Activation Of Insulin Receptor Signaling Research Articles

S-Propargyl-Cysteine Attenuates Diabetic Cardiomyopathy in db/db Mice Through Activation of Cardiac Insulin Receptor Signaling.

Background: Endogenous hydrogen sulfide (H2S) is emerging as a key signal molecule in the development of diabetic cardiomyopathy. The aim of this study was to explore the effect and underlying mechanism of S-propargyl-cysteine (SPRC), a novel modulator of endogenous H2S, on diabetic cardiomyopathy in db/db diabetic mice.Methods and Results: Vehicle or SPRC were orally administered to 8-month-old male db/db mice and their wild type littermate for 12 weeks. SPRC treatment ameliorated myocardial hypertrophy, fibrosis, and cardiac systolic dysfunction assessed by histopathological examinations and echocardiography. The functional improvement by SPRC was accompanied by a reduction in myocardial lipid accumulation and ameliorated plasma lipid profiles. SPRC treatment improved glucose tolerance in db/db mice, with fasting blood glucose and peripheral insulin resistance remaining unchanged. Furthermore, insulin receptor signaling involving the phosphorylation of protein kinase B (Akt/PKB) and glycogen synthase kinase 3β (GSK3β) were elevated and activated by SPRC treatment. Primary neonatal mice cardiomyocytes were cultured to explore the mechanisms of SPRC on diabetic cardiomyopathy in vitro. Consistent with the results in vivo, SPRC not only up-regulated insulin receptor signaling pathway in cardiomyocytes in dose-dependent manner in the basal state, but also relieved the suppression of insulin receptor signaling induced by high concentrations of glucose and insulin. Furthermore, SPRC also enhanced the expression of glucose transporter 4 (GLUT4) and 3H glucose uptake in cardiomyocytes.Conclusions: In this study, we found a novel beneficial effect of SPRC on diabetic cardiomyopathy, which was associated with activation of insulin receptor signaling. SPRC may be a promising medication for diabetic cardiomyopathy in type 2 diabetes mellitus patients.

Using Phosphatidylinositol Phosphorylation as Markers for Hyperglycemic Related Breast Cancer.

Studies have suggested that type 2 diabetes (T2D) is associated with a higher incidence of breast cancer and related mortality rates. T2D postmenopausal women have an ~20% increased chance of developing breast cancer, and women with T2D and breast cancer have a 50% increase in mortality compared to breast cancer patients without diabetes. This correlation has been attributed to the general activation of insulin receptor signaling, glucose metabolism, phosphatidylinositol (PI) kinases, and growth pathways. Furthermore, the presence of breast cancer specific PI kinase and/or phosphatase mutations enhance metastatic breast cancer phenotypes. We hypothesized that each of the breast cancer subtypes may have characteristic PI phosphorylation profiles that are changed in T2D conditions. Therefore, we sought to characterize the PI phosphorylation when equilibrated in normal glycemic versus hyperglycemic serum conditions. Our results suggest that hyperglycemia leads to: 1) A reduction in PI3P and PIP3, with increased PI4P that is later converted to PI(3,4)P2 at the cell surface in hormone receptor positive breast cancer; 2) a reduction in PI3P and PI4P with increased PIP3 surface expression in human epidermal growth factor receptor 2-positive (HER2+) breast cancer; and 3) an increase in di- and tri-phosphorylated PIs due to turnover of PI3P in triple negative breast cancer. This study begins to describe some of the crucial changes in PIs that play a role in T2D related breast cancer incidence and metastasis.

Nutrient restriction causes reversible G2 arrest in Xenopus neural progenitors.

Nutrient status affects brain development; however, the effects of nutrient availability on neural progenitor cell proliferation in vivo are poorly understood. Without food, Xenopus laevis tadpoles enter a period of stasis during which neural progenitor proliferation is drastically reduced, but resumes when food becomes available. Here, we investigate how neural progenitors halt cell division in response to nutrient restriction and subsequently re-enter the cell cycle upon feeding. We demonstrate that nutrient restriction causes neural progenitors to arrest in G2 of the cell cycle with increased DNA content, and that nutrient availability triggers progenitors to re-enter the cell cycle at M phase. Initiation of the nutrient restriction-induced G2 arrest is rapamycin insensitive, but cell cycle re-entry requires mTOR. Finally, we show that activation of insulin receptor signaling is sufficient to increase neural progenitor cell proliferation in the absence of food. A G2 arrest mechanism provides an adaptive strategy to control brain development in response to nutrient availability by triggering a synchronous burst of cell proliferation when nutrients become available. This may be a general cellular mechanism that allows developmental flexibility during times of limited resources.

