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J Am Coll Cardiol, 2006; 47:598-604, doi:10.1016/j.jacc.2005.09.030 (Published online 13 January 2006).
© 2006 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: DIABETES AND OBESITY

Increased Myocardial Fatty Acid Metabolism in Patients With Type 1 Diabetes Mellitus

Pilar Herrero, MS*, Linda R. Peterson, MD{dagger},{ddagger}, Janet B. McGill, MD§, Stanley Matthew, MD§, Donna Lesniak, RN*, Carmen Dence, MS* and Robert J. Gropler, MD*,{dagger},*

* Division of Radiological Sciences, Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri
{dagger} Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri
{ddagger} Division of Geriatrics and Nutritional Sciences, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
§ Division of Endocrinology and Metabolism, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri

Manuscript received January 11, 2005; revised manuscript received August 15, 2005, accepted September 12, 2005.

* Reprint requests and correspondence: Dr. Robert J. Gropler, Cardiovascular Imaging Laboratory, Mallinckrodt Institute of Radiology, 510 South Kingshighway, St. Louis, Missouri 63110 (Email: Groplerr{at}mir.wustl.edu).


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: The purpose of this study was to determine if myocardial fatty acid utilization (MFAU) and myocardial fatty acid oxidation (MFAO) are increased in diabetic patients.

BACKGROUND: Experimental models of diabetes mellitus demonstrate that MFAU and MFAO are increased, and that this dependence on myocardial fatty acid metabolism may be detrimental to cardiac function. Whether similar metabolic changes occur in humans with diabetes mellitus is unclear.

METHODS: Eleven healthy non-diabetic control patients (5 women, ages 25 ± 5 years) and 11 otherwise healthy patients with type 1 diabetes mellitus (T1DM) (8 women, ages 36 ± 10 years, HbA1c 8.4 ± 1.9%) underwent positron emission tomography for the determination of myocardial blood flow (MBF); myocardial oxygen consumption (MVO2); myocardial glucose utilization (MGU); and MFAU, MFAO, and %MFAO.

RESULTS: Plasma lactate, insulin, and MBF levels were similar between the two groups. However, plasma glucose (5.71 ± 0.98 µmol/ml vs. 5.28 ± 0.65 µmol/ml, p = 0.04), free fatty acid levels (0.60 ± 0.24 µmol/ml vs. 0.19 ± 0.07 µmol/ml, p < 0.0001), and MVO2 (6.64 ± 2.21 vs. 4.51 ± 1.39 µmol/g/min, p = 0.007) levels were higher in the T1DM subjects. Furthermore, compared with control patients, T1DM subjects exhibited higher MFAU (213 ± 135 nmol/g/min vs. 57 ± 28 nmol/g/min, p = 0.0004), MFAO (206 ± 131 nmol/g/min s. 50 ± 26 nmol/g/min, p = 0.0002), and %MFAO (94 ± 6% vs. 81 ± 19%, respectively, p = 0.04). In contrast, MGU was lower in T1DM subjects than in controls (207 ± 108 nmol/g/min vs. 403 ± 191 nmol/g/min, p = 0.0008).

CONCLUSIONS: Humans with diabetes mellitus exhibit increased MFAU and MFAO and reduced MGU consistent with observations obtained in experimental models of diabetes.

Abbreviations and Acronyms
  FFA = free fatty acid
  MBF = myocardial blood flow (ml/g/min)
  MFAEF = myocardial fatty acid extraction fraction
  MFAO = myocardial fatty acid oxidation (nmol/g/min)
  MFAU = myocardial fatty acid utilization (nmol/g/min)
  MGEF = myocardial glucose extraction fraction
  MGU = myocardial glucose utilization (nmol/g/min)
  MVO2 = myocardial oxygen consumption (µmol/g/min)
  PET = positron emission tomography
  PPAR = peroxisome proliferator-activated receptor
  T1DM/T2DM = type 1 diabetes mellitus/type 2 diabetes mellitus

Diabetes mellitus is a well-recognized major risk factor for cardiovascular disease in general and coronary artery disease in particular (1–3). For example, in patients with diabetes mellitus, both the prevalence and severity of manifestations of coronary artery disease are increased compared with non-diabetic subjects (2,3). Sudden death is increased in patients with diabetes mellitus, and survival after an ischemic event is reduced. Moreover, even in the absence of coronary artery disease, patients with diabetes mellitus have an increased incidence of left ventricular dysfunction and heart failure (4,5). The mechanisms by which diabetes mellitus confers this increased risk are multifactorial and complex, with possibilities including an increased prevalence of hyperlipidemia and hypertension, impaired fibrinolysis, abnormal myocardial endothelial function, and reduced sympathetic neuronal function (6–11).

