Published online before print July 14, 2008, doi: 10.1161/CIRCHEARTFAILURE.108.766402
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Original Articles |
Chronic Glucagon-Like Peptide-1 Infusion Sustains Left Ventricular Systolic Function and Prolongs Survival in the Spontaneously Hypertensive, Heart Failure–Prone Rat
From the Department of Medicine, Allegheny General Hospital, Pittsburgh, Pa (I.P., S.B., P.P., H.B., R.P.S.); and the Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pa (S.B.B., R.P.S.).
Correspondence to Richard P. Shannon, MD, Hospital of the University of Pennsylvania, 3400 Spruce Street, Centex 100, Philadelphia, PA 19104. E-mail Richard.Shannon{at}uphs.upenn.edu
Received January 20, 2008; accepted July 2, 2008.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background— Glucagon-like peptide-1 (GLP-1) treatment leads to short-term improvements in myocardial function in ischemic and nonischemic cardiomyopathy. It is unknown whether GLP-1 improves survival when administered over a longer time period. Spontaneously hypertensive, heart failure–prone (SHHF) rats progress to advanced heart failure and death over a 15-month period. The authors sought to determine whether a continuous infusion of GLP-1 would reduce mortality in this model.
Methods and Results— At 9 months of age, 50 SHHF rats were randomized to receive a 3-month, continuous infusion of either GLP-1 or saline. Metabolic parameters were measured and cardiac ultrasounds performed at study initiation and completion of treatment. Surviving rats were euthanized at 12 months. Hearts were perfused in an isolated, isovolumic heart preparation, and Tunel staining of myocardial samples was performed. Baseline metabolic and cardiac functional parameters were comparable. GLP-1–treated SHHF rats had greater survival (72% versus 44%, P=0.008) at 12 months of age. In addition, GLP-1 treatment led to higher plasma insulin, lower plasma triglycerides, and preserved left ventricular (LV) function. GLP-1–treated rats demonstrated decreased myocyte apoptosis by Tunel staining as well as reduced caspase-3 activation. No increase in p-BAD expression was seen. In isolated hearts, the LV systolic pressure and LV-developed pressure were greater in the GLP-1 group. Myocardial glucose uptake was also increased in GLP-1–treated SHHF rats.
Conclusions— Chronic GLP-1 treatment prolongs survival in obese SHHF rats. This is associated with preserved LV function and LV mass index, increased myocardial glucose uptake, and reduced myocyte apoptosis.
Key Words: apoptosis • diabetes mellitus • glucose • heart failure • mortality
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Glucagon-like peptide-1 (GLP-1; 7-36 amide) is a member of the proglucagon family of incretin peptides, which is implicated in the control of appetite and satiety. These agents have been shown to have significant clinical efficacy in the treatment of type 2 diabetes mellitus.1–3 Earlier studies have demonstrated that GLP-1 infusion has salutary cardiovascular effects in the presence or absence of diabetes, suggesting that GLP-1 may have cardioprotective effects independent of those attributable to tight glycemic control.4 Acute infusions of GLP-1 were associated with enhanced recovery after brief ischemic insults in conscious dogs5 and in intact6 and isolated rat hearts.6,7 Seventy-two–hour infusions of GLP-1 have been associated with increased myocardial glucose uptake and improved left ventricular (LV) function in conscious dogs with dilated cardiomyopathy induced by rapid pacing.8 Similar benefits have been seen in patients following acute myocardial infarction.9 However, to date, these studies have involved relatively brief infusions (days) and have consequently assessed only short-term improvements in cardiac performance in postischemic or cardiomyopathic states. There have been no longer-term studies to determine whether these acute cardiovascular benefits of GLP-1 are sustainable. Moreover, there are no studies to determine whether chronic GLP-1 infusion improves the survival in experimental or human models predisposed to cardiovascular mortality.
