Insulin Resistance In Essential Hypertension Research Articles

Diastolic function and insulin resistance in essential hypertension

We studied the relationship of insulin metabolism to diastolic function in 41 hypertensive patients and 24 healthy subjects. They underwent a 75-g oral glucose tolerance test. Integrated response of insulin to the glucose load was calculated as the area under the curve of insulin (AUC-I) and glucose (AUC-G). The ratio AUC-I/AUC-G was taken as an index of insulin resistance. Echocardiographic examination was performed to measure left ventricular mass. We used pulsed Doppler technique to assess the ratio of early to late transmitral peak velocity (E/A). The hypertensives had higher fasting insulin concentrations, insulin levels at 60 min and at 120 min after oral glucose load. They had higher AUC-I and higher index of insulin resistance compared to normotensives. Patients with hypertension had a lower E/A ratio in comparison to normotensive volunteers. In all subjects, the E/A ratio was negatively correlated with fasting insulin and insulin concentrations at 30, at 60 and at 120 min, AUC-I and insulin resistance index. Multiple regression analysis was performed to evaluate the above relationships, when the effects of confounding factors such as age, heart rate and systolic blood pressure were taken into account. We found that E/A ratio is negatively correlated to insulin concentrations at 120 min and to AUC-I in hyperinsulinemic subgroup of subjects (fasting insulin>10). We conclude, that insulin metabolism and E/A ratio, which reflects diastolic function of the left ventricle, are related in hypertension.

Insulin resistance in essential hypertension is related to plasma renin activity.

A high plasma renin activity (PRA) has previously been related to several cardiovascular risk factors as well as to later cardiovascular events. As insulin resistance has been suggested as the unifying factor in the insulin resistance metabolic syndrome, insulin resistance was evaluated by the euglycaemic hyperinsulinaemic clamp technique in 50 untreated hypertensive subjects in whom PRA and serum aldosterone were measured together with lipids and an intravenous glucose tolerance test (IVGTT). PRA was inversely related to insulin-mediated glucose disposal during the clamp (r=-0.31, P < 0.05), as well as to fasting insulin (r=0.32, P < 0.05) and to insulin at 60 min at the IVGTT (r=0.30, P < 0.05), but not to other risk factors. Serum aldosterone was not related to any of the metabolic risk factors. In conclusion, the present investigation showed that insulin resistance is associated with elevated levels of PRA in patients with untreated essential hypertension. It thus seems as if a high activity in the renin system should be included in the disturbances included in the insulin resistance metabolic syndrome, a syndrome with a major impact on future cardiovascular events.

F003 Elevated red blood cell sodium-lithium countertransport and low lymphocyte cytosolic calcium are markers of insulin resistance in essential hypertension

F003 Elevated red blood cell sodium-lithium countertransport and low lymphocyte cytosolic calcium are markers of insulin resistance in essential hypertension

Salt Sensitivity Is Associated With Insulin Resistance in Essential Hypertension

The relationship between salt sensitivity and insulin resistance was investigated in nondiabetic, nonobese (body mass index ≤ 28) untreated patients with uncomplicated, mild-to-moderate essential hypertension. Alterations in insulin-mediated glucose disposal were assessed by means of the insulin suppression test. Subjects were classified as salt sensitive and salt resistant according to their blood pressure response to low and high salt intake. Fasting serum glucose levels were within normal limits and did not differ between salt sensitive and salt resistant hypertensives, irrespectively of the level of salt intake. Fasting serum insulin levels increased in salt sensitive patients when on a high intake of salt. The insulin suppression test revealed the existence of marked differences in insulin-mediated glucose uptake between salt sensitive and salt resistant hypertensives. Much higher steady-state glucose values (nanomoles of glucose/liter) were obtained during the insulin suppression test in salt sensitive than in salt-resistant hypertensives (7.4 ± 1.6 v 3.5 ± 0.1 under low salt; and 12.5 ± 1.1 v 4.3 ± 0.1 under high salt intake). The product of glucose times insulin obtained at steady state during low and high salt intakes were 2.5 and 5 times greater, respectively, in salt sensitive than in salt resistant hypertensives. Therefore, the impairment in insulin-mediated glucose disposal observed in salt sensitive hypertensives was present both under low salt (60 to 70 mEq/day) and high salt intake (300 mEq/day). However, it was exacerbated under high salt intake. These results suggest that untreated salt sensitive hypertensives have a considerable impairment in insulin-mediated glucose disposal because of a state of insulin resistance. High salt intake increased BP, induced hyperinsulinemia, and worsened insulin-mediated glucose disposal only in salt sensitive patients. We propose that salt sensitivity contributes, separately from hypertension, to insulin resistance and thus be considered per se as an additional risk factor in the development of cardiovascular disease. Salt sensitivity and insulin resistance may be genetically associated conditions.

