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(Circulation. 1995;92:2151-2156.)
© 1995 American Heart Association, Inc.

Articles

Hyperinsulinemia Inhibits Myocardial Protein Degradation in Patients With Cardiovascular Disease and Insulin Resistance

Patrick H. McNulty, MD; Rita J. Louard, MD; Lawrence I. Deckelbaum, MD; Barry L. Zaret, MD; Lawrence H. Young, MD

From the Department of Internal Medicine, Veterans Affairs Medical Center, West Haven, Conn, and Yale University School of Medicine, New Haven, Conn.

Correspondence to Patrick H. McNulty, MD, Section of Cardiology/111B, West Haven VAMC, 950 Campbell Ave, West Haven, CT 06516.

	Abstract

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Background Insulin resistance, hyperinsulinemia, and myocardial hypertrophy frequently coexist in patients. Whether hyperinsulinemia directly affects myocardial protein metabolism in humans has not been examined, however. To test the hypothesis that hyperinsulinemia is anabolic for human heart protein, we examined the effects of insulin infusion on myocardial protein synthesis, degradation, and net balance in patients with ischemic heart disease.

Methods and Results Eleven men (aged 57±3 years) with coronary artery disease who had fasted for 12 to 16 hours received a constant infusion of insulin (50 mU · m^-2 · min^-1) while plasma concentrations of glucose and amino acids were kept constant. Rates of myocardial protein synthesis, degradation, and net balance were estimated from steady state extraction and isotopic dilution of L-[ring-2,6-³H]phenylalanine across the heart basally and 90 minutes into infusion. Subjects had elevated fasting plasma insulin concentrations (173±21 pmol/L) and used little exogenous glucose during insulin infusion, suggesting resistance to the effects of insulin on whole-body carbohydrate metabolism. Basally, myocardial protein degradation, as estimated by phenylalanine release (133±28 nmol/min), exceeded protein synthesis, estimated by phenylalanine uptake (31±15 nmol/min), resulting in net negative phenylalanine balance (-102±17 nmol/min). Insulin infusion reduced myocardial protein degradation by 80% but did not affect protein synthesis, returning net phenylalanine balance to neutral.

Conclusions Acute hyperinsulinemia markedly suppresses myocardial protein degradation in patients with cardiovascular disease who are resistant to its effects on whole-body glucose metabolism. This antiproteolytic action represents a potential mechanism by which hyperinsulinemia could contribute to the development of myocardial hypertrophy in patients with cardiovascular disease.

Key Words: insulin • myocardium • hypertrophy • hypertension

	Introduction

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Considerable experimental and epidemiological evidence supports an association between insulin resistance, hyperinsulinemia, and cardiovascular disease.¹ Patients with essential hypertension commonly exhibit impaired insulin-stimulated skeletal muscle glucose uptake, resulting in compensatory elevation of plasma insulin concentration.^{1 2 3} This tendency may be amplified by aging,⁴ obesity,⁵ physical deconditioning,⁶ or the development of congestive heart failure.⁷ Significantly, hypertension is a common antecedent of myocardial hypertrophy, a condition that confers substantial risk of morbidity and mortality.⁸ Hypertrophy is also frequently noted in patients with coronary artery disease in the absence of hypertension, and in this situation too is associated with a poor prognosis.⁹ In light of a large body of evidence indicating that insulin exerts an anabolic effect on muscle protein, these observations raise the question of whether hyperinsulinemia might independently contribute to the development of myocardial hypertrophy in patients.

Our laboratory has shown previously that rates of myocardial protein synthesis and degradation can be estimated in intact animals using steady state radiotracer infusion combined with arterial–coronary sinus catheterization, without the need for tissue biopsy.¹⁰ Using this technique, we have observed that protein in the human heart undergoes continual turnover, with a half-life of approximately 10 days.¹¹ More recently, we demonstrated that hyperinsulinemia acutely suppresses myocardial protein degradation in anesthetized dogs.¹² In the present study, we have combined substrate clamp techniques with steady state radiotracer infusion and coronary sinus catheterization to examine the acute effects of hyperinsulinemia on heart protein turnover in patients with coronary artery disease.