Editorial 147
Clinical Perspective 160
The spontaneously hypertensive, heart failure–prone (SHHF) rat is a model of obesity, insulin resistance, and hypertension that progresses to dilated cardiomyopathy over a 12- to 15-month period.10 The progressive development of the cardiac phenotype is associated with the onset of glucose intolerance. Treatment with both standard and novel heart failure therapies has been shown to moderate the development of LV dysfunction.11–14 As such, the model constitutes an attractive opportunity to study the long-term effects of GLP-1 on myocardial glucose uptake, cardiac structure and function, and survival. Accordingly, the purpose of the present study was to determine the effects of a chronic (3-month), continuous infusion of GLP-1 (7-36) amide on metabolic parameters in mature SHHF rats. A second goal was to determine the effects of chronic GLP-1 infusion on LV systolic function and myocardial structure. Last, we sought to determine whether and by what mechanism GLP-1 may increase the survival in this model vulnerable to premature cardiac mortality from progressive LV systolic dysfunction.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Seventy 6-month-old SHHF rats were purchased from Charles River Laboratories (Wilmington, Mass) and acclimated to the laboratory on a standard rat chow limited to 15 pellets per day to standardize caloric intake for 3 months before study. At 9 months of age, the rats were divided randomly into 2 cohorts: control and GLP-1. Ten rats in each cohort underwent baseline studies to define the metabolic, morphometric, and hemodynamic parameters at the time point. The remaining rats were randomized to receive either GLP-1 (1.5 pmol/kg/min; n=25) or an equivalent volume of saline as control (n=25), administered by intraperitoneal infusion using a catheter attached to an Alzet minipump inserted into the subcutaneous fat. Pumps were replenished every 21 days. The rats were followed for 3 months, and those that survived underwent similar analysis at 12 months. The care and use of animals were conducted under the Guidelines on Human Use and Care of Laboratory Animals for Biomedical Research, published by the National Institutes of Health, and according to the experimental protocol approved by the Institutional Animal Care Use Committee of Allegheny General Hospital.
Metabolic Parameters
Fasting plasma insulin, glucose, nonesterified fatty acid, adiponectin, leptin, and triglyceride levels were obtained at the time of euthanasia at either 9 (baseline) or 12 months. Blood was drawn in ice-cold tubes containing EDTA as an anticoagulant and Trasylol (Bayer, West Haven, Conn) and diprotin A (Bachem Bioscience, King of Prussia, Pa) as protease inhibitors. The samples were kept on ice and centrifuged within 30 minutes of collection at 1000g for 10 minutes. The plasma was removed and stored at –80°C. The metabolic parameters were assayed as described previously.8 Plasma leptin and adiponectin were assayed using the Linco leptin assay kit (Linco Research, St. Charles, Mo) on plasma stored at –20°C. The plasma concentration of total GLP-1, including both the (7-36) and (9-36) amides, was determined in plasma collected in ice-cooled tubes containing EDTA and a dipeptidyl peptidase-4 (DPP-4) inhibitor using an antibody directed against the carboxy-terminal portion of the peptides (Linco Research).
Echocardiography
M-mode and 2D echocardiography was performed under light isoflurane anesthesia in 10 rats in each group at baseline (9 months) and in the surviving rats at 12 months. Measurements of LV dimensions in end diastole and end systole, as well as respective measurements of the interventricular septum (interventricular septal) and posterior wall in systole and diastole, were recorded. The modified Quinones15 and Deveraux16 equations were used to calculate LV ejection fraction and LV mass, respectively. The volumetric and LV indices were normalized to body mass to account for the effect of obesity in these rats. The echo reader was blinded to the treatment groups.
Isolated Isovolumic Heart Preparations
The Langendorff methodology of isolated perfused rat hearts has been described previously in detail.7 Briefly, hearts were cannulated via ascending aorta for retrograde perfusion at 37°C under constant pressure (74 mm
) using KH buffer containing (in mM) 119 NaCI, 5.4 KCl, 1.2 MgSO4, 1.2 KH2PO4, 2.5 CaCl2, 25 NaHCO3, 0.25 EDTA, 5.0 mmol/L glucose, and 40 µU/mL of insulin. All buffer components were obtained from Sigma (St. Louis, Mo). A left atrial incision was made to expose the mitral annulus through which a water-filled latex balloon was passed into the LV. The balloon was attached via polyethylene tubing to a pressure transducer (Px 272, Baxter, Deerfield, Ill.) that was connected to a Triton System I (Triton Technology, San Diego, Calif.). The initial balloon volume was set to generate LV end-diastolic pressure (LVEDP) 
5 mm. Myocardial function was measured including LV-developed pressure, LVEDP, and LV dP/dt. LV-developed pressure was calculated by subtracting LVEDP from the peak systolic pressure. Coronary flow was calculated by a timed collection of the effluent.
