin treated animals. These results suggest that the defect in SR Ca(2+)-pump may not be due to changes at the transcriptional or translational levels in the diabetic heart.
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PMID:Cardiac sarcoplasmic reticulum Ca(2+)-ATPase expression in streptozotocin-induced diabetic rat heart. 807 44

In order to examine the relationship between heart dysfunction and subcellular abnormalities as well as molecular mechanisms during the development of diabetes, we studied changes in cardiac performance, myofibrillar as well as sarcoplasmic reticular (SR) activities, and cardiac gene expression at different time intervals upon inducing diabetes in rats by an injection of alloxan (65 mg/kg; i.v.). Cardiac dysfunction was associated with a depression in myofibrillar Ca2+-stimulated ATPase and changes in myosin isozyme composition at 2-12 weeks of inducing diabetes. A reduction in SR Ca2+-uptake and Ca2+-pump (SERCA2) activities was evident at 10 days to 12 weeks of inducing diabetes. Alterations in cardiac function during 2-12 weeks of diabetes show a linear relationship with changes in myofibrils and SR membranes. Furthermore, alterations in cardiac function as well as myofibrillar and SR activities in 4 week diabetic animals were normalized upon treatment with insulin for 4 weeks. The steady-state mRNA abundance for alpha-myosin heavy chain in the heart was decreased at 2 and 3 weeks but was unchanged at 5 and 6 weeks, whereas mRNA levels for beta-myosin heavy chain remained elevated during 2-6 weeks after inducing diabetes. SERCA2 mRNA abundance in diabetic heart was significantly increased at 3 and 5 weeks but was unaltered at 2 and 6 weeks. These results support the view that heart dysfunction in diabetes may be a consequence of myofibrillar and SR abnormalities; however, defects in myofibrillar proteins, unlike those in the SR membranes, appear to be due to changes in their gene expression.
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PMID:Differential changes in cardiac myofibrillar and sarcoplasmic reticular gene expression in alloxan-induced diabetes. 1056 79

Inhibitors of carnitine palmitoyl-transferase I (CPT I), the key enzyme for the transport of long-chain acyl-coenzyme A (acyl-CoA) compounds into mitochondria, have been developed as agents for treating diabetes mellitus Type 2. Findings that the CPT I inhibitor, etomoxir, has effects on overloaded heart muscle, which are associated with an improved function, were unexpected and can be attributed to selective changes in the dysregulated gene expression of hypertrophied cardiomyocytes. Also, the first clinical trial with etomoxir in patients with heart failure showed that etomoxir improved the clinical status and several parameters of heart function. In view of the action of etomoxir on gene expression, putative molecular mechanisms involved in an increased expression of SERCA2, the Ca(2+) pump of sarcoplasmic reticulum (SR) and alpha-myosin heavy chain (MHC) of failing overloaded heart muscle are described. The first 225 bp of human, rabbit, rat and mouse SERCA2 promoter sequence have high identity. Various cis-regularory elements are also given for the promoter of the rat cardiac alpha-MHC gene. It is hypothesised that etomoxir increases glucose-phosphate intermediates resulting in activation of signalling pathway(s) mediated by phosphatases. Regarding the possible direct action of etomoxir on peroxisome proliferator activated receptor alpha (PPAR-alpha) activation, it could upregulate the expression of various enzymes that participate in beta-oxidation, thereby modulating some effects of CPT 1 inhibition. Any development of alternative drugs requires a better understanding of the signal pathways involved in the altered gene expression. In particular, signals need to be identified which are altered in overloaded hearts and can selectively be re-activated by etomoxir.
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PMID:Therapeutic potential of CPT I inhibitors: cardiac gene transcription as a target. 1186 64

