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Insulin Secretion
The major function of insulin is to counter the concerted action of a number of hyperglycemia-generating hormones and to maintain low blood glucose levels. Because there are numerous hyperglycemic hormones, untreated disorders associated with insulin generally lead to severe hyperglycemia and shortened life span.
In addition to its role in regulating glucose metabolism, insulin stimulates lipogenesis, diminishes lipolysis, and increases amino acid transport into cells. Insulin also modulates transcription, altering the cell content of numerous mRNAs. It stimulates growth, DNA synthesis, and cell replication, effects that it holds in common with the insulin-like growth factors (IGFs) and relaxin.
Insulin is synthesized as a preprohormone in the β-cells of the islets of Langerhans. Its signal peptide is removed in the cisternae of the endoplasmic reticulum and it is packaged into secretory vesicles in the Golgi, folded to its native structure, and locked in this conformation by the formation of 2 disulfide bonds. Specific protease activity cleaves the center third of the molecule, which dissociates as C peptide, leaving the amino terminal B peptide disulfide bonded to the carboxy terminal A peptide.
Insulin secretion from β-cells is principally regulated by plasma glucose levels. Increased uptake of glucose by pancreatic β-cells leads to a concomitant increase in metabolism. The increase in metabolism leads to an elevation in the ATP/ADP ratio. This in turn leads to the inhibition of an ATP-sensitive potassium channel (KATP channel). The net result is a depolarization of the cell leading to Ca2+ influx and insulin secretion.
The KATP channel is a complex of 8 polypeptides comprising four copies of the protein encoded by the ABCC8 (ATP-binding cassette, sub-family C, member 8) gene and four copies of the protein encoded by the KCNJ11 (potassium inwardly-rectifying channel, subfamily J, member 11) gene. The ABCC8 encoded protein is also known as the sulfonylurea receptor (SUR). The KCNJ11 encoded protein forms the core of the KATP channel and is called Kir6.2. As might be expected, the role of KATP channels in insulin secretion presents a viable therapeutic target for treating hyperglycemia due to insulin insufficiency as is typical in type 2 diabetes.
Chronic increases in numerous other hormones, such as growth hormone, placental lactogen, estrogens, and progestins, up-regulate insulin secretion, probably by increasing the preproinsulin mRNA and enzymes involved in processing the increased preprohormone.
back to the topInsulin Regulation of Metabolism
Insulin, secreted by the β-cells of the pancreas, is directly infused via the portal vein to the liver, where it exerts profound metabolic effects. These effects are the response of the activation of the insulin receptor which belongs to the class of cell surface receptors that exhibit intrinsic tyrosine kinase activity (see Signal Transduction). The insulin receptor is a heterotetramer of 2 extracellular α-subunits disulfide bonded to 2 transmembrane β-subunits. With respect to hepatic glucose homeostasis, the effects of insulin receptor activation are specific phosphorylation events that lead to an increase in the storage of glucose with a concomitant decrease in hepatic glucose release to the circulation as diagrammed below (only those responses at the level of glycogen synthase and glycogen phosphorylase are represented).
Actions of insulin-insulin receptor interactions at the level of insulin receptor substrate-1 (IRS1) and activation of the kinase cascade leading to altered activities of glycogen phosphorylase and glycogen synthase. PI3K = phosphatidylinositol-3-kinase; PIP2 = phosphatidylinositol-4,5-bisphosphate; PIP3 = phosphatidylinositol-3,4,5-bisphosphate; PDK1 = PIP3-dependent protein kinase; Tsc1 and Tsc2 = Tuberous sclerosis tumor suppressors 1 (hamartin) and 2 (tuberin); Rheb = Ras homolog enriched in brain; mTOR = mammalian target of rapamycin. PKB/Akt = protein kinase B/Akt2; GSK3 = glycogen synthase kinase-3; S6K = 70kDa ribosomal protein S6 kinase, also called p70S6K. The insulin-mediated activation of mTOR also leads to changes in protein synthesis (see below).