For the measurement of myocardial glucose uptake during steady state, the perfusate leaving the heart was collected over 1 minute every 10 to 15 minutes. Glucose concentration in the effluent was measured using Yellow Springs Instruments (Yellow Springs, Ohio) glucose analyzer. Glucose uptake was calculated as described previously.7,17
Myocyte Apoptosis
TUNEL staining was performed on sections of LV myocardium to quantify myocyte and nonmyocyte apoptosis. 4'-6-diamidino-2-phenylindo staining was used to identify nuclei as a control. The percentage of apoptotic cells was calculated using the Metamorph system. Western blot analysis of whole-heart homogenate was performed as described previously18 to determine the protein levels of the activated form of caspase-3 and phosphorylated form of BAD at serine136. The anticaspase 3, anti-BAD, and anti p-BAD serine136 antibodies were obtained from Cell Signaling Technology (Danvers, Mass) and Santa Cruz Biotechnology (Santa Cruz, Calif), respectively.
Insulin Signaling
At baseline (9 months) and in surviving rats at 12 months, subsets of rats were euthanized, the myocardium was removed, and LV samples were snap frozen in liquid nitrogen. Components of the myocardial insulin signaling cascade were assayed by Western blot using rat-specific antibodies in purified sarcolemmal membrane preparations generated by density gradient centrifugation, as previously described from our laboratory.18 In half of the rats within each group, insulin (100 U SQ) was administered 5 minutes before removing the heart to assess the functional response of insulin-signaling proteins under physiological stimulation. The other half of the rats in each group was used to investigate the integrity of these cellular pathways under basal metabolic conditions. Immunoblotting for IR-β, IRS-1, and Akt-1 total protein expression, serine (Ser 472, 473) and threonine (Thr 308)-phosphorylated Akt-1, and serine307-phosphorylated IRS-1 was conducted using specific antibodies as described previously.18 All Western blots were performed using 10 µg of protein/lane. Adjustment for protein loading was accomplished by normalizing bands based on Coomassie staining of the blot.
For the measurement of glucose transporter-4 (GLUT-4) translocation, purified light (sarcolemmal) and heavy (intracellular) membrane vesicles were isolated from LV myocardium using a sucrose gradient.7,18 Membranes were probed with rabbit anti–GLU-4 polyclonal antibody (1:1000) (Santa Cruz Biotechnology) overnight at 4°C. Densitometric analysis of the bands was carried out using Personal Densitometer SI and ImageQuaNT Software (Molecular Dynamics, Sunnyvale, Calif) and expressed as the percentage of sarcolemmal membrane to total GLUT-4.18 The signaling data were expressed as the percentage of insulin stimulated in each group at the 2 time points.
Statistical Analysis
All measurements are expressed as mean±SEM. The data were analyzed by unpaired Student t test with a Bonferroni correction applied for multiple comparisons. The survival response with respect to time between groups was analyzed by 2-way ANOVA. Probability values were provided for all comparisons. Statistical significance was indicated when P<0.05.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
LV Weight, Body Weight, and Metabolic Parameters
There was no difference in body weight, body mass index, LV mass, or LV mass index between the groups at baseline, nor were there any differences in baseline metabolic parameters, with both groups demonstrating significant fasting hyperglycemia at 9 months of age (Table 1). GLP-1 treatment was associated with a significant reduction in body weight and body mass index and a trend (P=0.061) toward an increase in LV mass index over the 3-month period of treatment. These responses were significantly different compared with the response over time in the saline control group. There were significant declines in plasma glucose and triglyceride levels as well as significant increases in plasma insulin and adiponectin levels in the GLP-1 group during the 3-month period of treatment. These responses, as well as the glucagon response, over time were significantly different than those observed in the saline control group. As expected, plasma GLP-1 levels were significantly higher in the GLP-1–treated group compared with the saline controls (Table 1). Myocardial glucose uptake was also greater in the GLP-1–treated rats, and the response was significantly greater than that observed in the saline control (Table 2).
|
|
LV Hemodynamic Parameters
At baseline, there was no significant difference between groups in mean arterial pressure, heart rate, stroke volume, LV dimensions, or LV ejection fraction (Table 3). Notably, both groups had significant baseline hypertension, with mean arterial pressures in excess of 130 mmHg.
|
Following the 3-month treatment period, significant differences were observed between the groups. The saline control group demonstrated decreased stroke volume and LV ejection fraction and increased LV end-systolic dimension over 3 months. By contrast, cardiac output increased in the GLP-1–treated group, and LV end-systolic dimensions, LV ejection fraction, and heart rate remained unchanged (Table 3). These findings were corroborated by in vitro data, which showed that LV systolic pressure and LV-developed pressures were significantly greater in the GLP-1–treated rats (Table 2). The decline in LV systolic and LV-developed pressure in the isolated hearts of the saline-treated group reflects a decline in LV contractile performance under isovolumic conditions. Thus, GLP-1 treatment preserved LV size and function, preventing the deterioration observed in the saline control group.
