Ann Thorac Surg 2004;77:1408-1414
© 2004 The Society of Thoracic Surgeons
Original article: cardiovascular
Glucose-insulin-potassium solution improves left ventricular energetics in chronic ovine diabetes
Tharumenthiran Ramanathan, PhD, MBBSa*,
Shin Morita, MDa,
Yifei Huang, MD, PhDa,
Kazuaki Shirota, MD, PhDa,
Takashi Nishimura, MD, PhDa,
Xing Zheng, MD, PhDa,
Stephen N. Hunyor, MD, BS, MTMa
a Cardiac Technology Centre, Department of Cardiology, Royal North Shore Hospital, Sydney, Australia
Accepted for publication October 2, 2003.
* Address reprint requests to Dr Ramanathan, C/O Professor Stephen Hunyor, Cardiac Technology Centre, Block 4, Level 3, Royal North Shore Hospital, St Leonards, Sydney NSW 2065, Australia
e-mail: indranrama{at}yahoo.com
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Abstract
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BACKGROUND: Therapeutic modulation of myocardial metabolism improves outcomes in diabetic patients following myocardial infarction and coronary artery surgery. However, the mechanism of this beneficial effect has not been fully elucidated. This study evaluated the effect of glucose-insulin-potassium solution (GIK) on left ventricular (LV) energetics and oxygen utilization efficiency in a chronic ovine model of diabetes.
METHODS: Diabetes was induced in sheep with streptozotocin. Experiments were performed following 12 months untreated diabetes (n = 6) and in controls (n = 6). Open-chest anesthetized sheep were instrumented to determine the LV pressure-volume relationship, oxygen consumption, and free fatty acid uptake. Glucose-insulin-potassium was infused at 1.5 mL · kg−1 · h−1 for 60 minutes and assessment repeated.
RESULTS: Glucose-insulin-potassium decreased LV free fatty acid uptake in control: 0.090 ± 0.047 µg/beat/100 g to 0.024 ± 0.022 µg/beat/100 g, p = 0.02 and diabetes: 0.33 ± 0.32 µg/beat/100 g to 0.11 ± 0.13 µg/beat/100 g, p = 0.04. Similarly, GIK decreased unloaded left ventricular oxygen consumption (LVVO2) in both control (0.42 ± 0.05 to 0.37 ± 0.13J/beat/100 g, p < 0.001) and diabetic sheep (0.40 ± 0.24 to 0.23 ± 0.23J/beat/100 g, p < 0.001). The slope of the LVVO2-pressure-volume area relation (contractile efficiency) was unchanged in either group. Glucose-insulin-potassium improved LV contractility 58% ± 37% (p = 0.005) and stroke work efficiency 18% ± 10% (p = 0.009) in diabetic animals but not controls. Therefore, oxygen utilization efficiency (stroke work-LVVO2) increased only in diabetic animals (16.6% ± 4.8% to 26.9% ± 3.6%, p = 0.002) following GIK.
CONCLUSIONS: This study provides in vivo evidence that GIK improves LV energetics in diabetes. Oxygen utilization efficiency is improved as a result of improved stroke work efficiency and decreased unloaded LVVO2. Improved efficiency of oxygen utilization provides a physiologic rationale for the beneficial effect of GIK in diabetic patients.
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Introduction
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Coronary artery bypass surgery is the preferred revascularization strategy for diabetic patients with multivessel coronary artery disease because of demonstrated superior long-term survival compared to angioplasty [1, 2]. However, morbidity and both short-term and long-term mortality following coronary artery bypass surgery is increased in diabetics compared to nondiabetics [3, 4]. The increased sensitivity of the diabetic heart to ischemia [5], which may be explained in part by altered substrate metabolism [6] and impaired ventricular energetics [7], contributes to this adverse prognosis. Substrate enhancement with glucose-insulin-potassium (GIK) infusion commenced before coronary artery bypass surgery in diabetic patients increased postoperative cardiac indices, decreased the need for inotropic support, and shortened the duration of ventilator support and overall hospital stay [8]. Further, in diabetic patients with myocardial infarction, early initiation of GIK followed by multidose insulin therapy significantly reduced mortality compared to conventional treatment [9].
