Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the light of recent studies in humans and rodents, AMP-activated protein kinase (AMPK), a phylogenetically conserved serine/threonine protein kinase, has been described as an integrator of regulatory signals monitoring systemic and cellular energy status. AMP-activated protein kinase (AMPK) has been proposed to function as a 'fuel gauge' to monitor cellular energy status in response to nutritional environmental variations. Recently, it has been proposed that AMPK could provide a link in metabolic defects underlying progression to the metabolic syndrome. AMPK is a heterotrimeric enzyme complex consisting of a catalytic subunit alpha and two regulatory subunits beta and gamma. AMPK is activated by rising AMP and falling ATP. AMP activates the system by binding to the gamma subunit that triggers phosphorylation of the catalytic alpha subunit by the upstream kinases LKB1 and CaMKKbeta (calmodulin-dependent protein kinase kinase). AMPK system is a regulator of energy balance that, once activated by low energy status, switches on ATP-producing catabolic pathways (such as fatty acid oxidation and glycolysis), and switches off ATP-consuming anabolic pathways (such as lipogenesis), both by short-term effect on phosphorylation of regulatory proteins and by long-term effect on gene expression. As well as acting at the level of the individual cell, the system also regulates food intake and energy expenditure at the whole body level, in particular by mediating the effects of insulin sensitizing adipokines leptin and adiponectin. AMPK is robustly activated during skeletal muscle contraction and myocardial ischaemia playing a role in glucose transport and fatty acid oxidation. In liver, activation of AMPK results in enhanced fatty acid oxidation as well as decreased glucose production. Moreover, the AMPK system is one of the probable targets for the anti-diabetic drugs biguanides and thiazolidinediones. Thus, the relationship between AMPK activation and beneficial metabolic effects provide the rationale for the development of new therapeutic strategies in metabolic disorders.
Diabetes Metab 2007 Dec
PMID:Targeting AMP-activated protein kinase as a novel therapeutic approach for the treatment of metabolic disorders. 1799 41

1. AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase involved in the regulation of cellular and organismal metabolism. AMPK has a heterotrimeric structure, consisting of a catalytic alpha-subunit and regulatory beta- and gamma-subunits, each of which has two or more isoforms that are differentially expressed in various tissues and that arise from distinct genes. The AMPK system acts as a sensor of cellular energy status that is conserved in all eukaryotic cells. In addition, AMPK is activated by physiological stimuli and oxidants. 2. The importance of AMPK in cardiovascular functions is best demonstrated by recent studies showing that widely used drugs, including statins, metformin and rosiglitazone, execute cardiovascular protective effects at least partly through the activation of AMPK. As a consequence, AMPK has been proposed as a candidate target for therapeutic intervention in the treatment of both Type 2 diabetes and metabolic syndrome owing to its central role in the regulation of energy balance; it may also have a role in weight control. 3. In the present brief review, we summarize the recent progress of AMPK signalling and regulation focusing on vascular endothelial cells. We further hypothesize that AMPK is a dual sensor for energy and redox status within a cell and AMPK may be a therapeutic target for protecting vascular endothelial function.
 ...
PMID:AMP-activated protein kinase activation as a strategy for protecting vascular endothelial function. 1817 81

Mammalian AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that acts as a sensor of cellular energy status. It is activated by a large variety of cellular stresses that increase cellular AMP and decrease ATP levels and also by physiological stimuli, such as muscle contraction, or by hormones such as leptin and adiponectin. AMPK modulates multiple metabolic pathways. As a result, it has become a target for the development of new drugs for the treatment of type II diabetes, obesity or even cancer. In fact, it has been recently reported that drugs used in the treatment of diabetes, such as metformin and thiazolidinediones (TZDs), exert their beneficial effects through the activation of AMPK. AMPK is a heterotrimeric complex composed of a catalytic subunit (AMPK-alpha) and two regulatory subunits (AMPK-beta and AMPK-gamma). Functional orthologues of this kinase complex are found throughout eukaryotic kingdom, from yeast to humans, indicating that the function of this complex is evolutionarily conserved. This review summarizes the recent studies on the structure and regulation of the AMPK heterotrimeric complex.
 ...
PMID:AMP-activated protein kinase: structure and regulation. 1885 99

mTOR (mammalian target of rapamycin) is a highly conserved serine/threonine protein kinase that has roles in cell metabolism, cell growth and cell survival. Although it has been known for some years that mTOR acts as a hub for inputs from growth factors (in particular insulin and insulin-like growth factors), nutrients and cellular stresses, some of the mechanisms involved are still poorly understood. Recent work has implicated mTOR in a variety of important human pathologies, including cancer, Type 2 diabetes and neurodegenerative disorders, heightening interest and accelerating progress in dissecting out the control and functions of mTOR.
 ...
PMID:mTOR: dissecting regulation and mechanism of action to understand human disease. 1914 34

Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine protein kinase implicated in a wide array of cellular processes such as cell growth, proliferation, and survival. Analogous to the situation in yeast, mTOR forms two distinct functional complexes termed mTOR complex 1 and 2 (mTORC1 and mTORC2). mTORC1 activity is inhibited by rapamycin, a specific inhibitor of mTOR, whereas mTORC2 activity is resistant to short-term treatments with rapamycin. In response to growth factors, mTORC2 phosphorylates Akt, an essential kinase involved in cell survival. On the other hand, mTORC1 can be activated by both growth factors and nutrients such as glucose and amino acids. In turn, mTORC1 regulates the activity of the translational machinery by modulating S6 kinase (S6K) activity and eIF4E binding protein 1 (4E-BP1) through direct phosphorylation. Consequently, protein synthesis and cell growth are stimulated in a variety of different cell types. In addition, mTORC1 inhibits autophagy, an essential protein degradation and recycling system, which cells employ to sustain their viability in times of limited availability of nutrients. Recent studies have highlighted the fact that autophagy plays crucial roles in many aspects of human health including cancer development, neurodegenerative disease, diabetes, and aging. It is likely that dysregulation of the mTOR-autophagy pathway may contribute at least in part to these human disorders. Therefore, the assessment of mTOR activity is important to understand the status of autophagy in the cells being analyzed and its role in autophagy-related disorders. In this section, we describe methods to monitor mTOR activity both in vitro and in vivo.
 ...
PMID:Monitoring mammalian target of rapamycin (mTOR) activity. 1920 Aug 82

AMP-dependent protein kinase (AMPK) is an evolutionarily conserved serine/threonine protein kinase central to the regulation of energy balance at both the cellular and whole-body levels. In its classical role as an intracellular metabolic stress-sensing kinase, AMPK switches on fatty acid oxidation and glucose uptake in muscle, while switching off hepatic gluconeogenesis. AMPK also has a broader role in metabolism through the control of appetite. Regulation of AMPK activity at the whole-body level is coordinated by a growing number of hormones and cytokines secreted from adipose tissue, skeletal muscle, pancreas and the gut including leptin, adiponectin, insulin, interluekin-6, resistin, TNF-alpha and ghrelin. Understanding how these secreted signalling proteins regulate AMPK activity to control fatty acid oxidation, glucose uptake, gluconeogenesis and appetite may yield therapeutic treatments for metabolic disorders such as diabetes, insulin resistance and obesity.
 ...
PMID:AMPK-dependent hormonal regulation of whole-body energy metabolism. 1924 57

Type 2 diabetes is one of the fastest growing public health problems worldwide, resulting from both genetic factors and inadequate adaptation to environmental changes. It is characterized by abnormal glucose and lipid metabolism due in part to resistance to the actions of insulin in skeletal muscle, liver and fat. AMP-activated protein kinase (AMPK), a phylogenetically conserved serine/threonine protein kinase, acts as an integrator of regulatory signals monitoring systemic and cellular energy status. The growing realization that AMPK regulates the coordination of anabolic and catabolic metabolic processes represents an attractive concept for type 2 diabetes therapy. Recent findings showing that pharmacological activation of AMPK improves blood glucose homeostasis, lipid profile and blood pressure in insulin-resistant rodents suggest that this kinase could be a novel therapeutic target in the treatment of type 2 diabetes. Consistent with these results, physical exercise and major classes of antidiabetic drugs have recently been reported to activate AMPK. In the present review, we update these topics and discuss the concept of targeting the AMPK pathway for the treatment of type 2 diabetes.
 ...
PMID:Targeting the AMPK pathway for the treatment of Type 2 diabetes. 1927 82

