1,721,084 research outputs found
The IGF-I signaling pathway
No full textThe insulin-like growth factor (IGF)-I is implicated in the regulation of protein turnover and exerts potent mitogenic and differentiating effects on most cell types. IGF-I biological actions are mediated by the IGF-I receptor, comprised of two extra-cellular α-subunits, containing hormone binding sites, and two membrane-spanning β-subunits, encoding an intracellular tyrosine kinase. Hormone binding activates the receptor kinase, leading to receptor autophosphorylation and tyrosine phosphorylation of multiple substrates, including the IRS and Shc proteins. Through these initial tyrosine phosphorylation reactions, IGF-I signals are transduced to a complex network of intracellular lipid and sersine/threonine kinases that are ulitmately responsible for cell proliferation, modulation of tissue differentiation, and protection from apotosis. This review will focus on the IGF-I receptor structure and function, its intracellular signaling pathways, and some important implications of the activation of the IGF-I transduction system in specific tissues. © 2007 Bentham Science Publishers Ltd
Pathophysiology of type 2 diabetes: rationale for different oral antidiabetic treatment strategies
No full textCardiovascular disease and glycemic control in type 2 diabetes: now that the dust is settling from large clinical trials.
No full textLipodystrophic Diabetes Mellitus: a Lesson for Other Forms of Diabetes?
No full textLipodystrophies are a genetically heterogeneous group of disorders characterized by loss of subcutaneous adipose tissue and metabolic dysfunction, including insulin resistance, increased levels of free fatty acids, abnormal adipocytokine secretion, and ectopic fat deposition, which are also observed in patients with visceral obesity and/or type 2 diabetes mellitus. Pathophysiological, biochemical, and genetic studies suggest that impairment in multiple adipose tissue functions, including adipocyte maturation, lipid storage, formation and/or maintenance of the lipid droplet, membrane composition, DNA repair efficiency, and insulin signaling, results in severe metabolic and endocrine consequences, ultimately leading to specific lipodystrophic phenotypes. In this review, recent evidences on the causes and metabolic processes of lipodystrophies will be presented, proposing a disease model that could be potentially informative for better understanding of common metabolic diseases in humans, including obesity, metabolic syndrome, and type 2 diabetes
Regional differences of insulin action in adipose tissue: insights from in vivo and in vitro studies
No full textAdipose tissue is now recognized to have a multitude of functions that are of importance in the regulation of energy balance and substrate metabolism. Different hormones, in particular insulin and catecholamines, govern the storage and utilization of energy in the triglyceride depots. In addition, adipocytes produce several different substances with endocrine or paracrine functions, which regulate the overall energetic homeostasis. With excess energy storage, obesity develops, leading to increased risk for type 2 diabetes and cardiovascular disease. The distribution of body fat appears to be even more important than the total amount of fat. Abdominal and, in particular, visceral adiposity is strongly linked to insulin resistance, type 2 diabetes, hypertension and dyslipidaemia, leading to increased risk of cardiovascular disease. The adverse metabolic impact of visceral fat has been attributed to distinct biological properties of adipocytes in this depot compared with other adipose tissue depots. Indeed, regional variations in the metabolic activity of fat cells have been observed. Furthermore, expression studies aiming at defining the unique biological properties of adipose tissues from distinct anatomical sites have identified depot-related differences in the protein content of fat-produced molecules. In this review we wish to summarize important results from the literature and also some recent data from our own work. The main scope is to describe the biological functions of adipose tissue, and to focus on metabolic, hormonal, and signalling differences between fat depots
Clinical view on the need to develop new anti-diabetic drugs
No full textType 2 diabetes mellitus is a chronic metabolic disorder that results from defects in both insulin secretion and insulin action. Type 2 diabetic individuals are also characterized by reduced Î2-cell mass likely due to increased cellular apoptosis. Traditional strategies to treat diabetes have been developed with the main purpose of reducing hyperglycemia, and include insulin sensitizers, α-glucosidase inhibitors, and Î2-cell secretagogues. However, available drugs do not fully correct the phenotypic abnormalities in diabetes (e.g., insulin resistance, insulin deficiency) and have limited tolerability. Additionally, several available therapies are associated with weight gain or enhanced risk of hypoglycemia. Thus, newer approaches are urgently required. Particular emphasis should be placed on developing pharmacological interventions that are dependent on physiological responses and adequately target underlying defects, such as obesity, insulin resistance, increased glucose output from the liver, secretory dysfunction, or apoptosis of the Î2-cell. Individual phenotypic and genetic characterization of the diabetic patients will allow to define more and more personalized and effective algorithms for the treatment of hyperglycemia. © 2005 Bentham Science Publishers Ltd
