The potential influence of inflammation and insulin resistance on the pathogenesis and treatment of atherosclerosis-related complications in type 2 diabetes.

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.