Insulin Signaling and Energy Homeostasis
By: Linda Stephenson, Ph.D., Biofiles v6 n4, 2011
Glucose metabolism is regulated by the opposing actions of insulin and glucagon. Insulin is released from pancreatic ß cells in response to high blood glucose levels and regulates glucose metabolism through its actions on muscle, liver, and adipose tissue. The binding of insulin to its receptor activates multiple proteins including Phosphatidylinositol 3-Kinase (PI3K). PI3K activity controls pathways regulating glucose transporter 4 (Glut4) translocation to the membrane, lipolysis, and glycogen synthesis. The activation of PI3K results in the uptake of glucose into skeletal and adipose cells and the storage of excess glucose as glycogen. Insulin resistance in skeletal muscle is associated with impaired signaling through the insulin receptor/PI3K signaling axis with subsequent defects in Glut4 translocation and glycogen synthesis. In adipose tissue, insulin resistance is associated with decreased fat storage and increased fatty acid mobilization. Insulin affects two major processes within hepatocytes, gluconeogenesis and triglyceride synthesis. Upon insulin receptor signaling, the transcription factor FoxO1 becomes phosphorylated and is excluded from the nucleus. FoxO1 controls the transcription of factors involved in gluconeogenesis, and inactivation of this protein normally results in a down-regulation of gluconeogenic activities. Insulin also activates the transcription factor SREBP-1c, which controls triglyceride synthesis. Under normal conditions, insulin signaling results in decreased hepatocyte glucose production and increased triglyceride synthesis. Individuals with insulin resistance present with hyperglycemia and hypertriglyceridemia even in the presence of high plasma insulin levels (hyperinsulinemia). This strongly suggests that within the liver, insulin resistance is partial. Insulin fails to suppress gluconeogenesis while the triglyceride synthesis pathway remains sensitive to insulin. This results in hyperglycemia and hypertriglyceridemia.
Glucagon, which is released from pancreatic a cells in response to low blood glucose levels, acts on liver cells to promote glycogen breakdown (glycogenolysis) and to encourage glucose synthesis via gluconeogenesis. The net effect of glucagon signaling is an increase in blood glucose levels. For reasons that are not entirely clear, patients with type 2 diabetes often present with hyperglucagonaemia which results in continued glucose output by hepatic cells. This suggests that targeting glucagon signaling in hepatocytes may be a viable treatment option for type 2 diabetes.
Insulin binding to its receptor initiates multiple signaling molecules including those leading to Phosphatidylinositol (PI)-3-Kinase activation. PI-3-Kinase activation contributes to multiple tissue-specific biological processes, including Glut4 translocation from intracellular vesicles to the plasma membrane, the inhibition of lipolysis, and the upregulation of glycogen synthesis. The actions of insulin are countered by glucagon receptor signaling.
|Insulin human||powder||Regulates the cellular uptake, utilization, and storage of glucose, amino acids, and fatty acids and inhibits the breakdown of glycogen, protein, and fat.||I1507-.1MG
|Insulin solution human||solution||Two-chain polypeptide hormone produced by the β-cells of pancreatic islets. Its molecular weight is ~5800 Da. The α and β chains are joined by two interchain disulfide bonds. The α chain contains an intrachain disulfide bond. Insulin regulates the cellular uptake, utilization, and storage of glucose, amino acids, and fatty acids and inhibits the breakdown of glycogen, protein, and fat.||I9278-5ML|
|Insulin Receptor from rat liver||buffered aqueous glycerol solution||Receptor protein tyrosine kinase that mediates the activity of insulin.||I9266-1VL|
|InsR (1011-end), active, GST tagged human||buffered aqueous glycerol solution||InsR is the insulin receptor tyrosine kinase that is involved in insulin signaling. InsR is post-translationally cleaved into two chains, α and ß, that are covalently linked. Binding of insulin to the InsR stimulates glucose uptake. Insulin receptor signaling helps to maintain fuel homeostasis and prevent diabetes. Studies have shown that a conditional knockout of insulin receptor substrate 2 (IRS2) in mouse pancreas ß cells and parts of the brain—including the hypothalamus—increased appetite, lean and fat body mass, linear growth, and insulin resistance that progressed to diabetes. InsR signaling also increases the regeneration of adult ß cells and the central control of nutrient homeostasis.||I2535-10UG|