The mechanism whereby GIK improves cardiovascular outcomes in diabetic patients has not been clearly defined. Recently, Korvald and colleagues [10] demonstrated an energetic advantage of glucose oxidation over free fatty acid oxidation in the myocardium. The diabetic heart is characterized by markedly increased free fatty acid oxidation [6]. Glucose-insulin-potassium induces a shift in substrate metabolism towards glucose oxidation [11] as well as improving contractility and stroke work efficiency of the diabetic ventricle [12]. We hypothesized that in the diabetic heart GIK may improve left ventricular (LV) mechanics without increasing LV oxygen consumption (LLVO2), thereby improving LV oxygen utilization efficiency. To address this issue, the effects of GIK on the LV pressure-volume relationship and oxygen consumption were simultaneously determined in a chronic ovine model of diabetes. Ventricular energetics were investigated according to Suga's time-varying elastance model of the ventricle and the linear LVVO2-pressure-volume area (PVA) relationship [13]. The reciprocal of the slope of this relation reflects the chemomechanical conversion efficiency of the myocardium (contractile efficiency) and the LVVO2 intercept (unloaded LVVO2) represents the energy requirement for basal metabolism and excitation-contraction coupling. We present a study to investigate the effect of GIK on LV energetics and oxygen utilization efficiency in chronic diabetes.
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Material and methods
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The investigation complied with the Guide for the Care and Use of Laboratory Animals, published by the US National Institutes of Health (National Institutes of Health publication No. 85 to 23, revised 1996) and was approved by the Royal North Shore Hospital Animal Care and Ethics Committee.
Induction of diabetes mellitus
Diabetes mellitus was induced as previously described [7, 14] in six Merino-cross sheep, with two intravenous doses of streptozotocin (60 mg/kg) administered five to seven days apart. Blood glucose levels were measured between 8:00 and 9:00 am using a calibrated standard glucometer (Precision Plus, MediSense Inc, Bedford, MA). Diabetes was determined to be established when the nonfasted blood glucose level consistently exceeded 180 mg/dL. Hyperglycemia was confirmed weekly (203.3 ± 29.1 mg/dL) and untreated diabetes was maintained for twelve months. Following induction of diabetes polyuria (1.4 ± 0.3l/d baseline vs 3.3 ± 0.3l/d diabetes), polydipsia (2.8 ± 1.3l/d baseline vs 5.8 ± 1.0l/d diabetes), and glycosuria (0 ± 0 mg/dL baseline vs 1,555 ± 523 mg/dL diabetes) were observed. Clinically significant ketonuria (4 ± 8 mg/dL baseline vs 12 ± 8 mg/dL diabetes) or proteinuria (0.15 ± 0.17 g/L baseline vs 0.23 ± 0.15 g/L diabetes) were not seen.
Glucose-insulin-potassium solution
High-dose GIK solutions (Rackley regimen) have been shown to maximally suppress myocardial free fatty acid uptake, maximize myocardial glucose uptake [15], and in the setting of acute myocardial infarction have demonstrated superiority over lower dose solutions [16, 17]. Lazar and colleagues [8] successfully modified a high-dose GIK regimen for diabetic patients undergoing coronary artery surgery (500 mL dextrose in water (D5W) with 80IU regular insulin and 40 mmol KCl infused at 30 mL/h). Therefore, we evaluated a high-dose GIK regimen in control sheep: 1000 mL D50W with 100IU regular insulin (Actrapid, Novo Nordisk Pharmaceuticals, UK) and 90 mmol KCl infused at 1.5 mL · kg−1 · h−1 and a modified high-dose GIK regimen in diabetic sheep: 1,000 mL D5W with 100IU regular insulin (Actrapid, Novo Nordisk Pharmaceuticals) and 90 mmol KCl infused at 1.5 mL · kg−1 · h−1.