Slowed relaxation in diabetic cardiomyopathy (CM) is partially related to diminished expression of the sarcoplasmic reticulum (SR) Ca2+-ATPase SERCA2a. To evaluate the impact of SERCA2a overexpression on SR Ca2+ handling in diabetic CM, we 1) generated transgenic rats harboring a human cytomegalovirus enhancer/chicken beta-actin promotor-controlled rat SERCA2 transgene (SERCA2-TGR), 2) characterized their SR phenotype, and 3) examined whether transgene expression may rescue SR Ca2+ transport in streptozotocin-induced diabetes. The transgene was expressed in all heart chambers. Compared to wild-type (WT) rats, a heterozygous line exhibited increased SERCA2 mRNA (1.5-fold), SERCA2 protein (+26%) and SR Ca2+ uptake (+37%). Phospholamban expression was not altered. In SERCA2-TGR, contraction amplitude (+48%) and rates of contraction (+34%) and relaxation (+35%) of isolated papillary muscles (PM) were increased (P2+ uptake and SERCA2 protein of SERCA2-TGR were 1.3-fold higher (P2+ uptake, accelerates relaxation and compensates, in part, for depressed Ca2+ uptake in diabetic CM. Therefore, SERCA2 expression might constitute an important therapeutic target to rescue cardiac SR Ca2+ handling in diabetes.
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PMID:Transgenic overexpression of the sarcoplasmic reticulum Ca2+ATPase improves reticular Ca2+ handling in normal and diabetic rat hearts. 1220 92

We investigated left ventricular (LV) mechanoenergetics in acute and chronic failing hearts, induced by high Ca(2+), ischemic-reperfusion injury, diabetes mellitus (DM), and hypothyroidism, using cross-circulated excised rat heart preparations. After high Ca(2+) or ischemic-reperfusion, there was a contractile failure associated with a parallel downward shift of the linear relation between myocardial O(2) consumption per beat (VO(2)) and systolic pressure-volume area (PVA). This result indicated a decrease in VO(2) for total Ca(2+) handling in E-C coupling. We found proteolysis of a cytoskeletal protein, alpha-fodrin. A calpain inhibitor significantly suppressed contractile failure, decreased VO(2) for total Ca(2+) handling, and membrane alpha-fodrin degradation. In DM, the LV relaxation rate was significantly slower, resulting in the decreased O(2) consumption per min for total Ca(2+) handling in E-C coupling. In hypothyroidism, there were systolic and diastolic failures associated with the decreased O(2) consumption per beat for total Ca(2+) handling in E-C coupling. The protein level of sarcoplasmic reticulum Ca(2+) ATPase (SERCA2) was significantly lower in DM and hypothyroidism. We conclude that suppression of O(2) consumption for total Ca(2+) handling, mainly utilized by SERCA2, is a major cause of failing hearts, mediated through degradation of membrane alpha-fodrin via activation of calpain or suppressed expression of SERCA2.
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PMID:[Energy utility of failing heart]. 1474 27

The bradykinin-forming enzyme kallikrein-1 is expressed in the heart. To examine whether contractile performance and sarcoplasmic reticulum Ca2+ transport of the diabetic heart can be rescued by targeting the kallikrein-kinin system, we studied left ventricular function and sarcoplasmic reticular Ca2+ uptake after induction of streptozotocin-induced diabetes mellitus in transgenic rats expressing the human tissue kallikrein-1 gene. Six weeks after a single injection of either streptozotocin (70 mg/kg ip) or vehicle, left ventricular performance was determined using a Millar-Tip catheter system. The Ca2+-transporting activity of reticulum-derived membrane vesicles was determined in left ventricular homogenates as oxalate-supported 45Ca2+ uptake. Western blot analysis was used to quantify the reticular Ca2+-ATPase SERCA2a, phospholamban, and the phosphorylation status of the latter. Contractile performance and Ca2+ uptake activity were similar in nondiabetic wild-type and transgenic rats. Severely diabetic wild-type animals exhibited impaired left ventricular performance and decreased reticular Ca2+ uptake (-39% vs. wild-type rats, P<0.05, respectively). These changes were attenuated in diabetic transgenic rats that, in addition, exhibited a markedly increased phospholamban phosphorylation at the Ca2+/calmodulin kinase-specific site threonine17 (2.2-fold vs. diabetic wild-type rats, P<0.05). These transgene-related effects were abolished after treatment with the bradykinin B2 receptor antagonist icatibant (Hoe 140). The SERCA2-to-phospholamban ratio, phosphoserine16-phospholamban levels, and the apparent affinity for Ca2+ of the uptake reaction did not differ between the groups. Increasing the activity of the kallikrein-kinin system by expressing a human kallikrein-1 transgene protects rat heart against diabetes-induced contractile and reticular Ca2+ transport dysfunctions. An increased phosphorylation of the SERCA2 regulatory protein phospholamban at threonine17 via a B2 receptor-mediated mechanism is thereby involved.
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PMID:Improvement of defective sarcoplasmic reticulum Ca2+ transport in diabetic heart of transgenic rats expressing the human kallikrein-1 gene. 1544 11

