Number 25, 2004
Heart failure in diabetes

Metabolic derangements in insulin resistance

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Danielle Feuvray
Physiologie Cellulaire, Université Paris-Sud XI, France
Correspondence: Danielle Feuvray, Université Paris XI – CNRS UMR 8078, Hôpital M. Lannelongue, 92350 Le Plessis Robinson, France.
Tel: +33 1 40 94 67 32, fax: +33 1 46 30 45 64, e-mail: danielle.feuvray@ibaic.u-psud.fr

Introduction
The action of insulin on the heart, as in other tissues, is initiated by the binding of insulin to its specific cell-surface receptor. Insulin binds to its receptor in the major insulin-responsive tissues of the body, namely skeletal muscle, adipose tissue, liver, and myocardium. This triggers the activation of a signaling pathway the function of which is first to stimulate the transport of nutrients, such as glucose, from the blood supply to these tissues and, secondly, to promote the conversion of these nutrients into storage macromolecules such as glycogen. Failure to regulate the uptake and storage of nutrients efficiently after feeding results in diabetes. Type 1 (insulin-dependent) diabetes is characterized by the failure to synthesize insulin and is the underlying abnormality in approximately 10% of patients with diabetes; it normally occurs in childhood. In contrast, type 2 (non-insulin-dependent) diabetes accounts for about 90% of patients with diabetes and usually occurs in adults. In this form of diabetes, the target tissues become resistant to the effects of insulin, presumably because the insulin signaling pathway is impaired. Insulin resistance is an early event in the development of type 2 diabetes, in which insulin production is normal but there are deficient cellular responses to insulin. Patients suffering from both forms of diabetes suffer long-term complications, including heart disease that occurs independently of obstructive coronary artery disease [1–4] and is therefore termed diabetic cardiomyopathy. Although little is known about the pathogenesis of diabetic cardiomyopathy, evidence has emerged that it may be related to derangements in myocardial energy metabolism [5,6].

Derangements in myocardial metabolism
Under normal conditions, myocardial energy substrate preference varies in a dynamic manner to fulfill the tremendous energy needs of the postnatal mammalian heart. Whereas the fetal heart relies primarily on glucose and lactate, after birth the capacity for mitochondrial fatty acid oxidation increases markedly, affording the adult heart the option of using glucose or fatty acids to meet energy demands, depending on dietary and physiologic conditions (for review, see [7]). In diabetes, this capacity for switches in cardiac energy substrate becomes constrained because of the importance of insulin in the control of myocardial glucose uptake and utilization (Figure 1).