	Methods

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Study Population
Eleven men aged 57±3 years (range, 46 to 71 years) were enrolled from a population of patients referred for elective coronary angiography to evaluate angina pectoris. Because a principal hypothesis of this study was that the secondary hyperinsulinemia of insulin-resistant patients with cardiovascular disease may have an anabolic effect on myocardial protein, we chose study subjects with characteristics associated with insulin resistance and hyperinsulinemia. Our subjects were sedentary and mildly obese (body mass index, 28.1±1.1 kg/m²). Nine of 11 patients had a history of essential hypertension. All subjects had obstructive atherosclerosis (defined as >50% luminal narrowing) involving one or more (mean, 2.2±0.4) of the three major coronary arteries. Myocardial function was preserved, with left ventricular ejection fraction averaging 56±4%. Patients with a history of diabetes mellitus, unstable angina pectoris, Q-wave myocardial infarction affecting the anterior portion of the left ventricle, or recent myocardial infarction in any location were excluded. Seven subjects were using calcium channel antagonists, 6 were taking ß-adrenergic blockers, and 5 were using long-acting nitrates.

The protocol for this study was approved by the Human Studies Subcommittee of the Department of Veterans Affairs Medical Center, West Haven, Conn, and informed consent was obtained in writing from each subject.

Experimental Protocol
The study protocol is depicted in Fig 1. All studies were performed after a 12- to 16-hour fast and were begun in the morning between 9 and 11 AM. An 18-gauge plastic cannula was placed in a left antecubital vein for experimental infusions. Through an 8F introducer sheath in the right internal jugular vein, a 7F thermodilution catheter (Baim catheter, Electrocatheter Co) was advanced under fluoroscopy into the coronary sinus. This catheter was placed at the junction of the coronary sinus and great cardiac vein, sufficiently proximal in the coronary sinus to avoid admixture of right atrial blood during sampling. A 6F introducer sheath (USCI) was inserted into the right femoral artery for blood sampling.

View larger version (15K): [in this window] [in a new window]   Figure 1. Schematic of study design. L-[ring-2,6-3H]phenylalanine was infused at 1.0 µCi/min, beginning 75 to 90 minutes before basal blood sampling. Insulin, 20% dextrose, and an amino acid solution (10% Travasol, Baxter Healthcare Corp) were infused as indicated. Quadruplicate blood samples were obtained basally and after 90 minutes of insulin infusion from catheters in a femoral artery and the coronary sinus.

To estimate rates of myocardial protein synthesis and degradation, L-[ring-2,6-³H]phenylalanine was administered by continuous steady state intravenous infusion (1 µCi/min) and paired samples of arterial and coronary venous blood were drawn in quadruplicate over a 15-minute period for measurement of plasma ³H-phenylalanine SA and subsequent calculation of phenylalanine uptake and release from the heart.^{10 11} Next, a primed (100 mU · m^-2 · min^-1 for 10 minutes), continuous (50 mU · m^-2 · min^-1) infusion of regular insulin (Humulin, Lilly) was begun and arterial and coronary venous blood was sampled again after 90 minutes. During insulin infusion, whole blood glucose concentration was maintained slightly above the fasting level with a variable rate infusion of 20% dextrose (euglycemic clamp technique). Because insulin infusion lowers plasma concentrations of amino acids,¹³ which independently influences muscle protein synthesis,^{10 14} we also infused an amino acid solution (10% Travasol, Baxter Healthcare Corp; 0.08 mL · kg^-1 · min^-1, or 1.3 mg amino N₂ · kg^-1 · min^-1) to ensure similar basal and insulin-infused plasma concentrations of essential, branch chain, and total amino acids. Coronary venous blood flow was measured by use of the continuous thermodilution technique¹⁵ after each set of blood samples.

