Myocardial insulin resistance associated with chronic hypertriglyceridemia and increased FFA levels in Type 2 diabetic patients

Monti, Lucilla D.; Landoni, Claudio; Setola, Emanuela; Galluccio, Elena; Lucotti, Pietro; Sandoli, E. P.; Origgi, Anna; Lucignani, Giovanni; Piatti, PierMarco; Fazio, Ferruccio

doi:10.1152/ajpheart.00629.2003

Cited by 46 publications

(26 citation statements)

References 38 publications

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“…In line with these suggestions, our group (19), by means of positron emission tomography, showed that high FFA levels are to be considered an additional risk for myocardial insulin resistance associated with endothelial dysfunction, in type 2 diabetic patients without cardiovascular disease.…”

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confidence: 64%

Metabolic and endothelial effects of trimetazidine on forearm skeletal muscle in patients with type 2 diabetes and ischemic cardiomyopathy

Monti¹,

Setola²,

Fragasso³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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. Metabolic and endothelial effects of trimetazidine on forearm skeletal muscle in patients with type 2 diabetes and ischemic cardiomyopathy. Am J Physiol Endocrinol Metab 290: E54 -E59, 2006. First published September 20, 2005 doi:10.1152/ajpendo.00083.2005The aim of the present study was to evaluate the effect of prolonged inhibition of ␤-oxidation on glucose and lipid muscle forearm metabolism and cGMP and endothelin-1 forearm release in patients with type 2 diabetes mellitus and ischemic cardiomyopathy. Fifteen patients were randomly allocated in a double-blind cross-over parallel study with trimetazidine (20 mg tid) or placebo lasting 15 days. At the end of each period, all patients underwent euglycemic hyperinsulinemic clamps with forearm indirect calorimetry and endothelial balance of vasodilator and vasoconstricor factors. Compared with placebo, trimetazidine induced 1) an increase in insulin-induced forearm glucose uptake and glucose oxidation accompained by a reduction in forearm lipid oxidation and citrate release and 2) a decrease of endothelin-1 release paralleled by a significant increase in forearm cGMP release. Forearm glucose oxidation significantly correlated with cGMP release (r ϭ 0.37, P Ͻ 0.04), whereas forearm lipid oxidation positively correlated with endothelin-1 release (r ϭ 0.40, P Ͻ 0.03). In conclusion, for the first time, we demonstrated that insulin-induced forearm glucose oxidation and forearm cGMP release were increased whereas forearm endothelin-1 release was decreased during trimetazidine treatment. Muscle's metabolic and vascular effects of trimetazidine add new interest in the use of trimetazidine in type 2 diabetic patients with cardiovascular disease. endothelium; insulin resistance INSULIN RESISTANCE CHARACTERIZES type 2 diabetes. The impairment in insulin action in type 2 diabetes is multifaceted and has been found in both cardiac and skeletal muscle (29). Nuutila et al. (22) demonstrated that heart and arm skeletal muscle glucose uptakes are inversely related to serum free fatty acid (FFA) levels and increased FFA flux from adipose tissue to nonadipose tissue, resulting from abnormalities of fat metabolism, and participates in and amplifies many of the fundamental metabolic derangements that are characteristic of the insulin resistance syndrome and type 2 diabetes (17).In addition, new and interesting findings suggest that raised FFA levels not only impair glucose uptake in heart and skeletal muscle but also cause alterations in the metabolism of vascular endothelium, leading to premature cardiovascular disease (31).

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confidence: 64%

Metabolic and endothelial effects of trimetazidine on forearm skeletal muscle in patients with type 2 diabetes and ischemic cardiomyopathy

Monti¹,

Setola²,

Fragasso³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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“…Thus cardiac insulin resistance is a feature of db/db mice, at least with respect to deoxyglucose uptake. It must be acknowledged, however, that the degree of cardiac insulin resistance in db/db mice in vivo could be more pronounced because of the presence of circulating factors such as elevated plasma FA concentrations and adipokines (25,28,30). Therefore, an important objective for future investigations will be to investigate insulin sensitivity of the heart and other insulin target organs with in vivo methodologies applied to db/db mice.…”

Section: Discussionmentioning

confidence: 99%

Metabolic effects of insulin on cardiomyocytes from control and diabeticdb/dbmouse hearts

