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)

The glucose-phosphorylating enzyme glucokinase has structural, kinetic, and molecular genetic features that are ideal for its primary role as glucose sensor in a network of neuro/endocrine sentinel cells that maintain glucose homeostasis in many vertebrates including humans. The glucokinase-containing, insulin-producing beta-cells of the pancreas take the prominent lead in this network, functioning in the aggregate as the master gland. The beta-cells are also conceptualized as the prototype for all other glucose sensor cells, which determines our current understanding of many extrapancreatic glucose sensors. About 99% of the enzyme resides, however, in the hepato-parenchymal cells and serves its second role in a high-capacity process of blood glucose clearance. Two examples strikingly illustrate how pivotal a position glucokinase has in the regulation of glucose metabolism: 1) activating and inactivating mutations of the enzyme cause hypo- and hyperglycemia syndromes in humans described collectively as "glucokinase disease" and fully explained by the glucose sensor paradigm, and 2) glucokinase activator drugs (GKAs) have been discovered that bind to an allosteric site and increase the kcat and lower the glucose S(0.5) of the enzyme. GKAs enhance glucose-stimulated insulin release from pancreatic islets and glucose disposition by the liver. They are now intensively explored to develop a novel treatment for diabetes. Future biophysical, molecular, genetic, and pharmacological studies hold much promise to unravel the evolving complexity of the glucokinase glucose sensor system.
Diabetes 2006 Jan
PMID:The network of glucokinase-expressing cells in glucose homeostasis and the potential of glucokinase activators for diabetes therapy. 1638 Apr 70

Type 2 diabetes is primarily associated with beta-cell failure, insulin resistance and elevated hepatic glucose production. The islet beta-cell is specialized for the synthesis, storage and secretion of insulin. Beta-cell failure is characterized by the inability of the beta-cell to secrete sufficient insulin in response to glucose, which ultimately results in hyperglycemia- the clinical hallmark of Type 2 diabetes. Impairment in glucose sensing contributes to beta-cell dysfunction. The facilitative glucose transporter, GLUT-2, and glucose phosphorylating enzyme, glucokinase, are key for glucose sensing of the pancreatic beta-cell, the initial event in the pathway for glucose-stimulated insulin secretion. There is an increase in dietary fat intake, particularly saturated fat, in both the developing and Westernized world, which predisposes individuals to become obese and to potentially develop insulin resistance, beta-cell dysfunction and Type 2 diabetes. A high fat diet is known to reduce both GLUT-2 and glucokinase expression thereby impairing glucose-stimulated insulin secretion. Furthermore, a high fat diet and specific free fatty acids, induces oxidative stress and apoptosis which reduces beta-cell mass and compromises beta-cell function. Glucose sensing is the initial event of glucose-stimulated insulin secretion therefore it is imperative to maintain adequate expression levels of GLUT-2 and GK for ensuring normal beta-cell function. The development of pharmaceutical agents that improve glucose-stimulated insulin secretion may replenish expression of these glucose sensing genes after their attenuation by high fat feeding.
 ...
PMID:High fat diet modulation of glucose sensing in the beta-cell. 1717 17

Metformin is one of the most commonly used first line drugs for type II diabetes. Metformin lowers serum glucose levels by activating 5'-AMP-activated kinase (AMPK), which maintains energy homeostasis by directly sensing the AMP/ATP ratio. AMPK plays a central role in food intake and energy metabolism through its activities in central nervous system and peripheral tissues. Since food intake and energy metabolism is synchronized to the light-dark (LD) cycle of the environment, we investigated the possibility that AMPK may affect circadian rhythm. We discovered that the circadian period of Rat-1 fibroblasts treated with metformin was shortened by 1 h. One of the regulators of the period length is casein kinase Iepsilon (CKIepsilon), which by phosphorylating and inducing the degradation of the circadian clock component, mPer2, shortens the period length. AMPK phosphorylates Ser-389 of CKIepsilon, resulting in increased CKIepsilon activity and degradation of mPer2. In peripheral tissues, injection of metformin leads to mPer2 degradation and a phase advance in the circadian expression pattern of clock genes in wild-type mice but not in AMPK alpha2 knock-out mice. We conclude that metformin and AMPK have a previously unrecognized role in regulating the circadian rhythm.
 ...
PMID:Activation of 5'-AMP-activated kinase with diabetes drug metformin induces casein kinase Iepsilon (CKIepsilon)-dependent degradation of clock protein mPer2. 1752 64