Analytical Methods
L-[ring-2,6-³H]phenylalanine SA was measured in arterial and coronary venous plasma samples by a reverse-phase HPLC technique developed in our laboratory.^{10 11 12 16} Rates of myocardial protein synthesis and degradation in the basal and insulin-infused states were determined from the measured uptake of ³H-phenylalanine from arterial plasma and the fractional dilution of its SA in venous plasma respectively, as previously described.^{10 11 12} Briefly, because the only metabolic fate of phenylalanine in muscle is incorporation into and release from protein,¹⁷ at isotopic steady state the rate of extraction of ³H-phenylalanine from arterial plasma is proportional to the simultaneous rate of phenylalanine incorporation into protein. The dilution of ³H-phenylalanine SA between arterial and coronary venous plasma is likewise proportional to the rate of release of unlabeled phenylalanine from protein into coronary venous blood. The rate of phenylalanine uptake (nmol per minute) into myocardial protein was calculated using the formula

where DPM_A and DPM_CV are the measured number of ³H disintegrations per minute in phenylalanine per milliliter of arterial and coronary venous plasma, respectively, and SA_CV is ³H-phenylalanine SA (dpm/nmol) in venous plasma. The rate of phenylalanine release (nmol/min) from the heart was calculated by the formula

where SA_A and SA_CV represent SA of ³H-phenylalanine in arterial and coronary venous plasma, respectively, and [Phe]_A represents the arterial phenylalanine concentration. These formulas assume that infused ³H-phenylalanine equilibrates readily between arterial blood and the intracellular tRNA-bound phenylalanine pool; we have recently shown that this assumption is valid both in the fasted state and during insulin infusion.¹⁸ Measurements of ³H-phenylalanine SA and phenylalanine concentration by use of HPLC were made with 0.5 mL plasma. HPLC eluants typically contained 500 to 600 counts per minute of ³H activity above background; these column eluants were counted twice for 10 to 20 minutes, so that arteriovenous balance measurements for radioactivity were made on the basis of 10 000 to 20 000 observed ³H counts for each plasma sample. The coefficients of variation for measurement of plasma phenylalanine concentration and specific radioactivity with these methods in our laboratory average 1.8% and 2.2%, respectively.

Net myocardial phenylalanine balance was calculated by multiplying the difference between arterial and venous phenylalanine concentrations by coronary venous blood flow. This net phenylalanine balance provides an estimate of net myocardial protein balance independent of any tracer kinetic measurements.

To examine simultaneously the effect of insulin infusion on heart glucose and FFA balance, the myocardial uptake (µmol/min) of each in the fasting and insulin-infused state was calculated by multiplying their measured arterial-coronary venous concentration difference (µmol/L) by coronary venous blood flow (L/min) for glucose or plasma flow [(1-hematocrit)xblood flow] for FFA.

Because we did not independently measure hepatic glucose production in this study, the effect of insulin infusion on whole-body glucose utilization in these patients could not be known precisely. As an approximation, however, we did note the glucose infusion rate (µmol · kg^-1 · min^-1) needed to maintain euglycemia during the final 30 minutes of each glucose-insulin clamp.

After final blood samples were obtained, insulin and amino acid infusions were terminated. Selective coronary angiography and left ventriculography were performed, and left ventricular volume and mass were calculated using standard formulas.¹⁹ No radiographic contrast or heparin was given before or during the research study. This avoided any potential effects of these agents on myocardial substrate metabolism.

Data Analysis
Measurements from each quadruplicate set of plasma samples were averaged to yield one fasting and one insulin-infused value for each measured variable in each patient. Comparisons between fasting and insulin-infused periods in the 11 patients were then made by two-tailed paired Student's t tests. Data are presented as mean±SD.

	Results

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Hemodynamic Data
Left ventricular end-diastolic volume index averaged 89±20 mL/m² (normal, 70 to 79 mL/m²¹⁹ ) and left ventricular mass index averaged 116±35 g/m² (normal, 91 to 96 g/m²¹⁹ ). Systolic and diastolic blood pressure averaged 130±11 and 82±7 mm Hg, and heart rate averaged 68±7 bpm during the study; insulin infusion did not affect heart rate, systolic blood pressure, mean arterial pressure, or the surface ECG. A small but consistent increase in average coronary venous blood flow (from 61±6 to 68±7 mL/min, P<.01) was observed after 90 minutes of insulin infusion. The increase in coronary venous blood flow was accompanied by a proportionate narrowing in the difference between arterial and coronary venous blood oxygen saturation, such that calculated myocardial oxygen consumption did not change (fasting, 8.2±0.2 mL/min; insulin, 8.3±0.3 mL/min; P=NS).

