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Targeting metabolic disturbance in the diabetic heart.

Fuentes-Antrás J, Picatoste B, Ramírez E, Egido J, Tuñón J, Lorenzo Ó - Cardiovasc Diabetol (2015)

Bottom Line: In addition to the demonstrated burden of cardiovascular events associated with diabetes, diabetic cardiomyopathy partly explains why diabetic patients are subject to a greater risk of heart failure and a worse outcome after myocardial ischemia.The raising prevalence and accumulating costs of cardiovascular disease in diabetic patients underscore the deficiencies of tertiary prevention and call for a shift in medical treatment.It is becoming increasingly clearer that the effective prevention and treatment of diabetic cardiomyopathy require measures to regulate the metabolic derangement occurring in the heart rather than merely restoring suitable systemic parameters.

View Article: PubMed Central - PubMed

ABSTRACT
Diabetic cardiomyopathy is defined as ventricular dysfunction initiated by alterations in cardiac energy substrates in the absence of coronary artery disease and hypertension. In addition to the demonstrated burden of cardiovascular events associated with diabetes, diabetic cardiomyopathy partly explains why diabetic patients are subject to a greater risk of heart failure and a worse outcome after myocardial ischemia. The raising prevalence and accumulating costs of cardiovascular disease in diabetic patients underscore the deficiencies of tertiary prevention and call for a shift in medical treatment. It is becoming increasingly clearer that the effective prevention and treatment of diabetic cardiomyopathy require measures to regulate the metabolic derangement occurring in the heart rather than merely restoring suitable systemic parameters. Recent research has provided deeper insight into the metabolic etiology of diabetic cardiomyopathy and numerous heart-specific targets that may substitute or reinforce current strategies. From both experimental and translational perspectives, in this review we first discuss the progress made with conventional therapies, and then focus on the need for prospective metabolic targets that may avert myocardial vulnerability and functional decline in next-generation diabetic care.

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Metabolic disturbance in the diabetic heart and prospective therapeutic targets. Thickened lines denote activated pathways, and dotted lines denote reduced pathway. (1) The therapeutic reduction of FAT/CD36 activity may attenuate myocardial steatosis, inflammation and oxidative stress, and further improve the energetic yield by shifting metabolism to glucose utilization. (2) Induction of specific PPAR isoforms such as PPARβ/δ may provide cardioprotection by down-regulating FA transporters and TAG synthesis and up-regulating GLUT4, β-oxidation enzymes, and anti-inflammatory transcripts. (3) The elevation of incretin signaling by GLP-1 agonists (or DPP-4 inhibitors) may also control insulin resistance and hyperlipidemia. GLP-1R-dependent actions may include the regulation of glucose and FA receptors trafficking to the sarcolemma, and the amelioration of apoptosis and fibrosis. IR, insulin receptor; FA-CoA, fatty acid-coenzyme A.
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Fig1: Metabolic disturbance in the diabetic heart and prospective therapeutic targets. Thickened lines denote activated pathways, and dotted lines denote reduced pathway. (1) The therapeutic reduction of FAT/CD36 activity may attenuate myocardial steatosis, inflammation and oxidative stress, and further improve the energetic yield by shifting metabolism to glucose utilization. (2) Induction of specific PPAR isoforms such as PPARβ/δ may provide cardioprotection by down-regulating FA transporters and TAG synthesis and up-regulating GLUT4, β-oxidation enzymes, and anti-inflammatory transcripts. (3) The elevation of incretin signaling by GLP-1 agonists (or DPP-4 inhibitors) may also control insulin resistance and hyperlipidemia. GLP-1R-dependent actions may include the regulation of glucose and FA receptors trafficking to the sarcolemma, and the amelioration of apoptosis and fibrosis. IR, insulin receptor; FA-CoA, fatty acid-coenzyme A.

Mentions: As therapeutic resources currently allow diabetic patients to manage glucose homeostasis, reach near-normal life expectancy and delay microvascular complications, it is unacceptable that heart-risk reductions are not yet properly achieved. By targeting DCM we may prevent cardiac functional decline and improve the response to potentially lethal coronary events. Although the fine-tune mechanisms leading to DCM remain partially opaque, restoring cardiac energy metabolism seem to be a cornerstone. In light of the experimental data provided here, we may outline a potential therapeutic strategy focused on correcting the etiological imbalance between lipids and glucose as fuel substrates (Figure 1). Excessive FA uptake, accumulation, and utilization may be attenuated by down-modulating cardiac FAT/CD36 and/or stimulating its transcriptional regulator PPARβ/δ. Subsequent up-regulation of GLUT4 and glycolitic enzymes would elevate the ATP/O2-consumption ratio and reduce hyperglycemia and AGE generation. Insulin resistance and hyperlipidemia may be also controlled by statins, and perhaps more prospectively by incretin-based drugs, which would balance the content of sarcolemmal glucose and FA transporters and exert anti-apoptotic/fibrotic benefits in the cardiomyocyte. In addition, FAT/CD36 interference may provide further protection against myocardial inflammation and stiffness through the attenuation of TLR4-NLRP3 signaling. The design of these cardioprotective plans, however, may lead to difficulties concerning the possibility of provoking other end-organ complications associated with glucotoxicity. To overcome these hurdles, the assessment of differential traits, stages and pathogenic factors in each diabetic patient becomes a clinical priority.Figure 1


Targeting metabolic disturbance in the diabetic heart.