Survival
SHHF rats treated with GLP-1 had significantly greater survival (72%) after 3 months compared with saline controls (44%; Figure 1). This was associated with significantly reduced myocyte apoptosis as assessed by TUNEL staining. Notably, there was no difference in apoptotic cell death among nonmyocyte cells in either treatment group (Figure 2). The reduction in myocyte apoptosis in the GLP-1 treatment group was accompanied by reduced myocardial caspase-3 activation (Figure 3). In addition, GLP-1–treated rats had increased Akt phosphorylation and GLUT-4 translocation, consistent with the increase in plasma insulin. However, Akt activation was not associated with the inactivation of the proapoptotic protein BAD as assessed by the ratio of ser136p-BAD/total BAD (control: 0.49±0.03; GLP-1: 0.45±0.03). GLP-1 receptor (GLP-1R) expression was increased in GLP-treated rats (Figure 4).
|
|
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Obesity, hypertension, and diabetes are well-established risk factors for cardiovascular mortality in humans, but strategies designed to modify these risks have been largely elusive. In the present study, we demonstrate that a 3-month, continuous infusion of GLP-1 is associated with improvements in myocardial functional and systemic metabolic parameters and with prolonged survival in an obese, hypertensive rat model predisposed to accelerated cardiovascular disease and premature mortality. To our knowledge, there are no previous studies of the effects of GLP-1 on cardiovascular mortality in this type of high-risk animal model.
The current observations are consistent with our prior study in human heart failure subjects, in which a 5-week infusion of GLP-1 led to improvements in LV function, functional capacity, and systemic metabolic parameters.4 In both the current and referenced study, better glycemic control in the GLP-1–treated group may have contributed to improvements in cardiac function because elevated glucose levels have been shown to depress LV function in both in vitro19,20 and in vivo studies of normal subjects and diabetic patients.21,22 However, subjects without diabetes demonstrated similar improvements in myocardial function as diabetic patients, suggesting an effect of GLP-1 that is independent of glycemic control. Nevertheless, the inclusion of a positive control group receiving an antihyperglycemic agent other than GLP-1 would be required to clarify this issue further, although it is beyond the scope of the present investigation.
This is also the first study to demonstrate the ability of GLP-1 to reduce cardiac myocyte apoptosis. Notably, reduced programmed cell death was not seen in nonmyocyte cellular constituents. The ability of GLP-1 to protect cardiac myocytes from accelerated death was suggested in a study showing that infusion of GLP-1 is associated with improved LV function in patients after the successful reperfusion for myocardial infarction.9 To date, the antiapoptotic effects of GLP-1 have been examined most extensively in the pancreas, where reduced programmed cell death has been observed in diabetic rodents, islet cell lines, purified rat β-cells, heterologous cells expressing the GLP-1 receptor, and human islet cells.23–27 Liraglutide, a long-acting GLP-1 analogue, has also been shown to inhibit apoptosis in primary neonatal rat islets.28 In addition to pancreatic cells, GLP-1 receptor activation enhances neuronal survival in cellular and animal models of neuronal toxicity.29,30
The mechanism of the antiapoptotic action of GLP-1 remains the subject of intense investigation. Nevertheless, evidence has emerged for the involvement of increased phosphatidyl inositol-3 kinase/Akt signaling, leading to enhanced nuclear factor-
B DNA-binding activity and stimulation of inhibitors of apoptosis protein-2, Bcl-XL, and Bcl-2 expression.24,25,26,31 Activation of phosphatidyl inositol-3 kinase/Akt also functions to block BAD-mediated death by phosphorylating BAD at Ser-136, and increased levels of inactivated p-BAD have been demonstrated in rat hearts in response to treatment with GLP-1.6 In the present study, we observed increases in phosphorylation of Akt associated with reduced levels of the activated form of caspase-3. However, protein levels of p-BAD (Ser 136) were not different between the GLP-1–treated and control groups. Taken together, these data suggest that GLP-1 treatment favors survival through reduced apoptosis, but additional work will be required to determine the precise mechanism.