Surgical preparation
Anesthesia was induced with sodium thiopentone (20 mg/kg) after which sheep were intubated and mechanically ventilated (Bird model 8, Bird Australia Pty Ltd, Chatswood, NSW, Australia) with 2 L/min of oxygen, 2 L/min of nitrous oxide, and isoflurane 1.4% to 1.8% inspired. Rectal temperature was monitored and maintained throughout the experiment with warmed intravenous normal saline. Sheep were instrumented as previously described [7]. In brief, a left anterolateral thoracotomy enabled placement of a left main coronary artery flow probe (model 6S, Transonic Systems Inc, Ithaca, NY) and coronary sinus oximetry catheter (Edwards Lifesciences, Irvine, CA). Through a neck incision the jugular vein and carotid artery were exposed. The jugular vein was cannulated with a Swan Ganz catheter (Baxter International Inc, Irvine, CA) and an inferior vena cava occlusion catheter (Edwards Lifesciences, Irvine, CA). A micromanometer-tipped catheter (Millar Instruments, Houston, TX) and conductance catheter (Cardiodynamics, Rijinsberg, The Netherlands) were passed from the carotid artery and positioned longitudinally in the LV cavity.
Biochemical analyses
At baseline and following 60 minutes GIK, simultaneous arterial and coronary sinus blood samples were collected and transported on ice to determine free fatty acid uptake. An automated spectrophotometer (Cobas Fara II, F. Hoffman –La Roche Ltd, Basel, Switzerland) and the NEFA C kit (Wako Chemicals, Dallas TX) were used to measure free fatty acid levels in serum.
Data analysis
Left ventricular pressure and volume at end-systole and end-diastole, stroke volume, and stroke work were calculated as the average of steady state data obtained from 10 to 20 beats. The end-systolic pressure-volume relationship (ESPVR) was assessed from data obtained during transient caval occlusion using an iterative algorithm. Least squares linear regression of the end-systolic pressure-volume points was performed, generating the equation: End-systolic pressure = Ees · (End-systolic volume − V0). The slope of this relationship, end-systolic elastance (Ees), is a load-independent index of LV contractility and V0 represents the volume-axis intercept of the ESPVR. Ventricular energetics were evaluated according to Suga's time-varying elastance model [13]. This concept defines total mechanical energy generated by an ejecting contraction as equivalent to systolic pressure-volume area (PVA), which is the area bounded by the ESPVR, the end-diastolic pressure volume relationship, and the systolic portion of the pressure-volume loop. The SW represents the energy transferred from the LV to the arterial system and is defined by the area within the pressure-volume loop. The SW was calculated as the integral of the pressure-volume loop and PVA was calculated as PVA = {SW + [0.5 · ESP · (ESV − V0)] − 0.75 · [0.5 · EDP · (EDV − V0)]}, where EDV is end-diastolic volume, ESV is end-systolic volume, ESP is end-systolic pressure, and EDP is end-diastolic pressure. The efficiency of energy transfer from the LV to the arterial system (stroke work efficiency) represents the proportion of SW extracted from total mechanical energy generated during contraction and is calculated as the ratio of SW to PVA. Pressure-volume area is directly related to LVVO2. The ovine left main coronary artery exclusively supplies the LV and there is minimal overlap with the right ventricle. This enables calculation of LVVO2 rather than myocardial oxygen consumption [18]. Therefore, LV oxygen consumption per beat was calculated as LVVO2 = [(CBF · (SaO2 − SvO2) · Hb · 1.35)/HR], where CBF is the left main coronary artery blood flow, SaO2 is the arterial oxygen saturation, SvO2 is the coronary sinus (venous) oxygen saturation, Hb is hemoglobin, and HR is heart rate. The LVVO2-PVA relationship and oxygen utilization efficiency were determined after SW, PVA, and LVVO2 were normalized to 100 g LV weight and units converted to J/beat [19]. Oxygen utilization efficiency (%) was calculated as SW/LVVO2. The LVVO2-PVA relationship was generated using least squares linear regression. The reciprocal of the slope represents chemomechanical conversion efficiency or contractile efficiency and the y intercept represents unloaded LVVO2. Matching between the LV and the arterial system was derived according to the ventriculoarterial coupling framework of Sunagawa and colleagues [20]. Properties of the arterial system (effective arterial elastance) are represented by the slope of the end-systolic pressure-stroke volume relation while LV mechanical properties (end-systolic elastance) are described by the slope of the end-systolic pressure-volume relationship.
