| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Program in Human Molecular Biology and Genetics (J.B., P.K.M., G.C., M.W.R., U.J.Y., E.D.A.) and Division of Endocrinology, Metabolism, and Diabetes (R.C.C., E.D.A.), The University of Utah School of Medicine, Salt Lake City, Utah 84112; and Division of Cardiology (P.H., S.E.L.), University of Utah School of Medicine, Salt Lake City, Utah 84132
Address all correspondence and requests for reprints to: E. Dale Abel, M.D., Ph.D., Program in Human Molecular Biology and Genetics, Division of Endocrinology, Metabolism, and Diabetes, University of Utah, 15 North 2030 East, Building 533, Room 3410B, Salt Lake City, Utah 84112. E-mail: dale.abel{at}hmbg.utah.edu.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
regulated genes was observed only at 15 wk in both strains. These data indicate that altered myocardial substrate use and reduced myocardial efficiency are early abnormalities in the hearts of obese mice and precede the onset of hyperglycemia. Obesity per se does not cause contractile dysfunction in vivo, but loss of the hypercontractile phenotype of obesity and up-regulation of peroxisomal proliferator-activated receptor- regulated genes occur later and are most pronounced in the presence of longstanding hyperglycemia. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
A large body of work has suggested that altered myocardial substrate metabolism may contribute to contractile dysfunction in the hearts of diabetics (5, 6). Most studies have been performed in models of insulin-deficient (type 1) diabetes (7), and fewer studies have been performed in models of type 2 diabetes. For example, altered substrate use, namely reduced rates of glucose use (glycolysis and glucose oxidation) with a concomitant increase in rates of fatty acid (FA) oxidation were reported in isolated perfused hearts obtained from 12-wk-old db/db mice and 8-wk-old ob/ob mice (8, 9). Fewer studies have examined the temporal relationship between changes in cardiac metabolism and the onset of hyperglycemia. Aasum et al. (10) reported that 6-wk-old db/db mice did not exhibit elevated levels of glucose in random-fed animals. In hearts from these mice that were perfused in the absence of insulin and under relatively low FA concentrations, FA oxidation rates were elevated, but glucose oxidation rates were normal, whereas cardiac function was relatively preserved. The transition to hyperglycemia occurs at approximately 6 wk of age in db/db mice; thus, it is possible that these animals were already glucose intolerant. Contractile dysfunction and/or reduced rates of carbohydrate oxidation have been described in vivo and in vitro in the hearts of Zucker fatty rats, a model of obesity and type 2 diabetes (11, 12, 13). In these studies the changes in carbohydrate metabolism were observed shortly after the onset of diabetes, and the degree of hyperglycemia in this model is less severe than is the case in the studies of db/db mice. Thus, analysis of the cardiac phenotypes of obese and insulin-resistant mice, well before the onset of hyperglycemia, remains to be performed. Given the fact that hyperinsulinemia precedes the development of hyperglycemia in all of these models, it is possible that generalized insulin resistance per se may play a role in their cardiac phenotypes.
Acute changes in the expression of genes involved in the regulation of contractile function and substrate metabolism have been described in the hearts of animals with insulin-deficient diabetes (14, 15) and may precede the development of overt contractile dysfunction. Consistent changes include increased expression of the fetal myosin isoform ß-myosin heavy chain (MHC), increased expression of uncoupling protein (UCP) 3, and increased expression of pyruvate dehydrogenase kinase (PDK) 4. Increased expression levels of genes involved in the mitochondrial ß-oxidation of fatty acids have been observed in some but not other studies (14, 16). In models of type 2 diabetes, there may be an imbalance in the expression of genes involved in fatty acid import and mitochondrial fatty acid ß-oxidation such that FA entry into the myocyte might exceed mitochondrial oxidative capacity. This has been postulated to contribute to the increase in triglyceride accumulation in the hearts of these models (13). We have shown that selective disruption of insulin signaling in cardiomyocytes results in increased expression of ßMHC and reduced expression of genes involved in mitochondrial ß-oxidation (17). Thus, it is likely that impaired insulin signaling and hyperglycemia might have divergent or distinct effects on the regulation of gene expression in the myocardium.
