Cardiovascular implications of insulin resistance and non–insulin-dependent diabetes mellitus

REVIEW ARTICLE Martin J. London, MD Section Editor

Cardiovascular Implications of Insulin Resistance and Non–Insulin-Dependent Diabetes Mellitus Patrick H. McNulty, MD, Steven M. Ettinger, MD, Ian C. Gilchrist, MD, Mark Kozak, MD, and Charles E. Chambers, MD

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ATIENTS WITH TYPE 2 diabetes mellitus, or non–insulin-dependent diabetes mellitus (NIDDM), represent 10% to 15% of the population seen by physicians who regularly treat coronary artery disease (CAD). Given an increasing prevalence of NIDDM in developed countries and its association with obesity, high caloric intake, and sedentary lifestyle,1-3 this percentage is almost certain to rise. In the 1980s, the Framingham study showed that the presence of NIDDM increased cardiovascular mortality 2-fold in men and almost 4-fold in premenopausal women.4 NIDDM adversely affects the natural history of CAD and the therapeutic benefits from percutaneous and surgical coronary revascularization procedures.5,6 This adverse impact has been documented in all contemporary cardiovascular databases,7 and the association between macrovascular disease (eg, myocardial infarction and stroke) and NIDDM has become stronger over time.8,9 The pathophysiologic mechanisms responsible for this adverse impact are incompletely understood, however. Despite considerable improvements in pharmacologic and operative treatment of CAD, little improvement in outcome has occurred in these patients. Much of the toll exacted by NIDDM on cardiovascular mortality in the general population can be explained by its well-known acceleration of the atherosclerotic process.10 NIDDM also dramatically worsens the prognosis of patients with established CAD. Although the reasons for the poor prognosis are incompletely understood, the observation that NIDDM more than doubles mortality11,12 and the incidence of congestive heart failure13,14 after an index myocardial infarction suggests that at least some of the adverse risk may reflect a primary impairment in myocardial energy metabolism or ischemic tolerance or both. NIDDM is clinically the most extreme example of the phenomenon of impaired tissue insulin sensitivity, or insulin re-

From the Section of Cardiology, Penn State College of Medicine and The Milton S. Hershey Medical Center, Hershey, PA. Address reprint requests to Patrick H. McNulty, MD, Section of Cardiology, Penn State College of Medicine, H-047, PO Box 850, Hershey PA 17033. E-mail: [email protected] Copyright © 2001 by W.B. Saunders Company 1053-0770/01/1506-0023$35.00/0 doi:10.1053/jcan.2001.28338 Key words: diabetes mellitus, insulin resistance, cardiovascular complications 768

sistance. Longitudinal studies have shown that tissue insulin sensitivity, most commonly quantified as the glucose infusion rate (in mg/kg body weight/min) needed to maintain plasma glucose constant during a standard insulin infusion,15,16 is impaired 10 to 20 years before the onset of frank NIDDM in diabetes-prone populations17 and is the best predictor of clinical onset of disease.18 Impaired tissue insulin sensitivity also accompanies (and may predispose to the development of) such conditions as hypertension, obesity, and atherosclerosis.19 It is not widely appreciated that nondiabetic patients with CAD exhibit some degree of insulin resistance on formal testing (Fig 1). In addition to its well-known role in glucose homeostasis, insulin is involved in the regulation of such diverse biologic processes as vascular tone, cellular hyperplasia and hypertrophy, vascular and myocardial compliance, leukocyte function, and coagulation. The list of factors that may contribute to the adverse impact of NIDDM and insulin resistance on cardiovascular disease continues to grow. Reducing the impact of NIDDM requires a better understanding of the effects of insulin’s action on fundamental biologic processes in the myocardium and arterial wall. This article reviews perspectives on the cellular and molecular basis of insulin action and insulin resistance at the level of the myocardium and vasculature. Emerging evidence that normalizing metabolic abnormalities associated with the insulinresistant phenotype may ameliorate the adverse impact of NIDDM on cardiovascular disease is presented. It is evident, however, that NIDDM remains a difficult and incompletely understood challenge. INSULIN RESISTANCE IN SKELETAL AND CARDIAC MUSCLE

