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

The etiology of the atherosclerosis that occurs in diabetes mellitus is unclear. Adenosine has been shown to inhibit growth of rat aortic smooth muscle cells. Nucleoside transporters play an integral role in adenosine function by regulating adenosine levels in the vicinity of adenosine receptors. Therefore, we studied the effect of 25 mM d-glucose, which mimics hyperglycemia of diabetes, on adenosine transport in cultured human aortic smooth muscle cells (HASMCs). Although RT-PCR demonstrated the presence of equilibrative nucleoside transporter-1 (ENT-1) and ENT-2 mRNA, functional studies revealed that adenosine transport in HASMCs was predominantly mediated by ENT-1 and inhibited by nitrobenzylmercaptopurine riboside (NBMPR, IC(50) = 0.69 +/- 0.05 nM). Adenosine transport in HASMCs was increased by >30% after treatment for 48 h with 25 mM d-glucose, but not with equimolar d-mannitol and l-glucose. Kinetic studies showed that d-glucose increased V(max) of adenosine transport without affecting K(m). Similarly, d-glucose increased B(max) of high-affinity [(3)H]NBMPR binding, while the dissociation constant (K(d)) was not changed. Consistent with these observations, 25 mM d-glucose increased mRNA and protein expression of ENT-1. Treatment of serum-starved cells with the selective inhibitors of MAPK/ERK, PD-98059 (40 microM) and U-0126 (10 microM), abolished the effect of d-glucose on ENT-1. We conclude that d-glucose upregulates the protein and message expression and functional activity of ENT-1 in HASMCs, possibly via MAPK/ERK-dependent pathways. Pathologically, the increase in ENT-1 activity in diabetes may affect the availability of adenosine in the vicinity of adenosine receptors and, thus, alter vascular functions in diabetes.
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PMID:D-Glucose upregulates adenosine transport in cultured human aortic smooth muscle cells. 1569 55

Type 1 diabetes results from destruction of pancreatic beta cells by beta cell-specific autoreactive T cells in the nonobese diabetic (NOD) mouse. Defects in thymic negative selection are thought to result in failure to delete potential beta cell-reactive T cells, contributing to the development of autoimmune diabetes. We investigated this possibility by comparing the deletion profile of double-positive (DP) thymocytes in NOD mice with diabetes-resistant strains of mice after anti-CD3 Ab treatment to trigger the TCR-mediated signaling pathway. We found that immature NOD CD4+CD8+ DP thymocytes have a lower activation threshold than C57BL/6 and Balb/c thymocytes. This was confirmed by showing that NOD DP thymocytes have a higher level of ERK and JNK phosphorylation. The low activation threshold of immature thymocytes resulted in rapid deletion of strongly activated immature DP thymocytes by negative selection, whereas weakly activated immature thymocytes differentiated more efficiently into CD69+CD3high DP thymocytes by positive selection. SP thymocytes, particularly CD4-CD8+ T cells that were efficiently generated from activated DP thymocytes, could induce severe insulitis and diabetes in NOD.scid mice. We conclude that the development of autoreactive diabetogenic T cells results from inordinate positive selection due to the low activation threshold of DP thymocytes in NOD mice.
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PMID:Development of autoreactive diabetogenic T cells in the thymus of NOD mice. 1572 72