The goal of these studies was to identify the early changes that occur in the hearts of obese and insulin-resistant rodent models at a time point that clearly precedes the onset of hyperglycemia. We also chose to study two independent models of leptin deficiency or resistance that differ in the timing of the transition from normoglycemia to glucose intolerance to overt hyperglycemia. Here we show that as early as 4 wk of age, the hearts of ob/ob and db/db mice exhibit decreased glucose oxidation rates, increased rates of FA oxidation and myocardial oxygen consumption (MVO2), and decreased cardiac efficiency. These changes are associated with myosin isoform switching but with normal expression levels of peroxisomal proliferator-activated receptor (PPAR)- regulated genes. Of interest, in vivo analysis of cardiac function reveal hypercontractile left ventricular (LV) function, which declines only after hyperglycemia develops, and has been present for more than 6 wk. Thus, altered cardiac metabolism is an early characteristic of leptin-deficient mouse models, precedes the development of hyperglycemia, and appears to develop independently of changes in the expression of PPAR regulated genes.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Glucose tolerance tests and the determination of serum concentrations of insulin, free fatty acids (FFAs), and triglycerides
Glucose tolerance tests were performed after a 6-h fast. A glucose bolus was injected ip (1 mg/g body weight) and blood samples obtained from the tail vein at 30, 60, 90, and 120 min after glucose administration. Blood glucose was determined using a glucose oxidase method with one-touch test strips (Lifescan; Johnson & Johnson Co., Milpitas, CA). Concentrations of insulin, FFAs, and triglycerides were measured at 0500 h (peak feeding) and after a 6-h fast. Serum insulin concentrations were measured by RIA using the sensitive rat insulin RIA kit (Linco Research Inc., St. Charles, MO). Insulin assays were performed in duplicate 25-µl samples. FFA concentrations were determined in duplicate 50-µl serum samples that were obtained from all animals at 48 h or greater before performing the glucose tolerance tests. FFA concentrations were measured using the 1/2-micro-fatty acid test kit (Roche Diagnostics, Mannheim, Germany). Triglyceride concentrations were determined in 10-µl serum samples using the L-type TG H kit from Wako (Richmond, VA).
Determination of in vivo cardiac contractility
Mice were anesthetized with 1–1.5% isoflurane. LV pressure was then measured with a temperature-calibrated 1.4 Fr micromanometer-tipped catheter (Millar Instruments, Houston, TX) inserted through the right carotid artery and analyzed as previously described (18).
Substrate metabolism in isolated working mouse hearts
Cardiac metabolism was measured in hearts isolated from 4- and 15-wk-old male ob/ob, db/db mice and their age-matched controls. All hearts were prepared and perfused in the working mode, using protocols that have been previously described by our group (9). In brief, the working heart buffer was Krebs Henseleit buffer containing (in millimoles) 118.5 NaCl, 25 NaHCO3, 4.7 KCl, 1.2 MgSO4, 1.2 KH2PO4, 2.5 CaCl2, 0.5 EDTA, and 11 glucose, gassed with 95% O2-5% CO2 and supplemented with 1.0 mM palmitate bound to 3% BSA in the presence of 1 nM insulin to mirror the plasma concentrations of FFAs and insulin in db/db and ob/ob mice. Glycolytic flux was determined by measuring the amount of 3H2O released from the metabolism of exogenous [5-3H]glucose (specific activity 400 MBq/mol). Glucose oxidation was determined by trapping and measuring 14CO2 released by the metabolism of [U-14C]glucose (specific activity 400 MBq/mol). Palmitate oxidation was determined in separate perfused hearts by measuring the amount of 3H2O released from [9,10-3H]palmitate (specific activity 18.5 GBq/mol). MVO2 and cardiac efficiency were determined as previously described (9).
