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Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo and Kaleida Health, Buffalo, New York 14209
Address all correspondence and requests for reprints to: Paresh Dandona, M.D., Ph.D., Diabetes-Endocrinology Center of Western New York, 3 Gates Circle, Buffalo, New York 14209. E-mail: pdandona{at}kaleidahealth.org.
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Introduction |
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 Top Introduction Inflammation, insulin...Inflammation and drugs for...Antiinflammatory and antioxidant...ConclusionsReferences |
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Whereas microangiopathic complications lead to blindness (retinopathy) and renal failure (nephropathy) and may contribute to neuropathy, the most important complication leading to mortality in type 2 diabetes is macroangiopathy or atherosclerosis (3). Hyperglycemia may contribute to macrovascular disease, but the evidence related to its prevention by the control of hyperglycemia is limited (2, 4, 5). Whereas observational studies demonstrate a relationship between HbA1c and cardiovascular events, prospective interventional studies do not demonstrate an impressive reduction in cardiovascular events with a fall in HbA1c (2, 4, 5). In both Kumamoto (5) and UKPDS studies (2), the reduction in cardiovascular events was just short of statistical significance. Although the Kumamoto study results and correlations are based on a fall in HbA1c by more than 2%, the number of patients included was small. On the other hand, the UKPDS study was large, but the overall HbA1c fall was less than 1% (0.9%; Ref. 2). The Diabetes Control and Complications Trial, which was carried out over a period of 10 yr, achieved a consistent reduction in HbA1c of 2% and showed a decrease in cardiovascular events, but the reduction was again short of being statistically significant (1). In this case, the relative youth of the patients with type 1 diabetes may have contributed to a low overall rate of macrovascular events. It would thus appear that at best, glycemia levels do contribute to atherogenic complications of heart attack and stroke but that their contribution is small.
These considerations are important because we need to develop a rational strategy for the control/prevention of macrovascular complications. Macrovascular disease (atherosclerosis) accounts for 70% of the mortality in type 2 diabetes, making heart attacks and strokes two to four times more frequent in these patients when compared with controls (6). Thus, a type 2 diabetic patient without a history of coronary heart disease (CHD) carries the same risk of having a heart attack as a nondiabetic with a previous history of a heart attack (7). It is important that several epidemiological studies have shown that fasting hyperinsulinemia predicts cardiovascular events (8). This was initially interpreted as evidence that insulin is atherogenic. However, because hyperinsulinemia is a reflection of an insulin-resistant state, it is now increasingly accepted that insulin resistance rather than hyperinsulinemia is proatherogenic. Furthermore, there are recent data that insulin has a potent antiinflammatory effect that may inhibit atherogenesis in the long term (9). This action of insulin may also explain why insulin-resistant states may be proinflammatory and proatherogenic.
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Inflammation, insulin resistance, and atherosclerosis |
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TopIntroductionInflammation, insulin...Inflammation and drugs for...Antiinflammatory and antioxidant...ConclusionsReferences |
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is constitutively expressed by the adipose tissue; its tissue expression is increased in the ob/ob mouse and the Fa/Fa Zucker rat; its neutralization with soluble TNF receptor results in the restoration of insulin sensitivity (13, 14, 15). Similarly, inhibitor 
B (IB), Jun-N-Terminal kinase 1, and IB kinase ß have recently been shown to be involved in insulin resistance (16). Thus, the ob/ob mice with Jun-N-Terminal kinase 1 and aP2 knockouts have been shown to have normal insulin sensitivity despite the presence of obesity (17, 18). Clearly, therefore, proinflammatory processes contribute to insulin resistance in animal models, although we cannot at present be specific about the exact molecular mechanism that leads to the proinflammatory changes resulting in insulin resistance in the human.
In the obese human, TNF expression in adipose tissue and the plasma concentration of TNF are increased. Plasma TNF concentration is related to insulin resistance, and it falls with dietary restriction and weight loss, as does insulin resistance (19). IL-6 and C-reactive protein (CRP) are known to be increased in obesity and in type 2 diabetes, as are sialic acid and serum amyloid A (SAA) concentrations (10, 20, 21). There is also evidence that the concentration of some of these proinflammatory mediators is related to the occurrence of cardiovascular events and the intimal-medial thickness (IMT) of the internal carotid artery, a recognized index of the progress of atherosclerosis (22, 23, 24, 25, 26). It would thus appear that the processes underlying insulin resistance and atherosclerosis are related to each other and are similar.
