scholarly journals Dietary protein deprivation upregulates insulin signaling and inhibits gluconeogenesis in rat liver

2010 ◽  
Vol 45 (5) ◽  
pp. 329-340 ◽  
Author(s):  
Yuka Toyoshima ◽  
Reiko Tokita ◽  
Yoichiro Ohne ◽  
Fumihiko Hakuno ◽  
Tadashi Noguchi ◽  
...  
Keyword(s):  
Tyrosine Phosphorylation ◽  
Insulin Signaling ◽  
Dietary Protein ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Mrna Level ◽  
Mammalian Target Of Rapamycin ◽  
Insulin Injection ◽  
Regulatory Subunit ◽  
Protein Deprivation ◽  
Protein Free Diet

This study was undertaken to elucidate the effects of dietary protein deprivation on glucose metabolism and hepatic insulin signaling in rats. The results of glucose and pyruvate tolerance tests in rats fed with a 12% casein diet (12C) and a protein-free diet (PF) indicated that protein deprivation enhanced clearance of blood glucose and suppressed gluconeogenesis. Correspondingly, the mRNA level of hepatic phosphoenolpyruvate carboxykinase, a key gluconeogenic enzyme, was suppressed by dietary protein deprivation. In PF-fed rats, total tyrosine phosphorylation of insulin receptor (IR) in the liver induced by insulin injection was enhanced compared with 12C pair-fed rats due to an increase in IR protein level. In addition, protein deprivation caused an increase in protein levels of IR substrate 1 (IRS1) and IRS2, leading to the marked enhancement of insulin-induced tyrosine phosphorylation of IRS2 and its binding to the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K). Based on these results, we conclude that protein deprivation suppresses gluconeogenesis by a mechanism primarily mediated by the enhancement of the insulin signals through the IR/IRS/PI3K/mammalian target of rapamycin complex 1 pathway in the liver. Taken together with our previous report, these findings suggest that tissue-specific potentiation of insulin action in the liver and the skeletal muscle plays important roles in maintaining glucose homeostasis even when energy usage is reduced by dietary protein deprivation.

Immobilization depresses insulin signaling in skeletal muscle

2000 ◽  
Vol 279 (6) ◽  
pp. E1235-E1241 ◽  
Author(s):  
Munetaka Hirose ◽  
Masao Kaneki ◽  
Hiroki Sugita ◽  
Shingo Yasuhara ◽  
J. A. Jeevendra Martyn
Keyword(s):  
Skeletal Muscle ◽  
Protein Expression ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Glucose Transport ◽  
Insulin Signaling ◽  
Regulatory Subunit ◽  
Protein Levels ◽  
Essential Components ◽  
Prolonged Immobilization

Prolonged immobilization depresses insulin-induced glucose transport in skeletal muscle and leads to a catabolic state in the affected areas, with resultant muscle wasting. To elucidate the altered intracellular mechanisms involved in the insulin resistance, we examined insulin-stimulated tyrosine phosphorylation of the insulin receptor β-subunit (IR-β) and insulin receptor substrate (IRS)-1 and activation of its further downstream molecule, phosphatidylinositol 3-kinase (PI 3-K), after unilateral hindlimb immobilization in the rat. The contralateral hindlimb served as control. After 7 days of immobilization of the rat, insulin was injected into the portal vein, and tibialis anterior muscles on both sides were extracted. Immobilization reduced insulin-stimulated tyrosine phosphorylation of IR-β and IRS-1. Insulin-stimulated binding of IRS-1 to p85, the regulatory subunit of PI 3-K, and IRS-1-associated PI 3-K activity were also decreased in the immobilized hindlimb. Although IR-β and p85 protein levels were unchanged, IRS-1 protein expression was downregulated by immobilization. Thus prolonged immobilization may cause depression of insulin-stimulated glucose transport in skeletal muscle by altering insulin action at multiple points, including the tyrosine phosphorylation, protein expression, and activation of essential components of insulin signaling pathways.

