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Diabetic Cardiomyopathy: An Immunometabolic Perspective

View Article: PubMed Central - PubMed

ABSTRACT

The heart possesses a remarkable inherent capability to adapt itself to a wide array of genetic and extrinsic factors to maintain contractile function. Failure to sustain its compensatory responses results in cardiac dysfunction, leading to cardiomyopathy. Diabetic cardiomyopathy (DCM) is characterized by left ventricular hypertrophy and reduced diastolic function, with or without concurrent systolic dysfunction in the absence of hypertension and coronary artery disease. Changes in substrate metabolism, oxidative stress, endoplasmic reticulum stress, formation of extracellular matrix proteins, and advanced glycation end products constitute the early stage in DCM. These early events are followed by steatosis (accumulation of lipid droplets) in cardiomyocytes, which is followed by apoptosis, changes in immune responses with a consequent increase in fibrosis, remodeling of cardiomyocytes, and the resultant decrease in cardiac function. The heart is an omnivore, metabolically flexible, and consumes the highest amount of ATP in the body. Altered myocardial substrate and energy metabolism initiate the development of DCM. Diabetic hearts shift away from the utilization of glucose, rely almost completely on fatty acids (FAs) as the energy source, and become metabolically inflexible. Oxidation of FAs is metabolically inefficient as it consumes more energy. In addition to metabolic inflexibility and energy inefficiency, the diabetic heart suffers from impaired calcium handling with consequent alteration of relaxation–contraction dynamics leading to diastolic and systolic dysfunction. Sarcoplasmic reticulum (SR) plays a key role in excitation–contraction coupling as Ca2+ is transported into the SR by the SERCA2a (sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a) during cardiac relaxation. Diabetic cardiomyocytes display decreased SERCA2a activity and leaky Ca2+ release channel resulting in reduced SR calcium load. The diabetic heart also suffers from marked downregulation of novel cardioprotective microRNAs (miRNAs) discovered recently. Since immune responses and substrate energy metabolism are critically altered in diabetes, the present review will focus on immunometabolism and miRNAs.

No MeSH data available.


Related in: MedlinePlus

Schematic diagram showing changes in cardiac metabolism in diabetic cardiomyopathy. In the diabetic heart, glucose oxidation is inhibited at multiple steps: (i) uptake of glucose is inhibited by reduced expression of glucose transporter Glut4 as well as by blunted translocation of Glut4 in response to insulin (64, 65); (ii) inhibition of hexokinase activity by fatty acids (FAs) resulting in reduced conversion of glucose to glucose-6-phosphate (80); (iii) inhibition of phosphofructokinase activity by FA, leading to reduced formation of fructose-1,6-bisphosphate by fructose-6-phosphate (69); (iv) inhibition of pyruvate dehydrogenase phosphatase activity by FA resulting in reduced pyruvate dehydrogenase (PDH) activity, which leads to reduced conversion of pyruvate to acetyl CoA. In the diabetic heart, PPARα expression is activated by increased FA uptake (81, 82). Activated PPARα upregulates PDH kinase 4 enzymes, which inhibits PDH resulting in reduced production of acetyl CoA (83–85). FA transporters CD36 and FA transport protein import FAs into the cell. After import, FAs can be stored as triacylglycerol (TAG) or converted to fatty acyl CoA by fatty acyl-CoA synthetase (FACS). Carnitine palmitoyltransferase 1 (CPT1) transfers the acyl group of fatty acyl CoA to carnitine, which then shuttles into the mitochondria by carnitine translocase (CT). PPARα activates transcription of CPT1 (86). In the matrix, CPT2 reconverts the acylcarnitine back into free carnitine and fatty acyl CoA (87), which is then converted to acetyl CoA that can be used in the tricarboxylic acid to produce adenosine triphosphate by β-oxidation. Diabetes upregulates mitochondrial generation of reactive oxygen species (57, 88, 89), which affects Ca2+ signaling (90).
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Figure 1: Schematic diagram showing changes in cardiac metabolism in diabetic cardiomyopathy. In the diabetic heart, glucose oxidation is inhibited at multiple steps: (i) uptake of glucose is inhibited by reduced expression of glucose transporter Glut4 as well as by blunted translocation of Glut4 in response to insulin (64, 65); (ii) inhibition of hexokinase activity by fatty acids (FAs) resulting in reduced conversion of glucose to glucose-6-phosphate (80); (iii) inhibition of phosphofructokinase activity by FA, leading to reduced formation of fructose-1,6-bisphosphate by fructose-6-phosphate (69); (iv) inhibition of pyruvate dehydrogenase phosphatase activity by FA resulting in reduced pyruvate dehydrogenase (PDH) activity, which leads to reduced conversion of pyruvate to acetyl CoA. In the diabetic heart, PPARα expression is activated by increased FA uptake (81, 82). Activated PPARα upregulates PDH kinase 4 enzymes, which inhibits PDH resulting in reduced production of acetyl CoA (83–85). FA transporters CD36 and FA transport protein import FAs into the cell. After import, FAs can be stored as triacylglycerol (TAG) or converted to fatty acyl CoA by fatty acyl-CoA synthetase (FACS). Carnitine palmitoyltransferase 1 (CPT1) transfers the acyl group of fatty acyl CoA to carnitine, which then shuttles into the mitochondria by carnitine translocase (CT). PPARα activates transcription of CPT1 (86). In the matrix, CPT2 reconverts the acylcarnitine back into free carnitine and fatty acyl CoA (87), which is then converted to acetyl CoA that can be used in the tricarboxylic acid to produce adenosine triphosphate by β-oxidation. Diabetes upregulates mitochondrial generation of reactive oxygen species (57, 88, 89), which affects Ca2+ signaling (90).