Carroll

Carley

Dyck

et al. 2005

American Journal of Physiology-Endocrinology and Metabolism

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Diabetic db/db mice exhibit profound insulin resistance in vivo, but the specific degree of cardiac insensitivity to insulin has not been assessed. Therefore, the effect of insulin on cardiomyocytes from db/db hearts was assessed by measuring two metabolic responses (deoxyglucose uptake and fatty acid oxidation) and the phosphorylation of two enzymes in the insulinsignaling cascade [Akt and AMP-activated protein kinase (AMPK)]. Maximal insulin-stimulated deoxyglucose transport was reduced to 58 and 40% of control in cardiomyocytes from db/db mice at two ages (6 and 12 wk). Insulin-stimulated deoxyglucose uptake was also reduced in myocytes from transgenic db/db mice overexpressing the insulinsensitive glucose transporter (db/db-hGLUT4). Treatment of db/db mice for 1 wk with an insulin-sensitizing peroxisome proliferatoractivated receptor-␥ agonist (COOH) completely normalized insulinstimulated deoxyglucose uptake. Insulin had no direct effect on palmitate oxidation by either control or db/db cardiomyocytes, but the combination of insulin and glucose reduced palmitate oxidation, likely an indirect effect secondary to increased glucose uptake. Insulin had no effect on AMPK phosphorylation from either control or db/db cardiomyocytes. Insulin increased the phosphorylation of Akt in all cardiomyocyte preparations (control, db/db, COOH-treated db/db) to the same extent. Thus insulin has selective metabolic actions in mouse cardiomyocytes; deoxyglucose uptake and Akt phosphorylation are increased, but fatty acid oxidation and AMPK phosphorylation are unchanged. Insulin resistance in db/db cardiomyocytes is manifested by reduced insulin-stimulated deoxyglucose uptake. cardiac metabolism; glucose uptake; fatty acid oxidation DIABETIC DB/DB MICE PROVIDE a monogenic model of obesity and type 2 diabetes (13, 24). Insulin resistance is the earliest phenotypic change in db/db mice, evident at 10 -12 days of age (14). At 8 -12 wk, diabetic db/db mice exhibit glucose intolerance in response to an oral glucose challenge (18) and a reduced hypoglycemic response to a bolus injection of insulin (21) compared with nondiabetic control db/ϩ mice. Severe insulin resistance is also observed with hyperglycemic hyperinsulinemic clamps (9). Recently, Carley et al. (10) reported that chronic (6 wk) oral administration of an insulin-sensitizing peroxisome proliferator-activated receptor-␥ (PPAR␥) agonist (COOH) to db/db mice improved diabetic status by normalizing hyperglycemia.On the basis of glucose homeostasis, skeletal muscle is usually the dominant organ responsible for in vivo insulin resistance (34). However, mechanisms of insulin resistance can be tissue specific. In humans with type 2 diabetes, heart glucose uptake is insulin sensitive despite insulin resistance in skeletal muscle (20,35).Insulin has a number of acute metabolic actions on the heart (8): stimulation of glucose uptake, glycogen synthesis, glycolysis and glucose oxidation, and inhibition of fatty acid (FA) oxidation. Insulin stimulated glycolytic rates in perfused hea...

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“…Longterm estrogen replacement treatment might protect the cardiovascular system by decreasing blood pressure and inducing the expression of IRS-1 in myocardium. 22 Based upon (i) our recently published observation that E2 treatment decreases the FFA plasma level, 23 which is important for cardiac insulin sensitivity and heart fuel utilization, 24,25 (ii) data indicating that insulin and E2 regulate the same processes in the heart, 20 (iii) reports that E2 exerts non-genomic effects through the PI3K/Akt pathway, 26,27 and (iv) data indicating that E2 regulates genes of some insulin signaling molecules, [28][29][30] we initiated the present study on the hypothesis that E2 unquestionably influences heart insulin signaling.…”

Section: Introductionmentioning

confidence: 99%

Impact of estradiol on insulin signaling in the rat heart

Korićanac¹,

Milosavljevic²,

Stojiljković³

et al. 2009

Cell Biochemistry & Function

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It is well known that variation in the concentration of estrogens affects insulin action. In this study we examine the impact of estradiol (E2) on insulin signaling in the rat heart. Ovariectomized female rats were treated with E2 6 h prior to analysis of basal protein and mRNA content of insulin signaling molecules, and additionally with insulin 30 min before the experiment to delineate E2 effects on phosphorylations and molecular associations relevant for insulin signaling. The results show that E2 decreased insulin receptor (IR) tyrosine phosphorylation, while it did not alter IR protein and mRNA content. E2 administration did not change IR substrate 1 (IRS-1) protein content and tyrosine phosphorylation, while decreased mRNA content and increased its association with the p85 subunit of phosphatidylinositol 3-kinase (PI3K). E2 decreased protein and mRNA content of IR substrate 2 (IRS-2), while did not change IRS-2 tyrosine phosphorylation and IRS-2 association with p85. The increase of IRS-1/p85 is accompanied by increase of p85 protein and mRNA levels, and by stimulation of protein kinase B (Akt) Ser(473) phosphorylation. In contrast, Akt protein and mRNA content were not changed. In summary, although in some aspects cardiac insulin signaling is obviously improved by E2 treatment (increase of p85 mRNA and protein levels, enhancement of IRS-1/p85 association and Ser(473)Akt phosphorylation), the observed decrease of IR tyrosine phosphorylation, IRS-2 protein content, and IRSs mRNA contents, suggest very complex interplay of beneficial and suppressive effects of E2, both genomic and non-genomic, in regulation of heart insulin signaling.

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Myocardial insulin resistance associated with chronic hypertriglyceridemia and increased FFA levels in Type 2 diabetic patients

Cited by 46 publications

References 38 publications

Metabolic and endothelial effects of trimetazidine on forearm skeletal muscle in patients with type 2 diabetes and ischemic cardiomyopathy

Metabolic and endothelial effects of trimetazidine on forearm skeletal muscle in patients with type 2 diabetes and ischemic cardiomyopathy

Metabolic effects of insulin on cardiomyocytes from control and diabeticdb/dbmouse hearts

Impact of estradiol on insulin signaling in the rat heart

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