The c-jun N-terminal kinase (JNK) signaling pathway mediates IL-1beta-induced apoptosis in insulin-secreting cells, a mechanism relevant to the destruction of pancreatic beta-cells in type 1 and 2 diabetes. However, the mechanisms that contribute to IL-1beta activation of JNK in beta-cells are largely unknown. In this study, we investigated whether Ca(2+) plays a role for IL-1beta-induced JNK activation. In insulin-secreting rat INS-1 cells cultured in the presence of 11 mm glucose, combined pharmacological blockade of L- and T-type Ca(2+) channels suppressed IL-1beta-induced in vitro phosphorylation of the JNK substrate c-jun and reduced IL-1beta-stimulated activation of JNK1/2 as assessed by immunoblotting. Inhibition of IL-1beta-induced in vitro kinase activity toward c-jun after collective L- and T-type Ca(2+) channel blockade was confirmed in primary rat and ob/ob mouse islets and in mouse betaTC3 cells. Ca(2+) influx, specifically via L-type but not T-type channels, contributed to IL-1beta activation of JNK. Activation of p38 and ERK in response to IL-1beta was also dependent on L-type Ca(2+) influx. Membrane depolarization by KCl, exposure to high glucose, treatment with Ca(2+) ionophore A23187, or exposure to thapsigargin, an inhibitor of sarco(endo)plasmic reticulum Ca(2+) ATPase, all caused an amplification of IL-1beta-induced JNK activation in INS-1 cells. Finally, a chelator of intracellular free Ca(2+) [bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid-acetoxymethyl], an inhibitor of calmodulin (W7), and inhibitors of Ca(2+)/calmodulin-dependent kinase (KN62 and KN93) partially reduced IL-1beta-stimulated c-jun phosphorylation in INS-1 or betaTC3 cells. Our data suggest that Ca(2+) plays a permissive role in IL-1beta activation of the JNK signaling pathway in insulin-secreting cells.
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PMID:Calcium has a permissive role in interleukin-1beta-induced c-jun N-terminal kinase activation in insulin-secreting cells. 1583 71

Complications of diabetes mellitus within the nervous system are peripheral and central neuropathy. In peripheral neuropathy, defects in neurofilament and microtubules have been demonstrated. In this study, we examined the effects of insulin deficiency within the brain in insulin knockout mice (I-/-). The I-/- exhibited hyperphosphorylation of tau, at threonine 231, and neurofilament. In addition, we showed hyperphosphorylation of c-Jun N-terminal kinase (JNK) and glycogen synthase kinase 3 beta (GSK-3 beta) at serine 9. Extracellular signal-regulated kinase 1 (ERK 1) showed decrease in phosphorylation, whereas ERK 2 showed no changes. Ultrastructural examination demonstrated swollen mitochondria, endoplasmic reticulum, and Golgi apparatus, and dispersion of the nuclear chromatin. Microtubules showed decrease in the number of intermicrotubule bridges and neurofilament presented as bunches. Thus, lack of insulin brain stimulation induces JNK hyperphosphorylation followed by hyperphosphorylation of tau and neurofilament, and ultrastructural cellular damage, that over time may induce decrease in cognition and learning disabilities.
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PMID:The effect of insulin deficiency on tau and neurofilament in the insulin knockout mouse. 1603 5

Faster proliferation rate characterizes human skin fibroblasts from patients with Type 1 diabetes and nephropathy (DN), but the reason of this phenomenon is still unknown. Growth factors control cell proliferation through an intracellular mitogen-activated protein (MAP) kinase cascade. We have examined the effect of the inhibition of MAP kinase/ERK kinase (MEK), a key point of the MAP kinase cascade, on the proliferation rate of fibroblasts from 40 patients with Type 1 diabetes (20 with and 20 without DN) and from 10 nondiabetic participants. Proliferation rate was measured by cell count in the presence or absence of 30 mumol/l of the MEK inhibitor PD 098059. In normal cultural conditions, proliferation rate was faster in fibroblasts from patients with (0.175+/-0.009x10(5) cells day-1, mean+/-S.E.M.) than without DN (0.110+/-0.009) and in nondiabetic participants (0.094+/-0.008; ANOVA P<.0001). The inhibition of MEK induced a stronger reduction of proliferation rate in fibroblasts from patients with (0.079+/-0.006x10(5) cells day(-1); 55% of reduction) than without DN (0.068+/-0.006; 38% of reduction) and in nondiabetic participants (0.064+/-0.006; 32% of reduction), and differences among groups were lost. In parallel, PD 098059 induced a greater reduction of MEK-dependent phosphorylation in lysates of fibroblasts from patients with (73%) than without (40%) DN. In conclusion, the inhibition of MEK normalizes the proliferation rate of fibroblasts from patients with DN, suggesting that the MAP kinase cascade could be involved in this cellular dysfunction.
J Diabetes Complications
PMID:Inhibition of MAP-kinase cascade normalizes the proliferation rate of fibroblasts from patients with Type 1 diabetes and nephropathy. 1611 5

