Insulin Receptor Signal Transduction Research Articles

O-8: Localization of the class I disulfide bonds of the human insulin receptor and the role of class I disulfide bonds in insulin receptor signal transduction

O-8: Localization of the class I disulfide bonds of the human insulin receptor and the role of class I disulfide bonds in insulin receptor signal transduction

A novel, rapid, inhibitory effect of insulin on α1β2γ2s γ-aminobutyric acid type A receptors

In the CNS, GABA and insulin seem to contribute to similar processes, including neuronal survival; learning and reward; and energy balance and food intake. It is likely then that insulin and GABA may interact, perhaps at the GABA(A) receptor. One such interaction has already been described [Q. Wan, Z.G. Xiong, H.Y. Man, C.A. Ackerley, J. Braunton, W.Y. Lu, L.E. Becker, J.F. MacDonald, Y.T. Wang, Recruitment of functional GABA(A) receptors to postsynaptic domains by insulin, Nature 388 (1997) 686-690]; in it a micromolar concentration of insulin causes the insertion of GABA(A) receptors into the cell membrane, increasing GABA current. I have discovered another effect of insulin on GABA(A) currents. Using a receptor isoform, alpha(1)beta(2)gamma(2s) that is the likely main neuronal GABA(A) isoform expressed recombinantly in Xenopus oocytes, insulin inhibits GABA-induced current when applied simultaneously with low concentrations of GABA. Insulin will significantly inhibit currents induced by EC(30-50) concentrations of GABA by about 38%. Insulin is potent in this effect; IC(50) of insulin was found to be about 4.3 x 10(-10) M. The insulin effect on the GABA dose responses looked like that of an antagonist similar to bicuculline or beta-carbolines. However, an effect of phosphorylation on the GABA(A) receptor from the insulin receptor signal transduction pathway cannot yet be dismissed.

Mitochondrial respiratory chain is involved in insulin-stimulated hydrogen peroxide production and plays an integral role in insulin receptor autophosphorylation in neurons

BackgroundAccumulated evidence suggests that hydrogen peroxide (H2O2) generated in cells during insulin stimulation plays an integral role in insulin receptor signal transduction. The role of insulin-induced H2O2 in neuronal insulin receptor activation and the origin of insulin-induced H2O2 in neurons remain unclear. The aim of the present study is to test the following hypotheses (1) whether insulin-induced H2O2 is required for insulin receptor autophosphorylation in neurons, and (2) whether mitochondrial respiratory chain is involved in insulin-stimulated H2O2 production, thus playing an integral role in insulin receptor autophosphorylation in neurons.ResultsInsulin stimulation elicited rapid insulin receptor autophosphorylation accompanied by an increase in H2O2 release from cultured cerebellar granule neurons (CGN). N-acetylcysteine (NAC), a H2O2 scavenger, inhibited both insulin-stimulated H2O2 release and insulin-stimulated autophosphorylation of insulin receptor. Inhibitors of respiratory chain-mediated H2O2 production, malonate and carbonyl cyanide-4-(trifluoromethoxy)-phenylhydrazone (FCCP), inhibited both insulin-stimulated H2O2 release from neurons and insulin-stimulated autophosphorylation of insulin receptor. Dicholine salt of succinic acid, a respiratory substrate, significantly enhanced the effect of suboptimal insulin concentration on the insulin receptor autophosphorylation in CGN.ConclusionResults of the present study suggest that insulin-induced H2O2 is required for the enhancement of insulin receptor autophosphorylation in neurons. The mitochondrial respiratory chain is involved in insulin-stimulated H2O2 production, thus playing an integral role in the insulin receptor autophosphorylation in neurons.