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Inflammation and drugs for diabetes |
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TopIntroductionInflammation, insulin...Inflammation and drugs for...Antiinflammatory and antioxidant...ConclusionsReferences |
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It is, therefore, of great significance that TZDs, known to restore insulin sensitivity, have profound, comprehensive, and rapid antiinflammatory effects (27, 28, 29, 30). These effects may indeed contribute to their beneficial action on insulin sensitivity. Thus, troglitazone reduces plasma insulin concentrations by 50% within 1 wk of administration while also reducing reactive oxygen species (ROS) generation and nuclear factor-B (NFB) binding activity by 50% in the insulin-resistant obese (29). Similarly, the early antiinflammatory effects of rosiglitazone are evident after a mere 3–7 d of administration at a small dose (4 mg; Ref. 30). These actions are reflected in a reduction of ROS generation, intranuclear NFB binding activity, and plasma CRP concentrations. It is also relevant that both troglitazone and rosiglitazone suppress monocyte chemoattractant protein-1 (MCP-1) and soluble intercellular adhesion molecule-1 (ICAM-1), both of which are proinflammatory mediators and whose knockout in mice results in the protection from atherosclerosis (31, 32). Furthermore, both troglitazone and rosiglitazone cause a reduction in the expression of p47phox subunit, an essential protein component of nicotinamide adenine dinucleotide phosphate oxidase, the enzyme that converts molecular O2 to the superoxide radical. It is understandable, therefore, why both troglitazone and pioglitazone result in the arrest of the progression of IMT in the carotid artery of diabetic patients within 3 months, an effect that continues for at least 6 months (33, 34). Long-term studies are clearly required to confirm this important effect and to translate this effect in terms of clinical outcomes. Both troglitazone and rosiglitazone have been shown to improve the impaired postischemic vasodilation of the brachial arterial reactivity in the obese and the obese diabetic (27, 30). Because postischemic vasodilation is dependent on normal endothelial function, it is clear that TZDs probably restore this very rapidly, within weeks of treatment. Such an improvement in endothelial function is probably the result of a combination of effects: 1) a reduction in ROS and superoxide generation resulting in an increased bioavailability of nitric oxide; 2) a reduction in the inflammatory damage of the endothelium; and 3) a probable reduction in platelet and leukocyte aggregation, two effects that still need to be clearly demonstrated. Troglitazone has also been shown to reduce the increase in blood pressure after mental stress in insulin-resistant patients (35). These actions are important because they may have a beneficial effect on the proconstrictor state in obesity and type 2 diabetes. Indeed, troglitazone was shown to reduce the frequency and intensity of pain in patients with vasospastic angina with angiographically normal epicardial coronary arteries, and TZDs have been shown to have a mild hypotensive effect (36, 37). Although troglitazone and rosiglitazone have been shown to have antiinflammatory effects, such data are still awaited for pioglitazone.
Antiinflammatory effect of insulin.
It is also important that insulin has recently been shown to exert an antiinflammatory effect on human aortic endothelial cells in vitro and mononuclear cells in humans in vivo (9, 38, 39, 40). These effects were reflected in the suppression of the expression of ICAM-1 and MCP-1 and in the intranuclear binding activity of NFB in human aortic endothelial cells. In humans, in vivo, it was shown that insulin infused at a low dose (2 U/h), reaching concentrations of insulin from 13 µU/ml to 25–28 µU/ml over a period of 4 h, resulted in a rapid suppression of ROS generation by mononuclear cells, p47phox subunit expression, intranuclear NFB binding, and an increase in IB expression with a concomitant fall in plasma concentration of CRP, ICAM-1, MCP-1, and plasminogen activator protein-1 (PAI-1; Refs. 9 and 38, 39, 40). Two other proinflammatory transcription factors, activator protein-1 and Egr-1, were also suppressed, along with their respectively regulated genes, matrix metalloproteinase (MMP)-2, MMP-9, and tissue factor (40, 41). Thus, the action of insulin may not only be antiinflammatory in general; it may be particularly relevant to atherosclerotic plaque rupture in which MMPs play an important role: in the initiation of thrombosis, in which tissue factor is a major trigger; and fibrinolysis, which is inhibited by PAI-1. These rapid and potent effects of insulin are, therefore, of potential use in acute inflammatory states. Interestingly, the potency of 2 U/h infusion of insulin is similar to that observed after an iv bolus of 100 mg hydrocortisone (42, 43, 44). A fundamental difference between the antiinflammatory effects of hydrocortisone and insulin is that, whereas insulin is anabolic, hydrocortisone and other glucocorticoids are catabolic. While discussing the antiinflammatory and potential antiatherogenic effect of insulin, it is important to mention that insulin has recently been shown to inhibit atherogenesis in apolipoprotein E -/- mice (45). It also reduced superoxide production by macrophages, their lipid peroxide content, and cholesterol biosynthesis and content. Clearly, insulin appears to have an antiatherogenic effect in this animal model.
