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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Specific amino acids are now known to acutely and chronically regulate insulin secretion from pancreatic beta-cells in vivo and in vitro. Understanding the molecular mechanisms by which amino acids regulate insulin secretion may identify novel targets for future diabetes therapies. Mitochondrial metabolism is crucial for the coupling of amino acid and glucose recognition to the exocytosis of the insulin granules. This is illustrated by in vitro and in vivo observations discussed in the present review. Mitochondria generate ATP, which is the main coupling factor in insulin secretion; however, the subsequent Ca2+ signal in the cytosol is necessary, but not sufficient, for full development of sustained insulin secretion. Hence mitochondria generate ATP and other coupling factors serving as fuel sensors for the control of the exocytotic process. Numerous studies have sought to identify the factors that mediate the amplifying pathway over the Ca2+ signal in nutrient-stimulated insulin secretion. Predominantly, these factors are nucleotides (GTP, ATP, cAMP and NADPH), although metabolites have also been proposed, such as long-chain acyl-CoA derivatives and the key amino acid glutamate. This scenario highlights further the importance of the key enzymes or transporters, glutamate dehydrogenase, the aspartate and alanine aminotransferases and the malate/aspartate shuttle, in the control of insulin secretion. Therefore amino acids may play a direct or indirect (via generation of putative messengers of mitochondrial origin) role in insulin secretion.
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PMID:New insights into amino acid metabolism, beta-cell function and diabetes. 1554 73

The IMAP/IAN family of AIG1-like GTPases is conserved among vertebrates and angiosperm plants and has been postulated to regulate apoptosis, particularly in context with diseases such as cancer, diabetes, and infections. The human genes were recently renamed as gimap for GTPase of the immunity associated protein (GIMAP) family. Here we extend this new nomenclature to the murine gimap gene family. All gimap genes of the mouse are clustered on chromosome 6B with eight functional members and one pseudogene. The mGIMAP proteins contain one GTP-binding site and display molecular masses between 33 and 38 kDa except for the very unusual 77 kDa mGIMAP8 protein, which is the first characterized protein containing three GTP-binding domains. Northern blot analysis revealed expression of mgimap8 predominantly in the thymus. The low expression level observed in the spleen was further suppressed by Plasmodium chabaudi malaria. Confocal laser scanning microscopy demonstrated localization of mGIMAP8 at ER, Golgi, and mitochondria. Overexpression of mGIMAP8 could significantly impair anisomycin-induced activation of caspase 3. Our data support the view that mGIMAP8 exerts an anti-apoptotic effect in the immune system and is involved in responses to infections.
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PMID:Malaria-suppressible expression of the anti-apoptotic triple GTPase mGIMAP8. 1608 18

Glucose and other nutrients have been shown to stimulate insulin release from pancreatic islets under Ca2+-depleted condition when protein kinase A (PKA) and protein kinase C (PKC) are activated simultaneously. We investigated the role of metabolic nucleotide signals including ATP, ADP, and GTP in exocytosis of insulin secretory granules under Ca2+-depleted condition using electrically permeabilized rat islets. ATP under PKC activation augmented insulin release concentration-dependently by 100 nM 12-O-tetradecanoyl-phorbol-13-acetate (TPA) in Ca2+-depleted condition, while ADP could not suppress ATP-dependent insulin release in this condition. Neither GTP nor activated PKA in the absence of PKC activation increased insulin release under Ca2+-depleted condition in the presence of ATP, but both enhanced insulin secretion in the presence of ATP when PKC was activated. In conclusion, activated PKC and the presence of ATP both are required in the insulin secretory process under Ca2+-depleted condition. While PKA activation and GTP cannot substitute for PKC activation and ATP, respectively, under Ca2+-depleted condition, they enhance ATP-dependent insulin secretion when PKC is activated.
Diabetes Res Clin Pract 2005 Sep
PMID:ATP enhances exocytosis of insulin secretory granules in pancreatic islets under Ca2+-depleted condition. 1609 17