The Proinflammatory Cytokine Macrophage Migration Inhibitory Factor Regulates Glucose Metabolism during Systemic Inflammation

Inflammation provokes significant abnormalities in host metabolism that result from the systemic release of cytokines. An early response of the host is hyperglycemia and resistance to the action of insulin, which progresses over time to increased glucose uptake in peripheral tissue. Although the cytokine TNF-alpha has been shown to exert certain catabolic effects, recent studies suggest that the metabolic actions of TNF-alpha occur by the downstream regulation of additional mediators, such as macrophage migration inhibitory factor (MIF). We investigated the glycemic responses of endotoxemic mice genetically deficient in MIF (MIF(-/-)). In contrast to wild-type mice, MIF(-/-) mice exhibit normal blood glucose and lactate responses following the administration of endotoxin, or TNF-alpha. MIF(-/-) mice also show markedly increased glucose uptake into white adipose tissue in vivo in the endotoxemic state. Treatment of adipocytes with MIF, or anti-MIF mAb, modulates insulin-mediated glucose transport and insulin receptor signal transduction; these effects include the phosphorylation of insulin receptor substrate-1, its association with the p85 regulatory subunit of PI3K, and the downstream phosphorylation of Akt. Genetic MIF deficiency also promotes adipogenesis, which is in accord with a downstream role for MIF in the action of TNF-alpha. These studies support an important role for MIF in host glucose metabolism during sepsis.

Glucose enhances protein tyrosine phosphatase 1B gene transcription in hepatocytes

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin receptor signal transduction pathway. We investigated the effects of glucose on PTP1B transcription in the human hepatocyte cell line Huh7. Using a reporter gene assay, we found that d-glucose dose-dependently enhanced the PTP1B promoter activity. Real-time PCR demonstrated that d-glucose also increased PTP1B mRNA expression. Protein kinase C (PKC) inhibitors partially but significantly inhibited the transactivation by d-glucose. Mithramycin, a Sp1 inhibitor, completely abrogated this transactivation. The deletion of three possible Sp1 sites in the promoter region of PTP1B significantly reduced the basal promoter activity and transactivation by d-glucose. Sp1 activation by PKC is one of the key mechanisms in the regulation of several gene expressions. Our data suggested that glucose enhanced PTP1B transcription through Sp1 activation by PKC. Increased hepatic PTP1B expression may partly explain glucose toxicity in diabetes.

Toll-like Receptor-2 Is Essential for the Development of Palmitate-induced Insulin Resistance in Myotubes

Fatty acids can activate proinflammatory pathways leading to the development of insulin resistance, but the mechanism is undiscovered. Toll like receptor 2 (TLR2) recognizes lipids, activates proinflammatory pathways, and is genetically associated with inflammatory diseases. This study aimed to examine the role of TLR2 in palmitate-induced insulin resistance in C2C12 myotubes. Treatment with palmitate rapidly induced the association of myeloid differentiation factor 88 (MyD88) with the TLR2 receptor, activated the stress-linked kinases p38, JNK, and protein kinase C, induced degradation of IkappaBalpha, and increased NF-kappaB DNA binding. The activation of these pathways by palmitate was sensitive and temporally regulated and occurred within the upper physiologic range of saturated fatty acid concentrations in vivo, suggesting a receptor-mediated event and not simple lipotoxicity. When compared with an equimolar concentration of palmitate, fibroblast-stimulating lipopeptide-1, a known TLR2 ligand, was a slightly more potent activator of signal transduction and interleukin (IL)-6 production. Palmitate inhibited insulin signal transduction in C2C12 cells beginning 1-2 h after exposure and reached a maximum at 12-16 h. An antagonist TLR2 antibody, mAb 2.5, led to a 50-60% decrease in palmitate-induced IL-6 production and partially restored insulin signal transduction, whereas an isotype-matched control antibody had no effect. RNA interference-mediated inhibition of TLR2 and MyD88 expression in C2C12 muscle cells resulted in a near complete inhibition of palmitate-induced insulin resistance and IL-6 production. This study provides strong evidence that TLR2 mediates the initial events of fatty acid-induced insulin resistance in muscle.