Quantitative RT-PCR
Hearts were obtained from randomly fed 4- and 15-wk-old db/db, ob/ob mice and their age-matched controls, placed in RNAlater (Ambion, Austin, TX) and then frozen at –80 C. Tissues were homogenized, and total RNA was extracted by using TRIzol reagent (Invitrogen, Carlsbad, CA) according to the manufacturer’s recommendations. Chloroform was added to the homogenate, and the RNA-containing aqueous phase was further purified using the RNAeasy total RNA isolation kit (QIAGEN, Valencia, CA) according to the manufacturer’s instructions. Three micrograms of each total RNA were synthesized to cDNA using Superscript TMII RNase H-reverse transcriptase (Invitrogen) using the manufacturer’s protocols and oligo dT primers. Quantitative real-time PCR was performed with 8 ng cDNA as the template as previously described by our group (18). Transcript levels for the constitutive housekeeping gene product cyclophilin were also quantitatively measured in each sample and used to normalize the transcript data obtained. Data are expressed as the fold change relative to values obtained in age-matched wild-type mice. The transcripts that were analyzed and their respective primer sequences (forward primer and reverse primer) are summarized in Table 1
.
|
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
also confirm the transition from normal glucose tolerance to severe diabetes in db/db mice between 4 and 8 wk of age. Glucose tolerance was modestly impaired in 4-wk-old ob/ob, and the 4-wk glucose tolerance test results are similar to those previously reported by us in 8-wk-old ob/ob mice (9). Severe hyperglycemia is present at 15 wk in ob/ob mice, indicating a more delayed onset of hyperglycemia relative to db/db mice. Table 2 summarizes the body weights, fed and fasting concentrations of insulin, triglycerides, and FFAs in both groups of mice at 4 and 15 wk of age. It is evident from these data that in relation to their genetic controls, obesity and hyperinsulinemia are present in both groups of mice as early as 4 wk of age and become progressively more severe as they age. FFA and triglyceride concentrations were not increased in 4-wk-old ob/ob and db/db mice. However, at 15 wk, fed concentrations of serum triglycerides were significantly increased in both strains of mice relative to their age-matched controls. Moreover, triglyceride concentrations in db/db mice were 2.2-fold higher in 15-wk db/db mice vs. ob/ob mice of similar age. FFA concentrations were increased in 15-wk db/db relative to age-matched controls but were not elevated in 15-wk-old ob/ob mice.
|
|
). Palmitate oxidation rates were not statistically different between 4-wk-old ob/ob and db/db mice. Insulin-stimulated rates of glucose oxidation were reduced by 28% relative to controls in the hearts of ob/ob mice and by 37% in db/db hearts (Fig. 2B). Rates of glycolysis were similar (Fig. 2C). These changes in substrate metabolism were associated with significantly elevated rates of myocardial oxygen consumption in ob/ob and db/db mice relative to their respective controls (Fig. 3A), leading to a significant reduction in myocardial efficiency (Fig. 3B). Metabolic changes in 15-wk-old ob/ob mice were similar to those observed at 4 wk of age (Figs. 2 and 3). This was also true for db/db mice (Figs. 2 and 3) with the exception of palmitate oxidation rates that were 1.5-fold higher in 15-wk-old db/db mice vs. 4-wk-old db/db mice (P < 0.002, Fig. 2A). Also, although MVO2 remained increased in 15-wk db/db mouse hearts relative to age-matched controls, the extent of the increase was greater in younger mice. In 4-wk-old mice, cardiac power was increased in ob/ob and db/db mice relative to their age-matched controls, but this relative increase in cardiac performance was no longer apparent at 15 wk (Table 3).
|
|
|
and Fig. 4). In ob/ob mice, LV systolic pressures were increased at 4 and 15 wk, compared with controls, and there were no significant changes in LV end diastolic pressures. The rate of increase in LV pressure during systole (+dP/dt) was significantly increased in ob/ob mice at all ages. The rate of LV relaxation (–dP/dt) was also greater in 4-wk-old ob/ob hearts in vivo. In contrast, LV systolic pressure in db/db mice tended to be higher at 4 wk and was significantly increased at 8 wk but tended to be reduced in 15-wk-old mice. An increase in +dP/dt was present at 4 and 8 wk in db/db mice, but LV contractility decreased in 15-wk-old db/db mice. Similarly, whereas LV relaxation was enhanced in 4-wk-old db/db mice, there was a progressive reduction over time, and –dP/dt was significantly reduced in 15-wk-old db/db mice relative to age-matched controls (Table 3
and Fig. 4). Thus, db/db mice exhibit initial hypercontractility followed by a decline in LV function that appears to parallel the earlier onset of hyperglycemia. In contrast, ob/ob mice maintain a hyperdynamic state up to 15 wk of age. The function of ob/ob hearts gradually decline and become similar to that observed in control animals between 30 and 40 wk of age (data not shown).