Statistical analysis
Data are presented as mean ± standard deviation. Comparison between baseline and GIK was performed with the Student's paired t test or the Wilcoxon signed rank test, as appropriate. Assessment of the effect of GIK on the total pool of LVVO2 and PVA values was evaluated with analysis of covariance (ANCOVA) in a multiple linear regression model with dummy variables coding for baseline or GIK [7, 10]. The Bonferroni procedure was used to correct for multiple comparisons. Statistical significance was set at p less than 0.05. Calculations and statistical analyses were performed using Microsoft Excel 7.0 and SPSS 8.0.
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Results
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Hemodynamic parameters at baseline and following GIK are presented in Table 1.
Heart rate, LV pressure, and volume at end-diastole or end-systole did not change significantly in either control or diabetic animals. Infusion of GIK in control sheep increased blood glucose (79.7 ±15.1 mg/dL baseline to 170.1 ± 45.6 mg/dL GIK; p < 0.001) but did not change serum potassium (3.9 ± 0.4 mmol/L baseline vs 3.7 ± 0.4 mmol/L GIK; p = 0.28) or arterial pH (7.43 ± 0.03 baseline vs 7.40 ± 0.02 GIK; p = 0.07). In diabetic animals, GIK did not significantly alter blood glucose (226.9 ± 27.0 mg/dL baseline vs 227.5 ± 37.0 mg/dL GIK; p = 0.95), serum potassium (3.6 ± 0.5 mmol/L baseline vs 3.5 ± 0.2 mmol/L GIK; p = 0.33), or arterial pH (7.39 ± 0.06 baseline vs 7.40 ± 0.05 GIK; p = 0.57).
Left ventricular contractility, ventriculoarterial coupling, and stroke work efficiency
Infusion of GIK in control animals did not change end-systolic elastance (a load-independent index of LV contractility) or effective arterial elastance. In diabetic animals, end-systolic elastance improved 58% ± 37% (p = 0.005) without altering effective arterial elastance. Consequently, the ventriculoarterial coupling ratio (Ea/Ees) decreased (p = 0.01) reflecting improved matching between the LV and the arterial system. The effects of GIK on LV mechanics are shown in Table 2.
In diabetic animals, pressure volume area decreased by 13% ± 11% (p = 0.03) without altering stroke work. Consequently, potential energy decreased 29% ± 16% (p = 0.01) and stroke work efficiency improved 18% ± 10% (p = 0.009).
Left ventricular oxygen utilization efficiency
Glucose-insulin-potassium decreased the arteriovenous oxygen content difference in control (0.027 ± 0.010 mLO2/mL baseline vs 0.021 ± 0.007 mLO2/mL GIK; p = 0.03) and diabetes (0.031 ± 0.012 mLO2/mL baseline vs 0.024 ± 0.014 mLO2/mL GIK; p = 0.04). However, left main coronary artery blood flow was not significantly altered in either group (control 218 ± 59 mLl/min baseline vs 267 ± 18 mL/min GIK; p = 0.10 and diabetes 262 ± 99 mL/min baseline vs 254 ± 107 mL/min GIK; p = 0.44). Left ventricular oxygen consumption tended to decrease (p = 0.065) in diabetic animals and was not significantly altered in controls. As a result, LV oxygen utilization efficiency improved 72% ± 52% (p = 0.009) in diabetic sheep following GIK infusion (Table 2).
