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)

Physicians need to weigh the efficacy, adverse effects and cost of first-line antihypertensive agents. Calcium channel blockers lower blood pressure, improve coronary blood flow and depress cardiac contractility by relaxing smooth muscle and cardiac muscle. They have beneficial or neutral effects in hypertensive patients with angina, asthma, chronic obstructive pulmonary disease, postural hypotension, peripheral vascular disease, depression, sexual dysfunction, diabetes and hyperlipidemia. The major adverse effect of some calcium channel blockers is that they may worsen congestive heart failure in some patients. Because calcium channel blockers are metabolized in the liver, the dosage must be lowered in the elderly and in patients with hepatic disease. Diltiazem, verapamil and nifedipine represent prototypes of the three classes of calcium channel blockers, each with slightly different effects.
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PMID:Calcium channel blockers in the treatment of hypertension. 836 95

In streptozotocin (STZ)-induced diabetic rats, activities of Na(+)-K(+)-ATPase and the Na pump have been shown to be altered. Cellular mechanisms underlying such changes remain unclear. The present studies examined by immunoblotting the levels of Na(+)-K(+)-ATPase subunit isoforms in heart, skeletal muscle, and kidney of diabetic rats. Effects of insulin treatment on these levels were also studied. In cardiac muscle, STZ-induced diabetes caused a marked decrease in alpha 2-levels, a moderate decrease in beta 1-levels, and no significant change in alpha 1-levels. Corresponding to these changes, Na(+)-K(+)-ATPase activity, estimated by K(+)-dependent p-nitrophenylphosphatase activity, also decreased. By contrast, there were significant increases in alpha 1- and alpha 2-levels in skeletal muscle and in alpha 1- and beta 1-levels in kidneys of diabetic rats. There was also a detectable, but not significant, increase in beta 1-levels in diabetic skeletal muscle. In kidney, the increase in subunit levels was associated with significantly increased Na(+)-K(+)-ATPase activity, whereas, in skeletal muscle, no increase in enzyme activity was observed. In diabetic rats, 7 days of insulin treatment (10 U/kg sc) partially reversed the decreased alpha 2- and beta 1-levels in diabetic cardiac muscle, without significant effect on alpha 1-levels. In skeletal muscle, insulin treatment also partially reversed the elevated alpha 1- and alpha 2-levels but was without significant effect on beta 1-levels. It is concluded that STZ-induced diabetes exerted isoform- and tissue-specific regulation of the Na(+)-K(+)-ATPase subunit isoforms.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alterations in levels of Na(+)-K(+)-ATPase isoforms in heart, skeletal muscle, and kidney of diabetic rats. 839 32

Insulin resistance in diabetic rats involves pretranslational suppression of the GLUT 4 glucose transporter in muscle. Because the capacity for insulin-mediated glucose transport varies as a function of muscle group, we hypothesized that GLUT 4 was differentially expressed and regulated by diabetes in a muscle-specific manner. We studied control (C), streptozocin (STZ)-induced diabetic (D), and insulin-treated diabetic (Tx) rats and examined the following muscles that vary in fiber composition: soleus (type I fibers), gastrocnemius (mixed type IIa > IIb), vastus lateralis and rectus abdominis (type IIb > IIa), and cardiac muscle. In C animals, these muscles exhibited significant differences in the baseline expression of GLUT 4. Relative GLUT 4 content was highest in cardiac muscle, intermediate in soleus, and significantly lower in gastrocnemius, rectus abdominis, and vastus lateralis (1.8:1.0:0.6). The impact of diabetes and insulin therapy on GLUT 4 expression also varied as a function of muscle group. After four weeks of diabetes, GLUT 4 levels were reduced by approximately 50% in cardiac muscle, soleus, and gastrocnemius. In contrast, GLUT 4 content in rectus abdominis and vastus lateralis was similar to that in control rats. Exogenous insulin treatment of diabetic rats increased GLUT 4 content in soleus, cardiac muscle, and gastrocnemius, but had no effect in either vastus lateralis or rectus abdominis. Temporal effects of diabetes and insulin treatment were also examined in different skeletal muscle. Soleus showed a significant decrease in GLUT 4 content as early as 2 days with a further decrease at 4 weeks; rectus abdominis showed little change at either time point.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Muscle group-specific regulation of GLUT 4 glucose transporters in control, diabetic, and insulin-treated diabetic rats. 841 43

