Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucose homeostasis is impaired in patients with non-insulin dependent diabetes mellitus (NIDDM) and this defect in due in part, to defects in glucose transport in skeletal muscle. Intense interest is now focused on whether reduced insulin-mediated glucose transport in muscle from NIDDM patients results from alterations in the insulin signal transduction pathway or from alterations in traffic and/or translocation of GLUT4 to the plasma membrane. Recently, potential targets for impaired traffic/translocation of GLUT4 have been reported to include defective phosphorylation of IRS-1 and reduced PI-3 kinase activity. In addition to insulin signaling defects, impaired glucose transport may result from a defect(s) in the activation or functional capacity of GLUT4. Because GLUT4 is dysregulated in skeletal muscle from NIDDM patients, it is an attractive target for gene therapy. Overexpression of GLUT4 in muscle results in increased glucose uptake and metabolism, and protects against the development of insulin resistance in transgenic mice. Genetic ablation of GLUT4 results in impaired insulin tolerance and defects in glucose metabolism in skeletal muscle. Because impaired muscle glucose transport leads to reduced whole body glucose uptake and hyperglycemia, understanding the molecular regulation of glucose transport in skeletal muscle is necessary to develop effective strategies to prevent or reduce the incidence of NIDDM.
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PMID:Insulin signaling and glucose transport in insulin resistant skeletal muscle. Special reference to GLUT4 transgenic and GLUT4 knockout mice. 978 15

TNF-alpha (so-called cachectin), IL-1 and 6 are important regulating agents in the homeostasis of energy in the organism, as among others they control processes of apoptosis and thus also the volume of adipose and muscular tissues. They are produced not only in immunocompetent cells but also in adipocytes and muscle cells. The cytokine system is then activated not only in tumours and infections but elevated values were found also in obesity, NIDDM, in myocardial infarction and in advanced decompensated cardiac patients. By acting on phosphorylation of IRS-1 and PI-3 kinase TNF-alpha promotes significantly insulin resistance, causes deterioration of diabetes, as well as elevated body temperature, sleepiness and anorexia. In a group of 65 patients, mostly with android obesity, in hyperleptinaemic and insulin resistant probands with coronarographically confirmed microvascular angina pectoris (n = 22) or IHD, mostly after a myocardial infarction (n = 43) with one or more significant stenoses on the epicardial coronary arteries in half the patients positive or elevated TNF-alpha was found and in 28% also IL-6. This increase did not correlate however with BMI, the percentage of body fat, IRI and C peptide levels nor with cortisol and leptin levels. Insulin resistant subjects had more frequently elevated homocysteine and Lp(a) values which are further two independent risk factors of atherothrombogenesis. Hyperhomocysteinaemia can be favourably influenced by vitamin fortification of the diet or by administration of folate and pyridoxine (1 tablet per day) involving negligible financial costs.
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PMID:[Relation between cytokines (TNF-alpha, IL-1 and 6) and homocysteine in android obesity and the phenomenon of insulin resistance syndromes]. 1042 20

A new screening method was developed that evaluates physiologically relevant chemical selectivity of agonists for insulin-signaling pathways. Phosphorylation (pY939) by an insulin-activated insulin receptor of a target peptide (Y939) derived from an insulin receptor substrate-1 (IRS-1) and its subsequent binding to another downstream target, the SH2 domain of PI-3 kinase (SH2N), were detected by surface plasmon resonance (SPR) spectrometry. This method is based on competitive binding of SH2N to pY939 either in a solution or on the gold surface of the SPR sensor chip. With increasing the concentration of pY939 in solution by the insulin-induced kinase reaction of insulin receptor, SH2N bound to pY939 in solution increases and the one on the sensor chip decreases, thereby causing a decrease in the SPR signal. The amount of thus-detected complex pY939-SH2N was found to depend on added insulin concentrations, confirming that the method utilized part of the sequential transduction mechanism of the insulin-signaling pathways. The kinase activity of insulin receptor-agonist complexes increased in the order of IGF-II < IGF-I < insulin, and neither vanadium ions nor thiazolidine-type medicines for NIDDM, troglitazone and pioglitazone, directly acted on both the kinase reaction of insulin receptor or the binding of pY939 to SH2N. The present approach will thus become a general method for screening agonists for one specific pathway in tyrosine phosphorylation of IRS-1 in insulin signaling, which is regulated by specific protein-protein interaction between a phosphorylated tyrosine in IRS-1 and its corresponding SH2 domain-containing protein such as PI-3 kinase, Grb2-Sos, or SHP2.
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PMID:An SPR-based screening method for agonist selectivity for insulin signaling pathways based on the binding of phosphotyrosine to its specific binding protein. 1065 27

Insulin resistance is thought to be the primary defect in the pathophysiology of type 2 diabetes. Thus, understanding the cellular mechanisms of insulin action may contribute significantly to developing new treatments for this disease. Although the effects of insulin on glucose and lipid metabolism are well documented, gaps remain in our understanding of the precise molecular mechanisms of signal transduction for the hormone. One potential clue to understanding the unique cellular effects of insulin may lie in the compartmentalization of signaling molecules and metabolic enzymes. We review this evidence, and speculate on how PI-3 kinase-independent and -dependent signaling pathways both diverge from the insulin receptor and converge at discrete targets to insure the specificity of insulin action.
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PMID:Spatial compartmentalization of signal transduction in insulin action. 1122 78