Effects of contractile activity on tyrosine phosphoproteins and PI 3-kinase activity in rat skeletal muscle

1995 ◽  
Vol 268 (5) ◽  
pp. E987-E995 ◽  
Author(s):  
L. J. Goodyear ◽  
F. Giorgino ◽  
T. W. Balon ◽  
G. Condorelli ◽  
R. J. Smith
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Muscle Contraction ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Insulin Signaling ◽  
Kinase Activity ◽  
Contractile Activity ◽  
Insulin Injection ◽  
Kinase Activation

Insulin stimulates signaling reactions that include insulin receptor autophosphorylation and tyrosine kinase activation, insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, and phosphatidylinositol 3-kinase (PI 3-kinase) activation. Muscle contraction has metabolic effects similar to insulin, and contraction can increase insulin sensitivity, but little is known about the molecular signals that mediate the effects of contraction. To investigate the effects of muscle contraction on insulin signaling, rats were studied after contraction of hindlimb muscles by electrical stimulation, maximal insulin injection in the absence of contraction, or contraction followed by insulin injection. Insulin increased tyrosine phosphorylation of the insulin receptor and IRS-1, whereas contraction alone had no effect. Contraction before insulin injection decreased the insulin effect on receptor and IRS-1 phosphorylation by 20-25%. Increased tyrosine phosphorylation of other proteins by insulin and/or contraction was not observed. Contraction alone had little effect on PI 3-kinase activity, but contraction markedly blunted the insulin-stimulated activation of IRS-1 and insulin receptor-immunoprecipitable PI 3-kinase. In conclusion, skeletal muscle contractile activity does not result in tyrosine phosphorylation of molecules involved in the initial steps of insulin signaling. Although contractile activity increases insulin sensitivity and responsiveness in skeletal muscle, contraction causes a paradoxical decrease in insulin-stimulated tyrosine phosphorylation and PI 3-kinase activity.

scholarly journals Prolonged exposure to GH impairs insulin signaling in the heart

2011 ◽  
Vol 47 (2) ◽  
pp. 167-177 ◽  
Author(s):  
J G Miquet ◽  
J F Giani ◽  
C S Martinez ◽  
M C Muñoz ◽  
L González ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Insulin Signaling ◽  
Glucose Transporter ◽  
Prolonged Exposure ◽  
Interstitial Fibrosis ◽  
Total Content ◽  
Direct Consequence ◽  
Insulin Injection ◽  
Serine Phosphorylation ◽  
Regulatory Subunit

Acromegaly is associated with cardiac hypertrophy, which is believed to be a direct consequence of chronically elevated GH and IGF1. Given that insulin is important for cardiac growth and function, and considering that GH excess induces hyperinsulinemia, insulin resistance, and cardiac alterations, it is of interest to study insulin sensitivity in this tissue under chronic conditions of elevated GH. Transgenic mice overexpressing GH present cardiomegaly and perivascular and interstitial fibrosis in the heart. Mice received an insulin injection, the heart was removed after 2 min, and immunoblotting assays of tissue extracts were performed to evaluate the activation and abundance of insulin-signaling mediators. Insulin-induced tyrosine phosphorylation of the insulin receptor (IR) was conserved in transgenic mice, but the phosphorylation of IR substrate 1 (IRS1), its association with the regulatory subunit of the phosphatidylinositol 3-kinase (PI3K), and the phosphorylation of AKT were decreased. In addition, total content of the glucose transporter GLUT4 was reduced in transgenic mice. Insulin failed to induce the phosphorylation of the mammalian target of rapamycin (mTOR). However, transgenic mice displayed increased basal activation of the IR/IRS1/PI3K/AKT/mTOR and p38 signaling pathways along with higher serine phosphorylation of IRS1, which is recognized as an inhibitory modification. We conclude that GH-overexpressing mice exhibit basal activation of insulin signaling but decreased sensitivity to acute insulin stimulation at several signaling steps downstream of the IR in the heart. These alterations may be associated with the cardiac pathology observed in these animals.