Insulin resistance in essential hypertension is characterized by impaired insulin stimulation of blood flow in skeletal muscle.

To determine whether insulin-stimulated blood flow in patients with mild essential hypertension is altered. Eleven untreated mildly hypertensive patients [aged 35 +/- 2 years, body mass index 25.1 +/- 0.4 kg/m2, mean arterial pressure 110 +/- 2 mmHg (means +/- SEM) and 10 matched normotensive subjects (mean arterial pressure 94 +/- 3 mmHg). Blood flow was quantitated directly in skeletal muscle both basally and during supraphysiologic hyperinsulinemia (serum insulin approximately = 450 mU/l) using radiowater ([15O]H2O) and positron emission tomography. Whole-body and femoral muscle glucose uptakes were determined using the euglycemic insulin clamp technique, [18F]-2-fluoro-2-deoxy-D-glucose and positron emission tomography. Rates of whole-body and femoral muscle glucose uptake were significantly lower in the hypertensive than in the normotensive group. Insulin increased muscle blood flow by 91% in the normotensive group, but only by 33% in the hypertensive group. The ability of insulin to stimulate blood flow in patients with mild essential hypertension is impaired.

Nucleotide(-258) G-to-A transition variant of the liver glucokinase gene is associated with essential hypertension.

Hypertension is a complex disease with strong genetic influences. Essential hypertension has been shown to be associated with insulin resistance. A molecular variant with G-to-A transition at the nucleotide -258 of the liver glucokinase (GCK) promoter was found in diabetic patients. The variant A allele is associated with insulin resistance. We examine the role of this genetic variant in the pathogenesis of hypertension using a population association study. We recruited 205 Taiwanese subjects and they were divided into two groups based on either presence (65 subjects) or absence (140 subjects) of essential hypertension. Genomic DNA was extracted from peripheral leukocytes. Genotypes at this locus were determined by using a polymerase chain reaction restriction fragment length polymorphism. The distribution of genotypic frequency was different between the hypertensive and control groups (P = .009). The frequency of variant A allele was greater in hypertensive subjects than in control (23% v 10%, P = .001). Subjects with at least an A allele had a risk for hypertension by 2.52 times (95% confidence interval 1.29 to 4.91) as compared with those without an A allele. Thus, we first demonstrate the association between the G-to-A variants at the nucleotide -258 of the liver GCK gene and essential hypertension. This may explain the insulin resistance in essential hypertension and the variant A allele as a risk factor for essential hypertension in the Taiwanese population.

Insulin sensitivity, vascular reactivity, and clamp-induced vasodilatation in essential hypertension.