Antiinflammatory effect of metformin.
Metformin has previously been shown to reduce PAI-1 (46), an endogenous inhibitor of fibrinolysis (47); PAI-1 is itself a product of inflammation and is increased during septicemia (48). More recently, metformin has been shown to suppress plasma concentrations of macrophage migration inhibition factor (MIF) in the obese (our unpublished data). It is thus possible that metformin may also have some antiinflammatory activity. Thus metformin does, indeed, reduce cardiovascular morbidity and mortality, as was demonstrated in the UKPDS study (49). In a recent retrospective study from Saskatchewan, Canada (50), metformin was shown to reduce cardiovascular mortality by over 45% when compared with those treated with sulfonylurea for type 2 diabetes. Clearly, further work is required to confirm the cardiovascular benefit of metformin and the specific molecular mechanisms underlying it.
Proinflammatory effect of glucose.
In contrast to the antiinflammatory and potentially antiatherogenic effects of insulin and TZDs, glucose has been shown to produce oxidative stress and to exert a proinflammatory effect at the cellular and molecular level. Thus, glucose causes an increase in ROS generation (51); an increase in p47phox, the key component of nicotinamide adenine dinucleotide phosphate oxidase; an increase in intranuclear NFB binding; and a fall in IB (52). These effects reflect a comprehensive proinflammatory action of glucose. Hyperglycemic clamps in normal subjects, in whom endogenous insulin has been suppressed by concomitant administration of somatostatin, induce an increase of proinflammatory cytokines, TNF and IL6 (53). Thus, any means of reducing blood glucose concentration should also constitute a potential antiinflammatory measure. Therefore, sulfonylurea may exert an antiinflammatory action indirectly through a reduction in hyperglycemia, although there are no data to show that they have a specific antiinflammatory effect of their own. In this context, it is of interest that in a study comparing the effect of a sulfonylurea with insulin in type 2 diabetics, CRP concentrations fell only in the insulin-treated group (54).
In view of the antiinflammatory and potential antiatherogenic actions of insulin and agents causing a reduction in insulin resistance (TZDs and metformin) and the fact that obesity and type 2 diabetes are proinflammatory, and thus potentially atherogenic (Fig. 1
), our therapeutic strategies should be directed accordingly, because the major cause of mortality in type 2 diabetes is related to macrovascular disease and its complications.
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Clinical use of metformin.
The first line of treatment with drugs in type 2 diabetes is usually metformin. It reduces HbA1c by 1–1.5%, and it is known to reduce cardiovascular mortality/morbidity in clinical studies (49, 50). It is the only antidiabetic drug that does not cause weight gain and may actually aid weight loss. It is especially effective in limiting weight gain with insulin (60, 61) (62). Metformin may also have some antiinflammatory effects by way of reductions in PAI-1 and MIF. PAI-1 is antifibrinolytic and thus promotes thrombosis, whereas MIF is a proinflammatory cytokine (63). The main side effects of metformin are diarrhea and the other related gastrointestinal symptoms. Approximately 10% of patients may need to stop the drug because of gastrointestinal side effects (64). The more recent slow-release preparation of metformin may reduce the frequency and severity of these symptoms but does not eliminate them altogether. A rare but serious side effect of metformin is lactic acidosis due to an increase in plasma lactic acid concentrations. It is therefore contraindicated in conditions associated with either increased lactate production or diminished lactate clearance: renal impairment, hepatic dysfunction, and gross congestive cardiac failure (62).