Insulin, Glucose, FFA, and Amino Acid Concentrations
Basal arterial plasma insulin concentrations were high in these patients after an overnight fast, averaging 173±21 pmol/L (24±3 µU/mL), with normal for our assay being 35 to 70 pmol/L (5 to 10 µU/mL). During insulin infusion, arterial plasma insulin concentration rose to 1627±144 pmol/L (226±20 µU/mL). Fasting plasma FFA concentration averaged 915±97 µmol/L and, after 90 minutes of insulin infusion, had fallen to 354±82 µmol/L (P<.001). Fasting arterial glucose concentration averaged 4.8±0.2 mmol/L and was maintained between 5.0 and 6.0 mmol/L during insulin infusion (Fig 2a). The glucose infusion rate required to clamp whole blood glucose concentration during the last 30 minutes of insulin infusion averaged 11±1 µmol · kg^-1 · min^-1 (1.9 mg · kg^-1 · min^-1; Fig 2b).

View larger version (16K): [in this window] [in a new window]   Figure 2. a, Plot showing whole-blood glucose concentration (mmol/L) during infusion of insulin and 20% dextrose. b, Graph showing exogenous glucose infusion rate (µmol · kg-1 · min-1) during insulin infusion. All points represent mean±SD for 11 patients.

Infusion of an amino acid mixture during the insulin-glucose clamp resulted in similar fasting and insulin-infused concentrations of essential (621±32 versus 708±56 µmol/L, P=NS), branch chain (422±5 versus 431±12 µmol/L, P=NS), and total amino acids (1886±144 versus 2226±201 µmol/L, P=NS).

Myocardial Uptake of Glucose and FFA
The hearts of these patients exhibited a small but significant glucose uptake in the fasting state, averaging 8.0±2.0 µmol/min (3±1% fractional extraction, P<.05 versus zero). During insulin infusion, glucose uptake increased threefold, to 25.8±4.7 µmol/min (7±1% fractional extraction, P<.005 versus fasting), a level similar to that observed during hyperinsulinemia in lean, young subjects without heart disease.²⁰

An opposite trend was observed for FFA, where myocardial uptake declined by 88% from 8.6±1.9 µmol/min (23±5% fractional extraction) to 1.0±1.0 µmol/min (8±6% fractional extraction) during insulin infusion (P<.005). Myocardial FFA uptake in these patients was directly proportional (r=.72, P<.05) and myocardial glucose uptake inversely proportional (r=-.71, P<.02) to arterial FFA concentration.

Phenylalanine Kinetics
Observed heart phenylalanine arteriovenous balance, ³H-phenylalanine isotopic extraction, and dilution of ³H-phenylalanine specific radioactivity across the heart are shown in the Table. The calculated effect of insulin infusion on each patient's myocardial phenylalanine uptake, release, and net balance is shown in Fig 3. In the basal fasting state, the rate at which phenylalanine was released from the myocardium (133±28 nmol/min) exceeded its simultaneous rate of uptake (31±15 nmol/min) in every patient, leading to a negative net phenylalanine balance of -102±17 nmol/min (P<.02 versus zero). This net heart protein catabolism is consistent with our previous observations in patients¹¹ and dogs^{10 12} that had fasted overnight.

View this table: [in this window] [in a new window]   Table 1. Arterial and Coronary Venous Phenylalanine and L-[ring-2,6-3H]phenylalanine Data, Basally and During Insulin + Amino Acid Infusion

View larger version (15K): [in this window] [in a new window]   Figure 3. Plots showing L-[ring-2,6-3H]phenylalanine kinetics across the heart in the fasting and insulin-infused states for 11 patients: a, phenylalanine net balance; b, phenylalanine uptake; and c, phenylalanine release, all given in nmol/min phenylalanine. Each point is the mean of quadruplicate measurements at the indicated time (basal or insulin-infused) in 1 patient, with average values indicated by open circles. P values are for paired Student's t test comparisons between fasting and insulin-infused states.