P1-421: Impaired IGF-1 receptor and insulin receptor signal transduction in Alzheimer’s disease

P1-421: Impaired IGF-1 receptor and insulin receptor signal transduction in Alzheimer’s disease

Hyperglycemia, Nutrition Support, and Acute Illness

The impact of short-term hyperglycemia on morbidity and mortality of hospitalized patients has gained significant attention from clinicians since the landmark prospective, randomized clinical trial by van den Berghe et al, which demonstrated dramatic improvements in morbidity and mortality in critically ill surgical patients with improved glycemic control (80–110 mg/dL) compared to historically accepted glucose targets (180–200 mg/dL). Stress-induced hyperglycemia is a common phenomenon often observed in acutely ill patient populations due to impairments in insulin-mediated glucose uptake in the skeletal muscle, and failure of insulin to suppress hepatic gluconeogenesis. Parenteral nutrition (PN) is frequently a component of care for these patients and, because of its appreciable dextrose load, may further promote elevations in blood glucose. Clinicians responsible for PN administration face daily decisions over how to optimally manage their patients’ glycemic control. Although the overall impact of tight management has been demonstrated in surgical intensive care unit (ICU) patients, the potentially adverse contributions of PN have not been characterized in the setting of appropriate glycemic control and methods for optimal management have yet to be discerned. The purpose of the American Society of Parenteral and Enteral Nutrition 2005 research workshop sponsored by NIDDK (DK06190-04) on Hyperglycemia, Nutrition Support and Acute Illness was to summarize the research that had been conducted on glucose management in hospitalized patients, to describe the pathophysiology that induces the stress-induced hyperglycemia with a focus on the role of the inflammation and the immune system, and to describe protocols that have been endorsed by the American Diabetes Association for glucose monitoring in diabetic patients as well as others that have been utilized by clinicians and researchers providing nutrition support to the critically ill. The ultimate objective of the program was to provide clinical guidelines for optimal glycemic management based upon the current scientific knowledge. The next several issues of JPEN will include papers that were presented at this workshop. In this issue, Dr Jeffrey Mechanick presents the mechanisms of hyperglycemia in acutely ill patients. A comprehensive model of glucose allostasis, immunoneuroendocrine axis activation, and insulin receptor signal transduction is described. The “healthy chaos” that underlies the complex, interactive stress response is introduced, with the caveat that failure to recognize its importance can inject unintentional harm. This article is followed by Dr Anastassios Pittas’ meta-analysis of randomized controlled trials that investigated the impact of insulin therapy on mortality in critically ill patients. Included are trials conducted in cardiac ICU patients that received glucose-insulin and potassium replacement therapies. Also presented are randomized trials in critically ill patients which utilized more aggressive insulin management to achieve improved glycemic control vs those which utilized conventional insulin management and secured less rigid glucose control. The potential benefits of insulin therapy compared to euglycemia were also explored in discussing these trials. It is hoped that readers will find the summaries from the research workshop that are included in the next several JPEN issues useful in highlighting the high priority for improved glycemic control in critically ill patients. We further anticipate that these papers will serve to emphasize the many important research questions that remain, and will help to foster development of a future research agenda. While PN has proven to be life-saving in humans with permanent gastrointestinal failure, it also has well-recognized inherent risks. It is possible that many of the perceived risks of PN will be largely alleviated with more stringent attention to glycemic control.

Metabolic Mechanisms of Stress Hyperglycemia

Stress hyperglycemia has gained the attention of virtually every physician who encounters critically ill patients, with the emergence of clinical data supporting tight glycemic control and intensive insulinization for optimal outcome. In order to effectively manage stress hyperglycemia, newer theories of critical illness and the interactions of the brain, neuroendocrine axis, and immune system need to be explored. Nonlinear physiologic processes, glucose allostasis, immune-neuroendocrine axis activation, and molecular mechanisms of insulin receptor signal transduction contribute to a novel model of stress hyperglycemia. In chronic critical illness, allostatic overload leads to a plurality of organ-system derangements and eventually death. Intervention not only involves insulinization according to neurofuzzy logic but also targeting more proximate events with cognitive/behavioral therapy and hypothalamic releasing factors.