Pituitary adenylate cyclase activating polypeptide (PACAP) is a ubiquitous neuropeptide in the central and peripheral nervous systems. Previously we reported that PACAP38 is localized in pancreatic islets and serves as an endogenous amplifier of glucose-induced insulin secretion. PACAP activates Gs-cAMP system, stimulates voltage-dependent Ca(2+) channels, and increases cytosolic Ca(2+) concentration in beta-cells. On the other hand, PAC1 receptor is expressed in adipocytes. PACAP enhances insulin-stimulated glucose uptake in an adipocyte cell-line, 3T3-L1 cells. PACAP does not alter the tyrosine phosphorylation of insulin receptor and IRS-1, but increases the activity of PI-3 kinase, a distal site of insulin signaling. PACAP also promotes differentiation of 3T3-L1 cells from fibroblasts to adipocytes. In GK rats, an animal model of type 2 diabetes, daily i.p. injection of PACAP38 (6 pmol/kg) from the age of 3 weeks prevents development of hyperglycemia between 3 to 8 weeks. These results demonstrate that PACAP enhances glucose-stimulated insulin secretion in islets, enhances insulin action inadipocytes, and prevents hyperglycemia in diabetic animals. This finding presents a possible therapeutic use of PACAP in the treatment of diabetes.
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PMID:[Physiological and therapeutic roles of PACAP in glucose metabolism and diabetes]. 1505 42

Impaired glucose uptake and metabolism by peripheral tissues is a common feature in both type I and type II diabetes mellitus. This phenomenon was examined in the context of oxidative stress and the early events within the insulin signalling pathway using soleus muscles derived from non-obese, insulin-resistant type II diabetic Goto-Kakizaki (GK) rats, a well-known genetic rat model for human type II diabetes. Insulin-stimulated glucose transport was impaired in soleus muscle from GK rats. Oxidative and non-oxidative glucose disposal pathways represented by glucose oxidation and glycogen synthesis in soleus muscles of GK rats appear to be resistant to the action of insulin when compared to their corresponding control values. These diabetes-related abnormalities in glucose disposal were associated with a marked diminution in the insulin-mediated enhancement of protein kinase B (Akt/PKB) and insulin receptor substrate-1 (IRS-1)-associated phosphatidylinostol 3-kinase (PI 3-kinase) activities; these two kinases are key elements in the insulin signalling pathway. Moreover, heightened state of oxidative stress, as indicated by protein bound carbonyl content, was evident in soleus muscle of GK diabetic rats. Chronic administration of the hydrophobic/hydrophilic antioxidant alpha -lipoic-acid (ALA, 100 mg/kg, i.p.) partly ameliorated the diabetes-related deficit in glucose metabolism, protein oxidation as well as the activation by insulin of the various steps of the insulin signalling pathway, including the enzymes Akt/PKB and PI-3 kinase. Overall, the current investigation illuminates the concept that oxidative stress may indeed be involved in the pathogenesis of certain types of insulin resistance. It also harmonizes with the notion of including potent antioxidants such as ALA in the armamentarium of antidiabetic therapy.
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PMID:Alpha-lipoic acid mitigates insulin resistance in Goto-Kakizaki rats. 1532 64

Increased levels of C-peptide, a cleavage product of proinsulin, circulate in patients with insulin resistance and early type 2 diabetes mellitus. Recent data suggest a potential causal role of C-peptide in atherogenesis by promoting monocyte and T-lymphocyte recruitment into the vessel wall. The present study examined the effect of C-peptide on vascular smooth muscle cells (VSMCs) proliferation and evaluated intracellular signaling pathways involved. In early arteriosclerotic lesions of diabetic subjects, C-peptide colocalized with VSMCs in the media. In vitro, stimulation of human or rat VSMCs with C-peptide induced cell proliferation in a concentration-dependent manner with a maximal 2.6+/-0.8-fold induction at 10 nmol/L human C-peptide (P<0.05 compared with unstimulated cells; n=9) and a 1.8+/-0.2-fold induction at 0.5 nmol/L rat C-peptide (P<0.05 compared with unstimulated cells; n=7), respectively, as shown by [H3]-thymidin incorporation. The proliferative effect of C-peptide on VSMCs was inhibited by Src short interference RNA transfection, PP2, an inhibitor of Src-kinase, LY294002, an inhibitor of PI-3 kinase, and the ERK1/2 inhibitor PD98059. Moreover, C-peptide induced phosphorylation of Src, as well as activation of PI-3 kinase and ERK1/2, suggesting that these signaling molecules are involved in C-peptide-induced VSMC proliferation. Finally, C-peptide induced cyclin D1 expression as well as phosphorylation of Rb in VSMCs. Our results demonstrate that C-peptide induces VSMC proliferation through activation of Src- and PI-3 kinase as well as ERK1/2. These data suggest a novel mechanism how C-peptide may contribute to plaque development and restenosis formation in patients with insulin resistance and early type 2 diabetes mellitus.
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PMID:C-Peptide induces vascular smooth muscle cell proliferation: involvement of SRC-kinase, phosphatidylinositol 3-kinase, and extracellular signal-regulated kinase 1/2. 1712 42