Left ventricular free fatty acid uptake
Infusion of GIK in control and diabetic sheep lowered the serum free fatty acid level (control: 354 ± 203 mmol/L baseline vs 91 ± 67 mmol/L GIK; p = 0.03 and diabetes: 1871 ± 965 mmol/L baseline vs 467 ± 271 mmol/L GIK; p = 0.006). Left ventricular free fatty acid uptake decreased in control (0.090 ± 0.047 µg/beat/100g LV baseline vs 0.024 ± 0.023 µg/beat/100g LV GIK; p = 0.02) and diabetic animals (0.270 ± 0.268 µg/beat/100g LV baseline vs 0.087 ± 0.110 µg/beat/100g LV GIK; p < 0.05).
Contractile efficiency and unloaded left ventricular oxygen consumption
Figure 1
shows representative LVVO2-PVA relations obtained at baseline and following 60 minutes GIK in control and diabetic sheep. The changes in the parameters derived from the LVVO2-PVA relation are presented in Figure 2.
The correlations were highly linear in each animal; the median correlation coefficient was 0.965 at baseline and 0.960 following GIK infusion. Glucose-insulin-potassium did not alter the slope of the LVVO2-PVA relation in control (2.0 ± 0.1 baseline vs 2.1 ± 0.2 GIK; p = 0.66 ANCOVA) or diabetes (3.1 ± 0.7 baseline vs 2.8 ± 0.8 GIK; p = 0.24 ANCOVA). Therefore, contractile efficiency was maintained (control 51.1% ± 3.5% baseline vs 48.3% ± 4.2% GIK and diabetes 33.9% ± 7.8% baseline vs 37.7% ± 9.6% GIK). However, there was a small but statistically significant reduction in unloaded LVVO2 following GIK in control animals (0.42 ± 0.05 J baseline vs 0.37 ± 0.13 J GIK; p < 0.001 ANCOVA) and a more profound reduction in diabetic animals (0.46 ± 0.24 J baseline vs 0.23 ± 0.23 J GIK; p < 0.001 ANCOVA). Hence, the improvement in oxygen utilization efficiency in the diabetic ventricle following GIK resulted from improved stroke work efficiency and decreased unloaded LVVO2.
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Fig 1. Representative LVVO2-PVA relationships at baseline (circles) and following glucose-insulin-potassium infusion (triangles) in control (A) and diabetes (B). Glucose-insulin-potassium infusion shifted the LVVO2-PVA relation downward decreasing the LVVO2-axis intercept without effecting the slope of the relation. (LVVO2 = left ventricular oxygen consumption; PVA = pressure-volume area.)
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Fig 2. Effect of GIK infusion on (left) unloaded LVVO2 and (right) contractile efficiency in control and diabetes (DM). Black = baseline; white = GIK; * = p less than 0.001 compared to baseline analysis of covariance. (LVVO2 = left ventricular oxygen consumption.)
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Comment
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The mechanism whereby GIK improves cardiovascular outcomes in diabetic patients is not completely understood. We have previously shown GIK improves LV contractility and stroke work efficiency in diabetes [12]. The present study was designed to establish the oxygen cost or benefit of the GIK-mediated improvement in LV mechanics. Hence, we investigated the effect of GIK on the LVVO2-PVA relation and LV oxygen utilization efficiency in a chronic ovine model of diabetes. Our new data uniquely demonstrate substrate enhancement with GIK improves the efficiency of oxygen utilization by the diabetic ventricle. Further, we have established this is achieved through improved efficiency of energy transfer from the LV to the arterial system (stroke work efficiency) and decreased oxygen requirements for basal metabolism and excitation-contraction coupling (unloaded LVVO2).