Rin1 regulates insulin receptor signal transduction pathways

Rin1 is a multifunctional protein containing several domains, including Ras binding and Rab5 GEF domains. The role of Rin1 in insulin receptor internalization and signaling was examined by expressing Rin1 and deletion mutants in cells utilizing a retrovirus system. Here, we show that insulin-receptor-mediated endocystosis and fluid phase insulin-stimulated endocytosis are enhanced in cells expressing the Rin1:wild type and the Rin1:C deletion mutant, which contain both the Rab5-GEF and GTP-bound Ras binding domains. However, the Rin1:N deletion mutant, which contains both the SH 2 and proline-rich domains, blocked insulin-stimulated receptor-mediated and insulin-stimulated fluid phase endocytosis. In addition, the expression of Rin1:Δ (429–490), a natural occurring splice variant, also blocked both receptor-mediated and fluid phase endocystosis. Furthermore, association of the Rin1 SH 2 domain with the insulin receptor was dependent on tyrosine phosphorylation of the insulin receptor. Morphological analysis indicates that Rin1 co-localizes with insulin receptor both at the cell surface and in endosomes upon insulin stimulation. Interestingly, the expression of Rin1:wild type and both deletion mutants blocks the activation of Erk1/2 and Akt1 kinase activities without affecting either JN or p38 kinase activities. DNA synthesis and Elk-1 activation are also altered by the expression of Rin1:wild type and the Rin1:C deletion mutant. In contrast, the expression of Rin1:Δ stimulates both Erk1/2 and Akt1 activation, DNA synthesis and Elk-1 activation. These results demonstrate that Rin1 plays an important role in both insulin receptor membrane trafficking and signaling.

IGF-I and insulin receptor signal transduction in trout muscle cells

In this study, primary cultures of trout skeletal muscle cells were used to investigate the main signal transduction pathways of insulin and IGF-I receptors in rainbow trout muscle. At different stages of in vitro development (myoblasts on day 1, myocytes on day 4, and fully developed myotubes on day 11), we detected in these cells the presence of immunoreactivity against ERK 1/2 MAPK and Akt/PKB proteins, components of the MAPK and the phosphatidylinositol 3-kinase-Akt pathways, respectively, two of the main intracellular transduction pathways for insulin and IGF-I receptors. Both insulin and IGF-I activated both pathways, although the latter provoked higher immunoreactivity of phosphorylated MAPKs and Akt proteins. At every stage, increases in total MAPK immunoreactivity levels were observed when cells were stimulated with IGF-I or insulin, while total Akt immunoreactivity levels changed little under stimulation of peptides. Total Akt and total MAPK levels increased as skeletal muscle cells differentiated in culture. Moreover, when cells were incubated with IGF-I or insulin, MAPK-P immunoreactivity levels showed greater increases over the basal levels on days 1 and 4, with no effect observed on day 11. Although Akt-P immunoreactivity displayed improved responses on days 1 and 4 as well, a stimulatory effect was still observed on day 11. In addition, the present study demonstrates that purified trout insulin receptors possess higher phosphorylative activity per unit of receptor than IGF-I receptors. In conclusion, these results indicate that trout skeletal muscle culture is a suitable model to study the insulin and IGF-I signal transduction molecules and that there is a different regulation of MAPK and Akt pathways depending on the developmental stage of the muscle cells.

Altered subcellular distribution of IRS-1 and IRS-3 is associated with defective Akt activation and GLUT4 translocation in insulin-resistant old rat adipocytes

Insulin receptor signal transduction depends on the precise intracellular localization of signalling molecules. This study examines the compartmentalization and the insulin-induced translocation and tyrosine phosphorylation of insulin receptor substrates (IRS-1 and IRS-3) in epididymal white adipose tissue from adult and insulin-resistant old rats. We found that insulin induces the translocation of IRS-1 from plasma membrane (PM) and light microsomes (LM) to cytosol, whereas IRS-3 translocates from PM to LM and cytosol upon insulin stimulation. Old rat adipocytes are characterized by higher relative levels of IRS proteins, under basal conditions, in those fractions where they are intended to translocate in response to insulin and exhibit a higher phosphotyrosine content of IRS-1 and -3 in basal conditions and a lower maximal phosphorylation in response to insulin. Furthermore, old rat adipocytes are also characterized by a reduced ability of insulin to stimulate both, Akt/PKB activity and translocation of GLUT4 to the PM. We conclude that the lower stimulation of downstream insulin signalling involved in glucose metabolism in old rat adipocytes may be explained, at least in part, by the altered subcellular distribution of IRS-1 and -3 proteins. In addition, our data suggest that the mechanism of turning on/off insulin receptor-mediated signal is impaired with aging.

