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 mammalian insulin gene is exclusively expressed in the beta cells of the endocrine pancreas. Two decades of intensive physiological and biochemical studies have led to the identification of regulatory sequence motifs along the insulin promoter and to the isolation of transcription factors which interact to activate gene transcription. The majority of the islet-restricted (BETA2, PDX-1, RIP3b1-Act/C1) and ubiquitous (E2A, HEB) insulin-binding proteins have been characterized. Transcriptional regulation results not only from specific combinations of these activators through DNA-protein and protein-protein interactions, but also from their relative nuclear concentrations, generating a cooperativity and transcriptional synergism unique to the insulin gene. Their DNA binding activity and their transactivating potency can be modified in response to nutrients (glucose, NEFA) or hormonal stimuli (insulin, leptin, glucagon like peptide-1, growth hormone, prolactin) through kinase-dependent signalling pathways (PI3-K, p38MAPK, PKA, CaMK) modulating their affinities for DNA and/or for each other. From the overview of the research presented, it is clear that much more study is required to fully comprehend the mechanisms involved in the regulated-expression of the insulin gene in the beta cell to prevent its impairment in diabetes.
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PMID:Regulation of insulin gene transcription. 1191 36

Diabetes is known to activate MAP kinase p38 in sensory neurons in both rats and patients. In vitro, activation of p38 in sensory neurons by combined glucose and oxidant stress causes cell damage or death. Consequently we tested the hypothesis that inhibition of MAP kinase p38 might prevent neuronal dysfunction in rats with experimental diabetes, such as the classical defect of slowed nerve conduction. Thus, treatment of streptozotocin-diabetic rats with the p38 inhibitor SB239063 for the second half of a 12-week diabetes protocol selectively prevented the nerve conduction deficit in sensory neurons. This implicates activation of MAP kinase p38 as an early step in the signal pathway to dysfunction in experimental diabetic neuropathy.
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PMID:Inhibition of p38 MAP kinase corrects biochemical and neurological deficits in experimental diabetic neuropathy. 1248 93

Diabetes confers an increased propensity to atherosclerosis. Inflammation is pivotal in atherogenesis, and diabetes is a proinflammatory state. Interleukin (IL)-6, in addition to inducing the acute-phase response, contributes to insulin resistance. Monocytes from type 2 diabetic patients secrete increased IL-6. The aim of this study was to examine molecular mechanisms for increased IL-6 release from monocytes under hyperglycemia. Monocytic cells (THP-1) were cultured in the presence of 5.5 mmol/l (normal) or 15 mmol/l (high) glucose and mannitol. Secreted IL-6, intracellular IL-6, and IL-6 mRNA were significantly increased with hyperglycemia (P < 0.001). Incubation of cells with inhibitors of reactive oxygen species failed to affect high-glucose-induced IL-6 release. Pan-protein kinase C (PKC) inhibitors significantly decreased high-glucose-induced IL-6 release. A specific inhibitor of p38 mitogen-activated protein kinase (MAPK; SB 202190), but not the extracellular signal-regulated kinase inhibitor PD98059, significantly decreased high-glucose-induced IL-6 release. Furthermore, the PKC-alpha/beta2 inhibitor decreased p38MAPK and the resulting high-glucose-induced IL-6 release. Both antisense oligos to PKC-beta and -alpha as well as small interfering RNA (siRNA) to PKC-alpha and -beta resulted in significantly decreased high-glucose-induced IL-6 release. Nuclear factor-kappaB (NF-kappaB) inhibitors significantly decreased IL-6 mRNA and protein. siRNA to PKC-beta and -alpha also significantly decreased NF-kappaB activity and IL-6 release. The combination was not additive to either siRNA alone, suggesting that they work through a common pathway. Thus, IL-6 release from monocytes under hyperglycemia appears to be mediated via upregulation of PKC, through p38MAPK and NF-kappaB, resulting in increased mRNA and protein for IL-6. Thus, inhibition of PKC-alpha and -beta can ameliorate the proinflammatory state of diabetes.
Diabetes 2005 Jan
PMID:Hyperglycemia induces monocytic release of interleukin-6 via induction of protein kinase c-{alpha} and -{beta}. 1561 14

Methylglyoxal (MGO) is an alpha-dicarbonyl compound produced from triose phosphate intermediates of glycolysis. It reacts rapidly with proteins to produce advanced glycation products. We have studied the effect of MGO modification of fibronectin on retinal capillary cell viability. Our studies show that pericytes grown on MGO-modified fibronectin (FN) undergo enhanced apoptosis through the p38MAPK-mediated oxidative pathway and that alphaB-crystallin, a stress protein present in pericytes, can protect them from MGO-mediated apoptosis. Our studies with vascular endothelial cells show that hyperglycemia-induced apoptosis is inhibited by overexpression of alphaB-crystallin. These observations suggest a novel role of alphaB-crystallin in hyperglycemia-mediated damage to vascular cells in diabetes.
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PMID:Dicarbonyl stress and apoptosis of vascular cells: prevention by alphaB-crystallin. 1603 35