Insulin signaling and glucose metabolism
Insulin signaling is mediated by complex multiple cascade pathways characterized both spatially and temporally [11] (for reviews, see [12,13]). Insulin signaling is initiated by the binding of insulin to the insulin receptor. This activates the tyrosine kinase activity of the insulin receptor, leading to insulin receptor autophosphorylation and to the subsequent phosphorylation of insulin receptor substrate (IRS). Insulin signaling downstream of IRS is mediated by at least two pathways. The first leads to the activation of the mitogen-activated protein kinase (MAPK) cascade, which in turn activates MAPK-activated protein kinase-1 (also known as p90 ribosomal S6 kinase, p90rsk). There is no convincing evidence that this pathway is activated by insulin in the heart. The other pathway that is present in heart is specific for the short-term effects of insulin. It involves activation of a lipid kinase termed phosphatidylinositol 3-kinase (PI3-K). PI3-K phosphorylates its physiological substrate phosphatidylinositol (4,5) bisphosphate [PtdIns(4,5)-P₂] to generate phosphatidylinositol (3,4,5) triphosphate [PtdIns(3,4,5)-P₃]. It was the finding that inhibitors of PI3-kinase, or the overexpression of dominant negative mutants of this enzyme, inhibit most of the cellular responses to insulin that established PtdIns(3,4,5)-P₃ as a key second messenger in the insulin-signaling pathway. PtdIns(3,4,5)-P₃ binds in turn to the pleckstrin homology domain of at least two different serine/threonine protein kinases, namely phosphoinositide-dependent protein kinase-1 (PDK-1) and PKB (protein kinase B, also known as Akt). PDK-1 participates in the phosphorylation and activation of several downstream protein kinases, including PKB (for review, see [14]). It is now generally accepted that PKB mediates most short-term effects of insulin and can regulate glucose metabolism at several levels (Figure 1), which include, among others, the stimulation of glycogen synthesis by phosphorylation and inactivation of glycogen synthase kinase 3 (GSK3), and the stimulation of glucose uptake.
Increased knowledge has shown that GSK3 is a broadly influential enzyme that is a crucial regulator of many cellular functions (for review, see [15]). Insulin-induced inactivation of GSK3 normally contributes to cellular responses to insulin, such as stimulation of glycogen synthesis (Figure 1). The mechanisms contributing to insulin resistance and type 2 diabetes are multifactorial, but one factor is inadequate inhibitory control of GSK3 [16]. As a result, GSK3 activity is above normal in diabetic rodents [16], and in skeletal muscle from patients with type 2 diabetes [17]. GSK3 generally opposes the actions of insulin. Thus GSK3 inhibits glycogen synthesis and alters the expression of genes regulated by insulin [18]. GSK3 was also shown to phosphorylate the insulin receptor coupled protein, IRS, which, in turn attenuates insulin signaling [16]. Evidence that GSK3 is an important regulator in insulin resistance comes from studies in which inhibitors of GSK3 enhanced responses to insulin in a variety of model systems [19–21]. For example, GSK3 inhibitors decreased blood glucose concentrations and stimulated glucose transport and glycogen synthesis in skeletal muscle from insulin-resistant Zucker rats [22,23], and increased IRS expression and glucose uptake in human skeletal muscle [24]. These findings indicate that deficient inhibitory control of GSK3 is an important factor in type 2 diabetes and that inhibitors of GSK3 could be therapeutically beneficial.
PKB/Akt, the key effector of PtdIns(3,4,5)-P₃, participates in the stimulation of glucose uptake through the recruitment of GLUT 4 transporters to the plasma membrane, although the exact targets for the various protein kinases have not been identified. Moreover, recent findings have shown that the stimulation of glucose transport by insulin also implicates a pathway that is independent of PI3-K. This pathway involves the tyrosine phosphorylation of the proto-oncogene Cbl, which activates the TC10 family of Rho GTP-binding proteins. These proteins then interact with unknown effector proteins to allow insulin-stimulated GLUT 4 translocation [11]. The stimulation of heart glycolysis by insulin involves not only the recruitment of the glucose transporter GLUT 4 to the plasma membrane, but also the activation of 6-phosphofructo-2-kinase, which in turn increases the concentration of fructose 2,6-biphosphate, a well known stimulator of glycolysis. Therefore insulin forces the heart to consume glucose.

Insulin signaling and fatty acid oxidation
An additional effect of insulin that has emerged from recent studies is that it also inhibits fatty acid oxidation. This effect of insulin occurs through inhibition of AMP-activated protein kinase (AMPK), a heterotrimeric enzyme (for review, see [25]) that acts as a key “metabolic switch��_ in the heart in the control of fatty oxidation (Figure 2). AMPK phosphorylates and inactivates key enzymes involved in ATP-consuming pathways. In the heart, AMPK stimulates fatty acid oxidation by inactivating acetyl coenzyme (CoA) carboxylase and so decreasing the concentration of malonyl CoA, which inhibits the entry of long-chain fatty acids into the mitochondria and their subsequent oxidation [26,27]. It has been shown that AMPK activation is antagonized in hearts treated with insulin [28]. The anti-AMPK effect of insulin was wortmannin-sensitive, like most short-term effects of insulin, suggesting that it is mediated by PI3-K. The metabolic consequences of the interaction between insulin and AMPK would be to increase malonyl CoA concentration and consequently to limit fatty acid oxidation. Therefore, the resistance of target tissues to the effects of insulin in type 2 diabetes presumably results in the impairment in the insulin signaling pathway. As a consequence, in the uncontrolled diabetic state, because of the importance of insulin in the control of myocardial glucose uptake and utilization, the heart relies almost exclusively on fatty acid oxidation for its ATP requirements (for reviews, see [6,29]).