Peptide-chain initiation is inhibited in fast-twitch skeletal muscle, but not heart, of diabetic rats. We have investigated mechanisms that might maintain eukaryotic initiation factor (eIF)-2B activity, preventing loss of efficiency of protein synthesis in heart of diabetic rats but not in fast-twitch skeletal muscle. There was no change in the amount or phosphorylation state of eIF-2 in skeletal or cardiac muscle during diabetes. In contrast, eIF-2B activity was decreased in fast-twitch but not slow-twitch muscle from diabetic animals. NADP+ inhibited partially purified eIF-2B in vitro, but addition of equimolar NADPH reversed the inhibition. The NADPH-to-NADP+ ratio was unchanged in fast-twitch muscle after induction of diabetes but was increased in heart of diabetic rats, suggesting that NADPH also prevents inhibition of eIF-2B in vivo. The activity of casein kinase II, which can phosphorylate and activate eIF-2B in vitro, was significantly lower in extracts of fast-twitch, but not cardiac muscle, of diabetic rats compared with controls. The results presented here demonstrate that changes in eIF-2 alpha phosphorylation are not responsible for the effect of diabetes on eIF-2B activity in fast-twitch skeletal muscle. Modulation of casein kinase II activity may be a factor in the regulation of protein synthesis in muscle during acute diabetes. The activity of eIF-2B in heart might be maintained by the increased NADPH/NADP+.
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PMID:Regulation of eukaryotic initiation factor-2B activity in muscle of diabetic rats. 843 Jul 78

To examine the hormonal/metabolic as well as tissue-specific expression of the GLUT4/muscle-fat facilitative glucose transporter gene, we have generated several transgenic mouse lines expressing a human GLUT4 mini-gene which extends 5.3 kilobases (kb) upstream of transcription start and terminates within exon 10. This construct (hGLUT4-11.5) was expressed in a tissue-specific pattern identical to the endogenous mouse GLUT4 gene. The transcription initiation sites of the transgenic construct were similar to the GLUT4 gene expressed in human tissues. To investigate the hormonal/metabolic-dependent regulation of GLUT4, the transgenic animals were made insulin-deficient by streptozotocin (STZ) treatment. In these animals, STZ-induced diabetes resulted in a parallel decrease in endogenous mouse GLUT4 mRNA and the transgenic human GLUT4 mRNA in white adipose tissue, brown adipose tissue, and cardiac muscle. Similarly, insulin treatment of the STZ-diabetic animals restored both the endogenous mouse and transgenic human GLUT4 mRNA levels. To further define cis-regulatory regions responsible for this hormonal/metabolic regulation, the same analysis was performed on transgenic animals which carry 2.4 kb of the human GLUT4 5'-flanking region fused to a CAT reporter gene (hGLUT4[2.4]-CAT). This reporter construct responded similarly to the human GLUT4 mini-gene demonstrating that the element(s) controlling hormonal/metabolic regulation and tissue specificity all reside exclusively within 2.4 kb of the transcriptional initiation site.
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PMID:Hormonal/metabolic regulation of the human GLUT4/muscle-fat facilitative glucose transporter gene in transgenic mice. 848 63

We describe a family with three cases of "clinically incomplete mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome" in which heteroplasmic tRNA(Leu(UUR)) mutation at nucleotide 3243 of the mitochondrial DNA was present in three generations. The amount of mutant genome varied among tissues: it was 60% in the kidney, 72% in the cardiac muscle, and 91% in the liver of the female proband's affected brother and 63% in the kidney, 71% in the cardiac muscle, and 71% in the liver of the female proband's perinatally deceased son. The tRNA(Leu(UUR)) mutation was also carried by the siblings of the proband's affected mother. None of them had any clinical signs of MELAS syndrome. This syndrome has the new feature of being associated with adult-onset diabetes mellitus, neurosensory hearing loss, and short stature.
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PMID:Adult-onset diabetes mellitus and neurosensory hearing loss in maternal relatives of MELAS patients in a family with the tRNA(Leu(UUR)) mutation. 849 19

A 44-year-old woman with diabetes mellitus, cardiomyopathy, and a mitochondrial gene mutation, was reported. She was diagnosed as having diabetes at 33 years of age and was treated with insulin. However, she stopped treatment 6 months later and had no medical care until she developed diabetic ketoacidosis at 41 years of age. She had diabetic foot, diabetic retinopathy, and nephropathy with low insulin secretory capacity, leading to insulin treatment. A point mutation of the mitochondrial tRNA(Leu(UUR)) gene was identified in peripheral leukocytes at 43 years of age, and sensorineural hearing impairment was detected at the same time. Her mother also suffered from diabetes mellitus with deafness and her son, who was not diabetic at age 19, had the same mitochondrial DNA (mtDNA) mutation. At 44 years of age, she developed congestive heart failure due to cardiomyopathy, and the same mtDNA mutation was identified in the cardiac muscle. Thus, it is very likely that in this patient, diabetes and cardiomyopathy was caused by the same abnormality, the point mutation of mitochondrial tRNA(Leu(UUR)) gene.
Diabetes Res Clin Pract 1995 Jun
PMID:A patient with diabetes mellitus, cardiomyopathy, and a mitochondrial gene mutation: confirmation of a gene mutation in cardiac muscle. 852