Diabetes and insulin resistance are associated with increased disease risk and poor outcomes from cardiovascular interventions. Even drug-eluting stents exhibit reduced efficacy in patients with diabetes. We now report the first study of vascular response to stent injury in insulin-resistant and diabetic animal models. Endovascular stents were expanded in the aortae of obese insulin-resistant and type 2 diabetic Zucker rats, in streptozotocin-induced type 1 diabetic Sprague-Dawley rats, and in matched controls. Insulin-resistant rats developed thicker neointima (0.46+/-0.08 versus 0.37+/-0.06 mm2, P=0.05), with decreased lumen area (2.95+/-0.26 versus 3.29+/-0.15 mm2, P=0.03) 14 days after stenting compared with controls, but without increased vascular inflammation (ED1+ tissue macrophages). Insulin-resistant and diabetic rat vessels did exhibit markedly altered signaling pathway activation 1 and 2 weeks after stenting, with up to a 98% increase in p-ERK (anti-phospho ERK) and a 54% reduction in p-Akt (anti-phospho Akt) stained cells. Western blotting confirmed a profound effect of insulin resistance and diabetes on Akt and ERK signaling in stented segments. p-ERK/p-Akt ratio in stented segments uniquely correlated with neointimal response (R2=0.888, P=0.04) in insulin-resistant and type 1 and 2 diabetic rats, but not in lean controls. Transfemoral aortic stenting in rats provides insight into vascular responses in insulin resistance and diabetes. Shifts in ERK and Akt signaling related to insulin resistance may reflect altered tissue repair in diabetes accompanied by a shift in metabolic:proliferative balance. These findings may help explain the increased vascular morbidity in diabetes and suggest specific therapies for patients with insulin resistance and diabetes.
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PMID:Vascular neointimal formation and signaling pathway activation in response to stent injury in insulin-resistant and diabetic animals. 1612 36

Resistin (Rstn) is known as an adipocyte-specific secretory hormone that can cause insulin resistance and decrease adipocyte differentiation. By contrast, green tea catechins, especially (-)-epigallocatechin gallate (EGCG), have been reported as body weight and diabetes chemopreventatives. Whether EGCG regulates production of Rstn is unknown. Using 3T3-L1 adipocytes, we found that EGCG at 20 and 100 microM suppressed Rstn mRNA levels by approximately 35 and 50%, respectively, after 3 h. The basal half-life of Rstn mRNA induced by actinomycin D was >12 h but shifted to 3 h in the presence of EGCG. This suggests that EGCG regulates the stability of Rstn mRNA. Treatment with cycloheximide did not prevent EGCG-suppressed Rstn mRNA levels, which suggests that the effect of EGCG does not require new protein synthesis. Intracellular Rstn protein significantly decreased in the presence of 100 microM EGCG 3 h after treatment, whereas the release of the Rstn protein did not significantly change. This suggests that EGCG may modulate the distribution of Rstn protein between the intracellular and extracellular compartments. EGCG did not affect the amounts of extracellular signal-related kinase-1/2 (ERK1/2), phospho-JNK, phospho-p38, and phospho-Akt proteins but reduced the amounts of phospho-ERK1/2 proteins. Overexpression with MEK1 blocked EGCG-inhibited Rstn mRNA expression. These data suggest that EGCG downregulates Rstn expression via a pathway that is dependent on the ERK pathway.
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PMID:Inhibitory effect of green tea (-)-epigallocatechin gallate on resistin gene expression in 3T3-L1 adipocytes depends on the ERK pathway. 1615 6