Oxygen utilization efficiency critically influences the tolerance of the myocardium to reduced oxygen supply. Improved efficiency of oxygen utilization following GIK means the diabetic ventricle is able to perform the required stroke work at reduced oxygen cost. This may explain, in part, the enhanced tolerance to myocardial ischemia provided by GIK in diabetic patients [8, 9]. Oxygen utilization efficiency (SW/LVVO2) is determined by the conversion efficiency of LVVO2 to mechanical energy (PVA/LVVO2) and stroke work efficiency (SW/PVA). The relationship between LVVO2 and PVA is linear with a positive y intercept. Therefore, variation in the slope or y intercept of the LVVO2-PVA relation effects LV oxygen utilization efficiency. The oxygen requirement for nonmechanical processes is established from the y intercept of the LVVO2-PVA relation (unloaded LVVO2) and reflects energy expended for basal metabolism and excitation-contraction coupling. The inverse of the slope of the relation represents LV chemomechanical conversion efficiency. In the present study, GIK increased LV contractility and shifted the LVVO2-PVA relation downward. Therefore, GIK lowered the oxygen cost for nonmechanical processes while maintaining chemomechanical conversion efficiency of the diabetic ventricle.
Korvald and colleagues [10] have demonstrated the profound effect of myocardial substrate metabolism on ventricular energetics. They found unloaded LVVO2 was significantly lower following GIK than free fatty acid infusion, and the observed difference in unloaded LVVO2 was substantially greater than the 11% difference predicted by comparing the phosphate-to-oxygen ratios for glucose and free fatty acids [21]. In the present study, GIK administered to control and chronic streptozotocin-diabetic sheep decreased LV free fatty acid uptake and unloaded LVVO2. Decreased energy demand for basal metabolism is the most likely mechanism for the change in unloaded LVVO2. Insulin stimulates myocardial glucose metabolism by increasing glucose uptake, glycolysis, and glucose oxidation. Enhanced production of acetyl coenzyme (CoA) from glucose inhibits myocardial free fatty acid oxidation by increasing malonyl CoA levels [22]. Malonyl CoA decreases mitochondrial free fatty acid uptake by inhibiting the rate-limiting enzyme carnitine palmitoyltransferase 1 [6]. Hence, GIK induces a shift in myocardial substrate metabolism from free fatty acid to glucose oxidation. In the present study, the GIK-induced shift in substrate metabolism and decrease in unloaded LVVO2 was not isolated to diabetic hearts. However, the observed decrease in unloaded LVVO2 in control hearts was similar in magnitude to that predicted by comparing the oxygen cost of free fatty acid oxidation to glucose oxidation (phosphate-to-oxygen ratios) and may be explained entirely by a shift in substrate usage. In contrast, the decrease in unloaded LVVO2 in diabetic hearts was greater than in controls and greater than predicted on the basis of stoichiometry. Therefore in diabetic hearts, metabolic mechanisms in addition to a shift in substrate usage, must play a role. Glucose-insulin-potassium may further reduce oxygen consumption for basal metabolism by eliminating energy consuming futile metabolic cycles that are a consequence of intracellular accumulation of free fatty acids [21] and improving coupling of glycolysis and glucose oxidation [23]. Glucose-insulin-potassium did not alter arterial pH in control or diabetic animals and improvement in acid-base status is unlikely to underlie the observed improvement in ventricular energetics.