Clinical use of TZDs.
In the type 2 diabetic patient with mild to moderate hyperglycemia, the second line drug should ideally be a TZD. The two preparations currently available and in clinical use are rosiglitazone and pioglitazone. Troglitazone (29, 65) and rosiglitazone (30) have been shown to exert antiinflammatory effects and reverse and reduce carotid IMT as mentioned above and therefore may potentially prevent atherogenesis (33, 34, 66). Long-term, clinical outcome studies are underway to explore the hypothesis that the currently used TZDs, rosiglitazone and pioglitazone, reduce cardiovascular events. The other advantage of TZDs, is their potential in preserving ß-cell function and thus to exert a long-term antidiabetic effect without a decline in their efficacy. The preservation of the ß-cell has been well demonstrated in experimental animals with impending diabetes while there are early data in the human to demonstrate the same (67). The decrease in HbA1c ranges between 1 and 1.5%, and the effect is additive to that of sulfonylurea or metformin when given in combination. Despite their advantages, the use of TZDs has certain limitations: weight gain, edema, and hemodilutional reduction in hemoglobin are the known side effects (68). In practice, using smaller doses of these drugs, further guidance on dietary restriction, the avoidance of dihydropyridine for hypertension, salt restriction, and the concomitant use of ACE inhibitors and thiazides may minimize these side effects. The other factor that restricts their use in medically uninsured populations in the United States and other countries like Canada and Europe is their expense.
Clinical use of sulfonylureas.
In patients with more severe hyperglycemia and the symptoms of severe polyuria and polydipsia, sulfonylureas and insulin may be the preferred choices to control hyperglycemia rapidly. As mentioned above, sulfonylureas have not been shown to have an independent antiinflammatory effect of their own. However, a reduction in blood glucose concentration may produce an antiinflammatory effect because hyperglycemia is proinflammatory. Even in patients who require sulfonylurea or insulin to reduce hyperglycemia and symptoms, the concomitant use of metformin is desirable because of the beneficial effects on weight and cardiovascular complications. Indeed, in some patients, it may be possible to revert totally to oral hypoglycemic agents after symptoms of hyperglycemia have been treated with insulin and glucotoxicity has been reversed. However, the level of HbA1c that should be targeted is less than 7%; even lower levels are desirable if they can be achieved without a risk of hypoglycemia.
Clinical use of insulin.
Insulin can be used in type 2 diabetes for the maintenance of euglycemia at any stage in the evolution of this disease. However, it is usually used when maximal doses of oral agents have failed to restore HbA1c levels to the target of less than 7%. The initial approach to starting insulin therapy is to provide a basal insulin preparation, usually injected at night, to obtain fasting glucose concentrations of 90–110 mg/dl. The previous oral hypoglycemic agents are left on board because they may control postprandial glucose concentrations during the day. Should this not happen, additional insulin therapy with fast-acting preparations may be added during the day as necessary. The previous hesitation about the use of insulin therapy for fear of increasing hyperinsulinemia is unjustified because the underlying insulin resistance, and not hyperinsulinemia, is the probable cause of atherosclerosis. Insulin should also be the treatment of choice in hospitalized patients with uncontrolled hyperglycemia and when subjects are admitted to the critical care unit with or without acute coronary syndromes. Treatment with insulin in the setting of severe symptomatic hyperglycemia or when it is added to oral agents, when the latter are unable to achieve adequate glycemic targets, or in the hospitalized and critically ill patients has a dual benefit from both a reduction in glycemia and the direct antiinflammatory effect of insulin.
