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Scientific Research An Academic Publisher. Combettes-Souverain, M. Diabetes Metabolism, 24, Glucose homeostasis is critical for energy generation, neuronal maintenance, neurogenesis, neurotransmitter regulation, cell survival and synaptic plasticity. It also plays a key role in cognitive function. In an insulin resistance condition, there is a reduced sensitivity to insulin resulting in hyperinsulinemia; this condition persists for several years before becoming full blown diabetes. Toxic levels of insulin negatively influence neuronal function and survival, and elevation of peripheral insulin concentration acutely increases its cerebrospinal fluid CSF concentration.

This leads to cellular cascades that trigger a neurodegenerative phenotype and decline in cognitive function. However, the increase in brain insulin levels resulting from its peripheral administration at optimal doses has shown a cognition enhancing effect on patient with AD. Related Articles:. Ablation of IRS-3 is devoid of a clear phenotype 34 , whereas ablation of IRS-4 is associated with modest growth retardation and insulin resistance Finally, inactivation of Gab-1 has an embryonic lethal phenotype that suggests a role in hepatic growth factor, rather than insulin, signaling As IRS-1 and IRS-2 have widely overlapping tissue distribution, these finding are consistent with the possibility that each molecule subserves a specific set of functions.

To address this question, it is interesting to compare the phenotypes of insulin receptor- and IRS-deficient mice. In every case, ablation of IRS proteins is associated with a much milder phenotype than lack of insulin receptors. Even the lack of IRS-2 does not have such a rapidly lethal effect as the lack of insulin receptors. On the other hand, mice lacking both IRS-1 and IRS-2 die before implantation, resulting in one of the most dramatic embryonic lethal phenotypes observed in mice with targeted gene mutations This phenotype is substantially more severe than the phenotype due to combined lack of insulin and IGF-I receptors 18 , suggesting that IRS proteins play additional roles to mediate the actions of other receptors, as predicted by studies of cytokine receptor signaling The phenotype of insulin receptor-deficient mice indicates that multiple substrates are required to mediate insulin action.

The conclusion of these studies is that the search for IRSs is not over.

A Molecular Basis for Insulin Resistance

The enzyme PI 3-kinase catalyzes the addition of phosphate on the D3 position of the inositol ring of phospoinositol, leading to the generation of PI 3-phosphate. Thus, blocking PI 3-kinase with the fungal inhibitor wortmannin is associated with inhibition of insulin-stimulated glucose uptake 43 , 44 ; glycogen 45 , 46 , lipid 44 , and protein 47 , 48 synthesis; and modulation of gene expression 49 , PI 3-kinase appears to play a permissive, rather than a necessary and sufficient, role in insulin action The evidence generally offered to buttress this conclusion is that although several growth factors result in activation of PI 3-kinase, only insulin has the ability to stimulate processes such as glucose transporter 4 GLUT4 translocation.

This controversy has raged in the literature for the past decade and is not entirely settled. These mice develop hypoglycemia due to increased basal levels of glucose uptake in several insulin-sensitive tissues Although the latter point requires further investigation, these data indicate that PI 3-kinase is crucial for insulin action. Arguably, the most important question in insulin action is to identify targets of PI 3-kinase that may account for the specificity of insulin signaling.

Among the PIP 3 -dependent kinases, Akt has received much attention. The Akt kinase exists as three different isoforms, all of which are activated by phosphorylation on T and S 59 , Upon growth factor stimulation, Akt localizes near the plasma membrane, where it becomes phosphorylated. The activated enzyme has the ability to translocate to the nucleus 61 Fig.

Expression of constitutively active Akt stimulates glucose uptake in 3T3-L1 adipocytes 62 — 64 , whereas Akt inhibition through the use of dominant negative mutants does not completely inhibit the insulin effect on glucose transport These results suggest that regulation of glucose transport may involve multiple kinases.

Insulin Action: Molecular Basis of Diabetes

Akt has the ability to phosphorylate proteins that regulate lipid synthesis 66 , glycogen synthesis 67 , 68 , cell survival 69 , and protein synthesis 70 , This mechanism provides a direct link between insulin receptor signaling and biological effects. Nevertheless, it is not clear whether Akt plays a unique or redundant role in insulin action.

