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)

The possibility that glycosylated haemoglobin levels and/or blood pressure might correlate with cardiac sympathetic neuropathy and/or diabetic somatic neuropathy was investigated in patients with non-insulin-dependent diabetes mellitus. Sympathetic nerve function was quantified by analysis of [123I]metaiodobenzylguanidine accumulation in the cardiac muscle. Somatic nerve function was assessed by measuring the motor nerve conduction velocities of the peroneal and tibial nerves, and the sensory nerve conduction velocity of the sural nerve. None of the parameters of cardiac sympathetic neuropathy or diabetic somatic neuropathy showed any correlation with blood pressure, nor was there any evidence of a correlation between cardiac sympathetic neuropathy and glycosylated haemoglobin levels; there was, however, a significant correlation between diabetic somatic neuropathy (as indicated by tibial nerve conduction velocity) and glycosylated haemoglobin levels. The results are consistent with the view that different mechanisms are involved in the two types of neuropathies.
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PMID:Is there a correlation between cardiac sympathetic neuropathy or diabetic somatic neuropathy and glycosylated haemoglobin or blood pressure in patients with non-insulin-dependent diabetes mellitus? 874 14

Ligand gated potassium channels, such as the ATP-regulated potassium channel, play crucial roles in coupling of stimuli to insulin secretion in pancreatic beta cells. Mutations in the genes might lead to the insulin secretory defects observed in patients with non-insulin-dependent diabetes mellitus (NIDDM). We isolated a cDNA encoding a putative subunit of a ligand gated potassium channel from a human islet cDNA library. The channel, which we designated hiGIRK2, appeared to be an alternative spliced variant and a human homologue of recently reported mbGIRK2, KATP-2/BIR1. Transcripts were detected in human brain and pancreas, but not in other tissues including cardiac muscle. The sizes of transcripts in the pancreas differed from those in the brain, suggesting tissue-specific alternative splicing and possible isoforms. We then isolated human genomic clones, determined the complete genomic structure and localized the gene to chromosome 21 (21q22). The gene was comprised of four exons and the protein was encoded by three exons. The entire coding region of the hiGIRK2 gene was scanned by polymerase chain reaction-single strand conformation polymorphism analysis in 80 Japanese NIDDM patients. We found five nucleotide substitutions; three were silent mutations of the third base of codons, one in the first intron, 9 bases upstream of exon 2, and one in the 3'-untranslated region. We conclude that mutations in the gene encoding hiGIRK2, a (subunit of) ligand gated potassium channel, is not a major determinant of the susceptibility to NIDDM in Japanese.
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PMID:A human pancreatic islet inwardly rectifying potassium channel: cDNA cloning, determination of the genomic structure and genetic variations in Japanese NIDDM patients. 877 94

[Lys(B28),Pro(B29)]-human insulin (insulin lispro, CAS 133107-64-9, LY275585, Humalog) is a quick acting insulin analog which is currently undergoing clinical evaluation for the treatment of diabetes. The potential secondary pharmacological activity of insulin lispro was profiled in studies for the evaluation of effects on the central and autonomic nervous system, the cardiovascular system, urine and electrolyte excretion, and gastrointestinal function. In vivo doses ranged from 0.03 to 10 U/kg, administered by the subcutaneous route, while pharmacologic activity in vitro was examined in smooth and cardiac muscle at concentrations of 1 x 10(-9) to 1 x 10(-5) mol/l. Insulin lispro exhibited secondary pharmacological activity in central nervous system tests only at higher doses with the most prominent observations being sedation and decreased responsiveness. Insulin lispro was essentially inactive in tests of autonomic (smooth and cardiac muscle), cardiovascular (mean arterial pressure, heart rate, systolic pressure, diastolic pressure, and pulse pressure), renal (urine and electrolyte excretion) and gastrointestinal (motility) function. In summary, insulin lispro had minimal effect in these pharmacodynamic studies indicating that insulin lispro has minimal potential to produce adverse pharmacological side effects at clinically relevant doses.
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PMID:General pharmacology of insulin lispro in animals. 882 25