Diabetes mellitus, commonly referred to as diabetes, is a medical condition associated with abnormally high levels of glucose (or sugar) in the blood. Keeping this view, we demonstrate the phylogenetic motifs (PMs) identification in type 2 diabetes mellitus very likely corresponding to protein functional sites. In this article, we have identified PMs for all the candidate genes for type 2 diabetes mellitus. Glycine 310 remains conserved for glucokinase and potassium channel KCNJ11. Isoleucine 137 was conserved for insulin receptor and regulatory subunit of a phosphorylating enzyme. Whereas residues valine, leucine, methionine were highly conserved for insulin receptor. Occurrence of proline was very high for calpain 10 gene and glucose transporter.
 ...
PMID:Type 2 diabetes mellitus: phylogenetic motifs for predicting protein functional sites. 1791 41

Mutation in PRKAG2 encoding the gamma2 subunit of the AMP activated protein kinase (AMPK) cause human cardiomyopathy characterized by hypertrophy, Wolff-Parkinson-White syndrome, conduction system disease and glycogen storage in the myocardium. AMPK is a master metabolic regulator activated by hormones and energy deficient states. A heterotrimer enzyme comprising the catalytic alpha- and regulatory beta-and gamma-subunits was preserved through evolution and is ubiquitously expressed among mammalian tissues. AMPK is activated by AMP and inhibited by ATP that competes for binding to the regulatory sites on the gamma-subunit. Upstream kinases which phosphorylate Thr172 on the catalytic subunit activate the enzyme during exercise, ischemia, in response to sympathetic stimulation and hormones such as leptin and adiponectin. AMPK operates by phosphorylating its target proteins such as Acetyl CoA Carboxylase. Its classic functions include decreased fat synthesis in liver and adipose tissues, increased fatty acid oxidation, stimulating muscle glucose uptake and glycolysis. Altogether, these activities serve to restore the cellular and whole body energy balance. Human mutations which disrupt the nucleotide-binding affinity of the gamma2 subunit lead to loss of inhibition by ATP and inappropriate activate AMPK under resting conditions. As a result, myocytes recruit energy metabolites in excess of demand, causing storage of glycogen. Will AMPK ever emerge as a therapeutic target? Bench experiments suggest its potential in treating diabetes, ischemia and cell cycle regulation but much work is needed until these developments reach the bedside.
 ...
PMID:[AMP-activated protein kinase: how a mistake in energy gauge causes glycogen storage]. 1799 Mar 92

In proximal tubular epithelial cells (PTECs), depolymerization of actin by cofilin plays a crucial role in maintaining polarity and function. Cofilin is inactivated when phosphorylated by p-Lin-11/Isl-1/Mec-3 kinase (LIMK) to give p-cofilin. LIMK is phosphorylated by phosphorylated p21-activated kinase (PAK), a downstream signal of phosphoinositide 3-kinase (PI3K), or by Rho kinase (ROCK), and is dephosphorylated by slingshot (SSH). However, in PTECs the signaling pathways regulating phosphorylation and dephosphorylation of cofilin, and the influence of high glucose (HG) on these pathways remain to be elucidated. Here, we show that HG in cultured porcine PTECs (LLC-PK1) increases p-cofilin and p-LIMK1 beyond 6h and that the simultaneous presence of phlorizin reverses the increase. HG did not influence the levels of PI3K-p85, downstream signals to SSH1 and p-PAK1, and mRNA of cofilin, LIMK1 and SSH1. On the other hand, wortmannin and LY294002 markedly increased p-cofilin and p-LIMK1 without influencing on the level of SSH1 protein. HG-activated RhoA and ROCK2 beyond 3h, and phlorizin attenuated this activation. GF109203X inhibited HG-induced increase in membranous RhoA and ROCK2, and phorbol ester increased these proteins. Y27632 (a ROCK inhibitor) reversed HG-induced increases of p-cofilin and p-LIMK1. We conclude that HG increases p-cofilin by phosphorylating LIMK1 through activation of Rho/Rho kinase, probably due to diacylglycerol-sensitive PKC activation resulting from increased glucose influx. HG did not alter PI3K or its downstream signals, even though PI3K has a physiological role in maintaining the cofilin level by activating SSH1.
Diabetes Res Clin Pract 2008 Apr
PMID:High glucose increases phosphocofilin via phosphorylation of LIM kinase due to Rho/Rho kinase activation in cultured pig proximal tubular epithelial cells. 1809 81