Akt in insulin action. After insulin stimulation, Akt undergoes phosphorylation and nuclear translocation. Some of the known cellular targets of Akt are indicated. There are four subgroups of PKCs; the classical ones are activated by calcium binding, whereas the other three groups can be activated by diacylglycerol or other phospholipids, such as PIP 3 atypical PKCs.

Different isoforms of PKC have been shown to undergo translocation from the cytosol to the membrane in response to insulin stimulation in different tissues The nematode C. The life span of C.

When larvae are grown at high density or in the presence of high levels of pheromone, they enter the dauer stage, a reversible arrest of development characterized by reduced metabolic activity, increased fat content, and a near doubling of life span A constitutive dauer stage can be brought about by mutations in specific genes. The alleles causing a constitutive dauer phenotype have been dubbed Daf alleles. Mutations of the Daf-2 gene cause a constitutive dauer phenotype, as do mutations of the Age-1, Akt-1, and Akt-2 genes The Daf-2 gene encodes the C.

Considerable interest has been generated by the study of mutations that suppress the effects of the Daf-2, Age-1, Akt-1, and Akt-2 mutations. Two of them are especially relevant to insulin signaling through PI 3-kinase: Daf and Daf Daf mutations completely suppress the dauer phenotype due to Daf-2 mutations, whereas Daf mutations have a less complete ability to rescue Daf-2 mutations.

Daf encodes a transcription factor with homology to the mammalian forkhead transcription factors 83 , whereas Daf encodes a phosphoinositide phosphatase with homology to the mammalian phosphatase- and tensin-homolog deleted on chromosome 10 tumor suppressor gene Daf is a substrate of Akt The observations that Daf and Daf are important for insulin receptor signaling in C. Conserved insulin signaling pathways in C. The pathways regulating cellular metabolism and survival in mammalian cells are conserved in the nematode C. Activation of the insulin receptor ortholog Daf-2 leads to stimulation of Age-1, the PI 3-kinase ortholog.

Table of contents

Targets of Age-1 include Akt-1 and -2, which, in turn, phosphorylate Daf Age-1 is regulated by Daf, the PI phosphatase phosphate- and tensin-homolog deleted on chromosome 10 ortholog. The Daf gene product belongs to the forkhead family of transcription factors. These proteins were first identified as the homeotic gene product of the forkhead mutation in Drosophila They contain a highly conserved DNA-binding domain, the forkhead or winged helix domain A subgroup of forkhead proteins known as FKHR is the closest mammalian homolog of the Daf gene product.

These proteins were first identified as the products of chromosomal translocations associated with alveolar rhabdomyosarcoma, hence the acronym F or K head in H uman R habdomyosarcoma Indeed, based on the presence of binding sites for the forkhead transcription factor HNF-3, Unterman was the first to propose that such transcription factors might represent transcriptional regulators of insulin-responsive genes such as IGF-binding protein-1, phospho-enolpyruvate carboxykinase, and glucosephosphatase 49 , FKHR is a transcriptional enhancer, the targets of which include genes regulating apoptosis, glucose production, and entry into the cell cycle 69 , When cells are exposed to insulin or other known stimulators of PI 3-kinase, these transcription factors become phosphorylated at Akt consensus sites.

Phosphorylation is followed by nuclear exclusion and cytoplasmic retention 69 , It follows that FKHR phosphorylation is a powerful mechanism by which insulin inhibits gene transcription.

Insulin Signal Transduction Pathway

Insulin stimulation of glucose uptake is mediated by translocation of an intracellular pool of GLUT4 to the plasma membrane , Two approaches are being employed to identify elements in the signal transduction chain leading to GLUT4 translocation: a forward approach, starting from the insulin receptor, and a backward approach starting from GLUT4.