The major target tissues for insulin’s metabolic actions are muscle and adipose tissue. Although both tissues respond to insulin stimulation by increasing their uptake and metabolism of glucose, skeletal muscle is the major quantitative glucose sink, disposing of ⬎70% of an administered glucose load under most conditions.20 Uptake of glucose by muscle (including cardiac muscle) is regulated by 2 separate but interrelated influences, the local plasma concentration of insulin and of free fatty acids (FFA). The mechanism by which insulin and FFA together regulate muscle glucose metabolism was described by Randle et al21 in

Journal of Cardiothoracic and Vascular Anesthesia, Vol 15, No 6 (December), 2001: pp 768-777

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Fig 1. Comparison of glucose infusion rates necessary to maintain euglycemia during insulin clamp infusion in healthy young subjects (data from DeFronzo et al16), nondiabetic middle-aged men with coronary artery disease (CAD) (data from McNulty et al49), and middle-aged men with CAD and non–insulin-dependent diabetes mellitus (NIDDM) (P McNulty: unpublished data). Relative to healthy subjects, diabetic and nondiabetic CAD patients exhibit target tissue insulin resistance.

the 1960s (Fig 2). Insulin secretion or exogenous administration increases muscle glucose consumption by directly stimulating myocyte glucose uptake and by inhibiting release of FFA from adipose tissue, lowering plasma FFA levels. The magnitude of muscle glucose consumption observed at any particular insulin level is reduced by the extent to which prevailing conditions (eg, fasting state, heparin administration, catecholamine excess) concomitantly raise circulating FFA levels. This principle is sufficiently important that early investigators incor-

Fig 2. The Randle hypothesis21 for competition between glucose and free fatty acids (FFA) as oxidative substrates in muscle. Transmembrane transport of plasma glucose by the insulin-sensitive glucose transporter GLUT4 increases mitochondrial oxidation of glucose-derived acetyl-CoA by accelerating glucose carbon flux through phosphofructokinase (PFK) and the pyruvate dehydrogenase complex (PDC), which are the rate-limiting steps in glycolysis and glucose oxidation. Increased availability of plasma FFA leads to an increase in muscle uptake and oxidation, increasing the cellular acetyl-CoA-toCoA ratio and citrate concentration, which subsequently inhibits PDC and PFK.

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Fig 3. The primary steps involved in energetic metabolism of glucose by muscle. The rate-limiting step in glucose consumption is transmembrane transport by a family of glucose transport proteins (the insulin-sensitive transporter GLUT4 is shown) and subsequent hexokinase-mediated phosphorylation. Glucose-6-phosphate is subsequently distributed among energy neutral (glycogen synthesis), low-energy yield (glycolysis), or high-energy yield (Krebs cycle oxidation) cellular metabolic pathways in proportions determined by insulin action, oxygen availability, and the relative expression and activity of the rate-limiting enzymes in each pathway.