Previous studies suggested that loss of tetrahydrobiopterin (BH(4)) may play an important role in the pathogenesis of vascular endothelial dysfunction induced by diabetes and hypertension. In contrast, controversial results have been reported regarding BH(4) metabolism in experimental models of atherosclerosis. Therefore, the present study was designed to characterize the expression and activity of GTP-cyclohydrolase I, a rate-limiting enzyme in biosynthesis of BH(4), during atherogenesis. BH(4) levels were significantly increased in atherosclerotic aortas of apolipoprotein E (apoE)-deficient mice as compared with wild-type mice after 5 mo of Western diet treatment. This increase was further significantly enhanced in apoE-deficient mice fed for 9 and 14 mo. Removal of the endothelium almost eliminated BH(4) in wild-type mice but not in apoE-deficient mice, suggesting that a major component of increased BH(4) synthesis is localized in the vascular media of apoE-deficient mice. Oxidative products of BH(4) were low and did not differ between wild-type and apoE-deficient mice over the course of this study. Increased protein expression and enzymatic activity of GTP-cyclohydrolase I were detected in aortas of apoE-deficient mice (P < 0.05), providing molecular mechanisms responsible for elevation of vascular BH(4). In contrast to aortas, we did not detect any change in levels of BH(4) and in GTP-cyclohydrolase I expression in the brain. Our results demonstrate selective increase of intracellular BH(4) levels via elevation of GTP-cyclohydrolase I activity in vascular tissue of apoE-deficient mice.
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PMID:Increased vascular biosynthesis of tetrahydrobiopterin in apolipoprotein E-deficient mice. 1642 44

Changes in hormonal sensitivity of the adenylyl cyclase signaling system (ACS) and their possible molecular causes in the heart muscle of rats with experimental streptozotocin diabetes (type I diabetes) are investigated. An increase in stimulating effects of noradrenaline and isoproterenol on adenylyl cyclase (AC) activity have been shown. In the case of noradrenaline, this increase is due to suppression of Gi-protein function and Gi-coupled inhibitory AC signaling pathway. Meanwhile, in diabetic rats the influence of C-terminal peptide 346-355 of alphai2-subunit on hormonal activation of AC and GTP-binding is diminished. In the case of isoproterenol, along with its stimulating effect, at micromolar concentrations this hormone exerts inhibitory action, realized, presu- mably, through beta3-adrenergic receptors. Effect of isoproterenol on AC and GTP-binding in the heart of diabetic animals is modified by peptide 385-394 alphas, blocking Gs-coupled signaling pathways, and by peptide 346-355 alphai2, blocking transduction of inhibitory signals. In addition, a decrease in serotonin stimulating effect on components of ACS in diabetic animals was shown. The data obtained provide evidence for changes in ACS function in diabetes, which can be detected mainly at the G-protein level. The proposed peptide strategy is a new and perspective approach for studying molecular causes of functional violations in hormonal signaling systems arising at endocrine pathology.
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PMID:[Molecular causes of changes in sensitivity of adenylyl cyclase signaling system to biogenic amines in the heart muscle during experimental streptozotocin diabetes]. 1670 47

The prevalence of diabetes mellitus (DM), particularly Type 2 DM, has rapidly increased in industrialized and many developing countries. The predominant cause of death in diabetic patients is vascular complications. Dyslipidemia and hypercholesterolemia are common in diabetic patients. 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) were designed for lowering cholesterol synthesis. Landmark clinical trials indicated that statins effectively reduced cardiac death and events in patients with coronary artery disease or DM. The benefits of statins on the prevention of vascular events were independent from age, sex or baseline lipid levels in diabetic patients. Statins not only prevent atherosclerotic macrovascular complications, but also postpone the development of microvascular complications of DM, such as nephropathy and retinopathy. The non-cholesterol lowering or pleiotropic effects of statins have attracted vast attention. Results from experimental and clinical studies suggest that statins may attenuate inflammation, oxidative stress, coagulation, platelet aggregation, and improve insulin resistance, fibrinolysis and endothelial functions and help to prevent thrombosis, restenosis or organ transplantation rejection. Statins may affect the intracellular prenylation of proteins, which modulate the activity of small-GTP binding proteins. This may be an underlying mechanism for some pleiotropic effects of statins. Statins have an excellent safety profile and seldom cause adverse effects. Increasing evidence suggests that statins are the current treatment of choice to prevent vascular complications in diabetic patients with hypercholesterolemia.
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PMID:Statins for diabetic cardiovascular complications. 1684 42