Like two teams digging up a tunnel starting at both sides of a mountain, the two approaches will hopefully merge at some point, although none can predict when. In the worst-case scenario, we may end up with two tunnels. What do we know about the distal components of this pathway? The former would predict that GLUT4 molecules are prevented from joining the constitutive cellular recycling compartment from an inhibitory mechanism, or molecule, that would be inactivated by insulin.

It is easily realized that the two models need not be mutually exclusive. Many of the accessory components of GLUT4 vesicles have been identified, and intensive efforts are underway to isolate every single constituent of this important subcellular organelle. Adapter molecules that regulate the interaction between VAMP-2 and syntaxin-4 in an insulin-dependent manner have been cloned from protein-protein yeast interaction libraries from 3T3-L1 adipocytes. Synip is a syntaxin 4-binding protein Insulin catalyzes Synip dissociation from syntaxin 4.

Moreover, inhibition of Synip dissociation by a dominant negative mutant results in inhibition of GLUT4 translocation. The mechanism by which insulin causes Synip dissociation remains unknown. Another syntaxin 4-binding protein is Munc Insulin inhibits binding of Munc18c to syntaxin 4, thereby increasing binding of VAMP2 to syntaxin 4 One such example is the pathway mediated through the protein Cbl. Cbl is a substrate of the insulin receptor kinase in differentiated 3T3-L1 adipocytes, but not in preadipocytes This differential phosphorylation is due to expression of a Cbl-associated protein CAP Although CAP is not phosphorylated in response to insulin, it is able to target Cbl to the insulin receptor.

After phosphorylation, Cbl translocates to caveolae, a specialized subdomain of the plasma membrane. Inhibition of the CAP-Cbl interaction by dominant negative CAP correlates with inhibition of insulin-stimulated glucose transport and GLUT4 translocation in a wortmannin-independent fashion, suggesting that Cbl participates in a PI 3-kinase-independent mechanism whereby insulin stimulates GLUT4 translocation in adipocytes Tyrosine phosphatases play a key role in terminating the signal generated through tyrosine kinases. This family of enzymes comprises more than different genes.

Therefore, it has proven difficult to identify physiological phosphatases that regulate insulin signaling by dephosphorylating the insulin receptor and its targets. Experiments in various cell types have suggested that the receptor type leukocyte common antigen-related phosphatase is an insulin receptor phosphatase Accordingly, mice lacking leukocyte common antigen-related phosphatase exhibit a complex syndrome of insulin sensitivity and insulin resistance Likewise, mice lacking protein tyrosine phosphatase 1b present with an insulin sensitivity syndrome that has suggested that this phosphatase represents an important modulator of insulin action.

Ablation of PTP-1b in mice is associated with failure to develop insulin resistance when exposed to a high fat diet , These studies implicate PTP-1b as a physiological mediator of insulin action and as a potential therapeutic target to develop therapies against diet-induced obesity. Substantial progress has been made in understanding how insulin mediates its effects on fuel metabolism. Through a combination of approaches, from cellular and molecular techniques to transgenic and knockout mice, many pathways of insulin signaling have been reconstructed in detail.

As outlined in this review, significant questions remain unanswered. First and foremost is the identification of the complete chain of events leading from IRS phosphorylation and PI 3-kinase activation to the biological effects of insulin. Second and not less important is to dissect the role of PI 3-kinase-dependent and -independent pathways of insulin action. Finally, it remains to be determined how these complex pathways interact in vivo and how different tissues contribute to the pathogenesis of the insulin resistant state of type 2 diabetes. We apologize to colleagues whose work we are prevented from citing either in the text or in the reference section by space limitations.

The expert assistance of Ms. Sharon Jones in manuscript preparation is gratefully acknowledged. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search. Article Navigation.

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Molecular Basis of Insulin Action

Different roles of IRS proteins. Are all the actions of insulin mediated through IRS proteins? Role of phosphatidylinositol 3-kinase PI 3-kinase in insulin action. Targets of PI 3-kinase.

Signaling pathways in insulin action: molecular targets of insulin resistance

FKHR, the mammalian homologue of the C. What makes GLUT4 tick. PI 3-kinase independent pathways of insulin signaling.