rectly assumed NIDDM was secondary to chronic elevation in the plasma FFA level alone.20 Although overly simplistic, it is nevertheless important to recognize that most situations in which the anesthesiologist encounters patients with cardiovascular disease, the hallmark being the period during and immediately after coronary artery bypass graft (CABG) surgery, are characterized by this form of acquired muscle insulin resistance. Although a variety of specific metabolic defects have been described in individuals or families with NIDDM,22 a series of elegant studies by Shulman et al23-26 using 31P and 13C nuclear magnetic resonance spectroscopy to track glucose through its intracellular metabolic pathways in vivo have established that the insulin resistance of NIDDM muscle is primarily due to impaired glucose transmembrane transport. Even healthy offspring of patients with NIDDM exhibit impaired insulin stimulation of skeletal muscle glucose uptake, suggesting the disease involves genetically transmitted defects in glucose transporter function.27 After its transmembrane transport, the major metabolic fate of glucose in human skeletal muscle28 and heart29 is storage in the form of the polymer glycogen (Fig 3). In the human heart, glycogen synthesis is estimated to account for approximately 70% of the initial disposal of an administered glucose load, with smaller quantities committed to glycolytic formation of pyruvate and lactate and still smaller amounts to pyruvate oxidation in the Krebs cycle.29,30 In skeletal muscle, insulin stimulation of glycogen synthesis is specifically impaired in NIDDM,31 and this impairment quantitatively accounts for most of the reduction in net glucose consumption by NIDDM patients.32 Similar to the case of glucose transport, skeletal muscle glycogen synthesis has been shown to be already impaired in healthy offspring of patients with NIDDM.33 At the molecular level, insulin is the paradigm example of a hormone operating through receptor-mediated reversible phos-

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Fig 4. Insulin signal transduction in vascular endothelium. Insulin receptor occupancy and autophosphorylation induce receptor tyrosine kinase activity toward various intracellular substrates, initiating phosphorylation cascades, which result in specific biologic functions. Two pathways whose elements have been partially characterized include endothelial nitric oxide (NO) production by insulin receptor substrate (IRS) and phosphatidylinositol 3-kinase (PI 3K) activation and regulation of cell cycle events by protein kinase Akt/PKB and mitogen-activated protein (MAP) kinase. Abbreviations: SMC, smooth muscle cell; ECM, extracellular matrix.

phorylation of key regulatory enzymes.34-36 Major gains in understanding the molecular basis of insulin action have followed the identification of novel intracellular substrates for insulin receptor tyrosine kinase. Insulin binding to its plasma membrane receptor induces receptor tyrosine kinase activation, leading sequentially to receptor autophosphorylation and phosphorylation of various signaling molecules within the cell (Fig 4). Regarding glucose metabolism, numerous lines of evidence support that the most important step in insulin signaling is translocation of the insulinsensitive transport protein GLUT4 from intracellular storage vesicles to the sarcolemma.37 In the fasting state, only approximately 15% of total cardiomyocyte GLUT4 protein can be isolated from the sarcolemma, whereas this increases to ⬎80% within 30 minutes of insulin administration.37 Studies using specific inhibitors have revealed that the serial activation of at least 3 protein kinases is required to effect insulin-dependent GLUT4 translocation from the cytosol to the sarcolemma: phosphoinositol 3-kinase (PI 3-K), Akt/protein kinase B (PKB), and the ␪ and ⑀ isoforms of protein kinase C (PKC).38-40 Although molecular defects in the myocyte insulin receptor, insulin receptor substrates, PI 3-K, PKB, or PKC would seem logical candidates to explain the inherited nature of muscle insulin resistance, specific defects in these individual elements account for only sporadic cases of NIDDM.22 The molecular defect in insulin-stimulated muscle glucose transport associated with NIDDM remains obscure and presumably lies downstream of the steps identified to date in the GLUT4 translocation sequence. INSULIN RESISTANCE IN THE ARTERIAL CIRCULATION

It is well established that tissue blood flow in the systemic vasculature is regulated by a balance between local production and release of relaxing and constricting factors.41 NIDDM interferes with this balance by direct effects on endothelial