Phosphorylation by protein kinases is a central theme in biological systems. Aberrant protein kinase activity has been implicated in a variety of human diseases, therefore, modulation of kinase activity represents an attractive therapeutic approach for the treatment of human illnesses. Development and design of specific inhibitors for protein kinases thus became a major strategy in many drug discovery programs. Inhibition of protein kinase activity may be achieved by blocking the phosphorylation activity or by disrupting protein-protein interactions. Peptides that can mimic most truly these regulatory modes are favorite choice for protein kinase-targeting. Here we focus on important motifs regulating the protein kinase signaling network and described how they may be exploited for peptide drug design. Protein kinases are important regulators of most, if not all, biological processes. Their abnormal activity has been implicated as causal factors in many human diseases, including cancer, diabetes and neurodegenerative disorders [1-3]. Protein kinases are thus attractive targets for drug design and compounds that manipulate their cellular activity are of enormous therapeutic potential. With a target in hand, medicinal chemists can generate low molecular weight compounds that bind the target with high affinity and alter its biological behavior. In many cases, however, drugs fail as they lack appropriate pharmaceutical properties and are of limited specificity resulting in unfavorable side effects. Under these circumstances, the use of peptides, which copy 'natural' motifs that specifically influence kinase activity and/or its intracellular interactions with cognate partners, may be a promising approach for selective inhibition of protein kinases. In this review we focus on the strategies to design such peptide inhibitors, focusing mainly on the serine/threonine protein kinase family.
 ...
PMID:Peptide inhibitors targeting protein kinases. 1960 43

A reduced life span is an outcome associated with many prevalent diseases, including diabetes, obesity, and high blood pressure. In seeking to prevent these diseases, many researchers have looked into potential therapeutic benefits of naturally occurring compounds. AMP-activated protein kinase (AMPK) is a major metabolic-sensing protein implicated in the prevention of metabolic disorders, or in minimizing the effects thereof, via the regulation of both upstream and downstream target molecules. In the field of food and nutrition, the current focus lies in the finding of components that activate AMPK. AMPK is a serine/threonine protein kinase and is activated by several natural compounds, including resveratrol, epigallocatechin gallate, berberine, and quercetin. AMPK activation can induce ATP (adenosine triphosphate) generation through pathways such as glycolysis and beta-oxidation. By contrast, ATP-consuming pathways, including fatty acid and cholesterol syntheses, and gluconeogenesis, are suppressed by AMPK activation. In this review, we will discuss how the activation of AMPK by naturally occurring compounds could help to prevent the development of numerous diseases; the potential mechanism underlying these effects will also be addressed.
 ...
PMID:AMP-activated protein kinase: a potential target for the diseases prevention by natural occurring polyphenols. 1981 14

Glycogen synthase kinase 3beta (GSK3beta), a serine/threonine protein kinase, is a key target of drug discovery in several diseases, including diabetes and Alzheimer disease. Because lithium, a potent inhibitor of GSK3beta, causes nephrogenic diabetes insipidus, GSK3beta may play a crucial role in regulating water homeostasis. We developed renal collecting duct-specific GSK3beta knockout mice to determine whether deletion of GSK3beta affects arginine vasopressin-dependent renal water reabsorption. Although only mildly polyuric under normal conditions, knockout mice exhibited an impaired urinary concentrating ability in response to water deprivation or treatment with a vasopressin analogue. The knockout mice had reduced levels of mRNA, protein, and membrane localization of the vasopressin-responsive water channel aquaporin 2 compared with wild-type mice. The knockout mice also expressed lower levels of pS256-AQP2, a phosphorylated form crucial for membrane trafficking. Levels of cAMP, a major regulator of aquaporin 2 expression and trafficking, were also lower in the knockout mice. Both GSK3beta gene deletion and pharmacologic inhibition of GSK3beta reduced adenylate cyclase activity. In summary, GSK3beta inactivation or deletion reduces aquaporin 2 expression by modulating adenylate cyclase activity and cAMP generation, thereby impairing responses to vasopressin in the renal collecting duct.
 ...
PMID:GSK3beta mediates renal response to vasopressin by modulating adenylate cyclase activity. 2005 51


<< Previous 1 2 3 4 5 6 Next >>