Insulin resistance and vascular abnormalities have both been described in patients with essential hypertension. Whether these defects are associated with one another in the same individual has not been established. Whole-body insulin sensitivity (by the insulin clamp technique), forearm minimal vascular resistances, and the dose-response curve to acetylcholine, sodium-nitroprusside, and norepinephrine were measured in a group of 29 male patients with untreated essential hypertension. When the patients were divided into tertiles according to their level of insulin sensitivity, resistant and sensitive hypertensives were matched on several potential confounders of insulin action and vascular function. These subgroups showed similar minimal vascular resistances (2.5+/-0.2 versus 3.2+/-0.6 mm Hg per mL x min(-1) x dL(-1)) and superimposable responses to graded intraarterial infusions of acetylcholine, sodium-nitroprusside, and norepinephrine. No correlation was found between the vascular parameters (slope of the curve or maximal response) and insulin-mediated glucose uptake in the whole group. During the clamp, insulin sensitive patients tended to have greater increments in forearm blood flow when compared to their insulin resistant counterparts (+53+/-21 versus +9+/-7%, P=.06); in the whole group, clamp-induced vasodilatation was weakly related to insulin-mediated glucose uptake (r=.44, P<.02) as well as to the slope of the acetylcholine dose-response curve (r=.40, P<.04). Together, these two responses explained 30% (multiple r=.55, P<.01) of the variability in insulin-induced vasodilatation. Metabolic insulin resistance in essential hypertension is not associated with abnormalities in vascular structure, acetylcholine or nitroprusside-induced vasodilatation, or vascular adrenergic reactivity. Degree of insulin sensitivity and acetylcholine sensitivity explain a small portion of the variability of the clamp-induced vasodilatation in hypertensive patients.

Dietary protein restriction in combination with angiotensin converting enzyme inhibitor improves insulin resistance in patients with chronic renal disease

Insulin resistance (IR) and secondary hyperinsulinaemia are major risk factors of atherosclerosis and probably also of related glomerulosclerosis. Angiotensin converting enzyme inhibitors (ACEI), while improving IR in essential hypertension, do not improve it in patients with chronic renal disease. Thus, the combination of ACEI and low protein diet was evaluated. Thirty-eight patients with various kidney diseases and mild to moderate impairment of kidney function were included in the study. Thirteen of them suffered from IR. Their dietary protein intake was decreased from > or = 1.0 g/kg/d to 0.6-0.7 g/kg/d. Moreover, they were treated by ACEI enalapril at dosages of 2-10 mg/d depending on the absence/presence and severity of hypertension. The patients were followed for 8 months. No clinically relevant kidney disease progression (KDP) was found. IR patients improved remarkably. IR was examined by the oral glucose tolerance test and glucose, insulin and C-peptide determinations. Their increased plasma triglyceride, VLDL concentrations and proteinuria decreased, HDL concentration increased. Acid-base balance and anaemia did not change. It is concluded that protein restriction in combination with ACEI treatment improve IR and the associated dyslipoproteinaemia and proteinuria.

Oral Calcium Supplementation Reduces Intraplatelet Free Calcium Concentration and Insulin Resistance in Essential Hypertensive Patients

We evaluated the effect of oral calcium supplementation on blood pressure, calcium metabolism, and insulin resistance in essential hypertension. After receiving a standard diet with 500 mg of calcium per day during a 4-week period, 20 nondiabetic, essential hypertensive patients were randomized in a double-blind fashion to receive oral calcium supplementation (1500 mg of calcium per day) or placebo for 8 weeks. At the end of the 4-week period of low-calcium diet and after the 8-week period of intervention, we measured blood pressure (by both office and 24-hour ambulatory blood pressure monitoring), calcium-regulating hormones [urinary hydroxyproline and serum osteocalcin, parathormone, and 1,25(OH)2-vitamin D3], intraplatelet free calcium concentration, fasting plasma glucose and insulin levels, and the insulin-sensitivity index (euglycemic-hyperinsulinemic clamp). Compared with patients maintained at low calcium intake, essential hypertensive patients under oral calcium supplementation significantly reduced serum osteocalcin (from 22.2 +/- 1.9 to 17.9 +/- 2.0 micrograms/L; P = .0015), parathormone (from 4.20 +/- 0.38 to 3.30 +/- 0.36 pmol/L; P = .0003), and 1,25(OH)2-vitamin D3 (from 98.0 +/- 11.0 to 61.6 +/- 5.7 pmol/L; P = .0062). Likewise, we found a significant reduction in intraplatelet free calcium concentration (from 35.9 +/- 1.2 to 26.5 +/- 0.8 nmol/L; P = .0005) and fasting plasma insulin levels (from 71.8 +/- 5.9 to 64.6 +/- 6.2 pmol/L; P = .05) and a significant increase in the insulin-sensitivity index (from 2.89 +/- 0.77 to 4.00 +/- 0.95 mg.kg-1.min-1; P = .0007). None of these parameters were significantly modified in patients maintained at low calcium intake. Office and 24-hour mean values of systolic and diastolic blood pressure did not change after 8 weeks of oral calcium supplementation or placebo.