Results of studies in various experimental models of diabetes mellitus have consistently demonstrated that the normal plasticity in myocardial substrate preference is lost with the heart becoming nearly solely dependent upon the metabolism of fatty acids (12–14). In these models, both myocardial fatty acid utilization (MFAU) and myocardial fatty acid oxidation (MFAO) are increased. Although human validation is pending, this metabolic shift in diabetes mellitus may potentially have several detrimental effects on the myocardium. The increased dependence on MFAO increases the susceptibility to ischemia, both because of the increased oxygen cost of oxidizing fatty acids compared with glucose and the intrinsic sensitivity of beta-oxidation to ischemia. Moreover, the increased rates of fatty acid oxidation could result in accumulation of reactive oxygen species, ultimately decreasing the capacity of the myocardium to oxidize fatty acids. In the setting of continued accelerated fatty acid uptake, this reduced oxidative capacity could result in lipid accumulation, triggering the detrimental effects that have been associated with lipotoxicity (15,16). In addition, an energy deprivation state could arise secondary to the lack of adequate replenishment of Krebs cycle intermediates due to reduced anapleurosis (17).

However, despite the wealth of data obtained in experimental models of diabetes mellitus, little is known about the effects of this disease on myocardial fatty acid metabolism in humans with this disease. For example, although it has been demonstrated that MFAU is increased in patients with type 1 diabetes mellitus (T1DM), the impact of the disease on MFAO is unknown (18–20). Accordingly, the goal of this study was to confirm that MFAU and MFAO are increased in otherwise healthy humans with T1DM.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Study population.   We studied 11 healthy, sedentary, non-diabetic subjects (6 women, ages 25 ± 5 years) and 11 otherwise healthy, sedentary subjects with T1DM (8 women, ages 36 ± 10 years) (Table 1). Humans with T1DM were studied instead of those with T2DM to reduce the confounding effects of hypertension and obesity on myocardial fatty acid metabolism typically present in patients with type 2 diabetes mellitus (T2DM) (21,22). Sedentary subjects were chosen to minimize the confounding effects of variable levels in training-induced adaptations of myocardial substrate metabolism (23). All subjects underwent a screening process that included a history, a physical exam, and a rest and stress echocardiogram. The non-diabetic control patients also underwent a 2-h glucose tolerance test to exclude diabetes mellitus. The subjects with T1DM also underwent phlebotomy for determination of plasma creatinine and HbA1c. All subjects were non-smokers, normotensive (defined as a systolic blood pressure <140 mm Hg and a diastolic pressure <90 mm Hg), with a normal lipid profile based on National Cholesterol Education Program-2 guidelines (total cholesterol <220 mg/dl, low-density lipoprotein cholesterol <160 mg/dl, and high-density lipoprotein cholesterol >35 mg/dl) and without a family history of coronary artery disease. No subject had a significant cardiac structural or ischemic disease, or other major systemic illness. The subjects with T1DM were excluded if they had evidence of active retinopathy or clinically significant autonomic neuropathy, or if they had a serum creatinine >1.5 mg/dl. The study was approved by the Human Studies and the Radioactive Drug research committees at the Washington University School of Medicine. Written informed consent was obtained from all subjects before enrollment into the study.