SOCS1: a potent and multifaceted regulator of cytokines and cell‐mediated inflammation

Suppressor of cytokine signalling-1 (SOCS1), as the name implies, is a protein that functions as a negative regulator of cytokine signalling. Initially characterized for its ability to inhibit JAK phosphorylation and function, SOCS1 also targets proteins for degradation by the proteosome machinery. The expression of SOCS1 can be regulated at the transcription, translation and protein level. Despite the broad spectrum of cytokines that can induce SOCS1 expression and/or be inhibited by SOCS1 in vitro, the use of genetically modified mice has revealed a more specific role for SOCS1 in vivo including a critical role in the regulation of IFNgamma signalling. In addition, SOCS1 has a complex role in T cell activation, and studies have revealed significant roles for SOCS1 in the regulation of IL-4, IL-12 and IL-15 in vivo. Interestingly, SOCS1 action is not limited to the regulation of the classical JAK/STAT-signalling pathway, because SOCS1 also inhibits cytokines like insulin and toll-like receptor signal transduction, neither of which activates the JAK/STAT pathway. Evidence is emerging for a role for aberrant SOCS1 expression in human disease, particularly in a number of malignancies.

Peripheral Hyperinsulinemia Promotes Tau Phosphorylation In Vivo

Cerebral insulin receptors play an important role in regulation of energy homeostasis and development of neurodegeneration. Accordingly, type 2 diabetes characterized by insulin resistance is associated with an increased risk of developing Alzheimer's disease. Formation of neurofibrillary tangles, which contain hyperphosphorylated tau, represents a key step in the pathogenesis of neurodegenerative diseases. Here, we directly addressed whether peripheral hyperinsulinemia as one feature of type 2 diabetes can alter in vivo cerebral insulin signaling and tau phosphorylation. Peripheral insulin stimulation rapidly increased insulin receptor tyrosine phosphorylation, mitogen-activated protein kinase and phosphatidylinositol (PI) 3-kinase pathway activation, and dose-dependent tau phosphorylation at Ser202 in the central nervous system. Phospho-FoxO1 and PI-3,4,5-phosphate immunostainings of brains from insulin-stimulated mice showed neuronal staining throughout the brain, not restricted to brain areas without functional blood-brain barrier. Importantly, in insulin-stimulated neuronal/brain-specific insulin receptor knockout mice, cerebral insulin receptor signaling and tau phosphorylation were completely abolished. Thus, peripherally injected insulin directly targets the brain and causes rapid cerebral insulin receptor signal transduction and site-specific tau phosphorylation in vivo, revealing new insights into the linkage of type 2 diabetes and neurodegeneration.