Nigella sativa Oil and Chromium Picolinate Ameliorate Fructose-Induced Hyperinsulinemia by Enhancing Insulin Signaling and Suppressing Insulin-Degrading Enzyme in Male Rats.

In vivo and in vitro studies suggested that chromium enhances insulin sensitivity by promoting insulin receptor signaling. However, its effect on insulin clearance has not been yet identified. Nigella sativa, a widely used spice, possesses an antidiabetic activity. We, therefore, hypothesized that chromium picolinate may alter insulin clearance by modulating insulin-degrading enzyme (IDE) in insulin-resistant rats. We evaluated also the effect of Nigella sativa oil on insulin signaling and degradation with respect to chromium picolinate. To assess these hypotheses, insulin resistance was induced in 30 male Wistar albino rats through daily oral administration of high-fructose water (HFW, 20% w/v) for 45days. These rats were then divided into three groups (n=10/group). They were given either no treatment (control group) or Nigella sativa oil (500mg/kgbw/day) or chromium picoloinate (200μg/kgbw/day) orally along with HFW (20% w/v) for 45days. Nigella sativa oil or chromium picolinate concurrent administration with HFW significantly decreased body weight, serum lipids, glucagon, insulin resistance, and hepatic IDE level but increased its mRNA expression and insulin receptor phosphorlyation as well as high-density lipoprotein cholesterol (HDL-C) level as compared to control group values, suggesting their potential as modulators for insulin signaling and clearance. However, Nigella sativa oil exerted better improvement in feeding efficacy ratio as well as the levels of glucagon, insulin, insulin resistance, hepatic IDE level and insulin receptor phosphorylation than chromium picolinate, suggesting its greater insulin sensitizing capacity. Our data, for the first time, prove that Nigella sativa oil and chromium picolinate monotherapy can reduce fructose-induced insulin resistance by reduction of hepatic IDE protein and activation of insulin receptor signaling.

Retracted Article: Identifying the inhibitory mechanism of apigenin on the insulin ligand–receptor binding

Although apigenin, a plant flavone, has been shown to inhibit the activation of insulin receptor signaling, its inhibitory mechanism is largely unknown.

RETRACTED: Quercetin suppresses insulin receptor signaling through inhibition of the insulin ligand–receptor binding and therefore impairs cancer cell proliferation

Although the flavonoid quercetin is known to inhibit activation of insulin receptor signaling, the inhibitory mechanism is largely unknown. In this study, we demonstrate that quercetin suppresses insulin induced dimerization of the insulin receptor (IR) through interfering with ligand-receptor interactions, which reduces the phosphorylation of IR and Akt. This inhibitory effect further inhibits insulin stimulated glucose uptake due to decreased cell membrane translocation of glucose transporter 4 (GLUT4), resulting in impaired cancer cell proliferation. The effect of quercetin in inhibiting tumor growth was also evident in an in vivo model, indicating a potential future application for quercetin in the treatment of cancers.

FoxO1 ablation in hypothalamic pomc neurons reduces food intake and body weight

Insulin and leptin control food intake in part by regulating the transcription of orectic and anorectic neuropeptides in the hypothalamus. Activation of insulin receptor signaling results in nuclear exclusion of the transcription factor forkhead box-containing protein of the O subfamily (FoxO)-1, while Leptin activates the signal transducer and activator of transcription 3 (Stat3). We have previously shown that FoxO1 and Stat3 exert opposing actions on the expression of Agrp and Pomc, resulting in activation of Agrp and inhibition of Pomc transcription. We reported that hypothalamic adenoviral delivery of constitutively nuclear FoxO1 blunted leptin's effect to acutely reduce food intake and body weight. However, it remains unclear whether chronic changes in hypothalamic FoxO1 activity affect the physiological regulation of energy homeostasis by insulin and leptin. To investigate the role of hypothalamic FoxO1 signaling in a genetic system, we inactivated the Foxo1 gene specifically in Pomc neurons in vivo, using cre/loxP technology in mice. Pomc-Foxo–/– mice were born at normal Mendelian ratios and had normal appearance and body weight at birth. Starting at the age of 6–8 weeks, both female and male mutant mice exhibited significantly reduced body weights as compared to their wild type littermates. Pomc-Foxo–/– mice showed a sustained reduction of body weight by 7–10% until the end of the study period (29.0±0.50 vs. 31.0±0.52g in control males at wk.18, P≤0.05). Importantly, reduced body weight in female mutant mice was accompanied by marked reduction of body fat content (3.7±0.43 vs. 7.0±1.05% in controls at wk.14–15, P≤0.01). While food intake under steady state conditions appeared unaltered, male mice with Pomc-specific FoxO1-deficiency showed a blunted refeeding response to an overnight fast (79.7±4.6 vs. 93.9±3.5mg/g/6h in control males at wk.18, P≤0.05). These data are consistent with the hypothesis that FoxO1 is a critical player in hypothalamic Pomc neurons regulating energy homeostasis. Further physiologic analyses of Pomc-Foxo–/– mice are underway.