|
|
. In the adult mouse heart, MHC represents the predominant isoform and the ratio of MHC to ßMHC expression is greater than 1 (19). In both models, myosin isoform expression maintained a fetal pattern with predominant expression of the ßMHC isoform. Thus, MHC expression was reduced at 4 and 15 wk in both groups of animals. ßMHC expression was increased at both ages relative to controls in db/db hearts and did not change as the animals aged. The increase in ßMHC expression in ob/ob mice was most noticeable in 4-wk-old animals (Fig. 5A), and although the expression apparently fell at 15-wk, the ratio of ßMHC to MHC was still reversed because of the greater reduction in MHC expression.
|
-regulated genes [PDK4, medium-chain acyl-coenzyme A (acyl CoA) dehydrogenase (MCAD), long-chain acyl CoA dehydrogenase (LCAD), very long-chain acyl CoA dehydrogenase (VLCAD), UCP2, and UCP3], there was relatively little change in mRNA levels in 4-wk-old mice, indeed for some transcripts such as PDK4, MCAD, and UCP3, expression levels were actually lower in 4-wk-old ob/ob mice relative to age-matched controls (Fig. 5, B–D). However, there was a progressive increase in the expression levels of all genes in db/db mice and most genes in ob/ob relative to their controls as the animals aged. In general, the degree of transcriptional up-regulation of genes was greater in 15-wk db/db mice than in 15-wk –ob/ob mice, indicating a more robust degree of PPAR activation in db/db mice that parallels the earlier onset and greater severity of hyperglycemia and higher concentrations of FFAs and triglycerides. PPAR expression tended to increase in both models, but the degree of induction was less than that observed for PPAR-regulated genes, consistent with increased activation of PPAR by FA ligands. PPAR
coactivator (PGC) 1 expression was increased in 4-wk-old db/db mouse hearts but not at 15 wk, and its expression was not increased in ob/ob mouse hearts at any age (Fig. 5E). |
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-regulated genes. Indeed, the up-regulation of PPAR-mediated gene expression appears to occur in relation to the onset of hyperglycemia and hyperlipidemia.
The metabolic milieu of both ob/ob and db/db mice at 4 wk of age is characterized by hyperinsulinemia. In db/db mice there was no change in in vivo glucose homeostasis, and glucose homeostasis was marginally perturbed in 4-wk-old ob/ob mice. Concentrations of triglycerides and FFAs were not significantly different from controls in both strains. Despite the relatively normal concentrations of serum lipids, rates of FA oxidation are increased and glucose oxidation decreased in a PPAR-independent fashion. Insulin acutely increases glucose use and decreases FA oxidation in the heart. So it is possible that impaired insulin signaling in cardiomyocytes of 4-wk-old ob/ob and db/db mice could have resulted in increased rates of FA oxidation. However, cardiac insulin signaling (as evidenced by the ability of insulin to phosphorylate Akt) was normal in 4-wk-old ob/ob and db/db mice but was impaired in 15-wk-old animals (data not shown). Based on these observations, it might be difficult to invoke myocardial insulin resistance as a cause for these early metabolic changes. However, increased FA use in these hearts could be associated with increased acyl CoA synthetase activity that could lead to insulin resistance on the basis of protein acylation for example. Thus, the possibility remains that other aspects of insulin’s action on cardiac metabolism, which could be independent of Akt signaling, could be impaired, and these were not formally evaluated in this study.