The heart is known for its ability to produce energy from fatty acids (FA) because of its important beta-oxidation equipment, but it can also derive energy from several other substrates including glucose, pyruvate, and lactate. The cardiac ATP store is limited and can assure only a few seconds of beating. For this reason the cardiac muscle can adapt quickly to the energy demand and may shift from a 100% FA-derived energy production (after a lipid-rich food intake) or any balanced situation (e.g., diabetes, fasting, exercise). These situations are not similar for the heart in terms of oxygen requirement because ATP production from glucose is less oxygen-consuming than from FA. The regulation pathways for these shifts, which occur in physiologic as well as pathologic conditions (ischemia-reperfusion), are not yet known, although both insulin and pyruvate dehydrogenase activation are clearly involved. It becomes of strategic importance to clarify the pathways that control these shifts to influence the oxygen requirement of the heart. Excess FA oxidation is closely related to myocardial contraction disorders characterized by increased oxygen consumption for cardiac work. Such an increased oxygen cost of cardiac contraction was observed in stunned myocardium when the contribution of FA oxidation to oxygen consumption was increased. In rats, an increase in n-3 polyunsaturated FA in heart phospholipids achieved by a fish-oil diet improved the recovery of pump activity during postischemic reperfusion. This was associated with a moderation of the ischemia-induced decrease in mitochondrial palmitoylcarnitine oxidation. In isolated mitochondria at calcium concentrations close to that reported in ischemic cardiomyocytes, a futile cycle of oxygen wastage was reported, associated with energy wasting (constant AMP production). This occurs with palmitoylcarnitine as substrate but not with pyruvate or citrate. The energy wasting can be abolished by CoA-SH and other compounds, but not the oxygen wasting. Again, the calcium-induced decrease in mitochondrial ADP/O ratio was reduced by increasing the n-3 polyunsaturated FA in the mitochondrial phospholipids. These data suggest that in addition to the amount of circulating lipids, the quality of FA intake may contribute to heart energy regulation through the phospholipid composition. On the other hand, other intervention strategies can be considered. Several studies have focused on palmitoylcarnitine transferase I to achieve a reduction in beta-oxidation. In a different context, trimetazidine was suggested to exert its anti-ischemic effect on the heart by interfering with the metabolic shift, either at the pyruvate dehydrogenase level or by reducing the beta-oxidation. Further studies will be required to elucidate the complex system of heart energy regulation and the mechanism of action of potentially efficient molecules.
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PMID:Fatty acid oxidation in the heart. 889 66

The regulatory myosin light chain (MLC) is phosphorylated in cardiac muscle by Ca2+/calmodulin-dependent MLC kinase (MLCK) and is considered to play a modulatory role in the activation of myofibrillar adenosine triphosphatase (ATPase) and the process of force generation. Since the depression in cardiac contractile function in chronic diabetes is associated with a decrease in myofibrillar ATPase activity, we investigated changes in MLC phosphorylation in diabetic heart. Rats were made diabetic by injecting streptozotocin (65 mg/kg intravenously), and the hearts were removed 8 weeks later; some 6-week diabetic animals were injected with insulin (3 U/d) for 2 weeks. Changes in the relative MLC and MLCK protein contents were measured by electrophoresis and immunoblot assay, whereas phosphorylated and unphosphorylated MLCs were separated on 10% acrylamide/urea gel and identified by Western blot. MLC and MLCK contents were decreased markedly (40% to 45%) and MLC phosphorylation was decreased significantly (30% to 45%) in the diabetic rat heart homogenate in comparison to control values. The changes in MLC and MLCK content in diabetic heart were partially reversible, whereas changes in MLC phosphorylation were normalized upon treatment with insulin. These results suggest that decreased protein contents of MLC and MLCK and phosphorylation of MLC may contribute to the depression of cardiac myofibriliar ATPase activity and heart dysfunction in diabetic cardiomyopathy.
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PMID:Myosin light-chain phosphorylation in diabetic cardiomyopathy in rats. 900 73