Insulin Stimulates Postsynaptic Density-95 Protein Translation via the Phosphoinositide 3-Kinase-Akt-Mammalian Target of Rapamycin Signaling Pathway

Insulin receptors are highly enriched at neuronal synapses, but whose function remains unclear. Here we present evidence that brief incubations of rat hippocampal slices with insulin resulted in an increased protein expression of dendritic scaffolding protein postsynaptic density-95 (PSD-95) in area CA1. This insulin-induced increase in the PSD-95 protein expression was inhibited by the tyrosine kinase inhibitor, AG1024, phosphatidylinositol 3-kinase (PI3K) inhibitors, LY294002 and wortmannin, translational inhibitors, anisomycin and rapamycin, but not by LY303511 (an inactive analogue of LY294002), and transcriptional inhibitor, actinomycin D, suggesting that insulin regulates the translation of PSD-95 by activating the receptor tyrosine kinase-PI3K-mammalian target of rapamycin (mTOR) signaling pathway. A similar insulin-induced increase in the PSD-95 protein expression was detected after stimulation of the synaptic fractions isolated from the hippocampal neurons. Furthermore, insulin treatment did not affect the PSD-95 mRNA levels. In agreement, insulin rapidly induced the phosphorylation of 3-phosphoinositide-dependent protein kinase-1 (PDK1), protein kinase B (Akt), and mTOR, effects that were prevented by the AG1024 and LY294002. We also show that insulin stimulated the phosphorylation of 4E-binding protein 1 (4E-BP1) and p70S6 kinase (p70S6K) in a mTOR-dependent manner. Finally, we demonstrate the constitutive expression of PSD-95 mRNA in the synaptic fractions isolated from hippocampal neurons. Taken together, these findings suggest that activation of the PI3K-Akt-mTOR signaling pathway is essential for the insulin-induced up-regulation of local PSD-95 protein synthesis in neuronal dendrites and indicate a new molecular mechanism that may contribute to the modulation of synaptic function by insulin in hippocampal area CA1.

Insulin regulation of beta-cell function involves a feedback loop on SERCA gene expression, Ca(2+) homeostasis, and insulin expression and secretion.

The insulin receptor signaling pathway is present in beta-cells and is believed to be important in beta-cell function. We show here that insulin directly regulates beta-cell function in isolated rodent islets. Long-term insulin treatment caused a sustained increase in [Ca(2+)](i) and enhanced glucose-stimulated insulin secretion in rat islets, but failed to increase insulin content. Chronic activation of insulin receptor signaling by IRS-1 overexpression in the beta-cell inhibited gene expression of SERCA3, an endoplasmic reticulum Ca(2+)-ATPase. Insulin gene transcription was stimulated by insulin receptor signaling and insulin mimetic compound (L-783 281) in a glucose- and Grb2-dependent manner. Thus, beta-cell SERCA3 is a target for insulin regulation, which implies that beta-cell Ca(2+) homeostasis is regulated in an autocrine feedback loop by insulin. This study identifies a novel regulatory pathway of insulin secretion at the molecular level with two main components: (1) regulation of intracellular Ca(2+) homeostasis via SERCA3 and (2) regulation of insulin gene expression.

Activation of insulin receptor signaling by a single amino acid substitution in the transmembrane domain.

The insulin receptor is a ligand-activated tyrosine kinase composed of two alpha and two beta subunits. A single transmembrane domain composed of 23 hydrophobic residues is contained in each beta subunit. We examined the role of the transmembrane domain in regulating insulin receptor signaling by inserting a negatively charged amino acid (Asp) for Val938 (V938D). Chinese hamster ovary (CHO) cells were stably transfected with a plasmid containing both the neomycin-resistance gene and either the wild-type or the mutant (V938D) insulin receptor cDNA. Insulin binding increased similarly in CHO cells stably transfected with the wild-type and the V938D-mutant insulin receptor cDNA. Insulin stimulated glucose transport and cell growth in cells expressing the normal insulin receptor. By contrast, in the absence of insulin, glucose transport and cell growth in CHO-V938D cells were as high as in insulin-stimulated control cells and no longer responsive to insulin stimulation. Phosphorylation of the beta subunit of the insulin receptor was also increased in CHO-V938D cells not exposed to insulin. These results support an essential role of the transmembrane domain of the insulin receptor in the transduction of insulin signaling.