Sequential phosphorylation of insulin receptor substrate-2 by glycogen synthase kinase-3 and c-Jun NH2-terminal kinase plays a role in hepatic insulin signaling

2008 ◽  
Vol 294 (2) ◽  
pp. E307-E315 ◽  
Author(s):  
Hadar Sharfi ◽  
Hagit Eldar-Finkelman
Keyword(s):  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Insulin Signaling ◽  
Glycogen Synthase ◽  
Serine Phosphorylation ◽  
Glycogen Synthase Kinase ◽  
Regulatory Subunit ◽  
Insulin Receptor Substrate ◽  
Phosphorylation Sites ◽  
Hepatic Insulin Signaling

Serine phosphorylation of insulin receptor substrate (IRS) proteins is a potential inhibitory mechanism in insulin signaling. Here we show that IRS-2 is phosphorylated by glycogen synthase kinase (GSK)-3. Phosphorylation by GSK-3 requires prior phosphorylation of its substrates, prompting us to identify the “priming kinase.” It was found that the stress activator anisomycin enhanced the ability of GSK-3 to phosphorylate IRS-2. Use of a selective c-Jun NH2-terminal kinase (JNK) inhibitor and cells overexpressing JNK implicated JNK as the priming kinase. This allowed us to narrow down the number of potential GSK-3 phosphorylation sites within IRS-2 to four regions that follow the motif SXXXSP. IRS-2 deletion mutants enabled us to localize the GSK-3 and JNK phosphorylation sites to serines 484 and 488, respectively. Mutation at serine 488 reduced JNK phosphorylation of IRS-2, and mutation of each site separately abolished GSK-3 phosphorylation of IRS-2. Treatment of H4IIE liver cells with anisomycin inhibited insulin-induced tyrosine phosphorylation of IRS-2; inhibition was reversed by pretreatment with the JNK and GSK-3 inhibitors. Moreover, overexpression of JNK and GSK-3 in H4IIE cells reduced insulin-induced tyrosine phosphorylation of IRS-2 and its association with the p85 regulatory subunit of phosphatidylinositol 3-kinase. Finally, both GSK-3 and JNK are abnormally upregulated in the diabetic livers of ob/obmice. Together, our data indicate that IRS-2 is sequentially phosphorylated by JNK and GSK-3 at serines 484/488 and provide evidence for their inhibitory role in hepatic insulin signaling.

scholarly journals Dietary protein deprivation decreases the serine phosphorylation of insulin receptor substrate-1 in rat skeletal muscle

2004 ◽  
Vol 32 (2) ◽  
pp. 519-531 ◽  
Author(s):  
Y Toyoshima ◽  
Y Ohne ◽  
SI Takahashi ◽  
T Noguchi ◽  
H Kato
Keyword(s):  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Dietary Protein ◽  
Cultured Cells ◽  
Insulin Injection ◽  
The State ◽  
Protein Malnutrition ◽  
Serine Phosphorylation

Evidence has shown that protein malnutrition tends to increase peripheral insulin sensitivity, but the molecular mechanism underlying this increase is not yet clear. Here we show that, in rat muscle, the state of insulin receptor (IR) substrate-1 (IRS-1), a pivotal component of the signaling pathway of the IR, changes drastically according to protein supply. After rats were fed a protein-free diet (PF) or a 12% casein diet for 1 week, their IR and IRS-1 states were analyzed by immunoblotting using various antibodies. PF slightly increased the amount of IR without affecting the state of IR tyrosine phosphorylation. In contrast, PF decreased the amount of IRS-1 and markedly increased phosphorylation of IRS-1 tyrosine residues after insulin injection. Moreover, IRS-1 in PF rats exhibited faster mobility in SDS-PAGE as well as far less phosphorylation of Ser612 and Ser307, indicating hypophosphorylation on its serine residues. Results of additional experiments using energy-restricted (pair-fed) rats and streptozotocin-induced diabetic rats suggest that dietary protein deficiency by itself alters serine phosphorylation of IRS-1, while the up-regulation of tyrosine phosphorylation requires other factors, such as a reduction in basal plasma insulin. The serine dephosphorylation followed by up-regulation of insulin-dependent IRS-1 tyrosine phosphorylation in skeletal muscle of PF rats in vivo is similar to a phenomenon observed in cultured cells under restriction of amino acids in the medium. With these findings, it could be inferred that the reduction of serine phosphorylation contributes to the sensitization of IRS-1 to IR tyrosine kinase under protein malnutrition.

