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

Recent studies demonstrate that the mammalian target of rapamycin (mTOR) and its effector, S6 kinase 1 (S6K1), lie at the crossroads of a nutrient-hormonal signaling network that is involved in specific pathological responses, including obesity, diabetes and cancer. mTOR exists in two complexes: mTOR Complex1, which is rapamycin-sensitive and phosphorylates S6K1 and initiation factor 4E binding proteins (4E-BPs), and mTOR Complex2, which is rapamycin-insensitive and phosphorylates protein kinase B (PKB, also known as Akt). Both mTOR complexes are stimulated by mitogens, but only mTOR Complex1 is under the control of nutrient and energy inputs. Thus, to orchestrate the control of homeostatic responses, mTOR Complex1 must integrate signals from distinct cues. Here, we review recent findings concerning the regulation and pathophysiology associated with mTOR Complex1 and S6K1.
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PMID:mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancer. 1745 18

Since the bioenergetic capacity of skeletal muscle mitochondria is decreased in type 2 diabetes and obesity, the reduction of mitochondrial DNA (mtDNA) content may be involved in the development of insulin resistance in skeletal muscle. To elucidate the association of cellular mtDNA content and insulin resistance, we produced L6 GLUT4myc myocytes depleted of mtDNA by long-term treatment with ethidium bromide (EtBr). L6 GLUT4myc cells cultured with 0.2 microg/ml EtBr (termed depleted cells) revealed a marked decrease in cellular mtDNA, concomitant with a lack of mRNAs encoded by mtDNA. Interestingly, the mtDNA-depleted cells showed a drastic decrease in basal and insulin-stimulated glucose uptake, indicating that L6 GLUT4myc cells develop impaired glucose utilization and insulin resistance. The repletion of mtDNA normalized basal and insulin-stimulated glucose uptake. The plasma membrane (PM) GLUT4 in the basal state was decreased, and the insulin-stimulated GLUT4 translocation to the PM was drastically reduced by mtDNA depletion. Interestingly, the expression of IRS-1 associated with insulin signaling was decreased by 90% in the depleted cells, and the insulin-stimulated phosphorylation of IRS-1 and Akt2/PKB were drastically reduced in the depleted cells. Those changes returned to control levels after mtDNA repletion. Taken together, our data suggest that PM GLUT4 content and insulin signal pathway intermediates are modulated by the alteration of cellular mtDNA content, and the reduction in the expression of IRS-1 and insulin-stimulated phosphorylation of IRS-1 and Akt2/PKB are associated with insulin resistance in the mtDNA-depleted L6 GLUT4myc myocytes.
Diabetes Res Clin Pract 2007 Sep
PMID:The depletion of cellular mitochondrial DNA causes insulin resistance through the alteration of insulin receptor substrate-1 in rat myocytes. 1746 78

Dysmetabolic state in diabetes may lead to augmented synthesis of extracellular matrix (ECM) proteins. In the endothelial cells, we have previously demonstrated that glucose-induced fibronectin (FN) production and that of its splice variant, EDB(+)FN, is regulated by protein kinase B (PKB, also known as Akt). In this study, we investigated the role of Akt1 in ECM protein production in the organs affected by chronic diabetic complications. We studied Akt1/PKBalpha knockout mice and wild-type control littermates. To avoid confounding effects of systemic insulin, we used 30% galactose feeding to induce hyperhexosemia for 8 wk starting at 6 wk of age. We investigated FN mRNA, EDB(+)FN mRNA, and transforming growth factor (TGF)-beta mRNA expression, Akt phosphorylation, Akt kinase activity, and NF-kappaB and AP-1 activation in the retina, heart, and kidney. Renal and cardiac tissues were histologically examined. Galactose feeding caused significant upregulation of FN, EDB(+)FN, and TGF-beta in all tissues. FN protein levels paralleled mRNA. Such upregulation were prevented in Akt1-deficient galactose-fed mice. Galactose feeding caused ECM protein deposition in the glomeruli and in the myocardium, which was prevented in the Akt knockout mice. NF-kappaB and AP-1 activation was pronounced in galactose-fed wild-type mice and prevented in the galactose-fed Akt1/PKBalpha-deficient group. In the retina and kidney, Ser473 was the predominant site for Akt phosphorylation, whereas in the heart it was Thr308. Parallel experiment in streptozotocin-induced diabetic animals showed similar results. The data from this study indicate that hyperhexosemia-induced Akt/PKB activation may be an important mechanism leading to NF-kappaB and AP-1 activation and increased ECM protein synthesis in the organs affected by chronic diabetic complications.
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PMID:Akt activation and augmented fibronectin production in hyperhexosemia. 1766 88