In addition to the reduction in myocyte apoptosis, treatment with GLP-1 was associated with increased LV mass index. The ability of the LV to hypertrophy in the presence of increased afterload is an adaptive response that acts to normalize wall stress. As seen in the saline-treated group, failure of the ventricle to hypertrophy adequately leads to ventricular dilation and dysfunction. It is noteworthy that GLP-1 is known to promote hyperplasia in pancreatic β-cells.32,33 Several potential mediators of growth signaling by GLP-1 have been proposed, including protein kinase C
,32 epidermal growth factor receptor, c-src,33 and PDX-1.34 The mouse model of GLP-1 receptor knockout was associated with modest cardiac phenotype, characterized by decreased cardiac mass and impaired responses to superimposed metabolic stresses.35 Whether our observation of increased LV mass index is due to direct effects of GLP-1, or whether this is an indirect result of the increase in plasma insulin, remains uncertain. Increased activation of Akt is known to stimulate cardiac hypertrophy through both the activation of the mammalian target of rapamycin (mTOR) pathway36 and through the inactivation of glycogen synthase kinase 3 beta (GSK-3β).37 The inclusion of a control group receiving an alternative insulin secretagogue may help elucidate this issue in future studies.
We have shown previously that GLP-1 treatment in normal, isolated, isovolumic hearts has a distinctly different physiological and signaling profile compared with insulin, with stimulation of GLUT-1 translocation via a non–Akt-dependent mechanism.7 In the present study, GLP-1 infusion resulted in increased plasma insulin levels, and associated phosphorylation and activation of Akt led to GLUT-4 translocation. In vitro experiments confirmed that this was associated with increased myocardial glucose uptake. These apparently discrepant findings in these 2 rat models are present because in the current experiments, the administration of GLP-1 occurred in the setting of hyperglycemia. Under these circumstances, the insulinotropic actions of GLP-1 to stimulate pancreatic insulin release predominate over the insulinomimetic effects seen in isolated normal rat hearts under euglycemic conditons.
We also observed that GLP-1 infusion was associated with increased adiponectin expression. Both these pathways may have contributed to increased myocardial glucose uptake and normalization of plasma glucose. The relationship between adiponectin and LV mass is not completely elucidated, although epidemiological data in humans38,39 and experimental data in mice40 has suggested that adiponectin inhibits hypertrophic signaling in the myocardium in the setting of pressure overload. In this case, the inhibitory effect of increased adiponectin must have been outweighed by other, more potent, growth-stimulating pathways.
GLP-1R expression was more abundant in cardiac myocytes from GLP-1–treated rats. Very little is known about the regulation of the GLP-1R in the heart, and existing data from other tissues do not provide insight into our findings. High glucose concentrations upregulate receptor expression in pancreatic islets,41–44 but serum glucose was lower in the GLP-1–treated group than in controls in the current study (as would be expected with GLP-1 treatment). Leptin enhances GLP-1R expression in certain areas of the rat hypothalamus,43 but our GLP-1–treated and control rats had similar serum leptin levels. Increased GLP-1R expression cannot be explained by treatment with GLP-1 itself, as this was shown to downregulate the GLP-1R gene in a rat medullary thyroid carcinoma cell line.45 Additional studies will be needed to identify other determinants of GLP-1R expression that could explain our current observations.
GLP-1 (7-36) amide undergoes rapid enzymatic cleavage by the enzyme DPP-4, resulting in the formation of GLP-1 (9-36), the predominant plasma metabolite. We showed previously in a canine model of pacing-induced cardiomyopathy that infusion of the metabolite GLP-1 (9-36) mimics the effects of GLP-1 (7-36) in stimulating myocardial glucose uptake and improving LV and systemic hemodynamics.6 The relative contribution of each of these peptides to our current observations cannot be determined. Future studies using coadministration of GLP-1 (7-36) with a DPP-4 inhibitor or Exendin-4, which is resistant to degradation by DPP-4, are warranted.
In conclusion, a 3-month, continuous infusion of GLP-1 resulted in preservation of LV function and prolonged survival in an experimental animal model of obesity, insulin resistance, and hypertension that was otherwise predisposed to premature cardiac failure and death.
Obesity, hypertension, and diabetes are well-established risk factors for cardiovascular mortality in humans, but strategies designed to modify these risks have been largely elusive. GLP-1 treatment leads to short-term improvements in myocardial function in ischemic and nonischemic cardiomyopathy, demonstrated in both animal models and human disease. However, to date, these studies have involved relatively brief infusions (days) and have consequently assessed only short-term improvements in cardiac performance in postischemic or cardiomyopathic states. Moreover, there have been no studies to determine whether chronic GLP-1 infusion improves survival in experimental or human models predisposed to cardiovascular mortality. In the present study, we demonstrate that a 3-month, continuous infusion of GLP-1 is associated with improvements in myocardial functional and systemic metabolic parameters and also with prolonged survival in an obese, hypertensive rat model predisposed to accelerated cardiovascular disease and premature mortality. This is the first study to show the benefit of GLP-1 with regard to cardiovascular mortality in this type of high-risk model. Long-term GLP-1 administration may prove to be a useful addition to the armamentarium of medical therapy aimed at preventing the heart failure and premature cardiovascular death in patients with diabetes, hypertension, and obesity.
|
Acknowledgments |
|---|
Disclosures
Dr. Shannon holds a patent on the use of GLP-1 in the treatment of LV systolic dysfunction.