Glucose-insulin-potassium improves the efficiency of energy transfer from the LV to the arterial system (stroke work efficiency) in diabetes by increasing LV contractility and improving ventriculoarterial coupling [12]. In this study we have shown GIK does not improve LV contractility of nondiabetic controls and GIK infusion in chronic diabetes uniquely enhances LV contractility while decreasing unloaded LVVO2. This is in contrast to catecholamines, which increase LV contractility but shift the LVVO2-PVA relation upward and increase oxygen consumption for nonmechanical processes (the oxygen-wasting effect). Increased energy expenditure for excitation-contraction coupling underlies the catecholamine-induced increase in unloaded LVVO2 [19]. Hasenfuss and colleagues [24] have shown application of pyruvate to isolated failing myocardium achieves a similar inotropic response to isoprotenerol but, for a given increase in force, the increase in calcium transients was significantly smaller than that observed with the catecholamine. Hence, the increase in developed force seen with pyruvate may be mediated through increased calcium sensitivity of the myofilaments or through use of pyruvate as an energy substrate. Similarly, GIK may improve contractility through modulation of myocardial metabolism. Glucose-insulin-potassium stimulates production of adenosine triphosphate by glycolysis and this may improve LV contractility by enhancing sarcoplasmic reticular calcium adenosine triphosphatase activity [25]. This is in contrast to catecholamines that directly stimulate the calcium pump, albeit at increased energy cost. Further, GIK may improve contractility by decreasing the accumulation of negatively inotropic intermediaries of free fatty acid oxidation [23]. Therefore, GIK may decrease unloaded LVVO2 in the diabetic heart by reducing basal metabolic energy requirements and by improving contractility without substantially increasing energy demand for excitation-contraction coupling. Hence, GIK uniquely improves oxygen utilization efficiency of the diabetic ventricle by simultaneously decreasing the oxygen requirements for nonmechanical processes and improving the efficiency of energy transfer from the LV to the arterial system.
There are limitations to this study that warrant consideration. We have used a chronic ovine model of type I diabetes whose applicability to patients with treated type II diabetes and myocardial ischemia is unknown. We measured free fatty acid uptake only and did not directly determine myocardial free fatty acid oxidation or glucose oxidation. However, free fatty acids are not stored intracellularly and therefore myocardial free fatty acid uptake reflects oxidation. Further, the reciprocal relationship between glucose and free fatty acid oxidation is well established [19]. Myocardial ischemia exacerbates the derangement in substrate metabolism, leading to further inhibition of glucose oxidation and acceleration of fatty acid oxidation [22]. Insulin treatment has been shown to improve regional contractile performance and oxygen utilization efficiency during myocardial ischemia [26, 27]. Hence, the GIK-mediated improvement in oxygen utilization efficiency of the diabetic ventricle is likely to be maintained during ischemia. Hypothermia induces a shift in substrate metabolism towards glucose oxidation [28] and the additional utility of GIK in this setting remains to be clarified. Variation in sympathetic activity may influence LV contractility and unloaded LVVO2. Data were collected under light anesthesia and stable heart rate to minimize these effects. Autonomic blockade was not used because of confounding effects on free fatty acid oxidation.
In conclusion, GIK improves oxygen utilization efficiency in diabetes by improving LV contractility and stroke work efficiency while decreasing the oxygen demand for basal metabolism and excitation-contraction coupling. Improved oxygen utilization efficiency means the diabetic LV is able to perform the same stroke work at reduced oxygen cost. This provides insight into the mechanism whereby GIK improves cardiovascular outcomes in diabetic patients and supports the use of GIK in diabetic patients before coronary artery bypass surgery or early in the time course of acute myocardial ischemia.
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Acknowledgments
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This study was supported by funding from the North Shore Heart Research Foundation. Doctor Ramanathan is a Sir Roy McCaughey Surgical Research Fellow of the Royal Australasian College of Surgeons. Associate Professor Deborah Black, Department of Public Health and Community Medicine, University of New South Wales, performed the statistical analysis. We would like to thank Professor John Fletcher and Dr Errol Wilmshurst for their continued support. We gratefully acknowledge the technical assistance of Gabrial Gomes, Ray Kearns, Peter Darge, and Chi-Ming Lee.
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Abstract
Introduction