Diabetes is one of the most prevalent chronic conditions that has a high association with death from cardiovascular disease(s). An impaired cardiac function independent of vascular disease suggests the existence of a primary myocardial defect in diabetes mellitus. We and others have documented that myocardial performance is impaired in the hearts of chronically diabetic rats and rabbits. Abnormalities in the contractile proteins and regulatory proteins could be responsible for the mechanical defects in streptozotocin (STZ)-diabetic hearts. The major focus of research on contractile proteins in the diabetic state has been on myosin ATPase and its isoenzymes. However, in the contractile protein system, this could be only one of the mechanisms that might be a controlling factor in myofilament contraction in diabetes. To define the role of cardiac contractile as well as regulatory proteins (troponin-tropomyosin) as a whole in the regulation of actomyosin system in diabetic cardiomyopathy, individual proteins of the cardiac system were reconstituted under controlled conditions. Enzymatic data confirmed a diminished calcium sensitivity in the regulation of the cardiac actomyosin system when regulatory protein(s) complex was recombined from diabetic hearts. This diminished calcium sensitivity along with shifts in cardiac myosin heavy chain (V1-->V3) could contribute to the impaired cardiac function in the hearts of chronic diabetic rats. It has also been reported that sarcomeric proteins such as myosin light chain-2 (MLC-2) and troponin I (TnI) could be involved in regulating muscle contraction and in calcium sensitivity. Since phosphorylation of cardiac TnI is associated with altered maximum enzymatic activity and calcium force relationship in isolated muscle preparations. TnI phosphorylation could contribute to depressed myocardial contractility in experimental diabetes. While we have yet to understand the exact function of each component in cardiac muscle and their behavior in concert where all of them act in tandem, we have focussed on the role of contractile proteins and their regulation in diabetes in this review. We have also included a brief discussions on other relevant intracellular components. In summary, there is substantial evidence to suggest that there are independent processes associated with diabetes which effect cardiac performance in experimental animals and in man. The focus of this review has been the explication of a biochemical defect which underlies cardiac contractile dysfunction in experimental models of diabetes.
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PMID:Regulation of contractile proteins in diabetic heart. 921 70

Vanadyl sulfate was administered orally during a 10-week trial period to streptozotocin-diabetic and control male rats to test the hypothesis that chronic vanadyl supplementation would prevent the decline in cardiac muscle cell glucose transporter protein (GLUT-4) that otherwise manifests in conjunction with insulin deficiency. Isolated cardiac myocytes and cardiac sarcolemmal vesicles were prepared from heart tissue of rats that had been maintained on the following regimens: untreated control, oral vanadyl-supplemented control (0.6 mg/ml), untreated diabetic (streptozotocin-induced; 60 mg/kg), and vanadyl-supplemented diabetic. Myocytes isolated from untreated diabetic rat hearts had decreased rates of glucose oxidation. Chronic, oral administration of vanadyl to diabetic rats maintained glucose oxidation rates of cardiac myocytes at control levels. Immunoblot analyses revealed that total cardiac myocyte and sarcolemmal GLUT-4 glucose transporter protein levels were significantly lower in the diabetic group relative to control. Vanadyl treatment of diabetic rats produced a normalization of both sarcolemmal GLUT-4 and total cardiac myocyte levels towards control levels. The reduction of GLUT-4 mRNA levels seen with untreated diabetes was also completely prevented with vanadyl treatment. These results demonstrate that chronic-oral vanadyl sulfate supplementation limits the decline in glucose oxidative capacity of cardiac myocytes that otherwise manifests in the untreated diabetic state. This action of vanadyl may occur via a mechanism that is linked to the preservation of sarcolemmal GLUT-4 protein levels.
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PMID:Effects of oral vanadyl treatment on diabetes-induced alterations in the heart GLUT-4 transporter. 929 59