1 Bladder smooth muscle sensitivity to muscarinic agonists is increased in the overactive bladder. Treatment of rats with streptozotocin induces a diabetic state in which the bladder muscle is overactive and also supersensitive to muscarinic agonists. This study has examined bladder contraction, muscarinic receptor density and receptor/G-protein coupling in the streptozotocin-induced overactive bladder of the rat. 2 Diabetes was induced by a single intraperitoneal dose of streptozotocin. Seven days later contraction of isolated detrusor muscle strips was assessed in tissue bath experiments, while receptor density was assayed in saturation experiments with [3H]-QNB (quinuclidinyl benzilate, L-[benzilic-4,4'-3H]) and receptor/G-protein coupling was determined in agonist displacement experiments with this radioligand. 3 Isolated detrusor strips from diabetic animals displayed an enhanced degree of spontaneous activity (0.060 +/- 0.016 g mg(-1), compared with 0.015 +/- 0.004 g mg(-1), P < 0.05). Carbachol produced contractile responses in tissues from both control and diabetic rats, but the diabetic tissues were more sensitive to this agonist, the pEC50 being 6.52 +/- 0.17 compared with 5.93 +/- 0.06 in controls (P < 0.001). Maximum responses to carbachol were similar in both groups of animals. The increase in carbachol potency was accompanied by a 40% increase in receptor density from 158 +/- 5 to 221 +/- 22 fmol mg(-1) protein (P < 0.05), but this was not enough to fully account for the change in tissue sensitivity. 4 In the absence of GTP-gamma-S, carbachol displaced [3H]-QNB from two binding sites, the high-affinity site (pKi = 7.06 +/- 0.26) which represents the receptors coupled to G-proteins made up 43.1 +/- 5.9% of the total binding sites in control tissues and this value was similar (41.0 +/- 4.0%) in the diabetic tissues (pKi = 6.64 +/- 0.31). In the presence of GTP-gamma-S, carbachol displaced [3H]-QNB from a single binding site which had a low-affinity, similar to the low-affinity site observed in the absence of GTP-gamma-S. 5 These data demonstrate that detrusor supersensitivity is observed after only 1 week of untreated diabetes in the rat. The overactivity is associated with an enhanced sensitivity to carbachol, which is partly explained by an increase in receptor density, but there appears to be no change in receptor/G-protein coupling.
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PMID:Muscarinic receptor function, density and G-protein coupling in the overactive diabetic rat bladder. 1687 96

Despite emerging evidence to suggest that glucose-stimulated insulin secretion (GSIS) requires membrane targeting of specific small G proteins (e.g., Rac1), very little is known with regard to the precise mechanisms underlying subcellular trafficking of these proteins in the glucose-stimulated islet beta-cell. We previously reported activation of small G proteins by biologically active lipids via potentiation of relevant GDP/GTP exchange activities within the beta-cell. Herein, we studied putative regulatory roles for these lipids in the trafficking and membrane association of Rac1 in cell-free preparations derived from INS 832/13 beta-cells. Incubation of INS 832/13 cell lysates with polyphosphoinositides (e.g., PIP(2)), phosphatidic acid, phosphatidylcholine, and phosphatidylserine significantly promoted trafficking of cytosolic Rac1 to the membrane fraction. Lysophosphatidic acid, but not lysophosphatidylcholine or lysophosphatidylserine, also promoted translocation and membrane association of Rac1. Arachidonic acid, diacylglycerol, calcium, and cAMP failed to exert any clear effects on Rac1 translocation to the membrane. Together, our findings provide the first direct evidence in support of our recent hypothesis (Kowluru A, Veluthakal R. Diabetes 54: 3523-3529, 2005), which states that generation of biologically active lipids, known to occur in the glucose-stimulated beta-cell, may mediate targeting of Rac1 to the membrane for optimal interaction with its putative effector proteins leading to GSIS.
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PMID:Biologically active lipids promote trafficking and membrane association of Rac1 in insulin-secreting INS 832/13 cells. 1703 98