Insulin-insulin receptor actions on glycogen homeostasis showing the role of protein targeting glycogen (PTG) in complexing many of the enzymes and substrates together. PTG is a subunit of PP1. Also diagrammed is the response to insulin at the level of glucose transport into cells via GLUT4 translocation to the plasma membrane. GS/GP kinase = glycogen synthase: gycogen phosphorylase kinase. PP1 = protein phosphatase-1. Arrows denote either direction of flow or positive effects, T lines represent inhibitory effects.
In most nonhepatic tissues, insulin increases glucose uptake by increasing the number of plasma membrane glucose transporters: GLUTs. Glucose transporters are in a continuous state of turnover. Increases in the plasma membrane content of GLUTs stem from an increase in the rate of recruitment of the transporters into the plasma membrane, deriving from a special pool of preformed transporters localized in the cytoplasm. GLUT1 is present in most tissues, GLUT2 is found primarily in intestine, pancreatic β-cells, kidney and liver, GLUT3 is found primarily in neurons but also found in the intestine, GLUT4 is found in insulin-responsive tissues such as heart, adipose tissue and skeletal muscle and GLUT5 is expressed in intestine, kidney, testes, skeletal muscle, adipose tissue and brain.
In liver glucose uptake is dramatically increased because of increased activity of the enzymes glucokinase, phosphofructokinase-1 (PFK-1), and pyruvate kinase (PK), the key regulatory enzymes of glycolysis. The latter effects are induced by insulin-dependent activation of phosphodiesterase, with decreased PKA activity and diminished phosphorylation of pyruvate kinase and phosphofructokinase-2, PFK-2. Dephosphorylation of pyruvate kinase increases its' activity while dephosphorylation of PFK-2 renders it active as a kinase. The kinase activity of PFK-2 converts fructose-6-phosphate into fructose-2,6-bisphosphate (F2,6BP). F2,6BP is a potent allosteric activator of the rate limiting enzyme of glycolysis, PFK-1, and an inhibitor of the gluconeogenic enzyme, fructose-1,6-bisphosphatase. In addition, phosphatases specific for the phosphorylated forms of the glycolytic enzymes increase in activity under the influence of insulin. All these events lead to conversion of the glycolytic enzymes to their active forms and consequently a significant increase in glycolysis. In addition, glucose-6-phosphatase activity is down-regulated. The net effect is an increase in the content of hepatocyte glucose and its phosphorylated derivatives, with diminished blood glucose.
In addition to the above described events, diminished cAMP and elevated protein phosphatase activity combine to convert glycogen phosphorylase to its inactive form and glycogen synthase to its active form, with the result that not only is glucose funneled to glycolytic products, but glycogen content is increased as well.
All of the post-receptor responses initiated by insulin binding to its receptor are mediated as a consequence of the activation of several signal transduction pathways. These include receptor activation of phosphatidylinositol-3-kinase, PI3K. Activation of PI3K involves a linkage to receptor activation of insulin receptor substrates (of which there are four: IRS1, IRS2, IRS3 and IRS4). Activated PI3K phosphorylates membrane phospholipids, the major product being phosphatidylinositol-3,4,5-trisphosphate, (PIP3). PIP3 in turn activates the enzyme protein kinase B, PKB (also called Akt). There are three members of the PKB/Akt family of serine/threonine kinases identified as Akt1, Akt2, and Akt3. It is Akt2 that is important in insulin-mediated glucose homeostasis. Insulin-mediated activation of AKt also results in inhibition of lipolysis and gluconeogenesis and activation of protein synthesis and glycogen synthesis.
Additional enzymes activated by insulin receptor signaling are PIP3-dependent kinase, (PDK), some isoforms of protein kinase C, PKC (principally PKC-λ) and small ribosomal subunit protein 6 (p70) kinase, (p70S6K). The MAP kinase (MAPK) pathway is also activated either through insulin receptor phosphorylation of SRC homology 2 containing protein (Shc) which then interacts with growth factor receptor binding protein-2 (GRB2) or via IRS1 activation.