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function.42-44 Hyperglycemia and hyperinsulinemia associated with NIDDM may reduce arterial wall compliance by promoting plaque growth, vascular smooth muscle cell proliferation, and nonenzymatic glycosylation of vessel wall proteins.45,46 Similar to muscle, the vascular endothelium expresses plasma membrane insulin receptors and is a target for the biologic effects of insulin secretion. A proposed scheme of insulin’s actions on the endothelium is illustrated in Fig 4. Probably the most notable physiologic effect is to stimulate production of nitric oxide (NO). Raising the plasma insulin concentration from the physiologic nadir reached during an overnight fast to the postprandial level produces an endothelium-dependent, NO-mediated increase in blood flow across the forearm,47 leg,48 and coronary circulation49,50 in humans. This effect is presumed to have evolved as a mechanism for increasing the delivery of circulating glucose to muscle tissue after a meal, increasing the rate of glucose absorption from the bloodstream. Relative to skeletal muscles, the heart makes only a minor quantitative contribution to postprandial glucose absorption. Because capillary-myocyte diffusing distances are much shorter in cardiac than in skeletal muscle, however, it has been speculated that in the heart insulin-stimulated endothelial NO may serve additional functions, for example, acting in paracrine fashion to regulate some aspects of cardiomyocyte oxidative metabolism.50 The magnitude of insulin’s endothelium-dependent, NOmediated stimulation of limb blood flow is reduced in animal models of NIDDM and in humans with conditions associated with insulin resistance of skeletal muscle glucose uptake, including obesity,51,52 hypertension,53 and NIDDM.54,55 The precise nature of the link between insulin-resistance muscle glucose transport and of endothelial function in muscle bed afferent arteries is not yet known, and there is not much information available regarding insulin’s action on the human coronary circulation in vivo. The authors have made preliminary observations, however, on the effect of local intracoronary insulin infusion on coronary blood flow in CAD patients with NIDDM versus CAD patients without NIDDM (Fig 5). Local hyperinsulinemia consistently increases coronary sinus blood flow by approximately 20% in nondiabetic subjects, but this effect is significantly blunted in patients with NIDDM. Insulin resistance may include a specific impairment of endothelial function in the human coronary circulation. The impairment in vascular endothelial NO response in NIDDM is likely multifactorial. First, studies in cultured cells suggest a primary reduction in endothelial NO production, probably attributable to downregulation of PI 3-kinase activity and reduced insulin-stimulated uptake of the NO precursor amino acid L-arginine.56 Second, the elevation in circulating FFA levels characteristic of NIDDM and other insulin-resistant states appears to reduce endothelium-dependent NO production independently57,58 by reduction in endothelial NO synthase activity.59 Hyperglycemia itself increases release of the vasoconstricting peptide endothelin-1 from cultured endothelial cells,44 offsetting the vasodilating actions of NO.44 Finally, NIDDM is associated with increased intravascular formation of oxygen-derived free radicals, which have been shown to impair endothelium-dependent vasodilation by inactivating NO.60 These observations regarding dysregulation of vascular tone in NIDDM have potential implications for the perioperative

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Fig 5. Percent change in coronary sinus blood flow (CSBF) (left panel) and calculated myocardial oxygen consumption (right panel) during intracoronary infusion of regular insulin at 10 mU/min in coronary artery disease (CAD) patients with non–insulin-dependent diabetes mellitus (NIDDM) (dark bars) and nondiabetic controls (light bars). In nondiabetic CAD patients, raising the local coronary plasma insulin level within its physiologic range increases coronary blood flow without changing myocardial oxygen consumption, indicating a direct reduction in coronary tone. This insulin action is significantly blunted in NIDDM. (P McNulty: unpublished data).

cardiac surgical patient. Prolonged fasting and administration of catecholamines and heparin raise circulating FFA concentrations, whereas cardiopulmonary bypass and ischemia-reperfusion stimulate oxygen-derived free radical formation.61,62 Perioperative hyperglycemia is common in insulin-resistant patients as a result of the hyperadrenergic state commonly associated with the perioperative period. Available experimental evidence predicts most alterations in endothelial function associated with insulin resistance should be amenable to therapy. Theoretically, the simplest strategy would be to lower plasma glucose and fatty acid levels by insulin infusion. Perhaps more intriguing is experimental evidence (Fig 6) that NO modulation of vascular tone in NIDDM can be acutely restored by administration of antioxidants (eg., ascorbic acid).60 In addition to producing acute vasodilation, NO exerts other protective actions on the vessel wall. NO inhibits the expression of leukocyte-endothelial adhesion molecules, such as VCAM-1, ICAM-1, and E-selectin by decreasing the intracellular activity of the ubiquitous nuclear transcription factor