FFAs are ligands for PPAR signaling. Increased PPAR signaling has been suggested to be an important underlying mechanism that may be responsible for the metabolic changes in the diabetic heart (16), mediating its effects by increasing the expression of enzymes involved in FA mitochondrial ß-oxidation (e.g. carnitine palmitoyl transferase-1 and acyl CoA dehydrogenases) and increasing the expression of UCPs, which may increase mitochondrial FA flux. In the present study, evidence for increased PPAR signaling was present in 15-wk-old but not 4-wk-old animals. The increase in the expression of PPAR-regulated genes parallels increasing concentrations of FFA in db/db mice, increased triglycerides (which are the major source of FFAs to the heart in vivo) in both strains, and the development of hyperglycemia. Thus, whereas enhanced PPAR signaling may contribute to increased FA oxidation in the 15-wk animals, it is less likely that this is the case at 4 wk of age. The focused transcriptional analysis that we performed highlights the independence of the metabolic alterations of hearts obtained from 4-wk-old db/db and ob/ob mice from changes in the expression of PPAR-regulated genes. However, we cannot rule out the involvement of other transcriptional pathways, and future studies using global gene analysis approaches could shed additional mechanistic insights.
Two additional mechanisms that could be responsible for the early changes in substrate metabolism in these models warrant further discussion, namely increased expression or sarcolemmal localization of FA transporters and mitochondrial uncoupling. Insulin has been shown to acutely increase the expression and membrane localization of the fatty acid translocase (FAT)/CD36 via a phosphatidyl inositol-3 kinase/Akt-mediated mechanism (20, 21). In Zucker fatty rats that were normoglycemic but hypertriglyceridemic, FAT/CD36 was constitutively localized to the sarcolemmal membrane, and basal rates of FA uptake were increased (22). In contrast, in lean animals FAT/CD36 was predominantly located in intracellular vesicles under basal conditions. Whereas insulin acutely increased sarcolemmal content of FAT/CD36 in cardiomyocytes from lean animals, it is believed that the persistent hyperinsulinemia in the obese animals causes permanent translocation of these vesicles (22). Myocardial insulin signaling is not impaired in the hearts of 4-wk-old ob/ob and db/db mice (data not shown); thus, increased FA uptake, on the basis of increased translocation of FA transporters, is a plausible and testable hypothesis to account for increased FA use in these models.
The increased MVO2 that characterizes the hearts of 4-wk-old ob/ob and db/db mice raises the possibility that the mitochondria of ob/ob and db/db mice are uncoupled. Expression levels of UCPs were not increased in the hearts of 4-wk-old mice of both strains. However, recent data suggest that mitochondrial uncoupling can be activated by increased FA flux and even more potently by superoxides (23, 24). Moreover, recent studies in rodents and humans have shown that obesity per se is associated with increased oxidative stress (25). Increased UCP3 activity in skeletal muscle in vivo is also associated with increased FA oxidation rates (26). Thus, future studies will be needed to evaluate for the potential role of activation of mitochondrial UCPs in altering myocardial substrate use in obesity before development of hyperglycemia.
Transcriptional analyses revealed a persistent fetal pattern of MHC gene expression in ob/ob and db/db mouse hearts that precede the development of hyperglycemia. Thus, obesity per se or leptin deficiency can lead to myosin isoform switching in the rodent heart. Similar changes in myosin gene expression have been described in insulin-deficient diabetes (14), hypothyroidism (27, 28), pressure overload hypertrophy and heart failure (27), and cardiac atrophy (29) and were also noted in the hearts of mice with cardiomyocyte-restricted deletion of insulin receptors (17). There is no clear unifying mechanism that can account for the change in myosin isoform expression in these diverse situations. It is possible that myosin isoform switching represents a stereotypic adaptation of the heart to various neurohormonal or metabolic stressors. A common feature of all reported causes of altered myocardial myosin isoform expression are significant changes in myocardial substrate use. Thus, it will be important in future to studies to determine the metabolic or bioenergetic signals that may regulate myosin isoform expression in the heart.