With respect to insulin responses, activation of PKB and PKC-λ lead to translocation of GLUT4 molecules to the cell surface resulting in increased glucose uptake which is significant in skeletal muscle. Activation of PKB also leads to the phosphorylation and inhibition of glycogen synthase kinase-3 (GSK3), which is a major regulatory kinase of glycogen homeostasis. In addition, PKB phosphorylates and inhibits the activity of a transcription factor (FKHRL1), now called FoxO3a) that has pro-apoptotic activity. This results in reduced apoptosis in response to insulin action.
The role of insulin in the stimulation of protein synthesis occurs at the level of translational initiation and elongation and is exerted primarily via a cascade leading to the activation of mammalian target of rapamycin, mTOR, a protein with homology to a family of proteins first identified in yeast that bind to the immunosuppressant drug, rapamycin. mTOR is a kinase whose catalytic domain shares significant homology with lipid kinases of the PI3K family.
Insulin-mediated cascade leading to enhanced translation (not intended to be a complete description of all of the targets of insulin action that affect translation rates). Also shown is the effect of an increase in the AMP to ATP ratio which activates AMP-activated kinase, AMPK. STK11-LKB1-PJS = serine-threonine kinase 11, Peutz-Jeghers syndrome gene. IRS1 = insulin receptor substrate-1; PI3K = phosphatidylinositol-3-kinase; PIP2 = phosphatidylinositol-4,5-bisphosphate; PTEN = phosphatase and tensin homolog deleted on chromosome 10; PDK1 = PIP3-dependent protein kinase; Tsc1 and Tsc2 = Tuberous sclerosis tumor suppressors 1 (hamartin) and 2 (tuberin); Rheb = Ras homolog enriched in brain; mTOR = mammalian target of rapamycin. PKB/Akt = protein kinase B; GSK3 = glycogen synthase kinase-3; 4EBP1 = eIF-4E binding protein; p70S6K = 70kDa ribosomal protein S6 kinase, also called S6K.
Insulin action leads to an increase in the activity of PI3K which in turn phosphorylates membrane phospholipids generating phosphatidylinositol-3,4,5-trisphophate (PIP3) from phosphatidylinositol-4,5-bisphosphate (PIP2). PIP3 then activates the kinase PDK1 which in turn phosphorylates and activates PKB/Akt. Activated PKB/Akt will phosphorylate TSC2 (tuberin) of the TSC1/TSC2 complex on two residues (S939 and T1462) resulting in altered activity of the complex. The TSC1/TSC2 complex functions as a GTPase-activating protein (GAP) which increases GTP hydrolyzing activity of Rheb. The GAP activity resides in the C-terminal portion of tuberin. The faster the GTPase action of Rheb the faster will be the reduction in Rheb activation of mTOR. When TSC1/TSC2 is phosphorylated by PKB it is less effective at stimulating the GTPase activity of Rheb and therefore Rheb activation of mTOR will remain high as is the case in response to insulin action. AMPK phosphorylates TSC2 at two sites (T1271 and S1387) that are distinct from the sites that are the PKB/Akt targets for phosphorylation. Evidence indicates that the AMPK-mediated phosphorylation of TSC2 promotes the GTPase activity of Rheb resulting in inhibition of mTOR and thus a decrease in protein synthesis. Recent evidence has shown that PKB/Akt actually phosphorylates tuberin at 4 sites (S939, S1130, S1132, T1462) all of which result in inhibition of the Rheb-GAP activity of the TSC1/TSC2 complex.