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  		Table 1. Subject Characteristics and Echocardiographic Data
 
Experimental procedure.   Subjects were admitted to the General Clinical Research Center at Washington University School of Medicine the evening before the positron emission tomography (PET) study. At 6 PM the night before the study, both diabetic and non-diabetic subjects ingested a standard meal containing 12 kcal/kg body weight for non-obese subjects and 12 kcal/kg adjusted body weight for obese subjects (adjusted body weight = ideal body weight + [(actual body weight – ideal body weight) x (0.25)]. In the morning the normal volunteers ingested a second meal 2 h before starting the PET study. The diabetic patients remained fasting until the completion of the study the following day, but received an insulin drip at physiologic replacement doses (1 to 2 U/h) plus glucose as needed to maintain blood glucose levels of 5 to 7 mmol/l from evening until completion of the imaging study the next day in order to achieve normalization of metabolic parameters. In this way the two groups were studied under conditions of similar plasma insulin and glucose levels.

Cardiac PET imaging.   All studies were performed during resting conditions starting at 8 AM and ending at 1:30 PM to avoid circadian variations in myocardial metabolism. Measurements of myocardial blood flow (MBF), myocardial oxygen consumption (MVO2), myocardial glucose extraction fraction (MGEF) and myocardial glucose utilization (MGU), and myocardial fatty acid extraction fraction (MFAEF), MFAU, MFAO and %MFAO were obtained with PET with 15O-water, 1-11C-acetate, 1-11C-glucose, and 1-11C-palmitate, respectively, using validated techniques as reported previously (21–28). Percent MFAO represents the fraction of extracted fatty acid that is oxidized and is calculated by dividing MFAO by MFAU and multiplying by 100%. The procedure was well tolerated by the subjects.

Measurement of plasma substrates and insulin.   Plasma glucose and lactate levels were measured using a commercially available glucose-lactate analyzer (YSI, Yellow Springs, Ohio). Plasma fatty acid levels were determined by capillary gas chromatography and high-performance liquid chromatography (28). Plasma insulin was measured by radioimmunoassay (29).

Statistical analysis.   Results are expressed as mean ± SD. Comparisons of continuous variables between groups were performed the using the non-parametric Mann-Whitney U test, and comparisons of dichotomous variables were performed using the Fisher exact test. Pearson’s correlation coefficients were calculated to determine the relationship between free fatty acid (FFA) levels and %MFAO and the relationship between years of T1DM and %MFAO. The p values <0.05 were considered statistically significant.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
Baseline characteristics and echocardiographic data.   Table 1 shows the characteristics of the non-diabetic control patients and the T1DM subjects. The two groups were not statistically different with respect to percent of men, body mass index, total cholesterol levels, low-density lipoprotein levels, left ventricular mass index, or left ventricular ejection fraction. The subjects with T1DM were slightly older and had borderline higher high-density lipoprotein levels and lower triglycerides than the non-diabetic subjects. The T1DM subjects had an average duration of disease of 23 years and average HbA1c of 8.4%.

Plasma substrates and insulin.   Figure 1 shows the mean ± SD of the plasma glucose, FFAs, lactate, and insulin levels averaged over the entire imaging study for the two groups. Plasma lactate levels were similar between the groups. Plasma insulin levels tended to be higher in the T1DM subjects but did not reach statistical significance. However, the T1DM subjects exhibited slightly but significantly higher plasma glucose levels compared with non-diabetic control patients (5.71 ± 0.98 µmol/ml vs. 5.28 ± 0.65 µmol/ml, p = 0.04). In addition, plasma fatty acid levels were ~3x higher in the diabetic subjects compared with the non-diabetic control patients (0.60 ± 0.24 µmol/ml vs. 0.19 ± 0.07 µmol/ml, p < 0.0001).


Figure 1
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  		Figure 1 Plasma insulin, glucose, lactate, and free fatty acid (FFA) levels during positron emission tomography imaging in both the non-diabetics (ND) and diabetic (DM) subjects. *p = 0.04, **p < 0.0001.

 
Hemodynamics, MBF, and MVO2.   Table 2 shows the hemodynamics, MBF, and MVO2 results. The rate-pressure product was significantly higher in the T1DM subjects compared with the normal volunteers (p = 0.016). Myocardial blood flow trended towards being higher in the T1DM subjects (p = 0.12) when compared with the normal volunteers. Myocardial oxygen consumption was higher in the T1DM subjects when compared with normal volunteers (p = 0.007). However, both MBF and MVO2 corrected for rate-pressure product were similar between the two groups.