Fatty acid utilization or glucose utilization?
Cardiac fatty acid utilization pathways are controlled, in part, at the gene regulatory level. Recent studies have demonstrated an important role for the nuclear receptor peroxisome proliferator-activated receptor α (PPARα) in the transcriptional control of genes involved in cardiac fatty acid uptake and oxidation (for review, see [30]). In an attempt to model the metabolic derangements of the diabetic heart, mice with cardiac-specific overexpression of the nuclear receptor PPARα (MHC-PPAR) were produced and characterized [31]. The expression of PPARα target genes involved in cardiac fatty acid uptake and oxidation pathways was increased in MHC-PPAR mice. Surprisingly, the expression of genes involved in glucose transport and utilization was reciprocally repressed in MHC-PPAR hearts. Consistent with the gene expression profile, myocardial fatty acid oxidation rates were increased and glucose uptake and oxidation decreased in MHC-PPAR mice – a metabolic phenotype strikingly similar to that of the diabetic heart. In addition, MHC-PPAR hearts exhibited signatures of diabetic cardiomyopathy, including ventricular hypertrophy in association with activated expression of hypertrophic gene markers, and alterations in systolic ventricular function that were dependent on the expression of transgenes.
An important question raised by these results relates to the mechanistic link between altered myocardial energy metabolism and cardiac dysfunction in the diabetic heart. It is possible that, in the context of high-level fatty acid uptake and mitochondrial β-oxidation, toxic lipid intermediates accumulate within cardiac myocytes [5]. Reliance on fatty acid oxidation for ATP production, which results in greater mitochondrial oxygen consumption costs compared with glycolysis and glucose oxidation, could also contribute to ventricular dysfunction. Reduced myocardial utilization of glucose may also account for the observed cardiac dysfunction in the MHC-PPAR mice. Previous studies of the ischemic and reperfused heart have indeed indicated that reductions in glycolysis and glucose oxidation are associated with diminished ventricular function [32,33]. In addition, fatty acid-induced insulin resistance has been well described and has been proposed to play a part in the development of type 2 diabetes [34,35]. In this respect, recent evidence indicates that fatty acid-induced insulin resistance involves alterations at the level of glucose transport secondary to derangements in insulin signaling [36,37]. The observation that glucose uptake and utilization can be altered in the heart secondary to PPARα-mediated increases in fatty acid utilization suggests the intriguing possibility that some forms of insulin resistance or type 2 diabetes could be caused by alterations in components of the PPARα regulatory complex or downstream genes involved in cellular fatty acid utilization.

Conclusions
Taken together, these findings highlight the complexity of alterations in myocardial cell metabolism associated with diabetes or insulin resistance, or both. Obviously, insulin signaling represents an important link between cardiac energy substrate utilization and the expression of genes that determine energy generation and energy consumption. Furthermore, it is worth mentioning that insulin resistance may also account for electrophysiological abnormalities of the diabetic heart. Very recent studies have investigated changes in cardiac potassium currents in the db/db mouse, a model of type 2 diabetes that exhibits obesity and insulin resistance. These K⁺ currents, both transient and sustained, control repolarization of the action potential and their attenuation prolongs the action potential and the Q–T interval of the electrocardiogram. Their magnitude was attenuated over time in db/db mice [38]. Interestingly, the age-dependent pattern of attenuation of K⁺ currents was similar to changes in glucose oxidation [39].
Understanding the nature of repolarizing current attenuation and its underlying mechanisms is of vital importance. These results in mouse models may apply to humans, as a prolongation of the Q–T interval, measured in the electrocardiogram of diabetic patients [40,41] reflects a longer action potential, as would occur if repolarizing currents were attenuated. In addition, Shimoni et al [38] used cells isolated from cardiomyocyte-specific insulin receptor knockout mice. This allowed the direct demonstration that insulin regulated the magnitude of the K⁺ current, in the absence of other confounding factors.
In type 2 diabetes, the target tissues become resistant to the effects of insulin, presumably because the insulin signaling pathway is impaired. However, our understanding of derangements in this pathway and in other transduction pathway(s) [42] in myocardial cells is far from being complete. Future studies in genetically engineered animal models, such as mice with cardiomyocyte-selective ablation of the insulin receptor or transgenic mice overexpressing the human insulin-regulatable glucose transporter (hGLUT 4) [43,44] should help to dissect the complex pathophysiology of the action of insulin on the heart and contribute to the establishment of pharmacological interventions to improve cardiac metabolism and reduce the cardiac dysfunction that is induced by insulin resistance. ▪

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REFERENCES

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