Fuentes-Antrás J, Picatoste B, Ramírez E, Egido J, Tuñón J, Lorenzo Ó - Cardiovasc Diabetol (2015)

Metabolic disturbance in the diabetic heart and prospective therapeutic targets. Thickened lines denote activated pathways, and dotted lines denote reduced pathway. (1) The therapeutic reduction of FAT/CD36 activity may attenuate myocardial steatosis, inflammation and oxidative stress, and further improve the energetic yield by shifting metabolism to glucose utilization. (2) Induction of specific PPAR isoforms such as PPARβ/δ may provide cardioprotection by down-regulating FA transporters and TAG synthesis and up-regulating GLUT4, β-oxidation enzymes, and anti-inflammatory transcripts. (3) The elevation of incretin signaling by GLP-1 agonists (or DPP-4 inhibitors) may also control insulin resistance and hyperlipidemia. GLP-1R-dependent actions may include the regulation of glucose and FA receptors trafficking to the sarcolemma, and the amelioration of apoptosis and fibrosis. IR, insulin receptor; FA-CoA, fatty acid-coenzyme A.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4328972&req=5

Fig1: Metabolic disturbance in the diabetic heart and prospective therapeutic targets. Thickened lines denote activated pathways, and dotted lines denote reduced pathway. (1) The therapeutic reduction of FAT/CD36 activity may attenuate myocardial steatosis, inflammation and oxidative stress, and further improve the energetic yield by shifting metabolism to glucose utilization. (2) Induction of specific PPAR isoforms such as PPARβ/δ may provide cardioprotection by down-regulating FA transporters and TAG synthesis and up-regulating GLUT4, β-oxidation enzymes, and anti-inflammatory transcripts. (3) The elevation of incretin signaling by GLP-1 agonists (or DPP-4 inhibitors) may also control insulin resistance and hyperlipidemia. GLP-1R-dependent actions may include the regulation of glucose and FA receptors trafficking to the sarcolemma, and the amelioration of apoptosis and fibrosis. IR, insulin receptor; FA-CoA, fatty acid-coenzyme A.
Mentions: As therapeutic resources currently allow diabetic patients to manage glucose homeostasis, reach near-normal life expectancy and delay microvascular complications, it is unacceptable that heart-risk reductions are not yet properly achieved. By targeting DCM we may prevent cardiac functional decline and improve the response to potentially lethal coronary events. Although the fine-tune mechanisms leading to DCM remain partially opaque, restoring cardiac energy metabolism seem to be a cornerstone. In light of the experimental data provided here, we may outline a potential therapeutic strategy focused on correcting the etiological imbalance between lipids and glucose as fuel substrates (Figure 1). Excessive FA uptake, accumulation, and utilization may be attenuated by down-modulating cardiac FAT/CD36 and/or stimulating its transcriptional regulator PPARβ/δ. Subsequent up-regulation of GLUT4 and glycolitic enzymes would elevate the ATP/O2-consumption ratio and reduce hyperglycemia and AGE generation. Insulin resistance and hyperlipidemia may be also controlled by statins, and perhaps more prospectively by incretin-based drugs, which would balance the content of sarcolemmal glucose and FA transporters and exert anti-apoptotic/fibrotic benefits in the cardiomyocyte. In addition, FAT/CD36 interference may provide further protection against myocardial inflammation and stiffness through the attenuation of TLR4-NLRP3 signaling. The design of these cardioprotective plans, however, may lead to difficulties concerning the possibility of provoking other end-organ complications associated with glucotoxicity. To overcome these hurdles, the assessment of differential traits, stages and pathogenic factors in each diabetic patient becomes a clinical priority.Figure 1

Bottom Line: In addition to the demonstrated burden of cardiovascular events associated with diabetes, diabetic cardiomyopathy partly explains why diabetic patients are subject to a greater risk of heart failure and a worse outcome after myocardial ischemia.The raising prevalence and accumulating costs of cardiovascular disease in diabetic patients underscore the deficiencies of tertiary prevention and call for a shift in medical treatment.It is becoming increasingly clearer that the effective prevention and treatment of diabetic cardiomyopathy require measures to regulate the metabolic derangement occurring in the heart rather than merely restoring suitable systemic parameters.

View Article: PubMed Central - PubMed

ABSTRACT
Diabetic cardiomyopathy is defined as ventricular dysfunction initiated by alterations in cardiac energy substrates in the absence of coronary artery disease and hypertension. In addition to the demonstrated burden of cardiovascular events associated with diabetes, diabetic cardiomyopathy partly explains why diabetic patients are subject to a greater risk of heart failure and a worse outcome after myocardial ischemia. The raising prevalence and accumulating costs of cardiovascular disease in diabetic patients underscore the deficiencies of tertiary prevention and call for a shift in medical treatment. It is becoming increasingly clearer that the effective prevention and treatment of diabetic cardiomyopathy require measures to regulate the metabolic derangement occurring in the heart rather than merely restoring suitable systemic parameters. Recent research has provided deeper insight into the metabolic etiology of diabetic cardiomyopathy and numerous heart-specific targets that may substitute or reinforce current strategies. From both experimental and translational perspectives, in this review we first discuss the progress made with conventional therapies, and then focus on the need for prospective metabolic targets that may avert myocardial vulnerability and functional decline in next-generation diabetic care.

Show MeSH
Related in: MedlinePlus