Peripheral insulin stimulation promotes tau phosphorylation in the CNS in vivo

Insulin (IN) crosses the blood brain barrier by a receptor-mediated transport. However, less than 1% of peripheral injected IN reaches the CNS. Clinically, the association of altered glucose metabolism and neurodegenerative diseases has been described. Insulin-receptor(IR)-substrate-2-knockout-mice, as model of IN resistance and type 2 diabetes, display tau hyperphosphorylation. Hyperphosphorylated tau is a major component of tangles which were found in neurodegenerative conditions i.e. M. Alzheimer. To address, whether peripheral hyperinsulinemia influences cerebral IN signaling and contributes to tau hyperphosphorylation in vivo, we injected 0.01U (low dose group, LD) and 4U (high dose group, HD) IN into the inferior cava vein of anesthetized C57BL/6 mice and harvested brain tissue at 0,5,10,15,20min after injection. We investigated Akt-activity, IR-, Erk1/2-, GSK-3β- and Foxo1-phosphorylation as well as Ser202 and Thr231 tau phosphorylation. Blood glucose rose slightly after 5min and remained above baseline until 20min (LD&HD), excluding artifacts due to hypoglycemia. Injection of 0.01U IN led to a rapidly increased IR tyrosine phosphorylation within 5min (1.5fold, p≤0.01, n=10). Akt-activity increased 5min after injection with a maximum at 10min (2.8fold). GSK-3β phosphorylation increased within 10min (1.9fold, p≤0.05, n=11) and up to 2fold after 20min. Immunostainings of IN stimulated brains using pFoxo1 antibodies revealed a cytoplasmic neuronal staining in hypothalamus, thalamus, cortex and hippocampus. The LD group showed an increased Ser202 tau phosporylation 5min after injection, reaching significance after 15min (1.4fold, p≤0.01, n=10). Thr231 phosphorylation (LD&HD) remained unchanged. Injecting 4U IN revealed a further increase of Ser202 tau phosphorylation up to 2fold after 15min (p≤0.05, n=4) indicating a correlation between tau phosphorylation and peripheral IN levels. We conclude that peripherally injected IN leads to a rapid IR signal transduction in the CNS and contributes to a site-specific tau phosphorylation.

Hypoglycemic effect of Astragalus polysaccharide and its effect on PTP1B1

To examine the effects of Astragalus polysaccharide (APS), a component of an aqueous extract of Astragalus membranaceus roots, on protein tyrosine phosphatase 1B (PTP1B), a negative regulator of insulin-receptor (IR) signal transduction, and its potential role in the amelioration of insulin resistance. Ten-week-old fat-fed streptozotocin (STZ)-treated rats, an animal model of type II diabetes mellitus (TIIDM), were treated with APS (400 mg/kg p.o.) for 5 weeks. Insulin sensitivity was identified by the insulin-tolerance test. Further analyses on the possible changes in insulin signaling occurring in skeletal muscle and liver were performed by immunoprecipitation or Western blotting. PTP1B activity was measured by an assay kit. The diabetic rats responded to APS with a significant decrease in body weight, plasma glucose, and improved insulin sensitivity. The activity and expression of PTP1B were elevated in the skeletal muscle and liver of TIIDM rats. Thus the insulin signaling in target tissues was diminished. APS reduced both PTP1B protein level and activity in the muscle, but not in the liver of TIIDM rats. Insulin-induced tyrosine phosphorylation of the IR beta-subunit and insulin receptor substrate-1 (IRS-1) were increased in the muscle, but not in the liver of APS-treated TIIDM rats. There was no change in the activity or expression of PTP1B in APS-treated normal rats, and blood insulin levels did not change in TIIDM rats after treatment with APS. APS enables insulin-sensitizing and hypoglycemic activity at least in part by decreasing the elevated expression and activity of PTP1B in the skeletal muscles of TIIDM rats.

Tumor necrosis factor (TNF) interferes with insulin signaling through the p55 TNF receptor death domain

Tumor necrosis factor (TNF) contributes to insulin resistance by binding to the 55 kDa TNF receptor (TNF-R55), resulting in serine phosphorylation of proteins such as insulin receptor (IR) substrate (IRS)-1, followed by reduced tyrosine phosphorylation of IRS-1 through the IR and, thereby, diminished IR signal transduction. Through independent receptor domains, TNF-R55 activates a neutral (N-SMase) and an acid sphingomyelinase (A-SMase), that both generate the sphingolipid ceramide. Multiple candidate kinases have been identified that serine-phosphorylate IRS-1 in response to TNF or ceramide. However, due to the fact that the receptor domain of TNF-R55 mediating inhibition of the IR has not been mapped, it is currently unknown whether TNF exerts these effects with participation of N-SMase or A-SMase. Here, we identify the death domain of TNF-R55 as responsible for the inhibitory effects of TNF on tyrosine phosphorylation of IRS-1, implicating ceramide generated by A-SMase as a downstream mediator of inhibition of IR signaling.