We have developed a primary skeletal muscle cell culture model derived from normal prepubertal children to investigate the effects of insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3) and tumour necrosis factor alpha (TNFalpha) on growth, differentiation and metabolism. Cells of myoblast lineage were characterized morphologically by desmin staining and differentiated successfully into multinucleated myotubes. Differentiation was confirmed biochemically by an increase in creatine kinase (CK) activity and IGFBP-3 secretion over time. IGF-I promoted whilst TNFalpha inhibited myoblast proliferation, differentiation and IGFBP-3 secretion. IGF-I partially rescued the cells from the inhibiting effects of TNFalpha. Compared to adult myoblast cultures, children's skeletal muscle cells demonstrated higher basal and day 7 CK activities, increased levels of IGFBP-3 secretion, diminished IGF-I/TNFalpha action and absence of the inhibitory effect of exogenous IGFBP-3 on differentiation. Additional studies demonstrated that TNFalpha increased basal glucose transport via GLUT1, nitric oxide synthase and p38MAPK-dependent mechanisms. These studies provide baseline data to study the interactivity effects of growth factors and cytokines on differentiation and metabolism in muscle in relation to important metabolic disorders such as obesity, type II diabetes or chronic wasting diseases.
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PMID:Isolation and validation of human prepubertal skeletal muscle cells: maturation and metabolic effects of IGF-I, IGFBP-3 and TNFalpha. 1608 85

We investigated whether benidipine, a long-acting calcium channel blocker (CCB), can normalize cardiac expression profiles of the endothelin (ET)-1 system in insulin-resistant diabetes. Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of human Type 2 diabetes, were treated for 12 wk with vehicle or benidipine (3 mg.kg(-1).day(-1)). OLETF rats exhibited a significant increase in ET-1 in plasma and left ventricular (LV) tissues compared with nondiabetic controls. Expression of prepro-ET-1, ET-converting enzyme, and ET(A) and ET(B) receptors in LV tissues was also significantly higher in OLETF rats. The two MAPKs, JNK and p38MAPK, both of which are activated by ET-1, were more abundantly expressed in OLETF rat LV tissues. All these alterations were reversed to nondiabetic levels when OLETF rats were treated with the subdepressor dose of benidipine. Furthermore, benidipine therapy resulted in hindering cardiomyocyte hypertrophy and cardiac perivascular fibrosis in OLETF rats. The beneficial actions of benidipine at the subdepressor dose on cardiac remodeling in insulin-resistant diabetes may involve normalization of the upregulated ET-1 system.
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PMID:Subdepressor dose of benidipine ameliorates diabetic cardiac remodeling accompanied by normalization of upregulated endothelin system in rats. 1638 88

Phosphorylated p38 (pp38) mitogen-activated protein kinase (MAPK) regulates heat shock protein 25 (HSP25), stabilizing fibrillar actin (FA) and preventing cleavage to G-actin (GA). Cultured podocytes (Pods) were exposed to glucose (5.5-50 mM)+/-p38MAPK inhibitor SB202190 (SB) or control SB202474 to assess the effects on FA/GA and Pod structure. The relationship of p38MAPK with in vivo Pod structure and albuminuria (Ualb) was assessed in rats with streptozotocin (SZ)-induced diabetes (DM) for 1 week, 1 month, and 4 months. High glucose induced concentration-dependent increases in pp38MAPK and phosphorylated HSP25 (pHSP25) maintained actin cytoskeleton. Inhibition by SB diminished pp38MAPK and pHSP25, decreased FA/GA, and altered FA and GA immunohistochemical appearance. In SZ-DM, glomerular pp38MAPK and biphosphorylated HSP25 were increased after 1 week, declining at 1 month, and at or below C values at 4 months. Glomerular FA/GA in DM was normal at 1 week, declining at 1 month, and low at 4 months. Ualb/creatinine was similar in DM vs C at 1 week, and increased at 1 and 4 months. Morphometry demonstrated progressively diminishing slit pore density in DM over time, denoting evolving effacement. There were strong correlations between slit membrane density and both glomerular biphosphorylated HSP25 and ln Ualb/cr ratio. The data suggest that increased pp38MAPK and pHSP25 comprise an acute adaptation to glycemic stress. Later depletion of DM may contribute to Pod structural alterations and Ualb.
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PMID:Glucose and diabetes: effects on podocyte and glomerular p38MAPK, heat shock protein 25, and actin cytoskeleton. 1642 17