Glycogen synthase kinase 3 comprises two isoforms (GSK-3alpha and GSK-3beta) that are implicated in type II diabetes, neurodegeneration, and cancer. GSK-3 activity is elevated in human and rodent models of diabetes, and various GSK-3 inhibitors improve glucose tolerance and insulin sensitivity in rodent models of obesity and diabetes. Here, we report the generation of mice lacking GSK-3alpha. Unlike GSK-3beta mutants, which die before birth, GSK-3alpha knockout (GSK-3alpha KO) animals are viable but display enhanced glucose and insulin sensitivity accompanied by reduced fat mass. Fasted and glucose-stimulated hepatic glycogen content was enhanced in GSK-3alpha KO mice, whereas muscle glycogen was unaltered. Insulin-stimulated protein kinase B (PKB/Akt) and GSK-3beta phosphorylation was higher in GSK-3alpha KO livers compared to wild-type littermates, and IRS-1 expression was markedly increased. We conclude that GSK-3 isoforms exhibit tissue-specific physiological functions and that GSK-3alpha KO mice are insulin sensitive, reinforcing the potential of GSK-3 as a therapeutic target for type II diabetes.
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PMID:Glycogen synthase kinase 3alpha-specific regulation of murine hepatic glycogen metabolism. 1790 61

The serine/threonine kinase, protein kinase B (PKB, also known as Akt), is activated by a wide array of growth factors and insulin. PKB is a central player in the regulation of metabolism, apoptosis, transcription and the cell-cycle. PKB exists as three isoforms (alpha, beta and gamma) that may have unique as well as common functions within the cell. Deregulation of PKB is associated with several human diseases, including cancer, diabetes and schizophrenia. These findings underscore the medical relevance of the PKB pathway and make PKB an attractive drug target for the treatment of diseases that exhibit abnormal PKB signalling.
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PMID:Protein kinase B: signalling roles and therapeutic targeting. 1795 68

Iron depletion improves insulin resistance in patients with nonalcoholic fatty liver disease and diabetes and also stabilizes the hypoxia-inducible factor (HIF)-1, resulting in increased glucose uptake in vitro. This study investigated the effect of iron depletion by deferoxamine on insulin signaling and glucose uptake in HepG2 hepatocytes and in rat liver. In HepG2 cells, deferoxamine stabilized HIF-1alpha and induced the constitutive glucose transporter Glut1 and the insulin receptor. Up-regulation of insulin receptor by deferoxamine was mimicked by the intracellular iron chelator deferasirox and the hypoxia inducer CoCl2 and required the HIF-1 obligate partner ARNT/HIF-1beta. Iron depletion increased insulin receptor activity, whereas iron supplementation had the opposite effect. Deferoxamine consistently increased the phosphorylation status of Akt/PKB and its targets FoxO1 and Gsk3beta, which mediate the effect of insulin on gluconeogenesis and glycogen synthesis, and up-regulated genes involved in glucose uptake and utilization. Iron depletion of Sprague-Dawley rats increased HIF-1alpha expression, improved glucose clearance, and was associated with up-regulation of insulin receptor and Akt/PKB levels and of glucose transport in hepatic tissue. Conversely, gluconeogenic genes were not affected. In rats with fatty liver because of a high-calorie and high-fat diet, glucose clearance was increased by iron depletion and decreased by iron supplementation. Thus, iron depletion by deferoxamine up-regulates glucose uptake, and increases insulin receptor activity and signaling in hepatocytes in vitro and in vivo.
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PMID:Iron depletion by deferoxamine up-regulates glucose uptake and insulin signaling in hepatoma cells and in rat liver. 1824 13

Metabolic syndrome and type 2 diabetes are progressive, indolent, multi-organ diseases. Understanding the abnormalities of heat shock proteins (HSPs) in these diseases is paramount to understanding their pathogenesis. In insulin resistant states and diabetes, heat shock factor 1(HSF-1) is low in insulin sensitive tissues, resulting in low Hsp 60, 70, and 90 levels. We propose that low Hsps levels are the result of decreased insulin action leading to less phosphorylation of PI3K, PKB, and glycogen synthase kinase-3 (GSK-3). Importantly, less GSK-3 phosphorylation (and thus more GSK-3 activity) will lower HSF-1. Low Hsps make organs vulnerable to injury, impair the stress response, accelerate systemic inflammation, raise islet amyloid polypeptide, and increase insulin resistance. Feeding this cycle is excess saturated fat and calorie consumption, hypertension, inactivity, aging, and genetic predisposition- all of which are a associated with high GSK-3 activity and low Hsps. Support for the proposed "vicious" cycle is based on the observation that GSK-3 inhibition and Hsp stimulation result in increased insulin sensitivity, reduced accumulation of degenerative proteins with in the cell, improved wound healing, decreased organ damage and improved recovery from vascular ischemia. Recognizing GSK-3 and Hsps in the pathogenesis of insulin resistance, the central common feature of the metabolic syndrome, and type 2 diabetes will expand our understanding of the disease, offering new therapeutic options.
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PMID:Insulin Signaling, GSK-3, Heat Shock Proteins and the Natural History of Type 2 Diabetes Mellitus: A Hypothesis. 1837 Jul 76