Fig 6. (A) Forearm blood flow response to a graded intrabrachial arterial infusion of methacholine in non–insulin-dependent diabetes mellitus (NIDDM) (filled circles) and nondiabetic (open circles) subjects. (B) Study repeated in NIDDM subjects before (filled circles) and after (open circles) intra-arterial infusion of vitamin C. NIDDM is associated with an impairment in endothelium-dependent forearm flow reserve, which can be acutely reversed by vitamin C treatment. (Adapted from Ting et al60 with permission.)

NF␬B and by inhibiting the activity of proinflammatory cytokines.63-65 These effects prevent or attenuate coronary inflammation and perhaps prevent coronary artery plaque rupture. NO has been shown to inhibit growth and migration of vascular smooth muscle cells in rats66,67 and consequently may have favorable long-term effects on plaque composition and growth. In contrast, NIDDM is associated with increased vascular NF␬B and cytokine activity, increased expression of endothelial adhesion molecules and the procoagulant plasminogen activator inhibitor-1, and increased rates of neointimal proliferation and restenosis after percutaneous coronary angioplasty.68-70 Finally, the chronic hyperglycemia associated with insulin resistance reduces passive arterial compliance by promoting extracellular matrix type IV collagen deposition and nonenzymatic glycosylation of matrix and cell membrane proteins.71 INSULIN AND MYOCARDIAL ENERGY METABOLISM

Under aerobic conditions and at normal coronary perfusion pressure, the heart generates the energy required to maintain

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Fig 7. Schematic illustration of the mechanisms by which insulin (acting through phosphatidylinositol 3-kinase [PI 3K]) and ischemia (acting through adenosine monophosphate [AMP] kinase) accelerate energetic metabolism of glucose by myocardium. In each case, the initiating event is translocation of the insulin-sensitive glucose transport protein GLUT4 from an intracellular storage compartment to the sarcolemma. Obtaining maximal adenosine triphosphate (ATP) yield from imported glucose depends on the activation state of the pyruvate dehydrogenase complex (PDC), which regulates the entry of glycolytic pyruvate into mitochondrial oxidation.

systolic and diastolic function primarily by oxidizing FFA, with smaller contributions from glycolysis and oxidation of glycolytic pyruvate and other substrates.72 Theoretical considerations and empirical observations in animal preparations suggest, however, that glycolysis and pyruvate oxidation become more important cardiac energy sources during ischemia or hypoxia.73,74 In rat,75 rabbit,76,77 and canine78 hearts, glycolytic usage of exogenous glucose accelerates severalfold during graded coronary flow reduction and during the reperfusion period after an episode of no-flow ischemia.76 Glycolysis provides the only source of adenosine triphosphate (ATP) available to the myocardium during severe ischemia and restores myocardial systolic79,80 and diastolic80 performance during postischemic reperfusion. Evidence suggests myocardial energy formation and use is compartmentalized, with glycolytic ATP preferentially committed to specific functions necessary to preserve cellular viability, for example, preventing cellular Na⫹ and Ca⫹⫹ overload.81,82 The benefit of ischemic glycolysis accrues whether the glycolytic glucose source is exogenous (ie, circulating glucose)83 or endogenous (ie, glycogen)84 to the heart. As might be expected from these observations, artificially augmenting myocardial glycolytic flux, by increasing the glucose or insulin concentration of the perfusate, further improves the functional recovery from ischemia in isolated heart preparations.85,86 Although glycolytic ATP seems to play an important role in preserving myocardial viability in the setting of ischemic injury, obtaining an optimal ATP yield from glucose requires its complete oxidation. The rate-limiting step for this process is generation of mitochondrial acetyl-CoA by pyruvate flux through the pyruvate dehydrogenase complex (PDC). Because glucose oxidation requires less oxygen per mole ATP formed than FFA oxidation, myocardial PDC activity would be expected to positively correlate with contractile performance in the ischemic or postischemic heart; evidence from studies using isolated-perfused rat hearts suggests this is the case. PDC