GLP-1: a new approach for type 2 diabetes therapy
No full textβ-cell dysfunction is an early pathophysiological defect in type 2 diabetes mellitus. Conventional secretagogues, although effective in increasing insulin secretion, may be associated with undesirable side effects, including hypoglycemia, abnormalities in cardiovascular responses, and β-cell apoptosis. Glucagon-like peptide(GLP)-1 is an incretin hormone displaying glucose-dependent stimulation of insulin secretion, trophic effects on the pancreatic β-cells, and inhibitory effects on gastrointestinal motility, which has been shown to ameliorate hyperglycemia and reduce glycemic excursions. However, after parenteral administration native GLP-1 is rapidly degraded by plasma dipeptydil peptidase (DPP)-IV. Hence, degradation-resistant, long-acting GLP-1 receptor agonists have been proposed as novel agents for diabetes therapy. Alternatively, inhibitionof DPP-IV-mediated GLP-1 degradation represents another approach for exploiting GLP-1 beneficial effects on metabolic control. This review will summarize the biological effects of GLP-1, the general features of GLP-1 mimetics and DPP-IV inhibitors, and the promising results of recently published clinical trials testing these compounds for the treatment of type 2 diabetes. © 2006 Elsevier Ireland Ltd. All rights reserved
Cross-Talk between PPARgamma and Insulin Signaling and Modulation of Insulin Sensitivity
No full textPPARgamma activation in type 2 diabetic patients results in a marked improvement in insulin and glucose parameters, resulting from an improvement of whole-body insulin sensitivity. Adipose tissue is the major mediator of PPARgamma action on insulin sensitivity. PPARgamma activation in mature adipocytes induces the expression of a number of genes involved in the insulin signaling cascade, thereby improving insulin sensitivity. PPARgamma is the master regulator of adipogenesis, thereby stimulating the production of small insulin-sensitive adipocytes. In addition to its importance in adipogenesis, PPARgamma plays an important role in regulating lipid, metabolism in mature adipocytes by increasing fatty acid trapping. Finally, adipose tissue produces several cytokines that regulate energy homeostasis, lipid and glucose metabolism. Disturbances in the production of these factors may contribute to metabolic abnormalities, and PPARgamma activation is also associated with beneficial effects on expression and secretion of a whole range of cytokines
Biological specificity of visceral adipose tissue and therapeutic intervention
No full textWith excess energy storage, obesity develops, leading to increased risk for type 2 diabetes and cardiovascular diseases. The distribution of body fat appears to be even more important than the total amount of fat. Abdominal and, in particular, visceral adiposity is strongly linked to insulin resistance, type 2 diabetes, hypertension, dyslipidaemia, sleep apnea, and other complications of obesity. Visceral adiposity, manifested as a high waist circumference, is now accepted as a major component of the metabolic syndrome. However, the biological mechanisms underlying the adverse impact of visceral fat accumulation remain to be established. This review will focus on the analysis of the biological specificity of adipose tissue located in the abdominal region, and will explore intervention strategies targeting the impaired function of the visceral adipocyte as potential therapies for the cardio-metabolic outcomes of patients with the metabolic syndrome
p66Shc, a multifaceted protein linking Erk signalling, glucose metabolism, and oxidative stress
No full textp66Shc, a 66 kDa proto-oncogene Src collagen homologue (Shc) adaptor protein, is classically known as a signalling protein implicated in receptor tyrosine kinase signal transduction. The p66Shc isoform exerts a physiologically relevant, inhibitory signalling effect on the Erk pathway in skeletal muscle myoblasts, which is necessary for actin cytoskeleton polymerization and normal glucose transport responses. More recently, p66Shc has been also identified as a sensor of oxidative stress-induced apoptosis and as a longevity protein in mammals, actions which require Ser36 phosphorylation of the protein and consequent accumulation of intracellular reactive oxygen species. Oxidative stress plays a key role in dysfunction of several organs and tissues, and this is of interest in metabolic diseases such as type 2 diabetes. Thus changes in p66Shc expression and/or function may play an important role in the pathogenesis of type 2 diabetes and potentially serve as an effective target for its treatment
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