During brain aging and progression of Alzheimer's disease, the levels of Abeta and proinflammatory cytokines accumulate very early in the pathogenic process prior to any major degenerative changes. Accumulation of these molecules may impair with signal transduction pathways critical for neuronal health. Neurotrophin signaling is a critical mechanism involved in synaptic plasticity, learning and memory and neuronal health. We have recently shown that exposure to low levels of Abeta impairs BDNF trkB signal transduction, suppressing the Ras/ERK, and the PI3-K/Akt pathways but not the PLCgamma pathway. As a result, downstream regulation of gene expression and neuronal viability are impaired. Recently, we have found that at least three agents--Abeta, TNFalpha, Il-1beta--suppress TrkB signaling and act via a common and novel mechanism. These factors all regulate the docking proteins (e.g., IRS and Shc) that link the activated Trk receptor to downstream effectors. While this is a novel mechanism underlying regulation of Trk signaling, such a mechanism has been identified for the insulin/IGF-1 receptor in the presence of proinflammatory cytokines and is one of the mechanisms for insulin/IGF-resistance, which is a key risk factor for type II diabetes (1). We suggest that accumulation of AB and proinflammatory cytokines during aging generates in the brain a "neurotrophin resistance" state that places the brain at risk for cognitive decline and dementia.
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PMID:The role of neurotrophins in brain aging: a perspective in honor of Regino Perez-Polo. 1618 22

Insulin and cholesterol play important roles in basic metabolic processes in peripheral tissues. Both insulin and cholesterol can also act as signalling molecules in the central nervous system that participate in neuronal function, memory and neurodegenerative diseases. A high-cholesterol diet improves spatial memory in experimental animals. beta-Amyloid, the toxic peptide in neurons of AD (Alzheimer's disease) patients, binds cholesterol and catalyses its oxidation to 7beta-hydroxycholesterol, a highly toxic oxysterol that is a potent inhibitor of alpha-PKC (alpha-protein kinase C), an enzyme critical in memory consolidation and synaptic plasticity and implicated in AD. Oxidized cholesterol also can act as a second messenger for insulin. Oxidized low-density lipoprotein inhibits insulin-dependent phosphorylation of the signalling kinases ERK (extracellular-signal-regulated kinase) and PKB/Akt. In sporadic AD patients, insulin levels are decreased, suggesting links between AD and diabetes. Insulin signalling is also important in synaptic plasticity. Insulin receptors are up-regulated and undergo translocation after spatial learning. Insulin modulates the activity of excitatory and inhibitory receptors including the glutamate and gamma-aminobutyric acid receptors and activates two biochemical pathways: the shc-ras-mitogen-activated protein kinase pathway and the PI3K (phosphoinositide 3-kinase)/PKC pathway, both of which are involved in memory processing. These findings point to a convergence at the biochemical level between pathways involved in AD and those important for normal memory.
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PMID:Insulin and cholesterol pathways in neuronal function, memory and neurodegeneration. 1624 39

Insulin and angiotensin II are hormones that play pivotal roles in the control of two vital and closely related systems, the metabolic and the circulatory systems, respectively. A failure in the proper action of each of these hormones results, to a variable degree, in the development of two highly prevalent and commonly overlapping diseases-diabetes mellitus and hypertension. In recent years, a series of studies has revealed a tight connection between the signal transduction pathways that mediate insulin and angiotensin II actions in target tissues. This molecular cross-talk occurs at multiple levels and plays an important role in phenomena that range from the action of anti-hypertensive drugs to cardiac hypertrophy and energy acquisition by the heart. At the extracellular level, the angiotensin-converting enzyme controls angiotensin II synthesis but also interferes with insulin signaling through the proper regulation of angiotensin II and through the accumulation of bradykinin. At an early intracellular level, angiotensin II, acting through JAK-2/IRS-1/PI3-kinase, JNK and ERK, may induce the serine phosphorylation and inhibition of key elements of the insulin-signaling pathway. Finally, by inducing the expression of the regulatory protein SOCS-3, angiotensin II may impose a late control on the insulin signal. This review will focus on the main advances obtained in this field and will discuss the implications of this molecular cross-talk in the common clinical association between diabetes mellitus and hypertension.
Diabetes Metab Res Rev
PMID:The multi-faceted cross-talk between the insulin and angiotensin II signaling systems. 1638 35


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