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  		Table 2. Hemodynamics, MBF, and MVO2
 
MGEF and MGU.   Figure 2 shows the values for MGEF and MGU in the two groups. The MGEF was lower in the subjects with T1DM than in controls (0.034 ± 0.021 vs. 0.078 ± 0.029, p = 0.013). Despite a trend toward higher MBF and significantly higher plasma glucose levels observed in the T1DM group (Table 1, Fig. 1), the lower MGEF in T1DM patients resulted in significantly lower MGU levels when compared to the non-diabetic control subjects (207 ± 108 nmol/g/min vs. 403 ± 191 nmol/g/min, p = 0.0008).


Figure 2
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  		Figure 2 Measurements of myocardial glucose extraction fraction (MGEF) and overall utilization (MGU) in both the non-diabetic (ND) and diabetic (DM) subjects. *p = 0.013, **p = 0.0008.

 
MFAEF, MFAU, MFAO, and %MFAO.   The levels of MFAEF were not different between the T1DM group and the normal volunteers (0.31 ± 0.08 vs. 0.33 ± 0.10) (Fig. 3). However, MFAU in the T1DM subjects was higher than that observed in the non-diabetic control patients (213 ± 135 nmol/g/min vs. 57 ± 28 nmol/g/min, p = 0.0004). Similarly, MFAO was higher in the T1DM group compared with control subjects (206 ± 131 nmol/g/min vs. 50 ± 26 nmol/g/min, p = 0.0002). The higher levels of MFAU and MFAO in the T1DM subjects reflected the higher plasma FFA levels in this group compared with the non-diabetic control patients. Of note, the %MFAO (i.e., the fraction of extracted fatty acid that was oxidized) was significantly higher in the T1DM subjects compared with non-diabetic control patients (94 ± 6% vs. 81 ± 19%, p = 0.04).


Figure 3
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  		Figure 3 Measurements of myocardial fatty acid extraction fraction (MFAEF), overall myocardial fatty acid utilization (MFAU), myocardial fatty acid oxidation (MFAO), and myocardial fatty acid fractional oxidation (%MFAO) in both the non-diabetic (ND) and diabetic (DM) subjects. *p = 0.0004, **p = 0.0002, {dagger}p = 0.04.

 
The relationship between %MFAO and the plasma fatty acid level is depicted in Figure 4. As expected, it declined in the non-diabetic control subjects. In contrast, there was no relationship in the subjects with T1DM. Shown in Figure 5 is the relationship between %MFAO and duration of disease in the subjects with T1DM. There was progressive decline in %MFAO with the duration of T1DM.


Figure 4
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  		Figure 4 Correlation of fractional myocardial fatty acid oxidation (%MFAO) and plasma fatty acid levels in both non-diabetic and diabetic subjects. DM = diabetes mellitus; NV = normal volunteers.

 

Figure 5
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  		Figure 5 Correlation of fractional myocardial fatty acid oxidation (%MFAO) and duration of diabetes in the diabetic subjects. DM = diabetes mellitus.

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
The results of the current study demonstrate that the marked up-regulation in both MFAU and MFAO that is observed in various experimental models of diabetes mellitus is present in humans with T1DM. This up-regulation is driven in large part by an increase in plasma fatty acid levels. Further evidence for the up-regulation in fatty acid metabolism in T1DM is the presence of an increase in the fraction of the extracted fatty acid that is oxidized (%MFAO) and the relative insensitivity of this fractional oxidation to the amount of fatty acid delivery to the heart. However, it appears that the capacity of the myocardium to oxidize fatty acids declines with the duration of T1DM. In contrast, the myocardial extraction of glucose is decreased despite physiologic insulin delivery and euglycemia, which results in reduced MGU in T1DM.

