Twenty-five percent of the general nonobese nondiabetic population has insulin resistance of a magnitude similar to that seen in type 2 diabetes. These insulin-resistant nondiabetic individuals are at much higher risk for developing type 2 diabetes than insulin-sensitive persons. In addition to diabetes, these individuals have increased risk for elevated plasma triglycerides, lower high-density lipoproteins (HDLs), and higher blood pressure - a cluster of abnormalities termed syndrome X. These associations have now been expanded to include small, dense, low-density lipoprotein (LDL), hyperuricemia, abdominal obesity, prothrombotic state with increased levels of plasminogen activator inhibitor type 1 (PAI-1), and proinflammatory state. These clusters of abnormalities significantly increase the risk of atherosclerotic disease.

 
It has been postulated that hyperinsulinemia and insulin resistance play a direct role in these metabolic abnormalities, but supportive evidence is inconclusive. Although hyperinsulinism and hypertension often coexist in whites, that is not the case in blacks or Pima Indians. Moreover, patients with hyperinsulinism due to insulinoma are not hypertensive, and there is no fall in blood pressure after surgical removal of the insulinoma restores normal insulin levels. The main value of grouping these disorders as a syndrome, however, is to remind clinicians that the therapeutic goals are not only to correct hyperglycemia but also to manage the elevated blood pressure and dyslipidemia that result in increased cerebrovascular and cardiac morbidity and mortality in these patients. Clinicians aware of this syndrome are more cautious in prescribing therapies that correct hypertension but may raise lipids (diuretics, β-blockers) or that correct hyperlipidemia but increase insulin resistance, with aggravation of diabetes (niacin). Finally, the use of long-acting insulins and sulfonylureas that promote sustained hyperinsulinism may have to be moderated, with insulin-sparing drugs such as metformin or a thiazolidinedione being preferable, if the hypothesis behind the insulin resistance syndrome is ever substantiated.