trans-Resveratrol (t-RVT), a naturally occurring polyphenol found in Polygonum cuspidatum, grape, and red wine, has been reported to have anti-inflammatory, cardioprotective, and cancer chemopreventive properties. However antidiabetic effect of t-RVT has not yet been reported. In this study, we show that t-RVT increases glucose uptake in C2C12 myotubes by activating AMP-activated protein kinase (AMPK), uncovering an antidiabetic potential of t-RVT for the first time. AMPK plays a central role in the regulation of glucose and lipid metabolism, and hence it is considered a novel therapeutic target for metabolic syndrome such as type 2 diabetes. t-RVT significantly induced glucose uptake in C2C12 cells, via AMPK activation, but not a phosphatidylinositol-3 kinase (PI-3 kinase) signal pathway. The induced glucose uptake was attenuated by pretreatment with a pharmacological inhibitor for AMPK, indicating that the effect of t-RVT primarily depends on AMPK activation. However, in the presence of insulin, t-RVT also potentiated the effect of insulin on glucose uptake via AMPK activation, which led to further activation of PI-3 kinase/Akt signal pathway.
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PMID:Resveratrol stimulates glucose transport in C2C12 myotubes by activating AMP-activated protein kinase. 1746 84

The liver plays a key role in glucose homeostasis, lipid and energy metabolism. Its function is primarily controlled by the anabolic hormone insulin and its counterparts glucagon, catecholamines and glucocorticoids. Dysregulation of this homeostatic system is a major cause for development of the metabolic syndrome and type 2 diabetes mellitus. The features of the underlying dynamic molecular network that coordinates systemic nutrient homeostasis are less clear. But recently, considerable progress has been made in elucidating molecular pathways and potential factors involved in the regulation of energy and lipid metabolism and affected in diabetic states. In this review we will focus on important stations in the complex network of molecules that control the balance between glucose production, glucose utilization and regulation of lipid metabolism. Special attention will be paid to the insulin receptor substrate (IRS) proteins with the two major isoforms IRS-1 and IRS-2 as a critical node in hepatic insulin signalling. IRS proteins act as docking molecules to connect tyrosine kinase receptor activation to essential downstream kinase cascades, including activation of the PI-3 kinase or MAPK cascade. IRS-1 and IRS-2 are complementary key players in the regulation of hepatic insulin signalling and expression of genes involved in gluconeogenesis, glycogen synthesis and lipid metabolism. The function of IRS proteins is regulated by their expression levels and posttranslational modifications. This regulation within the dynamic molecular network that coordinates systemic nutrient homeostasis will be outlined in detail under the following conditions: after feeding, during fasting and during exercise. Dysfunction of IRS proteins initially leads to post-prandial hyperglycemia, increased hepatic glucose production, and dysregulated lipid synthesis and is discussed as major pathophysiological mechanism for the development of insulin resistance and type 2 diabetes mellitus. Understanding the molecular regulation and the pathophysiological modifications of IRS proteins is crucial in order to identify new sites for potential intervention to treat or prevent hepatic insulin resistance and type 2 diabetes mellitus.
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PMID:How insulin receptor substrate proteins regulate the metabolic capacity of the liver--implications for health and disease. 1853 11

An alcoholic extract of Artemisia dracunculus L (PMI 5011) has been shown to decrease glucose and improve insulin levels in animal models, suggesting an ability to enhance insulin sensitivity. We sought to assess the cellular mechanism by which this botanical affects carbohydrate metabolism in primary human skeletal muscle culture. We measured basal and insulin-stimulated glucose uptake, glycogen accumulation, phosphoinositide 3 (PI-3) kinase activity, and Akt phosphorylation in primary skeletal muscle culture from subjects with type 2 diabetes mellitus incubated with or without various concentrations of PMI 5011. We also analyzed the abundance of insulin receptor signaling proteins, for example, IRS-1, IRS-2, and PI-3 kinase. Glucose uptake was significantly increased in the presence of increasing concentrations of PMI 5011. In addition, glycogen accumulation, observed to be decreased with increasing free fatty acid levels, was partially restored with PMI 5011. PMI 5011 treatment did not appear to significantly affect protein abundance for IRS-1, IRS-2, PI-3 kinase, Akt, insulin receptor, or Glut-4. However, PMI 5011 significantly decreased levels of a specific protein tyrosine phosphatase, that is, PTP1B. Time course studies confirmed that protein abundance of PTP1B decreases in the presence of PMI 5011. The cellular mechanism of action to explain the effects by which an alcoholic extract of A dracunculus L improves carbohydrate metabolism on a clinical level may be secondary to enhancing insulin receptor signaling and modulating levels of a specific protein tyrosine phosphatase, that is, PTP1B.
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PMID:Bioactives of Artemisia dracunculus L enhance cellular insulin signaling in primary human skeletal muscle culture. 1855 56


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