|PKCθ, active, GST tagged human||buffered aqueous glycerol solution||Protein Kinase C, theta (PKCθ) is important component in the intracellular signaling cascade. Recent studies have suggested that local accumulation of fat metabolites inside skeletal muscle may activate a serine kinase cascade involving PKCθ leading to defects in insulin signaling and glucose transport in skeletal muscle. Insulin resistance plays a primary role in the development of type 2 diabetes and may be related to alterations in fat metabolism. PKCθ is a crucial component mediating fat-induced insulin resistance in skeletal muscle and is a potential therapeutic target for the treatment of type 2 diabetes.||K4643-10UG|
|Protein kinase CßII isozyme human||buffered aqueous glycerol solution||PKCßII is involved in glucose signaling pathways.||P3287-5UG
|Phosphoinositide 3-kinase p110γ human||buffered aqueous glycerol solution||PI 3-kinases have been implicated in diverse cellular responses triggered by mammalian cell surface receptors.||P8615-10UG|
|PI3 kinase (p110d/p85a) Active human||aqueous solution||–|
|ML-9||powder||Shown to inhibit insulin-induced translocation of both GLUT4 and GLUT1 in a dose-dependent manner. Also reported to inhibit agonist-induced Ca2+ entry into endothelial cells and catecholamine secretion in intact and permeabilized chromaffin cells.||C1172-5MG|
|Wortmannin, Ready Made Solution||DMSO solution||Wortmannin is a hydrophobic fungal metabolite with a sterol-like structure. Inhibition of PI3K/Akt signal transduction cascade by wortmannin enhances apoptotic effects.||W3144-250UL|
|Glycogen from bovine liver||–||–||G0885-1G
|Glycogen from rabbit liver||–||–||G8876-500MG
Insulin acts on hepatocyte cells to suppress gluconeogenesis, the metabolic pathway that generates glucose from non-carbohydrate sources. In insulin-resistant tissues, insulin fails to suppress gluconeogenesis resulting in chronically elevated blood glucose levels. Enzymes of the gluconeogenic pathway are attractive targets for pharmacological intervention in insulin-resistant and type 2 diabetic patients.
|Enolase from rabbit muscle||Enolase is a metalloenzyme that catalyzes the interconversion of 2-phosphoglycerate to phosphoenolpyruvate. Enolase is essential for both glycolysis and gluconeogenesis.||E0379-50UN
|Enolase from baker's yeast (S. cerevisiae)||Enolase is a metalloenzyme that catalyzes the interconversion of 2-phosphoglycerate to phosphoenolpyruvate. Enolase is essential for both glycolysis and gluconeogenesis.||E6126-500UN
|Glyceraldehyde-3-phosphate Dehydrogenase from human erythrocytes||GAPDH catalyzes the conversion of glyceraldehyde 3-phosphate to glycerate 1,3-biphosphate. GAPDH is essential for both glycolysis and gluconeogenesis. In addition to its roles in metabolism, GAPDH has been reported to function as a transcriptional coactivator and an apoptosis inducer.||G6019-100UN|
|Glyceraldehyde-3-phosphate Dehydrogenase from rabbit muscle||GAPDH catalyzes the conversion of glyceraldehyde 3-phosphate to glycerate 1,3-biphosphate. GAPDH is essential for both glycolysis and gluconeogenesis.||G2267-500UN
|Glyceraldehyde-3-phosphate Dehydrogenase from baker's yeast (S. cerevisiae)||GAPDH catalyzes the conversion of glyceraldehyde 3-phosphate to glycerate 1,3-biphosphate. GAPDH is essential for both glycolysis and gluconeogenesis.||G5537-100UN
|Glyceraldehyde-3-phosphate Dehydrogenase Agarose from baker's yeast (S. cerevisiae)||GAPDH catalyzes the conversion of glyceraldehyde 3-phosphate to glycerate 1,3-biphosphate. GAPDH is essential for both glycolysis and gluconeogenesis.||G0389-10UN|
|Glucose-6-Phosphatase from rabbit liver||Glucose-6-phosphatase catalyzes the hydrolytic cleavage of glucose-6-phosphate resulting in the production of a free glucose and a phosphate group. Glucose-6-phosphatase catalyzes the final step in both gluconeogenesis and glycogenolysis.||G5758-5UN
|Neuron-specific enolase from human brain||Neuron-specific enolase (NSE) is expressed in all neuronal cell types, and its expression marks the acquisition of synaptic function. Following acute neuronal injury, NSE levels are increased in neuronal cell bodies. Increased levels of NSE in serum and cerebrospinal fluid have been used as markers for injury and neuronal cell death. Tumors derived from many cell types, including most neuronal and neuroendocrine tumors, express NSE.||N4773-10UG|
|Pyruvate Carboxylase from bovine liver||Pyruvate carboxylase catalyzes the carboxylation of pyruvate to oxaloacetate. Pyruvate carboxylase activity is critical for gluconeogenesis, lipogenesis, and glyceroneogenesis.||P7173-10UN
|3-Phosphoglyceric Phosphokinase from baker's yeast (S. cerevisiae)||3-Phosphoglyceric Phosphokinase catalyzes the reversible transfer of a phosphate group from 1,3-diphosphoglycerate to ADP to generate ATP and 3-phosphoglycerate. 3-Phosphoglycerate Phosphokinase activity is essential for glycolysis and gluconeogenesis.||P7634-2KU