The other striking phenotype of the hearts of young ob/ob and db/db mice was evidence of increased myocardial contractility. The basis for these cardiovascular changes are likely multifactorial. However, we believe that a likely cause is the myocardial adaptation to increased intravascular volume, which has been shown to occur in obesity (30). Activation of the sympathetic nervous system could also contribute to these changes. However, studies in leptin-deficient rodents suggest that the ob/ob mice have reduced central activation of the sympathetic nervous system (31, 32). The increased MVO2 in 4-wk-old mice indicates that myocardial efficiency is decreased. The implication of this observation is the possibility that myocardial reserve might be decreased. As such it will be of interest to determine whether the hearts of ob/ob mice will exhibit an impaired response to inotropic or hypertrophic stressors. Indeed, studies of 10-wk-old ob/ob mice revealed a modest reduction in LV systolic function relative to controls after a single ip injection of dobutamine (33). The onset of hyperglycemia is clearly associated with loss of these adaptations in db/db mice between 8 and 15 wk and similar changes in ob/ob mice after 30 wk of age (data not shown). Although the onset of hyperglycemia is associated with normalization of LV hypercontractility in obese and insulin-resistant animals, it must be emphasized that even before the onset of hyperglycemia, the increased MVO2 and decreased cardiac efficiency and myosin isoform switch are clear indicators of a vulnerable myocardium. Recent studies in women with morbid obesity revealed remarkably similar results to those described in our study, namely increased cardiac output, increased FA oxidation, increased MVO2, and decreased cardiac efficiency (34). Taken together, these studies indicate that in obesity and insulin-resistant states, cardiac energy metabolism is compromised before the development of diabetes, and it is likely that efforts to reverse obesity and insulin resistance may reduce the future risk of adverse cardiovascular outcomes.
In summary we have shown that changes in myocardial FA and glucose use and myosin isoform switching are the earliest defects that occur in the context of obesity, insulin resistance, and leptin deficiency/resistance. The hearts are initially hypercontractile, but increased MVO2 indicates that myocardial efficiency is reduced. Although these early changes are largely independent of PPAR signaling, it is likely that enhanced PPAR signaling will exacerbate these metabolic disturbances after the onset of hyperglycemia. These early changes may create a vulnerable condition in which additional stresses or insults to the heart might lead to accelerated cardiac decompensation.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
First Published Online September 1, 2005
Abbreviations: acyl CoA, Acyl-coenzyme A; FAT/CD36, fatty acid translocase; FA, fatty acid; FFA, free fatty acid; LCAD, long chain acyl CoA dehydrogenase; LV, left ventricular; MCAD, medium chain acyl CoA dehydrogenase; MHC, myosin heavy chain; MVO2, myocardial oxygen consumption; PDK, pyruvate dehydrogenase kinase; PGC, PPAR coactivator; PPAR, peroxisome proliferator activated receptor; UCP, uncoupling protein; VLCAD, very long chain acyl CoA dehydrogenase.
Received July 25, 2005.
Accepted for publication August 26, 2005.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
overexpression mimics that caused by diabetes mellitus. J Clin Invest 109:121–130[CrossRef][Medline]
This article has been cited by other articles:
 |
|
 |
|