The aim of this study was to determine the ouabain receptor density, Na+,K(+)-ATPase function and contractile properties of cardiac muscle in insulin-dependent and non-insulin-dependent rat diabetes mellitus (IDDM and NIDDM, respectively) and the reversibility of the diabetes-induced changes by insulin or thyroxin substitution. IDDM and NIDDM were induced in Wistar rats by streptozotocin injection. Contractile parameters were measured in isolated left ventricular trabeculae. [3H]Ouabain binding to myocardium was measured in right and left ventricular strips obtained from diabetic animals and their age-matched controls. Both the maximum [3H]ouabain binding capacity (Bmax) and the Kd for [3H]ouabain binding, as well as maximum 86Rb+ uptake and rate of contraction, were decreased in IDDM myocardium compared with controls. Insulin or thyroxin substitution reversed the reduction in Bmax and contraction rate, but not the decrease in Kd. In young, but not old, control animals, both Bmax and maximum 86Rb+ uptake were higher in the right ventricular myocardium than in the left one. In contrast to changes observed in IDDM, both Bmax and Kd for [3H]oubain binding were increased in the left but not in the right ventricle of NIDDM animals. NIDDM caused no alterations in contractile properties. Prominent differences were observed in [3H]ouabain binding characteristics and myocardial contractility between young and old control animals. Bmax of [3H]ouabain binding and rate of contraction were inversely proportional in all preparations studied. It is concluded that IDDM and NIDDM induce different alterations in myocardial Na+,K(+)-ATPase, and these changes may influence the contractile properties of cardiac muscle.
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PMID:Altered [3H]ouabain binding to cardiac muscle in insulin-dependent and non-insulin-dependent diabetic rats. 948 20

Microsomes prepared from three rat tissues were examined for their ability to import glucose-6-phosphate (G-6-P). Microsomes from liver, which possess a high level of glucose-6-phosphatase activity, were compared with those from cerebral cortex and cardiac muscle, which are not involved in the export of glucose and in which glucose-6-phosphatase activity is relatively low. In all three, a selective permeability to G-6-P was detected by light scattering. However, the sugar-phosphate specificity of the transport process differed. G-6-P was able to enhance ATP-dependent Ca2+ sequestration in all three types of microsomes. In addition, enzymatic detection of G-6-P after the rapid filtration of microsomes determined that, in the absence of Ca2+ and ATP, a level of intramicrosomal G-6-P approaching a passive equilibrium with the extramicrosomal G-6-P concentration was rapidly achieved in all three tissues. However, under conditions in which Ca2+ was being actively accumulated, the intramicrosomal levels of G-6-P exceeded the equilibrium value by three- to fourfold. This enhanced sequestration was not observed in the presence of Ca2+ or ATP alone or in the presence of a Ca2+ ionophore or an inhibitor of the microsomal Ca2+ ATPase. These data are consistent with a selective import pathway into the endoplasmic/sarcoplasmic reticulum for G-6-P independent of glucose-6-phosphatase activity. In addition, they suggest an alternate explanation for the enhanced sequestration of Ca2+ by the endoplasmic/sarcoplasmic reticulum of intact cells seen when extracellular glucose is increased.
Diabetes 1998 Jun
PMID:Glucose-6-phosphate and Ca2+ sequestration are mutually enhanced in microsomes from liver, brain, and heart. 960 62

Long chain fatty acids (LCFAs) are an important source of energy for most organisms. They also function as blood hormones, regulating key metabolic functions such as hepatic glucose production. Although LCFAs can diffuse through the hydrophobic core of the plasma membrane into cells, this nonspecific transport cannot account for the high affinity and specific transport of LCFAs exhibited by cells such as cardiac muscle, hepatocytes, and adipocytes. Transport of LCFAs across the plasma membrane is facilitated by fatty acid transport protein (FATP), a plasma membrane protein that increases LCFA uptake when expressed in cultured mammalian cells [Schaffer, J. E. & Lodish, H. F. (1994) Cell 79, 427-436]. Here, we report the identification of four novel murine FATPs, one of which is expressed exclusively in liver and another only in liver and kidney. Both genes increase fatty acid uptake when expressed in mammalian cells. All five murine FATPs have homologues in humans in addition to a sixth FATP gene. FATPs are found in such diverse organisms as Fugu rubripes, Caenorhabditis elegans, Drosophila melanogaster, Saccharomyces cerevisiae, and Mycobacterium tuberculosis. The function of the FATP gene family is conserved throughout evolution as the C. elegans and mycobacterial FATPs facilitate LCFA uptake when overexpressed in COS cells or Escherichia coli, respectively. The identification of this evolutionary conserved fatty acid transporter family will allow us to gain a better understanding of the mechanisms whereby LCFAs traverse the lipid bilayer as well as yield insight into the control of energy homeostasis and its dysregulation in diseases such as diabetes and obesity.
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PMID:A family of fatty acid transporters conserved from mycobacterium to man. 967 28


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