Comparison with animal studies.   In the adult heart, MFAO is the chief energy source. However, the proportional contribution of other substrates, such as glucose and lactate, to oxidative metabolism are quite variable and dependent upon numerous factors such as the plasma substrate environment, neurohumoral milieu, and level of cardiac work (30). In numerous experimental models of diabetes mellitus, this plasticity in myocardial substrate preference is lost with the heart becoming dependent upon the metabolism of fatty acids (12–14). There are several reasons for this loss of plasticity. In experimental models of T1DM, plasma membrane levels of the putative fatty acid transport proteins FABPpm and FAT/CD36 are increased (31). The increase in protein levels is paralleled by an increase in fatty acid transport into the myocyte. Our data differ slightly in that we did not observe increased MFAEF, suggesting increased fatty acid transport was not present (Fig. 3). Indeed, the increase in overall uptake (MFAU) was driven in large part by the higher plasma fatty acid levels, which were approximately 3x higher in the diabetic patients, despite comparable plasma insulin levels and slightly higher plasma glucose levels, when compared with non-diabetic control subjects (Fig. 1). The higher plasma fatty acid levels likely reflect reduced suppression of FFAs from white adipose tissue despite insulin levels that are similar to post-prandial levels in a non-diabetic subject.

Studies of animal models of diabetes mellitus have demonstrated a central role for the up-regulation of the peroxisome proliferator-activated receptor (PPAR)-alpha gene regulatory pathway in the overdependence of the myocardium on fatty acid metabolism (32–34). Peroxisome proliferator-activated receptor {alpha} is a nuclear receptor that regulates the transcription of an array of genes responsible for cellular fatty acid utilization pathways including MFAU and MFAO. Tissue FFAs are ligands for PPAR-alpha. Our data are consistent with the up-regulation of this pathway. We observed that the fraction of extracted fatty acid that was oxidized, or %MFAO (Fig. 4) was increased in the T1DM subjects compared with non-diabetic subjects. Furthermore, the inverse relationship between %MFAO and the level of plasma FFAs seen in the non-diabetic control patients was not observed in the T1DM subjects (Fig. 4). In experimental models of diabetes mellitus, the accelerated MFAU ultimately exceeds MFAO, resulting in lipid accumulation and lipotoxicity (15,16). Also potentially increasing the likelihood of inadequate oxidative capacity is the accumulation of reactive oxygen species secondary to increased MFAO. The decline in %MFAO with duration of diabetes mellitus in our study (Fig. 5) suggests that fatty acid oxidative capacity does decrease over time in humans with T1DM. It should be noted that the decline in %MFAO is unlikely due to an aging effect, as we have observed similar levels of %MFAO in younger (ages 21 to 35 years) and moderately older (ages 50 to 65 years) healthy non-diabetic subjects (35).

In animal models of T1DM and humans with the disease, both insulin-mediated glucose transport and glucose transporter expression decline (18,36,37). Even with insulin replacement, the expression of GLUT-4 remains decreased compared with controls (36). This observation is supported by the lack of increase in myocardial glucose uptake in response to insulin supplementation in either animal models of T1DM or patients with the disease based on arterial-coronary sinus balance studies (18,19). However, MGU values are frequently normal in the presence of hyperglycemia (18). We observed similar changes in humans with T1DM, with a decline in both MGEF and MGU under conditions of near euglycemia and physiological levels in plasma insulin (Fig. 2).

Comparison with prior studies in humans.   Increased myocardial fatty acid uptake measured by arterial-coronary sinus balance studies has been reported in humans with T1DM without coronary artery disease (18–21). Although the impact of plasma levels of FFAs on the level of myocardial fatty acid uptake was not determined, a negative correlation between myocardial glucose uptake and plasma fatty acid levels is consistent with our data. Measurements of MFAO and %MFAO were not performed in these earlier studies, but measurements of myocardial fatty acid metabolism using single-photon emission computed tomography and the fatty acid analogue 123I-hepadecanoic acid have suggested reduced beta-oxidation in patients with T2DM (38). Interestingly, measurements of myocardial clearance of 11C-palmitate (an estimate of beta-oxidation) did not differ between normal subjects and patients with insulin resistance (39). However, neither study provided quantitative measurements of MFAU or MFAO. In addition, our understanding of the relationship of 123I-hepadecanoic acid myocardial kinetics to myocardial fatty acid beta-oxidative pathways is incomplete. Moreover, estimates of myocardial fatty acid metabolism based on exponential curve fitting of 11C-palmitate kinetics are limited by incomplete characterization of the tracer kinetics when compared with compartmental modeling.