Formation of new adipocytes from precursor cells contributes to adipose tissue expansion and obesity. In this study, we asked whether p38 mitogen-activated protein kinase (MAPK) pathway regulates normal and pathological adipogenesis. In both dietary and genetically (ob/ob) obese mice, adipose tissues displayed a marked decrease in p38MAPK activity compared with the same tissues from lean mice. Furthermore, p38MAPK activity was significantly higher in preadipocytes than in adipocytes, suggesting that p38MAPK activity decreases during adipocyte differentiation. In agreement with an inhibitory role of p38MAPK in this process, we found that in vitro inhibition of p38MAPK, with the specific inhibitor PD169316, increased the expression of adipocyte markers in several cellular models, from embryonic to adult stages. Importantly, the expression of adipocyte markers was higher in p38MAPKalpha knockout cells than in their wild-type counterparts. Phosphorylation of C/EBPbeta, which enhances its transcriptional activity, is increased after p38MAPK inhibition. Finally, either inhibition or disruption of p38MAPK increased peroxisome proliferator-activated receptor (PPAR)gamma expression and transactivation. Rescue of p38MAPK in knockout cells reduced PPARgamma activity to the low basal level of wild-type cells. We demonstrate here, by using multipronged approaches involving p38 chemical inhibitor and p38MAPKalpha knockout cells, that p38MAPK plays a negative role in adipogenesis via inhibition of C/EBPbeta and PPARgamma transcriptional activities.
Diabetes 2006 Feb
PMID:Inhibition of p38MAPK increases adipogenesis from embryonic to adult stages. 1644 58

Among several metals, vanadium has emerged as an extremely potent agent with insulin-like properties. These insulin-like properties have been demonstrated in isolated cells, tissues, different animal models of type I and type II diabetes as well as a limited number of human subjects. Vanadium treatment has been found to improve abnormalities of carbohydrate and lipid metabolism and of gene expression in rodent models of diabetes. In isolated cells, it enhances glucose transport, glycogen and lipid synthesis, and inhibits gluconeogenesis and lipolysis. The molecular mechanism responsible for the insulin-like effects of vanadium compounds have been shown to involve the activation of several key components of insulin-signaling pathways that include the mitogen-activated-protein kinases (MAPKs) extracellular signal-regulated kinase 1/2 (ERK1/2) and p38MAPK, and phosphatidylinositol 3-kinase (PI3-K)/protein kinase B (PKB). It is interesting that the vanadium effect on these signaling systems is independent of insulin receptor protein tyrosine kinase activity, but it is associated with enhanced tyrosine phosphorylation of insulin receptor substrate-1. These actions seem to be secondary to vanadium-induced inhibition of protein tyrosine phosphatases. Because MAPK and PI3-K/PKB pathways are implicated in mediating the mitogenic and metabolic effects of insulin, respectively, it is plausible that mimicry of these pathways by vanadium serves as a mechanism for its insulin-like responses.
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PMID:Insulin signal mimicry as a mechanism for the insulin-like effects of vanadium. 1645 36

We hypothesized that diabetes-induced oxidative stress may affect postischemic neovascularization. The response to unilateral femoral artery ligation was studied in wild-type or gp91(phox)-deficient control or type 1 diabetic mice or in animals treated with the anti-oxidant N-acetyl-l-cysteine (NAC) or with in vivo electrotransfer of a plasmid encoding dominant-negative Rac1 (50 microg) for 21 days. Postischemic neovascularization was reduced in diabetic mice in association with down-regulated vascular endothelial growth factor-A protein levels. In diabetic animals vascular endothelial growth factor levels and postischemic neovascularization were restored to nondiabetic levels by the scavenging of reactive oxygen species (ROS) by NAC administration or the inhibition of ROS generation by gp91(phox) deficiency or by administration of dominant-negative Rac1. Finally, diabetes reduced the ability of adherent bone marrow-derived mononuclear cells (BM-MNCs) to differentiate into endothelial progenitor cells. Treatment with NAC (3 mmol/L), apocynin (200 micromol/L), or the p38MAPK inhibitor LY333351 (10 micromol/L) up-regulated the number of endothelial progenitor cell colonies derived from diabetic BM-MNCs by 1.5-, 1.6-, and 1.5-fold, respectively (P < 0.05). In the ischemic hindlimb model, injection of diabetic BM-MNCs isolated from NAC-treated or gp91(phox)-deficient diabetic mice increased neovascularization by approximately 1.5-fold greater than untreated diabetic BM-MNCs (P < 0.05). Thus, inhibition of NADPH oxidase-derived ROS overproduction improves the angiogenic and vasculogenic processes and restores postischemic neovascularization in type 1 diabetic mice.
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PMID:NADPH oxidase-derived overproduction of reactive oxygen species impairs postischemic neovascularization in mice with type 1 diabetes. 1687 69


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