Insulin Resistance and Hypertension

      Insulin resistance, an impaired response to normal amounts of insulin, is seen in up to half of all patients with essential hypertension and is hypothesized to be a major cause of such hypertension. Reduced response to insulin, in addition to being dysfunctional glucose metabolism and a precursor to diabetes, usually stimulates the pancreas to deliver and maintain insulin levels that are considerably higher than normal; and the resulting hyperinsulinemia can be responsible for an array of untoward effects that predispose the patient to other cardiovascular complications. Though controversy has reigned over the question of whether hypertension or hyperinsulinemia are cause or effect, reduction of blood pressure has little effect on hyperinsulinema, while reducing insulin levels does reduce blood pressure.     
     Ingestion of food normally produces a temporary increase in activity of the sympathetic nervous system evidenced by higher levels of norepinephrine detectable in the urine. The sustained higher levels of insulin in the insulin resistant, though, perpetuate this elevated norepinephrine level, mimicking the effects of ingesting a meal and maintaining a higher level of sympathetic stimulation, which of course can result in elevated blood pressure. In addition, the higher levels of insulin increase sodium reabsorption in the kidney (also detectable by lower sodium levels in the urine), which contributes to elevated blood pressure by increasing blood levels of sodium.
     Bearing in mind insulin’s role in lipid metabolism, other effects of hyperinsulinemia become apparent. Insulin increases fatty acid synthesis and VLDL secretion, while decreasing lipolysis and beneficial HDL cholesterol secretion leading to abnormal lipoprotein metabolism, elevated triglyceride and total cholesterol levels, diminished HDL-cholesterol levels, generation of dense particles of harmful LDL cholesterol, microalbuminuria, and hyperuricemia. These are almost all considered risk factors for atherosclerosis.
     A number of factors have been shown to contribute to the development of hyperinsulinemia, not the least of which is advancing age. It appears that in spite of increased sympathetic nervous system stimulation, which would presume peripheral vasoconstriction, hyperinsulinemia also causes a concomitant direct dilation of blood vessels which has yet to be explained. This paradoxical dilation, hypothesized as a compensatory mechanism, is notably reduced in the elderly; and the level of sympathetic nervous activity is also increased in the elderly.
     Lack of exercise in adult life and obesity (particularly with fat distributed in the upper body/abdomen – the omental or visceral fat deep within the trunk) are known environmental contributors to hyperinsulinema; and low birth weight, poor growth in the first year of life, and poor nutrition tend to “imprint” a child for development of insulin resistance later in life. The most significant factor, though, seems to be heredity, for fully 70% of differences seen in patients’ insulin sensitivities are attributable to genetic makeup.
     Since the actual mechanism of insulin resistance development remains elusive, it has been dubbed “Syndrome X”; and recent evidence points toward a protein called glut-4, responsible for mediating the transport of glucose into muscle cells for metabolism, as the basis for Syndrome X. Lower concentrations of glut-4 are seen in association with omental fat, insulin resistance, and elevated blood pressures, while higher concentrations of glut-4 are seen in normotensive patients with normal insulin sensitivity. Unfortunately, only 25% of the differences seen in insulin sensitivities can be explained with glut-4 levels, so other factors are obviously at work in the process.
     Diabetic patients are more likely to suffer kidney disease, stroke, and ischemic heart disease and to have more difficulty in recovering from heart attack and stroke than the general population; so early adequate control of hypertension in the diabetic patient is essential in slowing the progression of complications, extending survival, and maintaining quality of life. Recommendation for intervention is made for diabetic patients with lower elevated blood pressure than for non-diabetic patients, as renal damage in diabetic patients carries a 100-fold increase in cardiovascular risk.
     Due to their lack of effect on carbohydrate and lipid metabolism, ACE inhibitors are considered the drugs of choice for treatment of hypertension in diabetics, though they may be less effective in Afro-Caribbean populations where calcium antagonists may be required. By inhibiting the conversion of Angiotensin-I to Angiotensin-II, ACE inhibitors 1) block arteriolar constriction, 2) retard Sodium retention and stimulate Potassium excretion by blocking the release of aldosterone, 3) reduce thirst by reducing the synthesis of ADH, and 4) redistribute blood flow away from nephrons to counter volume retention.
     In addition to an undefined beneficial effect on insulin resistance, ACE inhibitors slow the progression of diabetic nephropathy in IDDM by a mechanism independent of their pressor effects. They are also the mainstay of treatment (along with minimal doses of diuretics) of chronic cardiac failure also seen in the affected patient population.