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 TOR (mTOR) pathway is a key regulator of cell growth and proliferation and increasing evidence suggests that its deregulation is associated with human diseases, including cancer and diabetes. The mTOR pathway integrates signals from nutrients, energy status and growth factors to regulate many processes, including autophagy, ribosome biogenesis and metabolism. Recent work identifying two structurally and functionally distinct mTOR-containing multiprotein complexes and TSC1/2, rheb, and AMPK as upstream regulators of mTOR is beginning to reveal how mTOR can sense diverse signals and produce a myriad of responses.
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PMID:Growing roles for the mTOR pathway. 1622 44

Nutritional excess and/or obesity represent well-known predisposition factors for the development of non-insulin-dependent diabetes mellitus (NIDDM). However, molecular links between obesity and NIDDM are only beginning to emerge. Here, we demonstrate that nutrients suppress phosphatidylinositol 3 (PI3)-kinase/Akt signaling via Raptor-dependent mTOR (mammalian target of rapamycin)-mediated phosphorylation of insulin receptor substrate 1 (IRS-1). Raptor directly binds to and serves as a scaffold for mTOR-mediated phosphorylation of IRS-1 on Ser636/639. These serines lie close to the Y(632)MPM motif that is implicated in the binding of p85alpha/p110alpha PI3-kinase to IRS-1 upon insulin stimulation. Phosphomimicking mutations of these serines block insulin-stimulated activation of IRS-1-associated PI3-kinase. Knockdown of Raptor as well as activators of the LKB1/AMPK pathway, such as the widely used antidiabetic compound metformin, suppress IRS-1 Ser636/639 phosphorylation and reverse mTOR-mediated inhibition on PI3-kinase/Akt signaling. Thus, diabetes-related hyperglycemia hyperactivates the mTOR pathway and may lead to insulin resistance due to suppression of IRS-1-dependent PI3-kinase/Akt signaling.
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PMID:Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation. 1635 80

Several decades of research for treating type 2 diabetes have yielded new drugs but the actual experience with the available oral antidiabetic compounds clearly shows that therapeutic needs are not matched. This highlights the urgent need for exploring other pathways. All cell types have the capacity to take up glucose independently of insulin, whereby basal but also hyperglycaemia-promoted glucose supply is ensured. Although poorly explored, insulin-independent glucose uptake might nevertheless represent a therapeutic target, as an alternative to the clear limits of actual drug treatments. This review not only critically examines some major pathways not requiring insulin (although they may be influenced by the hormone) but importantly, this analysis extends to the clinical applicability of these potential therapeutic principles by also considering their predictable tolerability for long-term therapy. In particular vascular safety (the ultimate problem linked with diabetes) will be envisaged because of the ubiquitous distribution of glucose transporters and some linked mechanisms. Several mechanisms can be identified which do not require insulin for their functioning. The first part of this review deals with the description, the regulation and the limits of some mechanisms representing potential pharmacological targets capable of having a highly significant impact on glucose uptake. These selected topics are: a) unmasking and/or activation of glucose transporters in cell plasma membranes, b) insulin mimetics acting at postreceptor level, c) activation of AMPK, d) increasing nitric oxide and e) increasing glucose-6P and glycogen stores.
Diabetes Metab 2005 Nov
PMID:Is non-insulin dependent glucose uptake a therapeutic alternative? Part 1: physiology, mechanisms and role of non insulin-dependent glucose uptake in type 2 diabetes. 1635 85