Mentions: The heart consumes about 6 kg of ATP, or ~20 times its own weight, per day (48) that comes from the breakdown of fat, carbohydrate, protein, ketone bodies, or lactate. Of note, the amount of ATP in the heart is small (~10 mM, enough for only a few beats) compared with the demand (~10,000 times greater) (49). About 95% of total energy is generated from oxidative phosphorylation of FAs and glucose (50–52). A dramatic metabolic shift takes place in diabetic heart, as they rely almost completely on FAs for their energy source. As for example, 46 atoms of oxygen are required to generate 105 molecules of ATP from oxidation of 1 molecule of palmitate. By contrast, oxidation of 1 molecule of glucose utilizes 12 atoms of oxygen to generate 31 molecules of ATP. Therefore, oxidation of FAs consumes ~0.3 oxygen molecules more than glucose to generate each molecule of ATP. Thus, the diabetic heart suffers from metabolic inflexibility due to its reliance on FAs. The lack of insulin production in T1DM patients causes a dramatic decrease in cardiac glucose uptake (53, 54) where hyperglycemia increases glucose oxidation and mitochondrial generation of superoxide (55–57). Increased production of superoxide damages DNA and activates poly (ADP ribose) polymerase 1 (PARP-1) (58), which mediates inflammation and fibrosis in liver (59). PARP-1 inhibition improves cardiac function (60) and prevents hyperglycemia-induced pathological processes (61). While decreased glucose transporter type 4 (Glut4) expression in T1DM animals causes decreased glucose uptake in cardiac and skeletal muscle (62, 63), glucose uptake is impaired in T2DM hearts by decreased expression and translocation of Glut4/Glut1 (64, 65). Diabetic db/db mice show decreased glucose oxidation and increased reliance on FAs, indicating that insulin resistance is not responsible for metabolic switch (66–69). The high rate of FA oxidation in T2DM patients and rodents increases production of acetyl CoA and NADH, resulting in activation of pyruvate dehydrogenase kinase 4 (PDK4). PDK4 is also activated by peroxisome proliferator-activated receptor alpha (PPARα), which is overexpressed in diabetic rodents (70–73). Activated PDK4 inhibits pyruvate dehydrogenase complex, thereby preventing oxidation of pyruvate (74, 75) (Figure 1). In addition, increased accumulation of FAs and their derivatives fatty acyl CoA, diacylglycerol, and ceramide activate protein kinase C, c-Jun N-terminal kinases, mammalian target of rapamycin, and inhibitor of κB kinase β with consequent decrease in insulin signaling (76–79).