activity is reduced at the onset of postischemic repefusion,87,88 coincident with postischemic contractile dysfunction; subsequently, administering either pharmacologic activators of PDC (eg, dichloroacetate89,90 or ranolazine91,92) or supplemental pyruvate93 increases the relative contribution of glucose to overall oxidative flux and cardiac contractile power. Augmenting pyruvate oxidation also indirectly inhibits myocardial oxidation of FFA, which in the setting of ischemia is accompanied by cytosolic accumulation of incompletely oxidized arrhythmogenic intermediate compounds. Considerable evidence suggests that the myocardium adapts to ischemia at least in part through insulin-independent recruitment of an intrinsic myocardial insulin-response system, the most important elements of which are glucose transport proteins.73 Studies using specific kinase inhibitors showed that ischemia produces insulin-independent sarcolemmellar translocation of GLUT4 in rat94 and canine95 heart by a mechanism that requires AMP kinase, but not PI 3-K (Fig 7). The potential significance of ischemic GLUT4 translocation is illustrated by the demonstration that cardiac-specific GLUT4 knockout impairs postischemic contractile recovery in the mouse heart under conditions in which circulating insulin levels are also low (eg, fasting).96 The effects of NIDDM and insulin resistance on myocardial energy metabolism are complex because the circulating levels of glucose and FFA are usually increased in these conditions. The crucial factor influencing the heart’s metabolic adaptation to ischemia in NIDDM is likely the expression and functional integrity of the cardiac metabolic insulin response system. This same system is known to be functionally impaired in skeletal muscles of diabetic subjects,20,97 and evidence suggests the impairment is genetically programmed.23 Although the impact of NIDDM on the expression and function of the cardiac muscle insulin response system is just beginning to be examined, evidence suggests it may differ from the phenotype exhibited by skeletal muscles. Studies using 18F-fluorodeoxyglu-

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cose positron emission tomography to compare insulin’s effect on glucose uptake by heart and limb muscles in NIDDM subjects have suggested preserved insulin responsiveness of the heart in the face of insulin resistance in limb muscles.98,99 To the extent that the myocardium continues to express a competent insulin response system in NIDDM and lesser states of whole-body insulin resistance, therapeutic augmentation of myocardial glycolysis or PDC flux or both might be effective adjunctive treatments for insulin-resistant patients suffering acute myocardial ischemia. As reviewed in the following section, clinical data to support this approach are now emerging. CLINICAL IMPLICATIONS