Insulin infusion positively affected net phenylalanine balance in 10 of the 11 patients (Fig 3a), converting net phenylalanine balance from negative to neutral (29±42 nmol/min, P=.02 versus basal). Although isotopic phenylalanine uptake (Fig 3b) did not change significantly during insulin infusion (31±15 to 50±46 nmol/min, P=NS), phenylalanine release decreased by 80%, from 133±28 to 26±31 nmol/min (P=.03 versus basal, P=NS versus zero). Suppression of phenylalanine release was observed in 10 of 11 subjects (Fig 3c) and is consistent with significant inhibition of myocardial protein degradation during insulin infusion.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The results of this study demonstrate that hyperinsulinemia exerts an acute antiproteolytic effect on the myocardium of patients with ischemic heart disease. This effect is observed in the absence of any change in heart rate, blood pressure, or plasma concentrations of glucose or amino acid substrates. Thus, it may represent a primary effect of insulin on the myocardium. Several features of this observation deserve comment.

First, the negative myocardial phenylalanine balance we observed in these patients basally (equivalent to a net loss of 5.2% of myocardial protein per day) suggests that the myocardium enters a significant protein catabolic state after even a brief fast. This finding agrees with our previous observations in fasted canines^{10 12} and humans.¹¹ Although the heart does not undergo gross atrophy during sustained fasting, significant protein catabolism has been well documented during the early stages of fasting²¹ and may in fact reflect the effect of insulin withdrawal. This observation serves to emphasize that, even in fully grown adult humans, myocardial protein is relatively labile and may respond acutely to nonhemodynamic signals.

We observed inhibition of myocardial protein breakdown in this study after raising plasma insulin concentrations to 1627+144 pmol/L (226+20 µmol/L) for 90 minutes. This moderately supraphysiological level of hyperinsulinemia was chosen to examine the effect on myocardial protein of the pronounced hyperinsulinemia observed in many insulin-resistant patients after meals. Such patients also exhibit more modest yet sustained levels of hyperinsulinemia in the postabsorptive state; conceivably, this too could represent an anabolic stimulus for myocardial protein. Indeed, we recently observed an antiproteolytic effect of insulin on forearm muscle of lean young subjects after increasing its plasma concentration to only 150 to 200 pmol/L.²² Further insight into this possibility will require a direct comparison of the sensitivities of myocardial and skeletal muscle to insulin's antiproteolytic action.

The antiproteolytic effect of hyperinsulinemia we observed in these patients may be relevant to the recognized association between myocardial hypertrophy and states of insulin resistance. Patients with essential hypertension, a common antecedent of left ventricular hypertrophy, commonly exhibit insulin resistance with compensatory hyperinsulinemia, and the stimulus for hypertrophy may not be merely blood pressure elevation.^{1 2 3} Obese patients also exhibit hyperinsulinemia, both in the fasted state and in response to meals,^{23 24} and myocardial mass is known to increase in parallel with body mass index²⁵ and waist-to-hip ratio,²⁶ each an index of obesity. The antiproteolytic effect of insulin on myocardial protein in the current study would provide a potential mechanistic explanation for the association of myocardial hypertrophy with these insulin-resistant conditions.

Insulin, given in supraphysiological amounts, has long been recognized to stimulate heart protein synthesis in vitro.²⁷ More recent studies have failed to demonstrate such an effect in vivo in adult animals, however.²⁸ The failure of insulin to affect heart protein synthesis in this study is consistent with our previous observations in the rat¹⁶ and canine¹² heart and in human skeletal muscle²² that acutely increasing the plasma insulin concentration has little direct effect on muscle protein synthesis in vivo in intact organisms. The present observations thus agree with the emerging consensus that insulin's primary effect on muscle protein in vivo is an antiproteolytic one, acting to reduce the rate of amino acid release from tissues of the whole body^{14 29} and from forearm^{22 30} and leg³¹ muscle.