Kallikrein-kininogen-kinin systems are now topics of widespread interest. The long-standing appreciation of their diverse pharmacological properties and biochemical characteristics is being supplemented by modern definitions of their cellular receptors' signal-transduction mechanisms and physiological and pathological roles. The assignment of important homeostatic responsibilities for kinins, including those in autocrine and paracrine signaling for skeletal and cardiac muscle energy metabolism, is now subject to definitive experimental evaluation via the availability of better kallikrein inhibitors, specific kinin receptor antagonists, and techniques of genetic manipulation.
Diabetes 1996 Jan
PMID:Kallikreins and kinins. Molecular characteristics and cellular and tissue responses. 852 94

Our group has documented that myocardial performance is impaired in the hearts of chronically diabetic rats and rabbits. Abnormalities in the contractile proteins and regulatory proteins may be responsible for the mechanical defects in the streptozotocin (STZ)-diabetic hearts. Previously, the major focus of our research on contractile proteins in abnormal states has concentrated on myosin ATPase and its isoenzymes. Our present study is based on the overall hypothesis that regulatory proteins, in addition to contractile protein, myosin contribute to altered cardiac contractile performance in the rat model of diabetic cardiomyopathy. The purpose of our research was to define the role of cardiac regulatory proteins (troponin-tropomyosin) in the regulation of actomyosin system in diabetic cardiomyopathy. For baseline data, myofibrillar ATPase studies were conducted in the myofibrils from control and diabetic rats. To focus on the regulatory proteins (troponin and tropomyosin), individual proteins of the cardiac system were reconstituted under controlled conditions. By this approach, myosin plus actin and troponin-tropomyosin from the normal and diabetic animals could be studied enzymatically. The proteins were isolated from the cardiac muscle of control and STZ-diabetic (4 weeks) rats. Sodium dodecyl sulfate gel electrophoretic patterns demonstrate differences in the cardiac TnT and TnI regions of diabetic animals suggesting the different amounts of TnT and/or TnI or possibly different cardiac isozymes in the regulatory protein complex. Myofibrils probed with a monoclonal antibody TnI-1 (specific for adult cardiac TnI) show a downregulation of cardiac TnI in diabetics when compared to its controls. Enzymatic data confirm a diminished calcium sensitivity in the regulation of the cardiac actomyosin system when regulatory protein(s) complex was recombined from diabetic hearts. Actomyosin ATPase activity in the hearts of diabetic animals was partially reversed when myosin from diabetic rats was regulated with the regulatory protein complex isolated from control hearts. To our knowledge, this is the first study which demonstrates that the regulatory proteins from normal hearts can upregulate cardiac myosin isolated from a pathologic rat model of diabetes. This diminished calcium sensitivity along with shifts in cardiac myosin heavy chain (V1-->V3) may be partially responsible for the impaired cardiac function in the hearts of chronic diabetic rats.
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PMID:Troponin subunits contribute to altered myosin ATPase activity in diabetic cardiomyopathy. 856 62

Magnesium(Mg)-deficiency, whether dietary or an effect of a clinical condition such as diabetes, results in a variety of cardiovascular pathologies. Substance P (SP) has been implicated in the induction of cardiac focal inflammatory lesions that occur during Mg-deficiency. Blockade of SP receptors results in a significant reduction in the incidence of lesion formation. In an effort to identify potential endogenous cell populations of the heart, which may play a role in SP-dependent lesion formation, film- and light-microscopic autoradiography were used to map the distribution of specific SP binding sites in frozen sections of the normal rat heart and adjacent great vessels. Binding was assessed with 0.1 nM I-125 Bolton-Hunter labelled SP in the absence (total binding) or presence (non-specific binding) of excess unlabelled SP, prolactin, or L-703,606, a non-peptide antagonist of SP receptors. Film autoradiograms revealed prominent small foci of intense autoradiographic reactions dispersed intermittently around the periphery of the great vessels and coronary arteries, among the interstitial connective tissue of the heart, and along the cusps of the cardiac valves. Excess unlabelled SP caused a significant reduction (97.7% displacement; P < 0.001) in the focal autoradiographic reactions. L-703,606 caused a similar reduction in SP binding (97.3% displacement; P < 0.001), while prolactin had no statistically significant effect on the binding of radiolabelled SP. Light-microscopic autoradiograms revealed that the SP binding sites occurred within clusters of connective tissue cells or in rarely observed parasympathetic ganglia. No evidence was found to suggest the presence of SP receptors on endothelial cells, cardiac muscle fibers, or smooth muscle fibers. The connective tissue cells which bound SP within the heart will likely include types that are susceptible to SP activation and thus may play a role in initiation of the focal inflammation characteristic of Mg-deficiency.
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PMID:Distribution of specific substance P binding sites in the heart and adjacent great vessels of the Wistar white rat. 864 67


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