Protein tyrosine phosphatases

Insulin receptor signal transduction plays a critical role in regulating pancreatic β-cell function, notably the acute first-phase insulin release in response to glucose. The basis for insulin resistance in pancreatic β-cells is not well understood but may be related to abnormal regulation of tyrosine phosphorylation events, which, in turn, may alter organization of insulin-signaling molecules in space and time. Members of the protein tyrosine phosphatase (PTPase) family are both functionally and structurally diverse; and within the past few years data have emerged from many laboratories that suggest selectivity of the PTPase catalytic domains toward cellular substrates. Of significance, a subset of PTPases has been implicated in the regulation of insulin signaling in a number of insulin-sensitive tissues. Alteration in PTPase expression or activity has been associated with abnormal regulation of tyrosine phosphorylation events and is accompanied by modulation of insulin sensitivity in vivo. Manipulations aimed at reducing expression of physiologically relevant PTPases acting at a step proximal to the insulin receptor are accompanied by normalization of blood glucose levels and improved insulin sensitivity in both normal and diabetic animals. Hence, the development of tissue-specific gene inactivation strategies should facilitate the study of the potential role of PTPases in β-cell insulin signaling transduction.

Glucose metabolism and insulin receptor signal transduction in Alzheimer disease

Nosologically, Alzheimer disease is not a single disorder in spite of a common clinical phenotype. Etiologically, two different types or even more exist. (1) In a minority of about 5% or less of all cases, Alzheimer disease is due to mutations of three genes, resulting in the permanent generation of βA4. (2) The great majority (95% or more) of cases of Alzheimer disease are sporadic in origin, with old age as main risk factor, supporting the view that susceptibility genes and aging contribute to age-related sporadic Alzheimer disease. However, disturbances in the neuronal insulin signal transduction pathway may be of central pathophysiological significance. In early-onset familial Alzheimer disease, the inhibition of neuronal insulin receptor function may be due to competitive binding of amyloid beta (Aβ) to the insulin receptor. In late-onset sporadic Alzheimer disease, the neuronal insulin receptor may be desensitized by inhibition of receptor function at different sites by noradrenaline and/or cortisol, the levels of which both increase with increasing age. The consequences of the inhibition of neuronal insulin signal transduction may be largely identical to those of disturbances of oxidative energy metabolism and related metabolism, and of hyperphosphorylation of tau-protein. As far as the metabolism of amyloid precursor protein (APP) in late-onset sporadic Alzheimer disease is concerned, neuronal insulin receptor dysfunction may result in the intracellular accumulation of Aβ and in subsequent cellular damage. In this context, the desensitization of the neuronal insulin receptor in late-onset sporadic Alzheimer disease is different from that occurring in normal aging and early-onset familial Alzheimer disease. In late-onset sporadic Alzheimer disease changes in the brain are similar to those caused by non-insulin-dependent diabetes mellitus.

Protein tyrosine phosphatases: potential role in beta-cell insulin signal transduction.

Insulin receptor signal transduction plays a critical role in regulating pancreatic beta-cell function, notably the acute first-phase insulin release in response to glucose. The basis for insulin resistance in pancreatic beta-cells is not well understood but may be related to abnormal regulation of tyrosine phosphorylation events, which, in turn, may alter organization of insulin-signaling molecules in space and time. Members of the protein tyrosine phosphatase (PTPase) family are both functionally and structurally diverse; and within the past few years data have emerged from many laboratories that suggest selectivity of the PTPase catalytic domains toward cellular substrates. Of significance, a subset of PTPases has been implicated in the regulation of insulin signaling in a number of insulin-sensitive tissues. Alteration in PTPase expression or activity has been associated with abnormal regulation of tyrosine phosphorylation events and is accompanied by modulation of insulin sensitivity in vivo. Manipulations aimed at reducing expression of physiologically relevant PTPases acting at a step proximal to the insulin receptor are accompanied by normalization of blood glucose levels and improved insulin sensitivity in both normal and diabetic animals. Hence, the development of tissue-specific gene inactivation strategies should facilitate the study of the potential role of PTPases in beta-cell insulin signaling transduction.