Skeletal muscle blood flow is not a determinant of insulin resistance in essential hypertension.

To investigate the haemodynamic effects of insulin and their relationship to insulin resistance in essential hypertension. Group comparison between patients with essential hypertension and normal controls. Outpatient clinics serving the greater Belfast area. Eleven patients with essential hypertension and eight age-, sex- and weight-matched control subjects were recruited. Administration of all antihypertensive agents to the hypertensive patients was stopped 6 weeks prior to the study. Leg blood flow was measured using venous occlusion plethysmography. Insulin action was assessed using the hyperinsulinaemic euglycaemic clamp technique. The hypertensive subjects were insulin-resistant compared with the normal controls. Insulin infusion resulted in similar increases in calf blood flow in the two groups. There was no correlation between calf blood flow and measurements of insulin sensitivity in either group. Differences in whole-body glucose uptake in hypertensive and control subjects are not likely to be related to differences in insulin-induced stimulation of muscle blood flow.

Clinical significance of insulin resistance.

Insulin resistance has emerged in the last 20 years as a concept familiar to clinicians in many specialties. No easily performed laboratory test is available to assess insulin action in routine clinical practice. Several rare syndromes of severe insulin resistance are recognized but most clinicians will encounter insulin resistance as a manifestation of common diseases. Physiological and treatment induced changes in insulin sensitivity influence insulin doses required in insulin-dependent diabetes mellitus. In non-insulin-dependent diabetes mellitus insulin resistance is fundamental to pathogenesis but it is also influenced by standard dietary and pharmacological treatment, and probably mediated by changes in prevailing glycaemia. Antihypertensive agents appear to have diverse effects on the insulin resistance of essential hypertension though the long term significance of these remains unclear. The importance of insulin as a risk factor for coronary heart disease and the concept of an insulin resistance syndrome as a common precursor of conditions with increased vascular risk remains controversial.

Analysis of candidate genes for insulin resistance in essential hypertension.

To clarify the genetic basis of insulin resistance in hypertension, case-control association studies were performed to examine candidate genes for insulin resistance in hypertension. Since the main site of insulin resistance in hypertension is glycogen synthesis in skeletal muscle, genes that encode molecules involved in this pathway, i.e. insulin receptor (INSR), insulin-responsive glucose transporter (GLUT4) and glycogen synthase (GSY), were studied. In addition, since recent studies suggest the contribution of beta3 adrenergic receptor to the insulin resistance syndrome, the gene encoding beta3 adrenergic receptor (ADRB3) was also studied. Frequency of homozygotes for common C allele of a microsatellite polymorphism in the INSR gene was higher in the hyperinsulinemia group, but not in the normoinsulinemia group of hypertensive patients than in normotensive control subjects. Insulin sensitivity, however, was not significantly different between hypertensive patients with C/C genotype and those without this genotype. No significant differences were observed in the distribution of alleles or genotypes of the GLUT4, GSY and ADRB3 genes between hyperinsulinemia and normoinsulinemia groups of hypertensive patients or between these groups and the control group. These data suggest that the INSR polymorphism is associated with hyperinsulinemia, but not with insulin resistance, in hypertension.