Sequence of the human glycogen-associated regulatory subunit of type 1 protein phosphatase and analysis of its coding region and mRNA level in muscle from patients with NIDDM

Diabetes ◽  
1994 ◽  
Vol 43 (10) ◽  
pp. 1234-1241 ◽  
Author(s):  
Y. H. Chen ◽  
L. Hansen ◽  
M. X. Chen ◽  
C. Bjorbaek ◽  
H. Vestergaard ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Mrna Level ◽  
Regulatory Subunit ◽  
Coding Region

scholarly journals Differential Expression of Inflammatory Markers in Hypoglycemia Unawareness Associated with Type 1 Diabetes: A Case Report

2020 ◽  
Vol 11 (1) ◽  
pp. 17
Author(s):  
Yousef Al Zoubi ◽  
Bashair M. Mussa ◽  
Ankita Srivastava ◽  
Abdul Khader Mohammed ◽  
Elamin Abdelgadir ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Case Report ◽  
Differential Expression ◽  
Insulin Pump ◽  
Mrna Level ◽  
Insulin Injection ◽  
Hypoglycemia Unawareness ◽  
Tnf Α ◽  
Ifn Γ

The recurrence of hypoglycemic episodes leads to attenuation of the normal counter-regulatory mechanisms that are controlled by the hypothalamus, which results in hypoglycemia unawareness (HU). In this case report, we described for the first time the differential expression of TNF-α, IL-1β, IL-6, and IFN-γ in a blood sample that was taken from a 27-year-old patient with type 1 diabetes mellitus (T1DM) who was diagnosed with HU. The anti-diabetic regimen is currently based on insulin injection, but the patient is planning to start the use of an insulin pump to have better control of glucose levels. Our results showed a trend toward an increase in the expression of IL-1β, IL-6, and IFN-γ in T1DM patient with HU. However, the mRNA level of TNF-α showed a significant decrease. These observations suggest that systemic inflammation could be an underlying cause of HU.

scholarly journals The Role of Uncoupling Protein 1 in the Metabolism and Adiposity of RIIβ-Protein Kinase A-Deficient Mice

2004 ◽  
Vol 18 (9) ◽  
pp. 2302-2311 ◽  
Author(s):  
Michael A. Nolan ◽  
Maria A. Sikorski ◽  
G. Stanley McKnight
Keyword(s):  
Adipose Tissue ◽  
Oxygen Consumption ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Uncoupling Protein ◽  
Mrna Level ◽  
Regulatory Subunit ◽  
Uncoupling Protein 1 ◽  
Brown Adipose ◽  
Kinase A

Abstract Mice lacking the RIIβ regulatory subunit of protein kinase A exhibit a 50% reduction in white adipose tissue stores compared with wild-type littermates and are resistant to diet-induced obesity. RIIβ−/− mice also have an increase in resting oxygen consumption along with a 4-fold increase in the brown adipose-specific mitochondrial uncoupling protein 1 (UCP1). In this study, we examined the basis for UCP1 induction and tested the hypothesis that the induced levels of UCP1 in RIIβ null mice are essential for the lean phenotype. The induction of UCP1 occurred at the protein but not the mRNA level and correlated with an increase in mitochondria in brown adipose tissue. Mice lacking both RIIβ and UCP1 (RIIβ−/−/Ucp1−/−) were created, and the key parameters of metabolism and body composition were studied. We discovered that RIIβ−/− mice exhibit nocturnal hyperactivity in addition to the increased oxygen consumption at rest. Disruption of UCP1 in RIIβ−/− mice reduced basal oxygen consumption but did not prevent the nocturnal hyperactivity. The double knockout animals also retained the lean phenotype of the RIIβ null mice, demonstrating that induction of UCP1 and increased resting oxygen consumption is not the cause of leanness in the RIIβ mutant mice.

