Key points are not available for this paper at this time.
The rationale for the treatment of diabetes has hitherto been directed to the correction of hyperglycemia because hyperglycemia is known to be responsible for the symptoms of polyuria and polydipsia in the short term and microangiopathic complications of diabetes in the long term. The correction of hyperglycemia leads to immediate resolution of polydipsia and polyuria and the prevention of microvascular complications in the long term (1, 2). The relationship between the decline in glycosylated hemoglobin (HbA1c) and the reduction in the rate of complications is well established, and a fall in HbA1c can reasonably predict a fall in the rate of microangiopathic complications (1, 2). In view of this close relationship between glycemia and the microangiopathic complications of diabetes, it is now accepted that any means used to decrease blood glucose concentrations will result in a reduction in microangiopathic complications. Thus, glycemic control is the cardinal measure required to prevent microangiopathic complications. 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. The recent data that obesity and type 2 diabetes are associated with inflammatory processes with an increase in the expression of proinflammatory cytokines and other mediators, including adhesion molecules, suggests that these processes may contribute to atherogenesis because atherosclerosis is also an inflammatory condition (10–12). Indeed, there are data which demonstrate that in animal models of obesity, specific mediators in the proinflammatory pathways may contribute to insulin resistance and the suppression of their expression may lead to the reversal of insulin resistance. For example, TNFα 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 (13–15). Similarly, inhibitor κB (IκB), Jun-N-Terminal kinase 1, and IκB kinase β 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, TNFα expression in adipose tissue and the plasma concentration of TNFα are increased. Plasma TNFα 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 (22–26). It would thus appear that the processes underlying insulin resistance and atherosclerosis are related to each other and are similar. It is, therefore, of great significance that TZDs, known to restore insulin sensitivity, have profound, comprehensive, and rapid antiinflammatory effects (27–30). 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-κB (NFκB) 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 NFκB 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. 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, 38–40). These effects were reflected in the suppression of the expression of ICAM-1 and MCP-1 and in the intranuclear binding activity of NFκB 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 NFκB binding, and an increase in IκB expression with a concomitant fall in plasma concentration of CRP, ICAM-1, MCP-1, and plasminogen activator protein-1 (PAI-1; Refs. 9 and 38–40). 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 (42–44). 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. 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. 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 NFκB binding; and a fall in IκB (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, TNFα 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. The pathogenesis of insulin resistance and inflammation in obesity and the relationship to atherogenesis and type 2 diabetes. The primary initial strategy in the treatment of type 2 diabetes should be lifestyle change. Dietary restriction and weight loss cause a reduction in oxidative stress and proinflammatory cytokines (19, 55, 56). Physical exercise has recently been shown to reduce plasma CRP concentration (57), a marker and possibly a mediator of systemic inflammation; it is also known that physical exercise is associated with a reduction in cardiovascular events (58). Physical exercise also causes an increase in glucose uptake by the skeletal muscle through a mechanism independent of the insulin receptor (59). Although a lifestyle change is important in principle, clinical experience shows that it is extremely difficult to implement in practice. 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). In the type 2 diabetic patient with mild to moderate hyperglycemia, the second line drug should ideally be a TZD. The two preparations and in clinical use are rosiglitazone and pioglitazone. Troglitazone and rosiglitazone have been shown to exert antiinflammatory effects and and reduce carotid IMT as and therefore may potentially prevent atherogenesis (33, clinical studies are to the that the used TZDs, rosiglitazone and reduce cardiovascular events. 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Dandona et al. (Sun,) studied this question.