Prevalence of insulin resistance in essential hypertension

To establish the prevalence of insulin resistance in hypertensive subjects. The euglycaemic hyperinsulinaemic clamp was performed in 420 hypertensive patients taking no antihypertensive medication and in 51 age- and sex-matched healthy controls. No subjects with known diabetes mellitus or fasting hyperglycaemia were included in the study. The mean value for insulin-mediated glucose uptake (M-value at clamp) in the healthy control group (8.2 mg/kg per min) -2 SD was chosen as the cutoff limit for insulin resistance (4.4 mg/kg per min). At this cutoff limit, 27% of the hypertensive subjects were insulin resistant (mean value 3.1 mg/kg per min in this group, range 0.7-4.3). A similar prevalence of insulin resistance in hypertensive patients was found (31%) if the 95th percentile of the non-normally distributed insulin sensitivity index (M/I at clamp) was used to define the cutoff limit for insulin resistance: (4.4 mg/kg per min)/(mU/l x 100). In the insulin-resistant group, 50% showed elevated levels of serum triglycerides (> 2.0 mmol/l), 50% had abdominal obesity (waist:hip ratio > 0.95), 20% had elevated levels of serum uric acid (> 400 mumol/l) and 48% had low high-density lipid (HDL)-cholesterol levels (< 1.0 mmol/l). Half of the insulin-resistant hypertensives but only 20% of the non-insulin resistant group had two or more of these other four metabolic impairments (P < 0.001). Insulin resistance in hypertension was also associated with an increased heart rate (+3 beats/min faster than in non-insulin resistant hypertensive patients, P < 0.01), but no significant differences in blood pressure were found between insulin resistant and non-insulin resistant hypertensive patients. When insulin resistance was defined as an M-value at clamp of < 4.4 mg/kg per min, based on calculations from a healthy control sample, about 25% of a sample of hypertensive subjects, taking no antihypertensive treatment and with no history of diabetes mellitus or hyperglycaemia, was found to be insulin resistant. This group of insulin-resistant hypertensives also displayed a high degree of clustering of other metabolic impairments.

B25 - Insulin resistance in essential hypertension is characterized by impaired insulin stimulation of blood flow in skeletal muscle: Studies using 18FDG, H 218O and positron emission tomography

B25 - Insulin resistance in essential hypertension is characterized by impaired insulin stimulation of blood flow in skeletal muscle: Studies using 18FDG, H 218O and positron emission tomography

Na+/H+ antiporter activity in peripheral blood lymphocytes of obese and type 2 diabetic patients is increased only in the presence of arterial hypertension.

The aim of this work is to evaluate whether type 2 diabetes mellitus, obesity and arterial hypertension, three conditions characterized by the presence of insulin resistance, share some common genetic markers. A potential candidate is the Na+/H+ antiporter, the increased activity of which is considered a marker of essential hypertension. This ion exchanger seems to be related to the Na+/Li+ countertransport, that is considered a marker of insulin resistance in essential hypertension and in type 1 diabetes mellitus. In this study we wished to clarify whether the activity of the Na+/H+ antiporter is increased not only in hypertensive subjects, but also in obese and type 2 diabetic patients, both in the presence and in the absence of arterial hypertension. The activity of the ion exchanger was measured in peripheral blood lymphocytes (PBL) by clamping intracellular pH (pHi) at 5.8-6.2 and then detecting the rate of the proton efflux after sodium addition. In the absence of arterial hypertension, no significant difference in this parameter was observed in obese and type 2 diabetic patients in comparison with normal subjects. In the presence of arterial hypertension, there was a significant increase in the Na(+)-induced H+ efflux at the internal pH (pHi) values of 5.8 and 6.2 both in hypertensive controls and in hypertensive obese and type 2 diabetic patients (P = 0.05-0.0001 vs. normotensive subjects and patients).(ABSTRACT TRUNCATED AT 250 WORDS)

The role of beta 2-adrenoceptor on the pathogenesis of insulin resistance in essential hypertension