To elucidate the role of AMPK in hepatic glucose metabolism, dominant negative (DN), constitutively active (CA) forms of the AMPKalpha1 subunit and control vector LacZ were overexpressed by means of adenovirus-mediated gene transfer. Five days after virus injection, hepatic AMPK activity was five-fold higher in CA mice than in DN mice. DN mice were apparently glucose intolerant with a higher fasting plasma glucose level (DN 82.3+/-0.7mg/dl, CA 42.5+/-4.8mg/dl and LacZ 54.3+/-2.4mg/dl). PEPCK, a gluconeogenic key enzyme, mRNA was increased 131.54% and 48.92% in DN mice compared to that of CA and LacZ, respectively. Thus, hepatic AMPK activation plays a role in the suppression of gluconeogenesis and this might be the cause of decreased fasting plasma glucose level in CA mice. We also investigated the effects of dexamethasone on hepatic AMPK expression and activity in rat liver, mice liver, as well as primary cultured hepatocytes. Subcutaneously injecting mice with dexamethasone (1mg/day) for 5 days significantly upregulated hepatic AMPKalpha1 and alpha2 expressions. Similarly, the treatment of primary cultured rat hepatocytes with dexamethasone (1microM) increased expression of the AMPKalpha1 subunit, AICAR-induced AMPK phosphorylation and kinase activity. Although increased AMPK expression cannot be attributed to dexamethasone-induced glucose intolerance, taken together our results raise the possibility that AMPK control liver glucose output and its expression in liver might be modulated by various hormones and growth factors.
Diabetes Res Clin Pract 2006 Aug
PMID:Role of hepatic AMPK activation in glucose metabolism and dexamethasone-induced regulation of AMPK expression. 1650 64

The LKB1-->AMPK cascade is switched on by metabolic stresses that either inhibit ATP production (e.g. hypoxia, hypoglycaemia) or that accelerate ATP consumption (e.g. muscle contraction). Any decline in cellular energy status is accompanied by a rise in the cellular AMP: ATP ratio, and this activates AMPK by a complex and sensitive mechanism involving antagonistic binding of the nucleotides to two sites on the regulatory gamma subunits of AMPK. Once activated by metabolic stress, AMPK activates catabolic pathways that generate ATP, while inhibiting cell growth and biosynthesis and other processes that consume ATP. While the AMPK system probably evolved in single-celled eukaryotes to maintain energy balance at the cellular level, in multicellular organisms its role has become adapted so that it is also involved in maintaining whole body energy balance. Thus, it is regulated by hormones and cytokines, especially the adipokines leptin and adiponectin, increasing whole body energy expenditure while regulating food intake. Some hormones may activate AMPK by an LKB1-independent mechanism involving Ca2+/calmodulin dependent protein kinase kinases. Low levels of activation of AMPK are likely to play a role in the current global rise in obesity and Type 2 diabetes, and AMPK is the target for the widely used antidiabetic drug metformin.
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PMID:AMP-activated protein kinase--development of the energy sensor concept. 1664

The target of rapamycin (TOR) pathway regulates ribosome biogenesis, protein synthesis, nutrient import, autophagy and cell cycle progression. After 30 years of concentrated attention, how TOR controls these processes is only now beginning to be understood. Recent advances have identified a wide array of TOR inputs, including amino acids, oxygen, ATP and growth factors, as well the regulatory proteins that facilitate their effects on TOR. Such proteins include AMPK, Rheb and the tumor suppressors LKB1, p53, and Tsc1/2. It has only recently been appreciated that TOR resides in two distinct signaling complexes with differing regulatory roles, only one of which is rapamycin-sensitive, thus opening a new avenue of inquiry into TOR function. Finally, TOR appears to regulate feeding behavior by facilitating communication between organ systems, and is thus implicated in the regulation of glucose and fat homeostasis, and possibly diabetes and obesity. TOR thus functions to coordinate growth-permitting inputs with growth-promoting outputs on both a cellular and an organismal level.
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PMID:Thinking globally and acting locally with TOR. 1704 29

The SNF1-related kinases are considered to be crucial elements of transcriptional, metabolic and developmental regulation in response to stress. In yeast, SNF1 is one of the main regulators in the shift from fermentation to aerobic metabolism; AMPK, its mammalian counterpart, is a master metabolic regulator involved in a variety of metabolic disorders such as diabetes and obesity. The aim of this review is to examine the literature concerning SnRK1 proteins, the SNF1 homologues in plants. The remarkable structural similarities between the plant complexes and those of yeast and mammalian suggest the existence of a common ancestral function in the regulation of energy and carbon metabolism. We will also highlight some distinctive features acquired by the plant proteins during evolution.
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PMID:SNF1/AMPK/SnRK1 kinases, global regulators at the heart of energy control? 1716 59