Acute Coronary Syndromes In addition to promoting the development of coronary atherosclerosis, NIDDM is associated with adverse short-term outcome from clinical conditions characterized by acute myocardial ischemia-reperfusion injury, including virtually all acute coronary syndromes, such as unstable angina,100,101 non–Q wave myocardial infarction,100,102 and Q wave myocardial infarction treated with thrombolytic therapy.11,103,104 The magnitude of this adverse effect is considerable, with multicenter registries suggesting a 2-fold mortality excess for patients with NIDDM experiencing acute myocardial infarction.104 The effect appears to operate as a continuous function of tissue insulin sensitivity and so is apparent even in nondiabetic patients with mild degrees of insulin resistance. A study of nondiabetic patients undergoing elective percutaneous transluminal coronary angioplasty showed a 4-fold increase in 2-year mortality for patients with fasting blood glucose ⬎ 110 mg/dL compared with patients with fasting blood glucose ⬍110 mg/dL.105 Much of the adverse effect of NIDDM on acute coronary syndromes can be attributed to the greater prevalence among NIDDM patients of preexisting left ventricular systolic dysfunction, multivessel CAD, renal disease, and cerebrovascular disease.7,10 Nevertheless, the increased incidence of de novo heart failure among NIDDM patients experiencing an initial myocardial infarction,13,14 viewed in the context of the derangements in vascular and myocardial metabolism previously discussed, suggests that potentially reversible factors are also involved. Three independent lines of evidence suggest that measures designed to acutely normalize the circulating and cellular metabolic milieu may improve clinical outcome in insulin-resistant CAD patients suffering acute coronary syndromes. First, the hormonal response to acute coronary events and surgery includes elevation in plasma levels of catecholamines, glucagon, and cortisol, each of which acutely worsens myocardial insulin resistance by raising plasma FFA levels.106 Although FFA are the preferred myocardial oxidative substrate under aerobic conditions, elevated perfusate FFA levels impair contractility in the isolated heart during ischemic reperfusion.107 This effect is attributed to the fact that incomplete oxidation of FFA in the ischemic myocardium results in cytosolic accumulation of long-chain fatty acyl-CoA esters, which promote ischemic membrane instability by their detergent properties and impair usage of oxidative ATP by inhibiting mitochondrial adenine nucleotide translocase.108,109 The use of

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insulin to reduce circulating FFA levels and normalize myocardial glucose metabolism during ischemia would be analogous to the use of ␤-adrenergic blockers to counteract the adverse physiologic effects of catecholamines on myocardial oxygen demand in this setting. Second, randomized prospective trials of the role of longterm glycemic control in diabetics have shown that tight control (using insulin, oral hypoglycemic agents, or the combination of both) improves microvascular function in insulin-dependent110 and non–insulin-dependent111,112 patients. Although these trials have not been sufficiently powered to show an effect on macrovascular events (eg, myocardial infarction), they imply that tight glycemic control may ameliorate the adverse effects of insulin resistance on the vascular endothelium and arterial wall. An important caveat is that the long-term use of sulfonylureas as glucose-lowering agents has been associated with increased CAD mortality,113 perhaps as a consequence of their effect of blocking K⫹-ATP channel–mediated ischemic preconditioning.114 Third, evidence suggests that short-term infusion of a glucose-insulin-potassium solution improves outcome of NIDDM patients during acute myocardial infarction. Attempts to document this beneficial effect, based on theoretical considerations regarding myocardial energy metabolism, date back almost 4 decades. Although early studies were underpowered statistically, a meta-analysis of 9 of the largest suggests a 28% mortality reduction with glucose-insulin-potassium treatment.115 More recently, a multicenter trial in Swedish hospitals (the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction [DIGAMI] trial) prospectively compared the effect of intensive insulin treatment (acute 24-hour glucoseinsulin infusion followed by 3 months of daily subcutaneous insulin) with conventional therapy in 620 NIDDM patients with acute myocardial infarction.116 This study reported a statistically significant 29% mortality reduction at 1 year in the intensive treatment arm. Survival analysis suggested the inhospital acute intravenous insulin infusion and subsequent outpatient insulin treatment contributed equally to reduction in

Table 1. Insulin-Glucose Infusion Protocol Used in the DIGAMI Study Infusate mixed as 80 U of regular insulin in 500 mL of 5% dextrose solution Infusion begun at 30 mL/h (5 U of insulin/h) Blood glucose checked every 1-2 h and infusion adjusted to maintain glucose concentration at 7-10 mmol/L using the following formula: Glucose ⬎ 15 mmol/L, give 8 U of insulin bolus and increase infusion by 6 mL/h Glucose 11-15 mmol/L, increase infusion by 3 mL/h Glucose 7-11 mmol/L, no change Glucose 4-7 mmol/L, decrease infusion by 3 mL/h Glucose ⬍ 4 mmol/L, stop infusion until ⬎7 mmol/L, then resume at lower rate Infusion reduced by 50% during night hours or when patient is NPO Abbreviation: NPO, nothing per mouth.