It is estimated that 20% of subjects admitted with acute myocardial infarction (MI) have diabetes, and of those not known to have diabetes, 65% have either undiagnosed diabetes or impaired glucose tolerance (69). Hyperglycemia at the time of acute MI has been correlated to increased mortality in diabetics and nondiabetic patients (70). Impaired glucose metabolism, increased free fatty acid concentration, and preferential myocardial fatty acid use have been suggested as mechanisms for aggravating ischemia and inducing arrhythmias in these populations (71). Hyperglycemia has also been associated with increased incidence of no reflow after successful reperfusion (72). Insulin infusion of 5 U/h has been shown to reduce long-term mortality by 30–50% in diabetics and nondiabetics, presumably based on its glucose- and free fatty acid-lowering metabolic effect (73, 74, 75). However, a prothrombotic milieu promoted by thrombolytics, proinflammatory mediators resulting in the persistence of an unstable plaque, and an increase in MMPs affecting left ventricular remodeling could also lead to failure of reperfusion, reocclusion, and congestive heart failure post MI (76, 77, 78, 79). Commensurate with this hypothesis are the observations that CRP and PAI-1 are markers of thrombolytic efficacy in acute MI and that suppression of MMP decreases left ventricular remodeling after MI in animals (80, 81). Antiinflammatory properties of insulin as mentioned above and its vasodilatory (arterial and venous) and antiplatelet aggregatory properties could thus improve prognosis after acute MI, independent of its metabolic effect (82). On the basis of these hypotheses and the observation that insulin is most beneficial when given with thrombolysis and at the onset of reperfusion, an insulin infusion should be started to control hyperglycemia, preferably with the commencement of thrombolysis and reperfusion in type 2 diabetes (83). We recommend initiating therapy with blood glucose in the impaired fasting or impaired glucose-tolerant range and maintaining blood glucose between 100 and 140 mg/dl with the use of a minimum of 2.5 U insulin per hour for a period of time that the subjects are in the critical care unit.
It is possible that the antiinflammatory action of insulin may have a beneficial role in inflammatory conditions, unrelated to traditional hyperglycemia. Patients with critical illness including sepsis, as well as experimental endotoxemia, often have hyperglycemia and an insulin-resistant state even in the absence of diabetes (84). Sepsis and endotoxin administration impair insulin-mediated glucose uptake in skeletal muscle, and it has been suggested that lipopolysaccharides may alter multiple steps in the insulin signal transduction pathway (85). In fact, a recent prospective, randomized trial of insulin infusion in 1548 mechanically ventilated, critically ill patients (only 13% were diabetic) in an intensive care unit (ICU) setting has shown remarkable benefit (86). Insulin infusion to maintain normal blood glucose in the range of 80–110 mg/dl reduced ICU mortality by 43%, hospital mortality by 34%, and bacteremia by 46%. The greatest reduction in mortality involved deaths due to multiple-organ failure with a proven septic focus. There was also a significant reduction in the duration of ICU stay, need for dialysis, and need for prolonged ventilator support.
Whether these benefits of insulin infusion in conditions of acute coronary events or critically ill patients of diverse etiologies, including sepsis, are related to both improvement in glucose concentrations and the antioxidative and antiinflammatory actions of insulin needs to be explored further.
For the prevention and reduction of macrovascular complications of diabetes, control of other comorbidities and drugs other than those used for glycemic control also need to be considered (Table 1).
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Antiinflammatory and antioxidant properties of other drugs used in diabetes |
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TopIntroductionInflammation, insulin...Inflammation and drugs for...Antiinflammatory and antioxidant...ConclusionsReferences |
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These drugs reduce cardiovascular morbidity and mortality markedly. They are also found to lower triglycerides and to raise high-density lipoprotein to a small extent. It is of great interest that statins not only reduce low-density lipoprotein (LDL) cholesterol concentrations but also cause a reduction in CRP concentrations and thus exert an antiinflammatory effect, which may contribute to their antiatherogenic action (87, 88). This action may also be relevant to their ability to reduce the incidence of diabetes in the populations studied (89). More recently, it has been shown that CRP concentrations may be better predictors of cardiovascular events than LDL-cholesterol (90). There is some evidence that their benefit in diabetic populations may be even greater than that in nondiabetic populations. Thus, in diabetic patients, the target level of LDL-cholesterol is 100 mg/dl or less (91, 92).
ACE inhibitors and angiotensin receptor blockers (ARBs).