  I. Tabbi-Anneni, J. Buchanan, R. C. Cooksey, and E. D. Abel Captopril Normalizes Insulin Signaling and Insulin-Regulated Substrate Metabolism in Obese (ob/ob) Mouse Hearts Endocrinology, August 1, 2008; 149(8): 4043 - 4050. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. D. Abel, S. E. Litwin, and G. Sweeney Cardiac Remodeling in Obesity Physiol Rev, April 1, 2008; 88(2): 389 - 419. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Witteles and M. B. Fowler Insulin-Resistant Cardiomyopathy: Clinical Evidence, Mechanisms, and Treatment Options J. Am. Coll. Cardiol., January 15, 2008; 51(2): 93 - 102. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. R. McGaffin, C.-K. Sun, J. J. Rager, L. C. Romano, B. Zou, M. A. Mathier, R. M. O'Doherty, C. F. McTiernan, and C. P. O'Donnell Leptin signalling reduces the severity of cardiac dysfunction and remodelling after chronic ischaemic injury Cardiovasc Res, January 1, 2008; 77(1): 54 - 63. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sena, I. R. Rasmussen, A. R. Wende, A. P. McQueen, H. A. Theobald, N. Wilde, R. O. Pereira, S. E. Litwin, J. P. Berger, and E. D. Abel Cardiac Hypertrophy Caused by Peroxisome Proliferator- Activated Receptor-{gamma} Agonist Treatment Occurs Independently of Changes in Myocardial Insulin Signaling Endocrinology, December 1, 2007; 148(12): 6047 - 6053. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. S. Szczepaniak, R. G. Victor, L. Orci, and R. H. Unger Forgotten but Not Gone: The Rediscovery of Fatty Heart, the Most Common Unrecognized Disease in America Circ. Res., October 12, 2007; 101(8): 759 - 767. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sebastiani, C. Giordano, C. Nediani, C. Travaglini, E. Borchi, M. Zani, M. Feccia, M. Mancini, V. Petrozza, A. Cossarizza, et al. Induction of Mitochondrial Biogenesis Is a Maladaptive Mechanism in Mitochondrial Cardiomyopathies J. Am. Coll. Cardiol., October 2, 2007; 50(14): 1362 - 1369. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Boudina, S. Sena, H. Theobald, X. Sheng, J. J. Wright, X. X. Hu, S. Aziz, J. I. Johnson, H. Bugger, V. G. Zaha, et al. Mitochondrial Energetics in the Heart in Obesity-Related Diabetes: Direct Evidence for Increased Uncoupled Respiration and Activation of Uncoupling Proteins Diabetes, October 1, 2007; 56(10): 2457 - 2466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. D. Lopaschuk, C. D.L. Folmes, and W. C. Stanley Cardiac Energy Metabolism in Obesity Circ. Res., August 17, 2007; 101(4): 335 - 347. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Boudina and E. D. Abel Diabetic Cardiomyopathy Revisited Circulation, June 26, 2007; 115(25): 3213 - 3223. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Giger, A. X. Qin, P. W. Bodell, K. M. Baldwin, and F. Haddad Activity of the beta-myosin heavy chain antisense promoter responds to diabetes and hypothyroidism Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H3065 - H3071. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Hsueh, E. D. Abel, J. L. Breslow, N. Maeda, R. C. Davis, E. A. Fisher, H. Dansky, D. A. McClain, R. McIndoe, M. K. Wassef, et al. Recipes for Creating Animal Models of Diabetic Cardiovascular Disease Circ. Res., May 25, 2007; 100(10): 1415 - 1427. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Arikawa, R. C.W. Ma, K. Isshiki, I. Luptak, Z. He, Y. Yasuda, Y. Maeno, M. E. Patti, G. C. Weir, R. A. Harris, et al. Effects of Insulin Replacements, Inhibitors of Angiotensin, and PKC{beta}'s Actions to Normalize Cardiac Gene Expression and Fuel Metabolism in Diabetic Rats Diabetes, May 1, 2007; 56(5): 1410 - 1420. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Yue, T. Arai, M. Terashima, A. Y. Sheikh, F. Cao, D. Charo, G. Hoyt, R. C. Robbins, E. A. Ashley, J. Wu, et al. Magnetic resonance imaging of progressive cardiomyopathic changes in the db/db mouse Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2106 - H2118. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Fauconnier, D. C. Andersson, S.-J. Zhang, J. T. Lanner, R. Wibom, A. Katz, J. D. Bruton, and H. Westerblad Effects of Palmitate on Ca2+ Handling in Adult Control and ob/ob Cardiomyocytes: Impact of Mitochondrial Reactive Oxygen Species Diabetes, April 1, 2007; 56(4): 1136 - 1142. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Qi and B. Rodrigues Glucocorticoids produce whole body insulin resistance with changes in cardiac metabolism Am J Physiol Endocrinol Metab, March 1, 2007; 292(3): E654 - E667. [Abstract] |
, P < 0.001 vs. 4-wk-old db/db mice; 
, P = 0.06 vs. age-matched controls (ANOVA); **, P < 0.04 vs. age-matched controls (unpaired t test). gdw, Gram dry heart weight.