In muscle cells, insulin elicits recruitment of the glucose transporter GLUT4 to the plasma membrane. This process engages sequential signaling from insulin receptor substrate (IRS)-1 to phosphatidylinositol (PI) 3-kinase and the serine/threonine kinase Akt. GLUT4 translocation also requires an Akt-independent but PI 3-kinase-and Rac-dependent remodeling of filamentous actin. Although IRS-1 phosphorylation is often reduced in insulin-resistant states in vivo, several conditions eliciting insulin resistance in cell culture spare this early step. Here, we show that insulin-dependent Rac activation and its consequent actin remodeling were abolished upon exposure of L6 myotubes beginning at doses of C2-ceramide or oxidant-producing glucose oxidase as low as 12.5 micromol/l and 12.5 mU/ml, respectively. At 25 micromol/l and 25 mU/ml, glucose oxidase and C2-ceramide markedly reduced GLUT4 translocation and glucose uptake and lowered Akt phosphorylation on Ser473 and Thr308, yet they affected neither IRS-1 tyrosine phosphorylation nor its association with p85 and PI 3-kinase activity. Small interfering RNA-dependent Rac1 knockdown prevented actin remodeling and GLUT4 translocation but spared Akt phosphorylation, suggesting that Rac and actin remodeling do not contribute to overall Akt activation. We propose that ceramide and oxidative stress can each affect two independent arms of insulin signaling to GLUT4 at distinct steps, Rac-GTP loading and Akt phosphorylation.
Diabetes 2007 Feb
PMID:Ceramide- and oxidant-induced insulin resistance involve loss of insulin-dependent Rac-activation and actin remodeling in muscle cells. 1725 84

Disorders of L-type Ca2+ channels can cause severe cardiac arrhythmias. A subclass of small GTP-binding proteins, the RGK family, regulates L-type Ca2+ current (I(Ca,L)) in heterologous expression systems. Among these proteins, Rad (Ras associated with diabetes) is highly expressed in the heart, although its role in the heart remains unknown. Here we show that overexpression of dominant negative mutant Rad (S105N) led to an increase in I(Ca,L) and action potential prolongation via upregulation of L-type Ca2+ channel expression in the plasma membrane of guinea pig ventricular cardiomyocytes. To verify the in vivo physiological role of Rad in the heart, a mouse model of cardiac-specific Rad suppression was created by overexpressing S105N Rad, using the alpha-myosin heavy chain promoter. Microelectrode studies revealed that action potential duration was significantly prolonged with visible identification of a small plateau phase in S105N Rad transgenic mice, when compared with wild-type littermate mice. Telemetric electrocardiograms on unrestrained mice revealed that S105N Rad transgenic mice had significant QT prolongation and diverse arrhythmias such as sinus node dysfunction, atrioventricular block, and ventricular extrasystoles, whereas no arrhythmias were observed in wild-type mice. Furthermore, administration of epinephrine induced frequent ventricular extrasystoles and ventricular tachycardia in S105N Rad transgenic mice. This study provides novel evidence that the suppression of Rad activity in the heart can induce ventricular tachycardia, suggesting that the Rad-associated signaling pathway may play a role in arrhythmogenesis in diverse cardiac diseases.
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PMID:Dominant negative suppression of Rad leads to QT prolongation and causes ventricular arrhythmias via modulation of L-type Ca2+ channels in the heart. 1752 70


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