The ultimate activation of mTOR leads to phosphorylation and activation of p70S6K which in turn leads to increased phosphorylation of eEF2 kinase. eEF2 kinase normally phosphorylates eEF2 leading to a decrease in its’ role in translation elongation. When phosphorylated by p70S6K, eEF2 kinase is less active at phosphorylating eEF2, thus eEF2 is much more active in response to insulin action. In addition, insulin action leads to a rapid dephosphorylation of eEF-2 via activation of protein phosphatase 2A (PP2A). Taken together, reduced eEF2K-mediated phosphorylation and increased eEF-2 dephosphorylation lead to increased protein synthesis.
Both mTOR and p70S6K have been shown to phosphorylate the regulator of translation initiation, eIF-4E binding protein, 4EBP1. Phosphorylation of 4EBP1 prevents it from binding to eIF-4E. Binding of 4EBP1 to eIF-4E prevents eIF-4E from interaction with the cap structure of mRNAs which is necessary for translational initiation. Thus, the consequences of 4EBP1:eIF-4E interaction is a reduction in translation initiation. As a consequence of the concerted actions of mTOR and p70S6K, insulin results in increased protein synthesis.
PKB activation will also lead to phosphorylation and inhibition of glycogen synthase kinase-3 (GSK3). One of the targets of GSK3, relative to translation, is eIF2B. Phosphorylation of eIF2B prevents it from performing its GTPase activating (GAP) function in association with eIF2 (see the Protein Synthesis page for more details) and as a consequence results in reduced translational initiation. However, when GSK3 is inhibited by PKB phosphorylation the GAP activity of eIF2B remains high and consequently the rate of translational initiation by eIF2 remains high so protein synthesis is favored.
Insulin also has profound effects on the transcription of numerous genes, effects that are primarily mediated by regulated function of sterol-regulated element binding protein, SREBP. These transcriptional effects include (but are not limited to) increases in glucokinase, pyruvate kinase, lipoprotein lipase (LPL), fatty acid synthase (FAS) and acetylCoA carboxylase (ACC) and decreases in glucose 6-phosphatase, fructose 1,6-bisphosphatase and phosphoenolpyruvate carboxykinase (PEPCK).
In contrast, epinephrine diminishes insulin secretion by a cAMP-coupled regulatory path. In addition, epinephrine counters the effect of insulin in liver and peripheral tissue, where it binds to β-adrenergic receptors, induces adenylate cycles activity, increases cAMP, and activates PKA similarly to that of glucagon. The latter events induce glycogenolysis and gluconeogenesis, both of which are hyperglycemic and which thus counter insulin's effect on blood glucose levels. In addition, epinephrine influences glucose homeostasis through interaction with α-adrenergic receptors.
Pathways involved in the regulation of glycogen phosphorylase by epinephrine activation of α-adrenergic receptors. See Glycogen Metabolism for details of the epinephrine action. PLC-γ is phospholipase C-γ. The substrate for PLC-γ is phosphatidylinositol-4,5-bisphosphate, (PIP2) and the products are inositol trisphosphate, IP3 and diacylglycerol, DAG. Similar calmodulin-mediated phosphorylations lead to inhibition of glycogen synthase.
back to the topNutrient Intake and Hormonal Control of Insulin Action
Two of the many gastrointestinal hormones have significant effects on insulin secretion and glucose regulation. These hormones are the glucagon-like peptides (principally glucagon-like peptide-1, GLP-1) and glucose-dependent insulinotropic peptide (GIP). Both of these gut hormones constitute the class of molecules referred to as the incretins. Incretins are molecules associated with food intake-stimulation of insulin secretion from the pancreas.
Details of the actions of GLP-1 and GIP can be found in the Gut-Brain Interactions page. Briefly, GLP-1 is derived from the product of the proglucagon gene (gene symbol = GCG). This gene encodes a preproprotein that is differentially cleaved dependent upon the tissue in which it is synthesized. For example, in pancreatic α-cells prohormone convertase 2 action leads to the release of glucagon. In the gut prohormone convertase 1/3 action leads to release of several peptides including GLP-1. Upon nutrient ingestion GLP-1 is secreted from intestinal enteroendocrine L-cells that are found predominantly in the ileum and colon with some production from these cell types in the duodenum and jejunum. Bioactive GLP-1 consists of 2 forms; GLP-1(7-37) and GLP-1(7-36)amide, where the latter form constitutes the majority (80%) of the circulating hormone.