Sources of Funding
This study was supported by NIH grant RO-1 AG 0125.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Baggio LL, Drucker DJ. Harnessing the therapeutic potential of glucagon-like peptide-1: a critical review. Treat Endocrinol. 2002; 1: 117–125.[CrossRef][Medline]
2. Todd JF, Wilding JP, Edwards CM, Khan FA, Ghatei MA, Bloom SR. Glucagon-like peptide-1 (GLP-1): a trial of treatment in non-insulin-dependent diabetes mellitus. Eur J Clin Invest. 1997; 27: 533–536.[CrossRef][Medline]
3. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide-1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002; 359: 824–830.[CrossRef][Medline]
4. Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail. 2006; 12: 694–699.[CrossRef][Medline]
5. Nikolaidis LA, Doverspike A, Hentosz T, Zourelias L, Shen YT, Elahi D, Shannon RP. Glucagon-like peptide-1 limits myocardial stunning following brief coronary occlusion and reperfusion in conscious canines. J Pharmacol Exp Ther. 2005; 312: 303–308.
6. Bose AK, Mocanu MM, Carr RD, Brand CL, Yellon DM. Glucagon-like peptide-1 can directly protect the heart against ischemia/reperfusion injury. Diabetes. 2005; 54: 146–151.
7. Zhao T, Parikh P, Bhashyam S, Bolukoglu H, Poornima I, Shen YT, and Shannon RP. Direct effects of glucagon-like peptide-1 on myocardial contractility and glucose uptake in normal and postischemic isolated rat hearts. J Pharmacol Exp Ther. 2006; 317: 1106–1113.
8. Nikolaidis LA, Elahi D, Hentosz T, Doverspike A. Huerbin R, Zourelias L, Stolarski C, Shen YT, Shannon RP. Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy. Circulation. 2004; 110: 955–961.
9. Nikolaidis LA, Mankad S, Sokos GG, Miske G, Shah A, Elahi D, Shannon RP. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 2004; 109: 962–965.
10. Emter CA, McCune SA, Sparagna GC, Radin MJ, Moore RL. Low-intensity exercise training delays onset of decompensated heart failure in spontaneously hypertensive heart failure rats. Am J Physiol Heart Circ Physiol. 2005; 289: H2030–8.
11. Liang Q, Elson AC, Gerdes AM. p38 MAP kinase activity is correlated with angiotensin II type 1 receptor blocker-induced left ventricular reverse remodeling in spontaneously hypertensive heart failure rats. J Card Fail. 2006; 12: 479–486.[CrossRef][Medline]
12. Minhas KM, Saraiva RM, Schuleri KH, Lehrke S, Zheng M, Saliaris AP, Berry CE, Barouch LA, Vandegaer KM, Li D, Hare JM. Xanthine oxidoreductase inhibition causes reverse remodeling in rats with dilated cardiomyopathy. Circ Res. 2006; 98: 271–279.
13. Kambara A, Holycross BJ, Wung P, Schanbacher B, Ghos S, McCune SA, Bauer JA, Kwiatkowski P. Combined effects of low-dose oral spironolactone and captopril therapy in a rat model of spontaneous hypertension and heart failure. J Cardiovasc Pharmacol. 2003; 41: 830–837.[CrossRef][Medline]
14. Li H, Simon H, Bocan TM, Peterson JT. MMP/TIMP expression in spontaneously hypertensive heart failure rats: the effect of ACE- and MMP-inhibition. Cardiovasc Res. 2000; 46: 298–306.
15. Quinones MA, Waggoner AD, Reduto LA, Nelson JG, Young JB, Winters WL, Ribeiro LG, Miller RR. A new, simplified and accurate method for determining ejection fraction with two-dimensional echocardiography. Circulation. 1981; 64: 744–753.
16. Devereux RB, Reichek N. Echocardiographic determination of left ventricular mass in man: anatomic validation of the method. Circulation. 1977; 55: 613–618.