Secreted insulin from pancreatic beta cells exerts autocrine and paracrine effects within the islets. The present study has evaluated how exogenous insulin participates in cytosolic Ca(2+) response to high glucose, according to glucose concentration at which insulin is applied. When 100 nM insulin was pretreated to the bath solution containing islet cells in the presence of basal level of glucose, the elevation of cytosolic Ca(2+) concentration ([Ca(2+)](c)) by subsequently applied 10mM glucose was remarkably attenuated. In contrast, the glucose-stimulated [Ca(2+)](c) elevation was more potentiated when insulin was superimposed on the high glucose stimulation. These insulin actions were modestly inhibited by the application of LY294002, the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, but not completely, suggesting that another mechanism is also involved. By 100 nM insulin, phosphorylated form of AMP-activated protein kinases (p-AMPK) was dramatically decreased in basal glucose but increased in high glucose, when compared with their reciprocal controls. These results may suggest that the extent of AMPK activation may be a tool for insulin receptors to monitor blood glucose level, with which insulin-induced insulin receptor activation determines the way to go negatively or positively toward [Ca(2+)](c).
Diabetes Res Clin Pract 2007 Sep
PMID:Negative and positive feedback regulation of insulin in glucose-stimulated Ca2+ response in pancreatic beta cells. 1746 44

Low-grade chronic inflammation is a feature of Type 2 diabetes and appears to play a pathogenetic role in insulin resistance. It is well known that cytokines, besides their immunoregulatory roles, are important players in metabolism. Moreover, it has become evident that skeletal muscles express several cytokines, which belong to distinct cytokine classes. IL-6 (interleukin-6) is a pleiotropic cytokine produced by virtually all multinucleated cells including skeletal myocytes where it is produced in response to contraction. IL-6 is subsequently released into the circulation, where it works in a hormone-like fashion to induce lipolysis and fat oxidation. In more recent experiments, it has been shown that IL-6 infusion increases glucose disposal during a hyperinsulinaemic euglycaemic clamp in healthy humans. IL-6 treatment of myotubes increases fatty acid oxidation, basal and insulin-stimulated glucose uptake and translocation of GLUT4 to the plasma membrane. Furthermore, IL-6 rapidly and markedly increases AMPK (AMP-activated protein kinase) and the metabolic effects of IL-6 were abrogated in AMPK dominant negative-infected cells. Finally, IL-6 mediates anti-inflammatory effects by stimulating the production of anti-inflammatory cytokines and by suppressing TNFalpha (tumour necrosis factor alpha) production. We suggest that IL-6 and other muscle-derived cytokines (myokines) may play a role in defending Type 2 diabetes.
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PMID:IL-6 signalling in exercise and disease. 1795 34

Metabolic disorders such as obesity are major obstacles in improving the average life span. Therefore, a therapeutic approach using natural compounds has been proposed as a novel strategy for preventing metabolic disorders. Ginsenoside Rh2 is one of the ginsenosides that exert anti-diabetes, anti-inflammatory, and anti-cancer effects. However, the anti-obesity effects of Ginsenoside Rh2 remain unclear. Here, we investigated the anti-obesity ability of ginsenoside Rh2 using cell culture systems. Ginsenoside Rh2 effectively inhibited adipocyte differentiation via PPAR-gamma inhibition. Next, to find specific target molecules based on this result, we used cell culture systems to examine whether AMPK activation was involved in the anti-obesity ability of ginsenoside Rh2 since several published papers have indicated that AMPK signaling is involved in the regulation of metabolic disorders. Ginsenoside Rh2 significantly activated AMPK in 3T3-L1 adipocytes. In addition, we also examined the effect of AMPK on lipolysis molecules such as CPT-1 and UCP-2 by using an AMPK inhibitor. Ginsenoside Rh2 effectively induced CPT-1 and UCP-2 and this induction was abolished by AMPK inhibitor treatment. Moreover, we observed that ROS is an important upstream signal for AMPK activation during ginsenoside Rh2 treatment. Taken together, these results indicate that ginsenoside Rh2 is the most effective candidate for preventing metabolic disorders such as obesity and that it acts via the AMPK signaling pathway. Thus, AMPK signaling might contribute toward improving human health.
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PMID:Anti-obesity effects of ginsenoside Rh2 are associated with the activation of AMPK signaling pathway in 3T3-L1 adipocyte. 1797 Dec 95


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