The primary physiological responses to GLP-1 are glucose-dependent insulin secretion, inhibition of glucagon secretion and inhibition of gastric acid secretion and gastric emptying. The latter effect will lead to increased satiety with reduced food intake along with a reduced desire to ingest food. The action of GLP-1 at the level of insulin and glucagon secretion results in significant reduction in circulating levels of glucose following nutrient intake. This activity has obvious significance in the context of diabetes, in particular the hyperglycemia associated with poorly controlled type 2 diabetes. The glucose lowering activity of GLP-1 is highly transient as the half-life of this hormone in the circulation is less than 2 minutes. Removal of bioactive GLP-1 is a consequence of N-terminal proteolysis catalyzed by dipeptidylpeptidase IV (DPP IV or DPP4). For more complete information on the activities of DPP4 go to the DPP4 page.
back to the topWnt Signaling, GLP-1, and Insulin Secretion
Although much of the research that has led to a detailed understanding of the signal transduction pathways initiated by Wnts was carried out in models of early development, evidence has been accumulating demonstrating a significant role for the Wnts in the control of metabolism. In particular Wnt action has been shown to be involved in metabolic control via its actions in both the gut and pancreas. In addition, Wnt signaling has been shown to interact with signaling pathways induced by insulin.
In the gut Wnt has been shown to be involved in regulated expression of the GCG gene. In intestinal enteroendocrine L cells the expression of the GCG gene results in the production of GLP-1. As indicated above, GLP-1 exerts its effects on the gut, the pancreas and in the brain. In the gut its effects lead to a reduced rate of gastric acid secretion and reduced gastric emptying. In the pancreas GLP-1 induced β-cell proliferation and inhibition of β-cell apoptosis. In the brain GLP-1 actins result in increased satiety leading to reduced desire for food intake.
The GCG gene promoter region contains an enhancer that harbors a canonical Wnt response element that binds TCF factors, in particular the TCF7L2 protein. Genome wide screens for polymorphisms associated with type 2 diabetes demonstrated that two single nucleotide polymorphisms (SNPs) in the TCF7L2 gene were the most frequently occurring SNPs associated with this disease. The significance of Wnt in the control of GLP-1 production was demonstrated by the fact that reduction/loss of either β-catenin or TCF7L2 function completely blocks insulin-stimulated expression of the intestinal GCG gene. In addition, the effects of GLP-1 on the pancreas (i.e. proliferation and anti-apoptosis) are effected via the actions of β-catenin and TCF7L2. In the pancreas insulin inhibits expression from the GCG gene leading to reduced production of glucagon. This action has physiological significance because glucagon is the major counter-regulatory hormone to insulin action. The important role of TCF7L2 in pancreatic function can be demonstrated in experiments that lead to reduction in the levels of TCF7L2. In these types of experiments there is an increased rate of pancreatic β-cell apoptosis, reduced β-cell proliferation, and reduced glucose-dependent insulin secretion.
The demonstration of cross-talk between the Wnt and insulin signaling pathways is important as these observations may eventually lead to novel approaches to the treatment of type 2 diabetes.
back to the topInsulin Resistance
Insulin resistance (IR) refers to the situation whereby insulin interaction with its receptor fails to elicit downstream signaling events such as those depicted in the Figures above. Metabolically and clinically the most detrimental effects of IR are due to disruption in insulin-mediated control of glucose and lipid homeostasis in the primary insulin-responsive tissues: liver, skeletal muscle, and adipose tissue. IR is a characteristic feature found associated with most cases of type 2 diabetes. In addition, IR is the hallmark feature of the metabolic syndrome (MetS). IR can occur for a number of reasons however, the most prevalent cause is the hyperlipidemic and pro-inflammatory states associated with obesity. How does an abnormal metabolism, as is associated with obesity, lead to the development of IR? The answer to this question can be found in the effects of excess free fatty acids (FFAs) on the insulin receptor-mediated signaling pathways in adipose tissue, liver, and skeletal muscle as well as the pro-inflammatory status induced by the toxic effects of excess FFAs principally in the liver and adipose tissues.