The World Health Organization (WHO) predicts there will be 300 million people world-wide with diabetes mellitus by 2025. Currently it is estimated that there are 20 and 60 million people suffering from diabetes mellitus in North America and Europe, respectively. Within this huge population of diabetic persons approximately 50% will develop some form of sensory polyneuropathy, which involves the dying back of distal axons and a failure of axons to regenerate. This leads to incapacitating pain, sensory loss and poor wound healing. The end result is lower extremity amputation with approximately 90,000 diabetes-related amputations occurring each year in North America and the expectation of a 5-fold increase over the next 10 years due to increased incidence of type 2 diabetes. Abnormal neuronal Ca(2+) homeostasis and impaired mitochondrial function have been implicated in numerous CNS and PNS diseases including diabetic sensory neuropathy. The endoplasmic reticulum (ER), in part, regulates cellular Ca(2+) homeostasis and this process is linked to regulation of mitochondrial function and activity of anti-apoptotic signal transduction pathways. Here we review the current state of research regarding role of Ca(2+) dyshomeostasis and mitochondrial physiology in neuronal dysfunction in diabetes. The central impact of diabetes-induced alteration of Ca(2+) handling on sensory neurone function is discussed and related to abnormal ER performance. New results are presented showing suboptimal Ca(2+) concentration in the ER lumen in association with reduced SERCA2 expression in sensory neurones from type 1 diabetic rats. We hypothesize that deficits in neurotrophic factor support, specifically linked to diabetes-induced lowered expression of insulin and neurotrophin-3, triggers alterations of sensory neurone phenotype that are critical for the development of abnormal Ca(2+) homeostasis and associated mitochondrial dysfunction. The role of hyperglycaemia in diabetes is also discussed and we propose that high glucose concentration may impact at other sites to contribute to the heterogeneous aetiology of nerve damage in diabetes.
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PMID:Mitochondrial malfunction and Ca2+ dyshomeostasis drive neuronal pathology in diabetes. 1819 Nov 98

Sarco(endo)plasmic reticulum (SER) Ca2+ ATPases represent a highly conserved family of Ca2+ pumps which actively transport Ca2+ from the cytosol to the SER against a large concentration gradient. In humans, 3 genes (ATP2A1-3) generate multiple isoforms (SERCAla,b, SERCA2a-c, SECA3a-f) by developmental or tissue-specific alternative splicing. These pumps differ by their regulatory and kinetic properties, allowing for optimized function in the tissue where they are expressed. They play a central role in calcium signalling through regenerating SER Ca2+ stores, maintaining appropriate Ca2+ levels in this organelle and shaping cytosolic and nuclear Ca2+ variations which govern cell response. Defects in ATP2A1 encoding SERCA1 cause recessive Brody myopathy, mutations in ATP2A2 coding for SERCA2 underlie a dominant skin disease, Darier disease and its clinical variants. SERCA2a expression is reduced in heart failure in human and in mice models. Gene-targeting studies in mouse confirmed the expected function of these isoforms in some cases, but also resulted in unexpected phenotypes: SERCA1 null mutants die from respiratory failure, SERCA2 heterozygous mutant mice develop skin cancer with age and SERCA3 null mice display no diabetes. These unique phenotypes have provided invaluable information on the role of these pumps in specific tissues and species, and have improved our understanding of Ca2+ regulated processes in muscles, the heart and the skin in human and in mice. Although the understanding of the pathogenesis of these diseases is still incomplete, these recent advances hold the promise of improved knowledge on the disease processes and the identification of new targets for therapeutic interventions.
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PMID:SERCA pumps and human diseases. 1819 43