Members of the Forkhead box O (FOXO) class of transcription factors are key players in the regulation of cell-fate decisions, such as cell death, cell proliferation and cell metabolism. Furthermore, in model organisms, it has by now been demonstrated that FOXO function affects the life span of these organisms. Multiple signal transduction pathways regulate FOXO function, but most importantly, they are negatively regulated by protein kinase B (PKB/AKT)-mediated phosphorylation and constitute, therefore, an important downstream component of insulin signalling. This review issue provides a timely overview of our understanding of FOXO function and how signalling affects FOXO function. Taken together, the reviewed studies on FOXO function and regulation provide compelling evidence that FOXOs act at the crossroad between aging and age-related diseases including diabetes and cancer. With this perspective, further studies on FOXO function and regulation may shed light on how age impacts on the onset and progression of disease.
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PMID:A brief introduction to FOXOlogy. 1839 68

The molecular pathogenesis of diabetic nephropathy (DN), the leading cause of end-stage renal disease worldwide, is complex and not fully understood. Transforming growth factor-beta (TGF-beta1) plays a critical role in many fibrotic disorders, including DN. In this study, we report protein kinase B (PKB/Akt) activation as a downstream event contributing to the pathophysiology of DN. We investigated the potential of PKB/Akt to mediate the profibrotic bioactions of TGF-beta1 in kidney. Treatment of normal rat kidney epithelial cells (NRK52E) with TGF-beta1 resulted in activation of phosphatidylinositol 3-kinase (PI3K) and PKB/Akt as evidenced by increased Ser473 phosphorylation and GSK-3beta phosphorylation. TGF-beta1 also stimulated increased Smad3 phosphorylation in these cells, a response that was insensitive to inhibition of PI3K or PKB/Akt. NRK52E cells displayed a loss of zona occludins 1 and E-cadherin and a gain in vimentin and alpha-smooth muscle actin expression, consistent with the fibrotic actions of TGF-beta1. These effects were blocked with inhibitors of PI3K and PKB/Akt. Furthermore, overexpression of PTEN, the lipid phosphatase regulator of PKB/Akt activation, inhibited TGF-beta1-induced PKB/Akt activation. Interestingly, in the Goto-Kakizaki rat model of type 2 diabetes, we also detected increased phosphorylation of PKB/Akt and its downstream target, GSK-3beta, in the tubules, relative to that in control Wistar rats. Elevated Smad3 phosphorylation was also detected in kidney extracts from Goto-Kakizaki rats with chronic diabetes. Together, these data suggest that TGF-beta1-mediated PKB/Akt activation may be important in renal fibrosis during diabetic nephropathy.
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PMID:Protein kinase B/Akt activity is involved in renal TGF-beta1-driven epithelial-mesenchymal transition in vitro and in vivo. 1849 98

Type 2 diabetes recently has been identified as a risk factor for developing Alzheimer's disease (AD). The main reason for this appears to be insulin signaling failure in the brain. Furthermore, cholinergic neurons are particularly affected in the brains of AD patients. The aim of the present study is to investigate if insulin signaling-related proteins are co-located with cholinergic neuron in the CA1 region of hippocampus of mice, which could explain the early loss of cholinergic neurons in AD. Using immunohistochemistry, the insulin signaling-related proteins, such as insulin receptor (InsR), insulin receptor substrate-1 (IRS-1), protein kinase B (PKB, also named Akt), glycogen synthase kinase-3beta (GSK-3beta) and insulin-degrading enzyme (IDE) were analysed. Choline acetyltransferase (ChAT) was selected as a marker of cholinergic neurons. In the CA1 region of hippocampus of mice, several of the insulin signaling-related proteins we had chosen are co-located with ChAT, and most double immunoreactive positive cells were pyramidal cells. The coexistences indicated that the insulin signaling may play an important part in the activities of cholinergic neurons, and the impairment of the pathway may be important in the mechanisms that underlie neurodegeneration in AD.
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PMID:Coexistences of insulin signaling-related proteins and choline acetyltransferase in neurons. 1901 38


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