Abstract 350: Atorvastatin Attenuates Pressure Overload-induced Cardiac Hypertrophy and Dysfunction Through Enhanced Autophagy

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Zhuo Zhao ◽  
Wei Wang ◽  
Hua-Ting Wang ◽  
Qing-Xin Geng ◽  
Di Zhao ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Western Blot ◽  
Mrna Level ◽  
Mammalian Target Of Rapamycin ◽  
Pressure Overload ◽  
Oral Gavage ◽  
Atorvastatin Treatment ◽  
Developing Heart ◽  
Phosphorylated Akt

Aims: Cardiac hypertrophy is a maladaptive change in response to pressure overload and is also an important risk for developing heart failure. We previously demonstrated that atorvastatin inhibits cardiac hypertrophy and remodeling in a mouse model of transverse aorta constriction (TAC). This study was designed to determine the regulation of atorvastatin on cardiac autophagy and its association with the development of cardiac hypertrophy and dysfunction in the mice TAC model. Methods and results: TAC or sham operations were performed in male C57/L6 mice at 8 weeks of age. Atorvastatin (50 mg/kg/day) or vehicle (normal saline) were administered daily by oral gavage to TAC mice (n=10 per group). Echocardiography and real-time PCR data showed that chronic atorvastatin treatment for four weeks significantly attenuated pressure overload-induced cardiac hypertrophy and dysfunction, as well as cardiac mRNA level of atrial natriuretic factor (ANF), a biomarker of cardiac hypertrophy and heart failure. After 4 weeks of TAC, results from electron microscopy and Western blot showed that cardiac autophagy was activated, evidenced by the increased expression of microtubule-associated protein-1 light chain 3-II (LC3-II), Beclin-1, caspase-3, and the formation of autophagosomes. Interestingly, cardiac autophagy was further increased by the treatment of atorvastatin for 4 weeks. Western blot analysis showed phosphorylated Akt and mammalian target of rapamycin (p-mTor) decreased in the heart of TAC versus sham mice, which were further decreased by atorvastatin treatment. Conclusions: These findings suggest that atorvastatin attenuates cardiac hypertrophy and dysfunction in TAC mice probably through its regulation on cardiac autophagy via Akt/mTor pathways.

Reduced insulin receptor signaling in the obese spontaneously hypertensive Koletsky rat

1997 ◽  
Vol 273 (5) ◽  
pp. E1014-E1023 ◽  
Author(s):  
Jacob E. Friedman ◽  
Tatsuya Ishizuka ◽  
Sha Liu ◽  
Craig J. Farrell ◽  
David Bedol ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Glucose Intolerance ◽  
Leptin Receptor ◽  
Spontaneously Hypertensive Rat ◽  
Regulatory Subunit ◽  
Oral Glucose ◽  
Spontaneously Hypertensive

Insulin resistance is associated with both obesity and hypertension. However, the cellular mechanisms of insulin resistance in genetic models of obese-hypertension have not been identified. The objective of the present study was to investigate the effects of genetic obesity on a background of inherited hypertension on initial components of the insulin signal transduction pathway and glucose transport in skeletal muscle and liver. Oral glucose tolerance testing in SHROB demonstrated a sustained postchallenge elevation in plasma glucose at 180 and 240 min compared with lean spontaneously hypertensive rat (SHR) littermates, which is suggestive of glucose intolerance. Fasting plasma insulin levels were elevated 18-fold in SHROB. The rate of insulin-stimulated 3- O-methylglucose transport was reduced 68% in isolated epitrochlearis muscles from the SHROB compared with SHR. Insulin-stimulated tyrosine phosphorylation of the insulin receptor β-subunit and insulin receptor substrate-1 (IRS-1) in intact skeletal muscle of SHROB was reduced by 36 and 23%, respectively, compared with SHR, due primarily to 32 and 60% decreases in insulin receptor and IRS-1 protein expression, respectively. The amounts of p85α regulatory subunit of phosphatidylinositol-3-kinase and GLUT-4 protein were reduced by 28 and 25% in SHROB muscle compared with SHR. In the liver of SHROB, the effect of insulin on tyrosine phosphorylation of IRS-1 was not changed, but insulin receptor phosphorylation was decreased by 41%, compared with SHR, due to a 30% reduction in insulin receptor levels. Our observations suggest that the leptin receptor mutation fak imposed on a hypertensive background results in extreme hyperinsulinemia, glucose intolerance, and decreased expression of postreceptor insulin signaling proteins in skeletal muscle. Despite these changes, hypertension is not exacerbated in SHROB compared with SHR, suggesting these metabolic abnormalities may not contribute to hypertension in this model of Syndrome X.

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