The precise mechanisms that underlie the promotion of a pro-inflammatory state in obese individuals in not completely established. However, both adipose tissue and liver are important mediators of systemic inflammation in obesity. One model proposes that the expansion of adipose tissue that occurs in obesity results in large adipocytes that have metabolic capacities that exceed the local oxygen supply. The resultant hypoxia leads to the activation of cellular stress response pathways causing cell autonomous inflammation and the release of pro-inflammatory cytokines. As a part of the chronic inflammation adipocytes secrete chemokines such as IL-8 and macrophage chemotactic protein-1 (MCP-1) that attract pro-inflammatory macrophages into the adipose tissue. These activated adipose tissue macrophages secrete cytokines that further exacerbate the pro-inflammatory state. In the liver inflammatory processes are also activated due to the excess accumulation of fatty acids and triglycerides which is the consequence of activated stress response pathways. Within the liver, Kupffer cells (resident liver macrophages) become activated by the generation of reactive oxygen species (ROS) and induction of stress responses. These activated Kupffer cells release locally acting cytokines that, like in adipose tissue, exacerbates the pro-inflammatory environment. Within the vasculature, saturated FFAs can directly activate pro-inflammatory pathways in endothelial cells and myeloid-derived cells resulting in the induction and propagation of a systemic pro-inflammatory state.
Hepatic IR is induced by the excess accumulation of FFAs. Within the hepatocyte, metabolites of the FFA re-esterification process, including long-chain acyl-CoAs and diacylglycerol (DAG), accumulate. Excess FFAs also participate in the relocation of several protein kinase C (PKC) isoforms, from the cytosol to the membrane compartment. These PKC isoforms include PKC-β2, PKC-δ, and PKC-theta (PKC-θ). DAG is a potent activator of these PKC isoforms and the membrane-associated PKCs will phosphorylate the intracellular portion of the insulin receptor on serine residues which results in impairment of insulin receptor interaction with downstream signaling proteins including insulin receptor substrate 1 (IRS1) and IRS2. Loss of IRS1 and IRS2 interaction with the receptor prevents interaction with phosphatidylinositol 3-kinase (PI3K) and its' subsequent activation. In addition to serine phosphorylation of the insulin receptor, various PKCs have been shown to phosphorylate IRS1 and IRS2 further impairing the ability of these insulin receptor substrates to associate with the insulin receptor and downstream effector proteins such as PI3K.
The FFA-induced down-regulation of insulin signaling pathways results in activation of several kinases involved in stress responses. These kinases include Jun N-terminal kinase (JNK), inhibitor of nuclear factor kappa B kinase beta (IKKβ), and suppressors of cytokine signaling-3 (SOCS-3). Like PKC, JNK activity is also regulated by FFAs and is an important regulator of IR. The target of JNK action is the Ser307 of IRS-1 and this phosphorylation plays an important role in the progression to hepatic IR. Activation of IKKβ (which is required for the activation of nuclear factor kappa B, NFκB) may have the most pronounced effect on inflammatory responses in the liver and adipose tissue. NFκB is the most important transcription factor activating the expression of numerous pro-inflammatory cytokine genes such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-α) each of which have been shown to be involved in promoting IR. NFκB-dependent inflammatory mediators produced in hepatocytes act to reduce insulin sensitivity and to promote liver injury.