The role of beta 2-adrenoceptor on the pathogenesis of insulin resistance in essential hypertension (EH) was explored. After the measurement of blood pressure in 15 EH patients and 8 control subjects, EH patients were divided into two groups by the elevation of plasma NE (delta NE) 5 min after standing: 7 normoadrenergic EH (delta NE < 140 pg/ml) and 8 hyperadrenergic EH (delta NE > or = 140 pg/ml). On the morning after a 12-h overnight fast, regular insulin (0.1 U/kg) was injected intravenously, and glucose disappearance rate (GDR) was measured and used as an index of insulin sensitivity. On the following day, the test was reinvestigated following the administration of mabuterol, a beta 2 agonist. Plasma growth hormone (GH), cortisol, norepinephrine (NE) and epinephrine (Epi) were measured before and after the mabuterol administration. Although there were no significant differences of basal GDR among these three groups, mabuterol induced a considerable decrease in GDR in EH patients but not in control subjects. There was no significant difference in the decrease of GDR between normo- and hyperadrenergic EH. The decrease in GDR tended to correlate with the mean blood pressure at rest in EH but not in normal subjects. Plasma glucose and serum insulin in EH patients were increased more than in normal subjects. Plasma GH, cortisol and Epi were not elevated by mabuterol, but plasma NE increased in each group, significantly in hyperadrenergic EH. There was no correlationship between the increase in plasma NE and the decrease in GDR after mabuterol.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Significance of Decreased Insulin Resistance in Essential Hypertension using the Steady State Plasma Glucose Method

Clinical Significance of Decreased Insulin Resistance in Essential Hypertension using the Steady State Plasma Glucose Method

Close relationship between microalbuminuria and insulin resistance in essential hypertension and non-insulin dependent diabetes mellitus.

The aim of this study was to investigate the relationships among insulin resistance and albumin excretion rate in 25 nondiabetic patients with essential hypertension and in 28 patients with non-insulin dependent diabetes mellitus (NIDDM). Two groups of healthy subjects matched for age, sex, and weight served as controls. Patients with essential hypertension were divided into two subgroups: without (H1) and with (H2) microalbuminuria. Diabetic patients were divided into four subgroups: those with normoalbuminuria without (NIDDM1) and with (NIDDM2) hypertension and those with microalbuminuria without (NIDDM3) and with (NIDDM4) hypertension. Whole-body glucose utilization during euglycemic hyperinsulinemic clamp (40 mU/m2/min insulin infusion) was calculated by tracer dilution techniques (6,6 2H2 glucose tracer continuous infusion) and was significantly lower in hypertensives with microalbuminuria than in those without (H2 versus H1 versus controls: 3.41 +/- 0.51 versus 6.52 +/- 0.62 versus 7.03 +/- 0.48 mg/kg/min; mean +/- SE). Whole-body glucose utilization in NIDDM patients--NIDDM4 versus NIDDM3 versus NIDDM2 versus NIDDM1 versus controls--was: 1.86 +/- 0.31 versus 2.21 +/- 0.39 versus 2.01 +/- 0.40 versus 5.98 +/- 0.77 versus 5.52 +/- 0.92 mg/kg/min (mean +/- SE). Whereas the first three subgroups did not differ among themselves, they had significantly lower glucose utilization than did the normotensive NIDDM1 patients without microalbuminuria and nondiabetic controls (P < 0.01). Hypertensives with microalbuminuria had higher Vmax of sodium-lithium countertransport (Na/Li CTT) in red blood cells than did both hypertensives without microalbuminuria and controls. It was also observed that NIDDM patients with microalbuminuria had higher Vmax of Na/Li CTT than did NIDDM patients without microalbuminuria and controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Cellular calcium and magnesium metabolism in the pathophysiology and treatment of hypertension and related metabolic disorders