One hypothesis that has been advanced to explain the association of hyperinsulinemia and myocardial hypertrophy is that insulin may directly increase blood pressure and therefore left ventricular work. In support of this, insulin has been shown to activate the sympathetic nervous system in patients with essential hypertension.³² Although 9 of our 11 patients had essential hypertension, we noted no acute effect of insulin infusion on heart rate, blood pressure, or myocardial oxygen consumption in this study. Because all 11 patients were using either ß-adrenergic blockers, calcium antagonists, or long-acting nitrates, we cannot be certain that an effect of insulin would not have been seen had medications been withdrawn. Clearly, however, the inhibition of myocardial protein degradation observed during insulin infusion in these patients occurred in the absence of any change in myocardial work.

Previous studies have examined the effect of specific interventions on the balance between rates of synthesis and degradation of heart protein in laboratory animals. In these studies, protein degradation has generally been estimated indirectly by subtracting the absolute increase in the protein mass of a growing animal's heart over some interval from the protein synthetic rate measured at a single point in time. The technique used to measure myocardial protein degradation in the present study, isotopic dilution of L-[ring-2,6-³H]phenylalanine during steady state infusion, offers several advantages. Because the technique requires sampling only arterial and coronary sinus blood and not heart protein directly, it is applicable to the study of the human heart. For the same reason, rates of synthesis and degradation can be compared before and after an intervention in the same patient, permitting the effects of any intervention to be evaluated with considerable sensitivity using a small number of subjects.

Myocardial hypertrophy is a major risk factor for death and disability in patients with coronary artery disease and is of substantial interest to clinicians. Our understanding of this condition has been limited by the technical difficulty of studying the two independent components of myocardial protein metabolism (synthesis and degradation) in humans. Nevertheless, observations in laboratory animals (reviewed in Reference 33) suggest that growth factors may be involved in cardiomyocyte hypertrophy. In the current study, we have demonstrated that acutely raising the plasma concentration of insulin significantly reduces the rate of protein degradation in the myocardium of patients with cardiovascular disease. This constitutes direct evidence that a peptide hormone participates in the regulation of protein metabolism in the human heart. Further insights into the relation between hyperinsulinemia and the development of myocardial hypertrophy in patients will require defining the sensitivity of myocardial proteolysis to insulin, the duration of the antiproteolytic effect after an acute elevation in plasma insulin concentration, and the postreceptor mechanism by which insulin retards proteolysis in muscle.

	Selected Abbreviations and Acronyms

 

bpm = beats per minute FFA = free fatty acid HPLC = high-pressure liquid chromatography SA = specific activity

	Acknowledgments

 
This work was supported by a Merit Review grant from the Department of Veterans Affairs, by a Grant-in-Aid of the American Heart Association (92008910), and by the General Clinical Research Center of Yale-New Haven Hospital. Dr McNulty is a Clinician-Scientist Awardee (91004370) of the American Heart Association. The authors thank David Capuano, Cynthia Crocco, Kathy Onze, Edward Moran, Ralph Jacob, and the Yale Cardiovascular fellows for technical assistance and Dr Eugene Barrett for critical reading of the manuscript.

Received April 26, 1994; revision received April 6, 1995; accepted May 10, 1995.

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				R. Kuperstein and Z. Sasson Effects of Antihypertensive Therapy on Glucose and Insulin Metabolism and on Left Ventricular Mass : A Randomized, Double-Blind, Controlled Study of 21 Obese Hypertensives Circulation, October 10, 2000; 102(15): 1802 - 1806. [Abstract] [Full Text] [PDF]

				P. H. McNulty Comparison of local and systemic effects of insulin on myocardial glucose extraction in ischemic heart disease Am J Physiol Heart Circ Physiol, March 1, 2000; 278(3): H741 - H747. [Abstract] [Full Text] [PDF]

				R. A. Phillips, L. R. Krakoff, A. Dunaif, D. T. Finegood, R. Gorlin, and S. Shimabukuro Relation among Left Ventricular Mass, Insulin Resistance, and Blood Pressure in Nonobese Subjects J. Clin. Endocrinol. Metab., December 1, 1998; 83(12): 4284 - 4288. [Abstract] [Full Text]

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