Diabetic Cardiomyopathy: An Immunometabolic Perspective
Schematic diagram showing changes in cardiac metabolism in diabetic cardiomyopathy. In the diabetic heart, glucose oxidation is inhibited at multiple steps: (i) uptake of glucose is inhibited by reduced expression of glucose transporter Glut4 as well as by blunted translocation of Glut4 in response to insulin (64, 65); (ii) inhibition of hexokinase activity by fatty acids (FAs) resulting in reduced conversion of glucose to glucose-6-phosphate (80); (iii) inhibition of phosphofructokinase activity by FA, leading to reduced formation of fructose-1,6-bisphosphate by fructose-6-phosphate (69); (iv) inhibition of pyruvate dehydrogenase phosphatase activity by FA resulting in reduced pyruvate dehydrogenase (PDH) activity, which leads to reduced conversion of pyruvate to acetyl CoA. In the diabetic heart, PPARα expression is activated by increased FA uptake (81, 82). Activated PPARα upregulates PDH kinase 4 enzymes, which inhibits PDH resulting in reduced production of acetyl CoA (83–85). FA transporters CD36 and FA transport protein import FAs into the cell. After import, FAs can be stored as triacylglycerol (TAG) or converted to fatty acyl CoA by fatty acyl-CoA synthetase (FACS). Carnitine palmitoyltransferase 1 (CPT1) transfers the acyl group of fatty acyl CoA to carnitine, which then shuttles into the mitochondria by carnitine translocase (CT). PPARα activates transcription of CPT1 (86). In the matrix, CPT2 reconverts the acylcarnitine back into free carnitine and fatty acyl CoA (87), which is then converted to acetyl CoA that can be used in the tricarboxylic acid to produce adenosine triphosphate by β-oxidation. Diabetes upregulates mitochondrial generation of reactive oxygen species (57, 88, 89), which affects Ca2+ signaling (90).
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Figure 1: Schematic diagram showing changes in cardiac metabolism in diabetic cardiomyopathy. In the diabetic heart, glucose oxidation is inhibited at multiple steps: (i) uptake of glucose is inhibited by reduced expression of glucose transporter Glut4 as well as by blunted translocation of Glut4 in response to insulin (64, 65); (ii) inhibition of hexokinase activity by fatty acids (FAs) resulting in reduced conversion of glucose to glucose-6-phosphate (80); (iii) inhibition of phosphofructokinase activity by FA, leading to reduced formation of fructose-1,6-bisphosphate by fructose-6-phosphate (69); (iv) inhibition of pyruvate dehydrogenase phosphatase activity by FA resulting in reduced pyruvate dehydrogenase (PDH) activity, which leads to reduced conversion of pyruvate to acetyl CoA. In the diabetic heart, PPARα expression is activated by increased FA uptake (81, 82). Activated PPARα upregulates PDH kinase 4 enzymes, which inhibits PDH resulting in reduced production of acetyl CoA (83–85). FA transporters CD36 and FA transport protein import FAs into the cell. After import, FAs can be stored as triacylglycerol (TAG) or converted to fatty acyl CoA by fatty acyl-CoA synthetase (FACS). Carnitine palmitoyltransferase 1 (CPT1) transfers the acyl group of fatty acyl CoA to carnitine, which then shuttles into the mitochondria by carnitine translocase (CT). PPARα activates transcription of CPT1 (86). In the matrix, CPT2 reconverts the acylcarnitine back into free carnitine and fatty acyl CoA (87), which is then converted to acetyl CoA that can be used in the tricarboxylic acid to produce adenosine triphosphate by β-oxidation. Diabetes upregulates mitochondrial generation of reactive oxygen species (57, 88, 89), which affects Ca2+ signaling (90).
Mentions: The heart consumes about 6 kg of ATP, or ~20 times its own weight, per day (48) that comes from the breakdown of fat, carbohydrate, protein, ketone bodies, or lactate. Of note, the amount of ATP in the heart is small (~10 mM, enough for only a few beats) compared with the demand (~10,000 times greater) (49). About 95% of total energy is generated from oxidative phosphorylation of FAs and glucose (50–52). A dramatic metabolic shift takes place in diabetic heart, as they rely almost completely on FAs for their energy source. As for example, 46 atoms of oxygen are required to generate 105 molecules of ATP from oxidation of 1 molecule of palmitate. By contrast, oxidation of 1 molecule of glucose utilizes 12 atoms of oxygen to generate 31 molecules of ATP. Therefore, oxidation of FAs consumes ~0.3 oxygen molecules more than glucose to generate each molecule of ATP. Thus, the diabetic heart suffers from metabolic inflexibility due to its reliance on FAs. The lack of insulin production in T1DM patients causes a dramatic decrease in cardiac glucose uptake (53, 54) where hyperglycemia increases glucose oxidation and mitochondrial generation of superoxide (55–57). Increased production of superoxide damages DNA and activates poly (ADP ribose) polymerase 1 (PARP-1) (58), which mediates inflammation and fibrosis in liver (59). PARP-1 inhibition improves cardiac function (60) and prevents hyperglycemia-induced pathological processes (61). While decreased glucose transporter type 4 (Glut4) expression in T1DM animals causes decreased glucose uptake in cardiac and skeletal muscle (62, 63), glucose uptake is impaired in T2DM hearts by decreased expression and translocation of Glut4/Glut1 (64, 65). Diabetic db/db mice show decreased glucose oxidation and increased reliance on FAs, indicating that insulin resistance is not responsible for metabolic switch (66–69). The high rate of FA oxidation in T2DM patients and rodents increases production of acetyl CoA and NADH, resulting in activation of pyruvate dehydrogenase kinase 4 (PDK4). PDK4 is also activated by peroxisome proliferator-activated receptor alpha (PPARα), which is overexpressed in diabetic rodents (70–73). Activated PDK4 inhibits pyruvate dehydrogenase complex, thereby preventing oxidation of pyruvate (74, 75) (Figure 1). In addition, increased accumulation of FAs and their derivatives fatty acyl CoA, diacylglycerol, and ceramide activate protein kinase C, c-Jun N-terminal kinases, mammalian target of rapamycin, and inhibitor of κB kinase β with consequent decrease in insulin signaling (76–79).

