Insulin Increases Ceramide Synthesis in Skeletal Muscle

Hansen, Melissa E.; Tippetts, Trevor S.; Anderson, Madeline C.; Holub, Z; Moulton, Emma R.; Swensen, Adam; Prince, John T.; Bikman, Benjamin T.

doi:10.1155/2014/765784

Cited by 26 publications

(33 citation statements)

References 60 publications

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“…In mice, we found that prolonged insulin treatment resulted in reduced glucose and insulin tolerance, suggesting that insulin alone, independent of other variables, is capable of inducing insulin resistance. This observation corroborates evidence from several previous reports in humans and rodents wherein hyperinsulinemia from endogenous (e.g., insulinoma) [ 40 ] and exogenous (e.g., injections) [ 26 , 41 , 42 ] sources causes insulin resistance. This insulin-desensitizing effect of prolonged hyperinsulinemia is likely at least partially mediated via ceramide accrual [ 26 ].…”

Section: Discussionsupporting

confidence: 92%

“…), insulin has distinct downstream mediators; one mediator may be the sphingolipid ceramide. Ceramides are increasingly recognized as an injurious mediator of heart pathologies [ 21 – 25 ] and we have recently found that insulin increases ceramide biosynthesis and accrual in skeletal muscle [ 26 , 27 ]. In light of the evidence suggesting a role for insulin in the etiology of heart complications, the purpose of these experiments was to determine the effect of insulin on heart ceramides, as well as possible ceramide-induced alterations in mitochondrial function.…”

Section: Introductionmentioning

confidence: 99%

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Insulin treatment increases myocardial ceramide accumulation and disrupts cardiometabolic function

Hodson¹,

Tippetts²,

Bikman³

2015

Cardiovasc Diabetol

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BackgroundStates of hyperinsulinemia, particularly insulin resistance and type 2 diabetes mellitus, are becoming remarkably common, with roughly half a billion people likely to suffer from the disorder within the next 15 years. Along with this rise has been an associated increased burden of cardiovascular disease. Considering type 2 diabetics treated with insulin are more likely to suffer from heart complications, we sought to determine the specific effect of insulin on ceramide-dependent cardiometabolic risk factors, including insulin resistance and altered heart mitochondrial physiology.MethodsH9c2 cardiomyocytes and adult mice were treated with insulin with or without myriocin to inhibit ceramide biosynthesis. Insulin and glucose changes were tracked throughout the study and mitochondrial bioenergetics was determined in permeabilized cardiomyocytes and myocardium.ResultsHerein, we demonstrate that insulin is sufficient to disrupt heart mitochondrial respiration in both isolated cardiomyocytes and whole myocardium, possibly by increasing mitochondrial fission. Further, insulin increases ceramide accrual in a time-dependent manner, which is necessary for insulin-induced alterations in heart mitochondrial respiration and insulin resistance.ConclusionsCollectively, these observations have two implications. First, they indicate a pathological role of insulin in heart complications stemming from mitochondrial disruption. Second, they identify ceramide as a possible mediator of insulin-related heart disorders.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Insulin treatment increases myocardial ceramide accumulation and disrupts cardiometabolic function

Hodson¹,

Tippetts²,

Bikman³

2015

Cardiovasc Diabetol

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“…[29][30][31] Therefore, insulin is the most important factor in the regulation of plasma glucose homeostasis. Hyperinsulinemia is characterized as a condition where excess insulin is circulating in the blood, resulting from reduced sensitivity to insulin and disturbances in insulin .…”

Section: Discussionmentioning

confidence: 99%

Anti-Diabetic Effect ofAster sphathulifoliusin C57BL/KsJ-db/dbMice

Yin

Huang

Jung

et al. 2015

Journal of Medicinal Food

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In this study, we investigated the anti-diabetic effect of Aster sphathulifolius (AS) extract in C57BL/KsJ-db/db mice. The db/db mice were orally administered with AS 50% ethanol extract at concentrations of 50, 100, and 200 mg/kg/day (db/db-AS50, db/db-AS100, and db/db-AS200, respectively) for 10 weeks. Food and water intake, fasting blood glucose concentrations, blood glycosylated hemoglobin levels, and plasma insulin levels were significantly lower in the db/db-AS200 group than in the vehicle-treated db/db group; whereas glucose tolerance was significantly improved in the db/db-AS200 group. Moreover, AS dose dependently increased both insulin receptor substrate 1 and glucose transporter type 4 expression in skeletal muscle, significantly increased glucokinase expression, and decreased glucose 6-phosphatase and phosphoenolpyruvate carboxykinase expressions in the liver. The expressions of transcription factors, such as sterol-regulatory element-binding protein, peroxisome proliferator-activated receptor γ, and adipocyte protein 2, were upregulated in adipose tissue. Furthermore, immunohistochemical analysis showed that AS upregulated insulin production by increasing pancreatic β-cell mass. In summary, AS extract normalized hyperglycemia by multiple mechanisms: inhibition of glyconeogenesis, acceleration of glucose metabolism and lipid metabolism, and increase of glucose uptake. Using in vivo assays, this study has shown the potential of AS as a medicinal food and suggests the efficacy of AS for the use of prevention of diabetes.

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“…The organic phase was collected in a fresh vial and dried via vacuum centrifugation (Eppendorf Concentrator Plus). Lipids were then characterized and quantified using shotgun lipidomics on a Thermo ScientificLTQ Orbitrap XL mass spectrometer, as previously described (12).…”

Section: Methodsmentioning

confidence: 99%

Cardiomyocyte mitochondrial respiration is reduced by receptor for advanced glycation end-product signaling in a ceramide-dependent manner

Nelson

Swensen

Winden

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Cigarette smoke exposure is associated with an increased risk of cardiovascular complications. The role of advanced glycation end products (AGEs) is already well established in numerous comorbidities, including cardiomyopathy. Given the role of AGEs and their receptor, RAGE, in activating inflammatory pathways, we sought to determine whether ceramides could be a mediator of RAGE-induced altered heart mitochondrial function. Using an in vitro model, we treated H9C2 cardiomyocytes with the AGE carboxy-methyllysine before mitochondrial respiration assessment. We discovered that mitochondrial respiration was significantly impaired in AGE-treated cells, but not when cotreated with myriocin, an inhibitor of de novo ceramide biosynthesis. Moreover, we exposed wild-type and RAGE knockout mice to secondhand cigarette smoke and found reduced mitochondrial respiration in the left ventricular myocardium from wild-type mice, but RAGE knockout mice were protected from this effect. Finally, conditional overexpression of RAGE in the lungs of transgenic mice elicited a robust increase in left ventricular ceramides in the absence of smoke exposure. Taken together, these findings suggest a RAGE-ceramide axis as an important contributor to AGE-mediated disrupted cardiomyocyte mitochondrial function.

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Insulin Increases Ceramide Synthesis in Skeletal Muscle

Cited by 26 publications

References 60 publications

Insulin treatment increases myocardial ceramide accumulation and disrupts cardiometabolic function

Insulin treatment increases myocardial ceramide accumulation and disrupts cardiometabolic function

Anti-Diabetic Effect ofAster sphathulifoliusin C57BL/KsJ-db/dbMice

Cardiomyocyte mitochondrial respiration is reduced by receptor for advanced glycation end-product signaling in a ceramide-dependent manner

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