Similarly, measurements of MGU in healthy individuals with T1DM have yielded somewhat conflicting results. For example, myocardial extraction of glucose is decreased in T1DM patients in the setting of hyperglycemia and low plasma insulin levels and, as mentioned above, does not increase despite tripling the plasma insulin levels (18). We observed reduced values for MGEF and MGU in the T1DM group consistent with these results. However, MGU, as measured by PET with 18F-fluorodeoxyglucose, could be normalized by instituting a hyperinsulinemic-euglycemic clamp (40,41). As previously mentioned, we observed decreased MGU in T1DM patients despite euglycemia and physiological levels in plasma insulin. Potential explanations for this discrepancy include differences in the levels of plasma insulin achieved (higher in those with the hyperinsulinemic-euglycemic clamp), different duration and severity of T1DM in the patients studied, or differences in the accuracy of MGU measurements using 18F-fluorodeoxyglucose compared with 1-11C-glucose (42).

Study limitations.   By study design, plasma insulin and glucose levels were similar between the two groups. However, as a consequence, plasma fatty acids were higher in the T1DM group, which in turn likely contributed to the higher MFAU and MFAO when compared with control patients. However, it should be noted that the higher plasma fatty acid levels in the T1DM patients compared with non-diabetic control subjects occurred in the setting of similar plasma insulin levels, consistent with the well-documented insulin resistance that occurs the T1DM patients (43). Reduced insulin-stimulated uptake of glucose and fatty acids into adipose tissue and impaired suppression of fatty acid release are well described in T1DM and result in increased delivery of fatty acids to skeletal muscle, liver, and heart. The long-term effect of this imperfect energy partitioning varies in different tissues (44). We present data that suggest myocardial effects are present in patients with long-standing T1DM despite short-term metabolic stabilization. The PET approach used to quantify myocardial fatty acid metabolism does not account for the contribution of plasma triglycerides to the delivery of fatty acids to the myocardium. Recently, it has been reported that in both type 1 and type 2 models of diabetes mellitus, myocardial oxidation rates of extracted fatty acids derived from plasma chylomicrons (via lipoprotein lipase) are increased. The increase was similar to that for oxidation rates of extracted fatty acids derived from plasma fatty acid bound to albumin (45). Currently available methods also do not provide any insight into energy produced from the breakdown of endogenous myocardial fatty acid sources such as triglycerides. In experimental models of diabetes mellitus, it appears that myocardial tissue levels of triglycerides are increased (15). Utilization of fatty acids from circulating triglycerides and from myocyte stores was not accounted for in this study; thus it is possible that our measurements underestimated total MFAU and MFAO. Since we only studied patients with T1DM, further studies are required to verify that similar changes occur in people with T2DM, and to determine the relative contribution of hypertriglyceridemia in both groups (46,47). It is known that MGU is decreased in patients with T2DM, suggesting a relative increase in fatty acid metabolism (47). Finally, because we did not assess left ventricular function (particularly during stress) at the time of the PET study, further studies are necessary to determine if the metabolic changes we observed impact left ventricular function in healthy T1DM patients.

Clinical implications.   As mentioned previously, despite metabolic stabilization and the attainment of near-euglycemia in patients with T1DM, persistently elevated plasma FFA levels may have several detrimental effects on the myocardium. The increased dependence on MFAO increases the susceptibility to ischemia, both because of the increased oxygen cost of oxidizing fatty acid compared with glucose and the intrinsic sensitivity of beta-oxidation to ischemia. This would provide a partial explanation for the more pronounced manifestations of coronary artery disease, such as increased infarct size, heart failure, and sudden death that occur with ischemic events in diabetic patients. Moreover, the overdependence on fatty acid metabolism could lead to an energy deprivation state due to reduced anapleurosis or a decline in oxidative capacity (with possibly the development of lipid accumulation and lipotoxicity). Finally, if increased plasma fatty acid levels are found to induce abnormalities in myocardial substrate metabolism in T1DM patients, reduction of fatty acid levels or normalization of substrate use may become an important therapeutic target for reducing cardiovascular morbidity and mortality in patients with diabetes mellitus.


   Footnotes
 
This work was supported in part by National Institutes of Health grants P01-HL13581, R01-AG15466, M01-RR00036, and P60-DK020579.


   References
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 Methods
 Results
 Discussion
 References
 

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