17. Bolukoglu H, Goodwin GW, Guthrie PH, Carmical SG, Chen TM, Taegtmeyer H. Metabolic fate of glucose in reversible low-flow ischemia of the isolated working rat heart. Am J Physiol. 1996; 270: H817–26.[Medline]
18. Nikolaidis LA, Sturzu A, Stolarski C, Elahi D, Shen YT, Shannon RP. The development of myocardial insulin resistance in conscious dogs with advanced dilated cardiomyopathy. Cardiovasc Res. 2004; 61: 297–306.
19. Ren J, Davidoff AJ. Diabetes rapidly induces contractile dysfunctions in isolated ventricular myocytes. Am J Physiol. 1997; 272: H148–H58.[Medline]
20. Davidoff AJ, Ren J. Low insulin and high glucose induce abnormal relaxation in cultured adult rat ventricular myocytes. Am J Physiol. 1997; 272: H159–H67.[Medline]
21. Andersen NH, Bojesen A, Christiansen JS, Gravholt CH. Glycemia, lipidemia and systolic left ventricular function evaluated by myocardial strain rate: a tissue doppler echocardiographic study. Ultrasound Med Biol. 2008; 34: 151–154.[CrossRef][Medline]
22. Andersen NH, Hansen TK, Christiansen JS. Changes in glycaemic control are related to the systolic function in type 1 diabetes mellitus. Scand Cardiovasc J. 2007; 41: 85–88.[CrossRef][Medline]
23. Farilla L, Hui H, Bertolotto C, Kang E, Bulotta A, Di Mario U, Perfetti R. Glucagon-like peptide-1 promotes islet cell growth and inhibits apoptosis in zucker diabetic rats. Endocrinology. 2002; 143: 4397–4408.
24. Li Y, Hansotia T, Yusta B, Ris F, Halban PA, Drucker DJ. Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis. J Biol Chem. 2003; 278: 471–478.
25. Hui H, Nourparvar A, Zhao X, Perfetti R. Glucagon-like peptide-1 inhibits apoptosis of insulin-secreting cells via a cyclic 5'-adenosine monophosphate-dependent protein kinase A- and a phosphatidylinositol 3-kinase-dependent pathway. Endocrinology. 2003; 144: 1444–1455.
26. Wang Q, Brubaker PL. Glucagon-like peptide-1 treatment delays the onset of diabetes in 8 week-old db/db mice. Diabetologia. 2002; 45: 1263–1273.[CrossRef][Medline]
27. Farilla L, Bulotta A, Hirshberg B, Li Calzi S, Khoury N, Noushmehr H, Bertolotto C, Di Mario U, Harlan DM, Perfetti R. Glucagon-like peptide-1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology. 2003; 144: 5149–5158.[CrossRef][Medline]
28. Bregenholt S, Moldrup A, Blume N, Karlsen AE, Nissen Friedrichsen B, Tornhave D, Knudsen LB, Petersen JS. The long-acting glucagon-like peptide-1 analogue, liraglutide, inhibits beta-cell apoptosis in vitro. Biochem Biophys Res Commun. 2005; 330: 577–584.[CrossRef][Medline]
29. During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, Bland RJ, Klugmann M, Banks WA, Drucker DJ, Haile CN. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med. 2003; 9: 1173–1179.[CrossRef][Medline]
30. Perry T, Haughey NJ, Mattson MP, Egan JM, Greig NH. Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4. J Pharmacol Exp Ther. 2002; 302: 881–888.
31. Buteau J, El-Assaad W, Rhodes CJ, Rosenberg L, Joly E, Prentki M. Glucagon-like peptide-1 prevents beta cell glucolipotoxicity. Diabetologia. 2004; 47: 806–815.[CrossRef][Medline]
32. Buteau J, Foisy S, Rhodes CJ, Carpenter L, Biden TJ, Prentki M. Protein kinase czeta activation mediates glucagon-like peptide-1-induced pancreatic beta-cell proliferation. Diabetes. 2001; 50: 2237–2243.
33. Buteau J, Foisy S, Joly E, Prentki M. Glucagon-like peptide-1 induces pancreatic beta-cell proliferation via transactivation of the epidermal growth factor receptor. Diabetes. 2003; 52: 124–132.
34. Movassat J, Beattie GM, Lopez AD, Hayek A. Exendin 4 up-regulates expression of PDX 1 and hastens differentiation and maturation of human fetal pancreatic cells. J Clin Endocrinol Metab. 2002; 87: 4775–4781.