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Fig 8. Proportional contribution to the myocardial Krebs cycle acetate pool of pyruvate flux through pyruvate dehydrogenase complex (PDC) (filled bars) versus alternative substrate sources (eg, fatty acids) (open bars) in rats given steady-state infusions of [1-13C]glucose to label Krebs cycle intermediary metabolite pools at various plasma insulin and glucose concentrations. Conditions shown are Fasting (nadir glucose and insulin levels), Glucose (infusion of lowdose glucose), Insulin (infusion of low-dose insulin), Glu-Ins (infusion of glucose plus insulin at doses 3-fold greater than those used in the DIGAMI trial99), and Glu-Insⴙⴙ (infusion of insulin plus glucose at doses 10-fold greater than DIGAMI trial99). These data show that the effect of plasma insulin and glucose levels on the contribution of glucose to myocardial energy formation are dose dependent in vivo well above the range tested in clinical trials to date. Under fasting conditions, myocardial use of glucose as an oxidative substrate is minimal. 䊐, Other sources; ■PDC flux.(Adapted from McNulty et al118 with permission.)

mortality. The insulin treatment protocol used in this landmark trial is presented in Table 1. A similar South American trial reported equivalent benefit in nondiabetic patients (who, for reasons previously discussed, would also be expected to exhibit acquired metabolic insulin resistance).117 These observations are more interesting in light of evidence (illustrated in Fig 8) that the insulin doses used in these trials were well below those required to maximally stimulate glycolysis and PDC flux in animal experiments.118 Coronary Revascularization Although percutaneous transluminal coronary angioplasty and CABG surgery are effective strategies for coronary revas-

cularization in CAD patients with NIDDM, 3 randomized prospective trials comparing the 2 procedures (Bypass Angioplasty Revascularization Investigation,5 Emory Angioplasty Surgery Trial,119 and Coronary Angioplasty versus Bypass Revascularization Investigation120) have confirmed a long-term survival benefit for NIDDM patients randomized to CABG surgery. Most authorities, therefore, now recommend CABG surgery as the coronary revascularization procedure of choice in diabetic patients.121 Nevertheless, short-term and long-term outcomes of CABG surgery in NIDDM patients have historically been worse than those of nondiabetics.122 A review of the Duke University experience, showing an approximately 25% shortterm mortality excess for NIDDM, suggests this difference persists even at expert centers.123 Just as in the case of acute coronary syndromes, perioperative normalization of the diabetic metabolic milieu may reduce the impact of NIDDM on CABG surgery outcome. Preliminary trials have shown that infusion of insulin in modest doses (approximately 1 mU/kg/min), begun at induction of anesthesia and continued for 12 hours postoperatively, increases postoperative cardiac index and reduces the duration of inotropic support and mechanical ventilation after elective124 and emergent125 operations. Smaller studies suggest glucose-insulin infusion may be a useful adjunctive treatment for refractory shock after CABG surgery, acting to increase cardiac output, reduce inotrope requirements, and improve survival.126,127 Available evidence supports the perioperative use of insulinglucose solutions in patients with significant insulin resistance undergoing CABG surgery. CAD patients using sulfonylureas for glycemic control may particularly benefit from perioperative substitution of insulin because sulfonylureas seem to block ischemic114 and inhalation anesthetic–induced128 preconditioning of the myocardium. CONCLUSION

NIDDM is among the most adverse accompaniments of CAD, and its prevalence is increasing. Some degree of resistance to insulin action on muscle and vascular tissue is nearly universal in patients with CAD. Serious efforts to reduce the adverse impact of NIDDM and insulin resistance on cardiovascular morbidity and mortality are just beginning and require a better understanding of the cellular and molecular mechanisms of insulin action on biologic processes in the myocardium and vascular endothelium. Accumulating clinical data support the use of insulin-based regimens designed to normalize circulating glucose and FFA levels in the perioperative and peri-infarct periods.

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