Diacylglycerol (DAG) kinase (DGK) modulates the balance between the two signaling lipids, DAG and phosphatidic acid (PA), by phosphorylating (consuming) DAG to yield PA. Ten mammalian DGK isozymes have been identified to date. In addition to two or three cysteine-rich C1 domains (protein kinase C-like zinc finger structures) commonly conserved in all DGKs, these isoforms possess a variety of regulatory domains of known and/or predicted functions, such as a pair of EF-hand motifs, a pleckstrin homology domain, a sterile alpha motif domain, a MARCKS (myristoylated alanine-rich C kinase substrate) phosphorylation site domain and ankyrin repeats. Recent studies have revealed that DGK isozymes play pivotal roles in a wide variety of mammalian signal transduction pathways conducting growth factor/cytokine-dependent cell proliferation and motility, seizure activity, immune responses, cardiovascular responses and insulin receptor-mediated glucose metabolism. It is suggested that several DGK isozymes can serve as potential drug targets for cancer, epilepsy, autoimmunity, cardiac hypertrophy, hypertension and type II diabetes. Unfortunately, there are no DGK isozyme-specific inhibitors/activators at present. Development of these compounds is eagerly awaited for the development of novel drugs targeting DGKs.
 ...
PMID:Diacylglycerol kinases as emerging potential drug targets for a variety of diseases. 1869 Oct 10

Aberrant glycogen synthase kinase 3beta (GSK-3beta) activity is associated with the progression of several pathological conditions such as diabetes, Alzheimer's, and cancer. GSK-3beta regulates cellular processes by directly phosphorylating metabolic enzymes and transcription factors. Here, we discovered a new target for GSK-3beta phosphorylation: the human glucocorticoid receptor (GR). Glucocorticoid signaling is essential for life and regulates diverse biological functions from cell growth to metabolism to apoptosis. Specifically, we found hormone-dependent GR phosphorylation on serine 404 by GSK-3beta. Cells expressing a GR that is incapable of GSK-3beta phosphorylation had a redirection of the global transcriptional response to hormone, including the activation of additional signaling pathways, in part due to the altered ability of unphosphorylatable GR to recruit transcriptional cofactors CBP/p300 and the p65 (RelA) subunit of NF-kappaB. Furthermore, GSK-3beta-mediated GR phosphorylation inhibited glucocorticoid-dependent NF-kappaB transrepression and attenuated the glucocorticoid-dependent cell death of osteoblasts. Collectively, our results describe a novel convergence point of the GSK-3beta and the GR pathways, resulting in altered hormone-regulated signaling. Our results also provide a mechanism by which GSK-3beta activity can dictate how cells will ultimately respond to glucocorticoids.
 ...
PMID:Glycogen synthase kinase 3beta-mediated serine phosphorylation of the human glucocorticoid receptor redirects gene expression profiles. 1883 40

Protein Tyrosine Phosphatases (PTPs) are important contributors to vascular cells normal function, by balancing signaling proteins activation exerted by phosphorylating kinases. Type 2 diabetes related insults, such as hyperglycemia, oxidative stress, and insulin resistance disturb the phosphorylation/dephosphorylation equilibrium towards an abnormal augmented phosphorylation of signaling proteins associated with changes in PTPs expression, enzymatic activity and interaction with cellular substrates. We briefly review here: (i) the new findings on receptor and non-receptor PTPs and their role in vascular cells, (ii) several data on oxidation and phosphorylation of these molecules in endothelial and smooth muscle cells, (iii) vascular PTPs intrinsic activity and dysregulation under the insults of diabetic milieu, and (iv) the potential use of PTPs and their inhibitors as therapeutic targets in Type 2 diabetes-associated vascular dysfunction.
 ...
PMID:Vascular PTPs: current developments and challenges for exploitation in Type 2 diabetes-associated vascular dysfunction. 1971 73

We investigated mechanisms underlying progressive axonal dysfunction and structural deficits in type 1 BB/Wor-rats from 1 week to 10 month diabetes duration. Motor and sensory conduction velocities were decreased after 4 and 6 weeks of diabetes and declined further over the remaining 9 months. Myelinated sural nerve fibers showed progressive deficits in fiber numbers and sizes. Structural deficits in unmyelinated axonal size were evident at 2 month and deficits in number were present at 4 mo. These changes were preceded by decreased availability of insulin, C-peptide and IGF-1 and decreased expression of neurofilaments and beta-III-tubulin. Upregulation of phosphorylating stress kinases like Cdk5, p-GSK-3beta, and p42/44 resulted in increased phosphorylation of neurofilaments. Increasing activity of p-GSK-3beta correlated with increasing phosphorylation of NFH, whereas decreasing Cdk5 correlated with diminishing phosphorylation of NFM. The data suggest that impaired neurotrophic support results in sequentially impaired synthesis and postranslational modifications of neuroskeletal proteins, resulting in progressive deficits in axonal function, maturation and size.
Exp Diabetes Res 2009
PMID:Dynamic changes of neuroskeletal proteins in DRGs underlie impaired axonal maturation and progressive axonal degeneration in type 1 diabetes. 1983 68


<< Previous 1 2 3 4 5 6 7 8 9 Next >>