35. Gros R, You X, Baggio LL, Kabir MG, Sadi AM, Mungrue IN, Parker TG, Huang Q, Drucker DJ. Husain, M.Cardiac function in mice lacking the glucagon-like peptide-1 receptor. Endocrinology. 2003; 144: 2242–2252.
36. Bodine SC, Stitt TN, Gonzalez M, Kline WO, Stover GL, Bauerlein R, Zlotchenko E, Scrimgeour A, Lawrence JC, Glass DJ, Yancopoulos GD. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol. 2001; 3: 1014–1019.[CrossRef][Medline]
37. Hardt SE, Sadoshima J. Glycogen synthase kinase-3beta: a novel regulator of cardiac hypertrophy and development. Circ Res. 2002; 90: 1055–1063.
38. Mitsuhashi H, Yatsuya H, Tamakoshi K, Matsushita K, Otsuka R, Wada K, Sugiura K, Takefuji S, Hotta Y, Kondo T, Murohara T, Toyoshima H. Adiponectin level and left ventricular hypertrophy in japanese men. Hypertension. 2007; 49: 1448–1454.
39. Hong SJ, Park CG, Seo HS, Oh DJ, Ro YM. Associations among plasma adiponectin, hypertension, left ventricular diastolic function and left ventricular mass index. Blood Press. 2004; 13: 236–242.[CrossRef][Medline]
40. Shibata R, Ouchi N, Ito M, Kihara S, Shiojima I, Pimentel DR, Kumada M, Sato K, Schiekofer S, Ohashi K, Funahashi T, Colucci WS, Walsh K. Adiponectin-mediated modulation of hypertrophic signals in the heart. Nat Med. 2004; 10: 1384–1389.[CrossRef][Medline]
41. Abrahamsen N, Nishimura E. Regulation of glucagon and glucagon-like peptide-1 receptor messenger ribonucleic acid expression in cultured rat pancreatic islets by glucose, cyclic adenosine 3',5'-monophosphate, and glucocorticoids. Endocrinology. 1995; 136: 1572–1578.[Abstract]
42. Yamato E, Ikegami H, Takekawa K, Fujisawa T, Nakagawa Y, Hamada Y, Ueda H, Ogihara T. Tissue-specific and glucose-dependent expression of receptor genes for glucagon and glucagon-like peptide-1 (GLP-1). Horm Metab Res. 1997; 29: 56–59.[Medline]
43. Sanz C, Vazquez P, Navas MA, Alvarez E, Blazquez E. Leptin but not neuropeptide Y up-regulated glucagon-like peptide-1 receptor expression in GT1-7 cells and rat hypothalamic slices. Metabolism. 2008; 57: 40–48.[CrossRef][Medline]
44. Xu G, Kaneto H, Laybutt DR, Duvivier-Kali VF, Trivedi N, Suzuma K, King GL, Weir GC, Bonner-Weir S. Downregulation of GLP-1 and GIP receptor expression by hyperglycemia: possible contribution to impaired incretin effects in diabetes. Diabetes. 2007; 56: 1551–1558.
45. Lamari Y, Boissard C, Moukhtar MS, Jullienne A, Rosselin G, Garel JM. Expression of glucagon-like peptide-1 receptor in a murine C cell line: regulation of calcitonin gene by glucagon-like peptide-1. FEBS Lett. 1996; 393: 248–252.[CrossRef][Medline]
 |
|
 |
|
  R. Abu-Hamdah, A. Rabiee, G. S. Meneilly, R. P. Shannon, D. K. Andersen, and D. Elahi The Extrapancreatic Effects of Glucagon-Like Peptide-1 and Related Peptides J. Clin. Endocrinol. Metab., June 1, 2009; 94(6): 1843 - 1852. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. D. Nguyen and T. Doenst Letter by Nguyen and Doenst Regarding Article "Chronic Glucagon-like Peptide-1 Infusion Sustains Left Ventricular Systolic Function and Prolongs Survival in the Spontaneously Hypertensive, Heart-Failure Prone Rat" Circ Heart Fail, May 1, 2009; 2(3): e1 - e1. [Full Text] [PDF]
|
|
|
|
 |
|
 I. G. Webb, R. Williams, and M. S. Marber Lizard spit and reperfusion injury. J. Am. Coll. Cardiol., February 10, 2009; 53(6): 511 - 513. [Full Text] [PDF]
|
|
|
|
|
|
D. J. Hausenloy and D. M. Yellon GLP-1 Therapy: Beyond Glucose Control Circ Heart Fail, September 1, 2008; 1(3): 147 - 149. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||