View Article: PubMed Central - PubMed

ABSTRACT

The heart possesses a remarkable inherent capability to adapt itself to a wide array of genetic and extrinsic factors to maintain contractile function. Failure to sustain its compensatory responses results in cardiac dysfunction, leading to cardiomyopathy. Diabetic cardiomyopathy (DCM) is characterized by left ventricular hypertrophy and reduced diastolic function, with or without concurrent systolic dysfunction in the absence of hypertension and coronary artery disease. Changes in substrate metabolism, oxidative stress, endoplasmic reticulum stress, formation of extracellular matrix proteins, and advanced glycation end products constitute the early stage in DCM. These early events are followed by steatosis (accumulation of lipid droplets) in cardiomyocytes, which is followed by apoptosis, changes in immune responses with a consequent increase in fibrosis, remodeling of cardiomyocytes, and the resultant decrease in cardiac function. The heart is an omnivore, metabolically flexible, and consumes the highest amount of ATP in the body. Altered myocardial substrate and energy metabolism initiate the development of DCM. Diabetic hearts shift away from the utilization of glucose, rely almost completely on fatty acids (FAs) as the energy source, and become metabolically inflexible. Oxidation of FAs is metabolically inefficient as it consumes more energy. In addition to metabolic inflexibility and energy inefficiency, the diabetic heart suffers from impaired calcium handling with consequent alteration of relaxation–contraction dynamics leading to diastolic and systolic dysfunction. Sarcoplasmic reticulum (SR) plays a key role in excitation–contraction coupling as Ca2+ is transported into the SR by the SERCA2a (sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a) during cardiac relaxation. Diabetic cardiomyocytes display decreased SERCA2a activity and leaky Ca2+ release channel resulting in reduced SR calcium load. The diabetic heart also suffers from marked downregulation of novel cardioprotective microRNAs (miRNAs) discovered recently. Since immune responses and substrate energy metabolism are critically altered in diabetes, the present review will focus on immunometabolism and miRNAs.

No MeSH data available.


Related in: MedlinePlus