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.

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A systems biology analysis connects insulin receptor signaling with glucose transporter translocation in rat adipocytes

Journal of Biological Chemistry ◽

10.1074/jbc.m117.787515 ◽

2017 ◽

Vol 292 (27) ◽

pp. 11206-11217 ◽

Cited By ~ 4

Author(s):

Niclas Bergqvist ◽

Elin Nyman ◽

Gunnar Cedersund ◽

Karin G. Stenkula

Keyword(s):

Systems Biology ◽

Insulin Receptor ◽

Glucose Transporter ◽

Receptor Signaling ◽

Rat Adipocytes ◽

Insulin Receptor Signaling

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PDGF-induced vascular smooth muscle cell proliferation is associated with dysregulation of insulin receptor substrates

AJP Cell Physiology ◽

10.1152/ajpcell.00670.2008 ◽

2011 ◽

Vol 300 (6) ◽

pp. C1375-C1385 ◽

Cited By ~ 24

Author(s):

Yan Zhao ◽

Swarajit K. Biswas ◽

Patrick H. McNulty ◽

Mark Kozak ◽

John Y. Jun ◽

...

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Insulin Receptor ◽

Serine Phosphorylation ◽

Phenotypic Switching ◽

Dependent Manner ◽

Receptor Signaling ◽

Vsmc Proliferation ◽

Insulin Receptor Substrates ◽

Insulin Receptor Signaling

In vascular smooth muscle cells (VSMCs), platelet-derived growth factor (PDGF) plays a major role in inducing phenotypic switching from contractile to proliferative state. Importantly, VSMC phenotypic switching is also determined by the phosphorylation state/expression levels of insulin receptor substrate (IRS), an intermediary signaling component that is shared by insulin and IGF-I. To date, the roles of PDGF-induced key proliferative signaling components including Akt, p70S6kinase, and ERK1/2 on the serine phosphorylation/expression of IRS-1 and IRS-2 isoforms remain unclear in VSMCs. We hypothesize that PDGF-induced VSMC proliferation is associated with dysregulation of insulin receptor substrates. Using human aortic VSMCs, we demonstrate that prolonged PDGF treatment led to sustained increases in the phosphorylation of protein kinases such as Akt, p70S6kinase, and ERK1/2, which mediate VSMC proliferation. In addition, PDGF enhanced IRS-1/IRS-2 serine phosphorylation and downregulated IRS-2 expression in a time- and concentration-dependent manner. Notably, phosphoinositide 3-kinase (PI 3-kinase) inhibitor (PI-103) and mammalian target of rapamycin inhibitor (rapamycin), which abolished PDGF-induced Akt and p70S6kinase phosphorylation, respectively, blocked PDGF-induced IRS-1 serine phosphorylation and IRS-2 downregulation. In contrast, MEK1/ERK inhibitor (U0126) failed to block PDGF-induced IRS-1 serine phosphorylation and IRS-2 downregulation. PDGF-induced IRS-2 downregulation was prevented by lactacystin, an inhibitor of proteasomal degradation. Functionally, PDGF-mediated IRS-1/IRS-2 dysregulation resulted in the attenuation of insulin-induced IRS-1/IRS-2-associated PI 3-kinase activity. Pharmacological inhibition of PDGF receptor tyrosine kinase with imatinib prevented IRS-1/IRS-2 dysregulation and restored insulin receptor signaling. In conclusion, strategies to inhibit PDGF receptors would not only inhibit neointimal growth but may provide new therapeutic options to prevent dysregulated insulin receptor signaling in VSMCs in nondiabetic and diabetic states.

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Faculty Opinions recommendation of Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1116068.573945 ◽

2008 ◽

Author(s):

Thomas Biederer

Keyword(s):

Insulin Receptor ◽

Receptor Signaling ◽

Dendritic Plasticity ◽

Insulin Receptor Signaling ◽

Circuit Function

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Faculty Opinions recommendation of Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1116068.572043 ◽

2008 ◽

Author(s):

Elke Stein

Keyword(s):

Insulin Receptor ◽

Receptor Signaling ◽

Dendritic Plasticity ◽

Insulin Receptor Signaling ◽

Circuit Function

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Insulin-mimetic and insulin-sensitizing activities of a pentacyclic triterpenoid insulin receptor activator

Biochemical Journal ◽

10.1042/bj20061123 ◽

2007 ◽

Vol 403 (2) ◽

pp. 243-250 ◽

Cited By ~ 77

Author(s):

Seung H. Jung ◽

Yun J. Ha ◽

Eun K. Shim ◽

Soo Y. Choi ◽

Jing L. Jin ◽

...

Keyword(s):

Insulin Receptor ◽

Tyrosine Phosphorylation ◽

Glucose Transporter ◽

Glycogen Synthase ◽

Chinese Hamster Ovary Cells ◽

Chinese Hamster ◽

Β Subunit ◽

Insulin Sensitizer ◽

Insulin Mimetic ◽

Pentacyclic Triterpenoid

Five pentacyclic triterpenoids isolated from Campsis grandiflora were tested for insulin-mimetic and insulin-sensitizing activity. The compounds enhanced the activity of insulin on tyrosine phosphorylation of the IR (insulin receptor) β-subunit in CHO/IR (Chinese-hamster ovary cells expressing human IR). Among the compounds tested, CG7 (ursolic acid) showed the greatest enhancement and CG11 (myrianthic acid) the least. We characterized the effect of CG7 further, and showed that it acted as an effective insulin-mimetic agent at doses above 50 μg/ml and as an insulin-sensitizer at doses as low as 1 μg/ml. Additional experiments showed that CG7 increased the number of IRs that were activated by insulin. This indicates that a major mechanism by which CG7 enhances total IR auto-phosphorylation is by promoting the tyrosine phosphorylation of additional IRs. CG7 not only potentiated insulin-mediated signalling (tyrosine phosphorylation of the IR β-subunit, phosphorylation of Akt and glycogen synthase kinase-3β), but also enhanced the effect of insulin on translocation of glucose transporter 4 in a classical insulin-sensitive cell line, 3T3-L1 adipocytes. The results of the present study demonstrate that a specific pentacyclic triterpenoid, CG7, exerts an insulin-sensitizing effect as an IR activator in CHO/IR cells and adipocytes. The enhancement of insulin activity by CG7 may be useful for developing a new class of specific IR activators for treatment of Type 1 and Type 2 diabetes.

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