We have investigated the cellular basis for the clinical and epidemiologic linkage of hypertension, left ventricular hypertrophy (LVH), obesity, and non-insulin-dependent diabetes mellitus (NIDDM) and have studied cytosolic free calcium and free magnesium levels in these syndromes. Specifically, intracellular free calcium is elevated and free magnesium is deficient in hypertension, and both are related (directly and inversely, respectively) to the ambient level of blood pressure, to LV mass index (and thus to the degree of cardiac hypertrophy), and to the hyperinsulinemia and insulin resistance of essential hypertension. Dynamically, the ability of dietary salt loading to elevate blood pressure corresponds to its ability to elevate cytosolic free calcium and reciprocally to suppress free magnesium levels. Conversely, the ability of calcium channel blockade to reverse salt-induced hypertension is related to its ability to prevent these transmembrane ionic effects. Higher steady-state free calcium or lower free magnesium, or both, are also observed in clinical states linked to hypertension, such as obesity and NIDDM. Oral glucose loading in normal subjects itself elevates free calcium and suppresses free magnesium levels, as does hyperglycemia in vitro. These data suggest an ionic hypothesis of cardiovascular and metabolic disease, in which a generalized defect in cell ion handling is present in all tissues, resulting in higher steady-state free calcium and lower free magnesium levels. In pancreatic β cells, this would produce hyperinsulinemia; in fat and skeletal muscle, cause peripheral insulin resistance; and in renal tissue, increase proximal sodium resorption and increase urinary calcium excretion—all features of essential hypertension. In vascular smooth muscle, high cytosolic free calcium would increase smooth muscle tone and cause vasoconstriction, and in heart muscle, independent of blood pressure, would increase contractility and predispose to LVH. Therefore, what may appear clinically to be the separate syndromes of hypertension, obesity, and NIDDM may pathophysiologically be different manifestations of the same underlying cellular defect, thus explaining their frequent clinical coexistence. Therapeutically, reversal of this excess free calcium accumulation and/or free magnesium deficit with ion-specific agents, such as calcium channel blocking drugs, may thus ameliorate not only the elevated blood pressure of hypertension but also the concurrent excess morbidity and mortality of the concurrent cardiac, vascular, and metabolic aspects of the hypertensive state.

Insulin resistance, hyperinsulinemia, and coronary artery disease: a complex metabolic web.

Diabetes mellitus is commonly associated with systolic and diastolic hypertension, and a wealth of epidemiological data suggest that this association is independent of age and obesity. Much evidence indicates that the link between diabetes and essential hypertension is hyperinsulinemia. Thus, when hypertensive patients, whether obese or of normal body weight, are compared with age- and weight-matched normotensive controls, a heightened plasma insulin response to a glucose challenge is found consistently. A state of cellular resistance to insulin action subtends the observed hyperinsulinism. Using the insulin/glucose clamp technique in combination with tracer glucose infusion and indirect calorimetry, it has been demonstrated that the insulin resistance of essential hypertension is located in peripheral tissues (muscle), is limited to nonoxidative pathways of glucose disposal (glycogen synthesis), and correlates directly with the severity of hypertension. The reasons for the association of insulin resistance and essential hypertension can be sought in at least four general types of mechanisms: sodium retention, sympathetic nervous system overactivity, disturbed membrane ion transport, and proliferation of vascular smooth-muscle cells. Physiological maneuvers, such as caloric restriction (in the overweight patient) and regular physical exercise, can improve tissue sensitivity to insulin; good evidence indicates that these maneuvers also can lower blood pressure in both normotensive and hypertensive individuals. Insulin resistance and hyperinsulinemia also are associated with an atherogenic plasma lipid profile. Elevated plasma insulin concentrations enhance very-low-density lipoprotein (VLDL) synthesis, leading to hypertriglyceridemia. Progressive elimination of lipid and apolipoproteins from the VLDL particle leads to an increased formation of intermediate density and low-density lipoproteins, both of which are atherogenic. Last, insulin per se, independent of its effects on blood pressure and plasma lipids, is known to be atherogenic. The hormone enhances cholesterol transport into arteriolar smooth-muscle cells and increases endogenous lipid synthesis by these cells. Insulin also stimulates the proliferation of arteriolar smooth-muscle cells, augments collagen synthesis in the vascular wall, increases the formation of and decreases the regression of lipid plaques, and stimulates the production of a variety of growth factors. In summary, insulin resistance appears to be a syndrome that is associated with a clustering of metabolic disorders, including type II diabetes mellitus, obesity, hypertension, lipid abnormalities, and atherosclerotic cardiovascular disease.