These agents have been shown to be effective in preventing the progression of nephropathy in both nondiabetic and diabetic populations (93, 94, 95, 96). However, there is evidence now that they reduce macrovascular complications in these populations, too (97). Angiotensin II is a proinflammatory peptide, and therefore the inhibition of its formation through ACE inhibition (ACE-I) and the blockage of its action through ARBs is likely to exert an antiinflammatory action (98, 99). Valsartan, an ARB, has been shown to exert a suppressive effect on ROS (100) generation and inflammatory mediators, and although detailed studies on the antiinflammatory action of ACE-I are still awaited, ACE-I treatment has been shown to reduce cardiovascular events (101). ACE-I or ARB treatment should be given in all patients with microalbuminuria, which is a marker for both nephropathy and CHD, because it reflects endothelial dysfunction. Such treatment should also be provided to diabetic patients with established CHD with or without hypertension. In diabetics with hypertension, ACE-I or ARBs should be the first line antihypertensive drugs. It is relevant that in two large studies on cardiovascular outcomes, ramipril, an ACE inhibitor (102), and losartan, an ARB, caused a reduction in the incidence of diabetes type 2 (97). This may again be secondary to an antiinflammatory effect of these drugs because angiotensin II is proinflammatory.
ß-Blockers.
ß-Blockers have been shown to be of benefit in reducing cardiovascular events (103). They were similar to ACE-I in their effectiveness in the UKPDS study (101). They have been shown to exert an antioxidant effect through the suppression of ROS generation (nadolol and carvedilol) and to suppress lipid peroxidation and oxidative damage of amino acids (104, 105). Carvedilol has an additional -blocker effect that may have interesting implications in terms of 1) -adrenergically mediated coronary vasoconstriction, and 2) the protection of insulin secretion by the ß-cell.
Aspirin.
Aggressive control of hypertension and dyslipidemia and the use of aspirin, according to the recommendations of the American Diabetes Association, are also important in the reduction of cardiovascular morbidity and mortality (106). Aspirin exerts important antiplatelet and antiinflammatory effects. A recent trial has shown an impressive absolute reduction of 20% in cardiovascular outcomes with this multifactorial approach (107).
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Conclusions |
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TopIntroductionInflammation, insulin...Inflammation and drugs for...Antiinflammatory and antioxidant...ConclusionsReferences |
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Footnotes |
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B, inhibitor B; IMT, intimal-medial thickness; LDL, low-density lipoprotein; MCP-1, monocyte chemoattractant protein-1; MI, myocardial infarction; MMP, matrix metalloproteinase; MIF, migration inhibition factor; NFB, nuclear factor-B; PAI-1, plasminogen activator protein-1; ROS, reactive oxygen species; TZD, thiazolidinedione. Received February 4, 2003.
Accepted March 5, 2003.
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References |
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TopIntroductionInflammation, insulin...Inflammation and drugs for...Antiinflammatory and antioxidant...ConclusionsReferences |
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B and stimulates IB in mononuclear cells in obese subjects: evidence for an anti- inflammatory effect? J Clin Endocrinol Metab 86:3257–3265: direct role in obesity-linked insulin resistance. Science 259:87–91. J Clin Invest 94:1543–1549
- and obesity-induced insulin resistance. Science 271:665–668[Abstract]
B-. Diabetes 51:2005–2011[CrossRef][Medline]
in sera of obese patients: fall with weight loss. J Clin Endocrinol Metab 83:2907–2910B and stimulation of inhibitor B by troglitazone: evidence for an anti-inflammatory effect and a potential antiatherosclerotic effect in the obese. J Clin Endocrinol Metab 86:1306–1312B and MCP-1 expression in human aortic endothelial cells. J Clin Endocrinol Metab 86:450–453B expression and diminished nuclear NF-B in human mononuclear cells following hydrocortisone injection. J Clin Endocrinol Metab 84:3386–3389B and p47phox in mononuclear cells. Program of the 82nd Annual Meeting of The Endocrine Society, Toronto, Canada, 2000, p 84 (Abstract 313)
B suppressive and inhibitor-B stimulatory effects of troglitazone in obese patients with type 2 diabetes: evidence of an antiinflammatory action? J Clin Endocrinol Metab 86:3250–3256b (NF-B), and activator protein-1(AP-1) in mononuclear cells (MNC) of normal subjects: evidence of an anti-inflammatory action. J Clin Endocrinol Metab, in press
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