Abnormal glucose and insulin metabolism
In recent years there has been growing interest in the presence of insulin resistance (syndrome X) in hypertensive patients. Multiple clinical studies have now demonstrated that there is an increased relative risk of cardiovascular events in patients who have insulin resistance. Physicians have long been aware that diabetes mellitus and hypertension often coexist. There is growing evidence that many hypertensive patients can be characterized as having borderline glucose intolerance and insulin resistance. These patients usually have normal fasting blood glucose concentrations and are not regarded as having clinical diabetes. A large-scale population survey has indicated that approx 50% of untreated hypertensive patients have glucose intolerance as measured by plasma glucose levels 2 h after glucose load. This prevalence is far higher than in normotensive control subjects. The explanation for this finding appears to be resistance to the action of insulin. In a recent study of well-matched groups of normal volunteers and hypertensive patients given a standard oral glucose tolerance test, glucose levels were found to be slightly higher in the hypertensive group than in the normotensive control subjects. More impressive, this study showed that plasma insulin concentrations were significantly higher in the hypertensive patients than in their normotensive counterparts during much of the 3-h study. The study also demonstrated that the problem is exaggerated by thiazide treatment, especially when β-blockers are added. Thus, patients with insulin resistance may have almost normal blood glucose levels but still spend significant proportions of the day hyperinsulinemic.
These findings are potentially important in explaining the high instances of atherosclerotic disease in hypertensive patients. Insulin is a powerful growth factor that directly stimulates smooth muscle cell proliferation. In addition, it plays an important role in promoting the action of other growth factors on vascular tissue. Moreover, insulin appears to enhance the formation of atherosclerotic plaques by facilitating the transport of atherogenic lipid particles into the media of the vessel wall. In a recent comparison of patients with increased and normal plasma insulin levels, those with higher insulin levels had increased concentrations of triglycerides and total cholesterol and decreased levels of high-density lipoprotein. Increased insulin levels also appear to be associated with higher blood pressure. Several actions of insulin may result in increased blood pressure. It stimulates the sympathetic nervous system probably through a glucose-mediated effect on the hypothalamus. It also causes readsorption of sodium by the kidney. These observations provide a possible explanation for the association of noninsulin-dependent diabetes mellitus (NIDDM) and hypertension. Other important effects of hyperinsulinemia may include an increase in the pressor action of angiotensin II and angiotensin II-stimulated production of aldosterone. In one study, chronic administration of insulin to rats increased blood pressure, which remained increased for several days after the insulin was discontinued.
It appears that insulin resistance and elevated insulin levels may precede the onset of high blood pressure. In a study comparing age-, sex-, and body mass index-matched normotensive patients with and without a family history of hypertension, insulin levels were significantly higher in patients with a family history of hypertension than in those without a family history of hypertension. Furthermore, the insulin:glucose ratio, which correlates well with insulin resistance measured by the euglycemic clamp technique, demonstrated that patients with a family history of hypertension were less sensitive to their own insulin than those without a family history of hypertension, despite the presence of normal blood pressure. Similar findings were reported in a study of young African-American men; fasting plasma insulin concentrations were significantly greater in patients with borderline hypertension than in normal control subjects, and the young hypertensive subjects exhibited a diminished capacity to clear glucose from their plasma. A similar picture of impaired glucose tolerance and compensatory hyperinsulinemia has been observed in normal offspring of patients with type II diabetes, suggesting a possible link between the mechanisms that mediate an increase in blood pressure and diabetes.
There is good evidence that insulin resistance and hyperinsulinemia are important cardiovascular risk factors. Early evidence linking diabetes and atherosclerosis came from the International Atherosclerosis Project. Later, in prospective population studies, increased insulin concentrations were implicated in the development of coronary artery disease. These studies have also shown that hyperinsulinemia is associated with increased triglycerides and decreased concentrations of high-density lipoprotein cholesterol. Other studies have shown that changes in lipoprotein composition that are characteristic of NIDDM are extremely atherogenic. In the Paris Prospective Study, plasma insulin concentrations were a patient-independent predictor of coronary artery disease. The Helsinki Policemen Study, a prospective study of 982 men, showed that high plasma insulin was predictive of coronary artery disease, death, or nonfatal myocardial infarction over a 9.5-yr follow-up. In the prospective Cardiovascular Munster study, hypertension, NIDDM and hyperinsulinemia were shown to be independent risk factors for coronary artery disease.
Thus, abnormalities of glucose and insulin metabolism are yet another genetically determined cardiovascular risk factor that may occur in patients prone to the development of hypertension. These abnormalities appear to be genetically determined and linked to hypertension. However, they appear to clinically manifest independent of blood pressure. Furthermore, they may play a role in the development of atherosclerotic disease and reduce arterial compliance, which ultimately may also be important in the pathogenesis of high blood pressure.
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