Analysis of the effects of FFAs on macrophages in cell culture demonstrated that they can activate inflammatory signaling through the toll-like receptors (TLRs), specifically TLR4. The TLRs are a family of cell surface receptors involved in key events triggered via the innate immune system. The TLRs are pattern recognition receptors that recognize structurally conserved molecules from microbial pathogens. TLR4 is responsive to bacterially derived lipopolysacchardie (LPS) which is an endotoxin secreted by gram-negative bacteria. LPS stimulation of TLR4 results in activation of both the JNK and IKKβ signal transduction pathways leading to secretion of pro-inflammatory cytokines such as IL-1β, IL-6, MCP-1, and tumor necrosis factor alpha (TNFα). These cell culture experiments demonstrated that FFA addition to macrophages results in activation of NFκB and that this activation was deficient in macrophages from TLR4 knock-out mice. In the livers of TLR4 knock-out mice there is reduced inflammation even in the presence of hepatic steatosis suggesting that Kupffer cell TLR4 is important in hepatic inflammatory responses to excess FFA loading.
back to the topInsulin Action and Endothelial Functions
The metabolic functions of insulin are primarily reflective of its role in glucose and lipid homeostasis in skeletal muscle, adipose tissue, and liver. However, insulin also exerts important functions in other non-classical insulin target tissues such as the brain, pancreas, and the vascular endothelium. The ability of insulin to exert vasodilator action in the vascular endothelium as a result of increased nitric oxide (NO) production is an important component of the ability of this hormone to enhance glucose uptake by skeletal muscle. The insulin-mediated signaling pathway that triggers production of NO in vascular endothelium involves the same signaling proteins (PI3K, PKD, and Akt/PKB) that are components of metabolic regulatory pathways induced by insulin. Therefore, it is understandable why the same disruptions to insulin signaling that lead to IR (see above) caused by excess FFAs and hyperglycemia result in endothelial dysfunction.
The production of NO in endothelial cells is the result of the activation of endothelial nitric oxide synthase (eNOS). The production and actions of NO and the various NOSs involved are discussed in more detail in the Amino Acid Derivatives page. With respect to insulin action, the activation of endothelial Akt/PKB leads to phosphorylation and activation of eNOS and thus increased NO production. In addition to modulating vascular tone by activating signaling events in the underlying vascular smooth muscle cells, endothelial cell-derived NO reduces the production of pro-inflammatory cytokines, reduces leukocyte and monocyte recruitment and adhesion to the endothelium, inhibits the proliferation of vascular smooth muscle cells, inhibits apoptosis, and attenuates platelet aggregation. Inactivation of endothelial cell NO production, as occurs due to IR, results in endothelial dysfunction and promotes the development of atherosclerosis. As described above for the liver and adipose tissue, elevated levels of circulating FFAs lead to impaired insulin signaling via the PI3K-PDK-Akt/PKB pathway in vascular endothelial cells.
Insulin exerts its mitogenic, growth promoting, and differentiation effects via a signaling pathway that involves mitogen-activated protein kinase (MAPK) which is distinct from the PI3K-PDK-Akt/PKB pathway that is involved in metabolic regulation by insulin. The MAPK-induced pathway does not play a role in the production of NO by insulin. This MAPK-induced pathway plays a significant role in the development of atherosclerosis in the IR state. When insulin signaling via PI3K-PDK-Akt/PKB is impaired as described above for the IR state, the MAPK signaling pathway in endothelial cells is enhanced. In the endothelium MAPK activation by insulin results in increased expression of endothelin-1 (ET-1), plasminogen activator inhibitor type-1 (PAI-1), and the adhesion molecules intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. ET-1 is a potent vasoconstrictor and contributes to endothelial cell dysfunction in the presence of IR. The increased expression of numerous cell adhesion molecules accelerates the adherence to the endothelium of pro-inflammatory leukocytes which in turn contributes to the development of atherosclerosis. Therefore, the molecules beneficial to vascular endothelial health that are induced by insulin (e.g. NO) are reduced in the IR state and those that are proatherogenic (e.g. ET-1, PAI-1) are increased.
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Michael W King, PhD | © 1996–2011 themedicalbiochemistrypage.org, LLC | info @ themedicalbiochemistrypage.org
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