The insulin signaling pathway is of pivotal importance in metabolic diseases, such as diabetes, and in cellular processes, such as aging. Insulin activates a tyrosine phosphorylation cascade that branches to create a complex network affecting multiple biological processes. To understand the full spectrum of the tyrosine phosphorylation cascade, we have defined the tyrosine-phosphoproteome of the insulin signaling pathway, using high resolution mass spectrometry in combination with phosphotyrosine immunoprecipitation and stable isotope labeling by amino acids in cell culture (SILAC) in differentiated brown adipocytes. Of 40 identified insulin-induced effectors, 7 have not previously been described in insulin signaling, including SDR, PKCdelta binding protein, LRP-6, and PISP/PDZK11, a potential calcium ATPase binding protein. A proteomic interaction screen with PISP/PDZK11 identified the calcium transporting ATPase SERCA2, supporting a connection to calcium signaling. The combination of quantitative phosphoproteomics with cell culture models provides a powerful strategy to dissect the insulin signaling pathways in intact cells.
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PMID:Dissection of the insulin signaling pathway via quantitative phosphoproteomics. 1826 50

Diabetes increases mortality and accelerates left ventricular (LV) dysfunction following myocardial infarction (MI). This study sought to determine the impact of impaired myocardial insulin signaling, in the absence of diabetes, on the development of LV dysfunction following MI. Mice with cardiomyocyte-restricted knock out of the insulin receptor (CIRKO) and wildtype (WT) mice were subjected to proximal left coronary artery ligation (MI) and followed for 14 days. Despite equivalent infarct size, mortality was increased in CIRKO-MI vs. WT-MI mice (68% vs. 40%, respectively). In surviving mice, LV ejection fraction and dP/dt were reduced by >40% in CIRKO-MI vs. WT-MI. Relative to shams, isometric developed tension in LV papillary muscles increased in WT-MI but not in CIRKO-MI. Time to peak tension and relaxation times were prolonged in CIRKO-MI vs. WT-MI suggesting impaired, load-independent myocardial contractile function. To elucidate mechanisms for impaired LV contractility, mitochondrial function was examined in permeabilized cardiac fibers. Whereas maximal ADP-stimulated mitochondrial O(2) consumption rates (V(ADP)) with palmitoyl carnitine were unchanged in WT-MI mice relative to sham-operated animals, V(ADP) was significantly reduced in CIRKO-MI (13.17+/-0.94 vs. 9.14+/-0.88 nmol O(2)/min/mgdw, p<0.05). Relative to WT-MI, expression levels of GLUT4, PPAR-alpha, SERCA2, and the FA-Oxidation genes MCAD, LCAD, CPT2 and the electron transfer flavoprotein ETFDH were repressed in CIRKO-MI. Thus reduced insulin action in cardiac myocytes accelerates post-MI LV dysfunction, due in part to a rapid decline in mitochondrial FA oxidative capacity, which combined with limited glucose transport capacity that may reduce substrate utilization and availability.
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PMID:Impaired insulin signaling accelerates cardiac mitochondrial dysfunction after myocardial infarction. 1924 10


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