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(Hypertension. 1995;26:789.)
© 1995 American Heart Association, Inc.

Articles

Insulin Resistance in Microalbuminuric Hypertension

Sites and Mechanisms

Stefano Bianchi; Roberto Bigazzi; Alfredo Quiñones Galvan; Elza Muscelli; Giorgio Baldari; Neda Pecori; Demetrio Ciociaro; Ele Ferrannini; Andrea Natali

From the Nephrology Unit, Spedali Riuniti, Livorno (S.B., R.B.), and Metabolism Unit of the CNR Institute of Clinical Physiology, Pisa (A.Q.G., E.M., G.B., N.P., D.C., E.F., A.N.), Italy.

Correspondence to Dr Roberto Bigazzi, U.O. di Nefrologia, Spedali Riuniti, Viale Alfieri 36, 57100 Livorno, Italy.

	Abstract

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Abstract Microalbuminuria in patients with essential hypertension is a marker of incipient glomerular dysfunction and clusters with lipid and hemodynamic abnormalities. Recent evidence has shown that hypertensive patients with microalbuminuria have a hyperinsulinemic response to oral glucose, suggesting the presence of insulin resistance. To directly test this possibility we studied insulin action in two accurately matched groups (n=10 each) of hypertensive patients with or without microalbuminuria (14±2 versus 52±7 mg · 24 h^-1, mean of three 24-hour collections). In response to glucose ingestion microalbuminuric patients showed slight hyperglycemia (area under the curve, 928±43 versus 784±19 mmol ·L^-1 · 2 h^-1, P<.02) and a marked hyperinsulinemia (26.8±3.3 versus 49.8±3.7 nmol · L^-1 · 2 h^-1, P<.001). Basal arterial blood pressure, heart rate, and forearm blood flow were similar in the two groups and did not change significantly during a 2-hour euglycemic insulin clamp. Insulin-stimulated whole-body glucose uptake was 25% lower in microalbuminuric patients (33.5±2.5 versus 25.2±2.1 µmol · min^-1 · kg^-1, P<.02). This difference was entirely due to a 40% reduction in glycogen synthesis (12.9±1.8 versus 21.3±3.2 µmol ·min^-1 ·kg^-1, P<.05) as glucose oxidation was similarly stimulated in the two groups. In contrast, there was no difference in the ability of insulin to suppress hepatic glucose production (by approximately 100% at the end of the clamp), to decrease fractional sodium and potassium excretions (by 35%), to lower circulating free fatty acids (by 80%), and to reduce plasma potassium concentrations (by 10%). Insulin sensitivity was inversely related to albumin excretion rate even after adjustment for body mass index (partial r=.51, P<.03). When both insulin sensitivity and the insulin area under the curve were entered into a multiple regression equation, the insulin area was more strongly related to albumin excretion and, together with 24-hour mean blood pressure, explained approximately 60% of its variability (P<.001). In conclusion, microalbuminuria in essential hypertension signals the presence of a selective impairment in peripheral insulin-mediated glucose uptake and an enhanced insulin secretory response to glucose. Insulin levels rather than insulin sensitivity appear to be related to urinary albumin excretion.

Key Words: hypertension, essential • albuminuria • insulin resistance

	Introduction

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Population studies have shown that hyperinsulinemia is frequent among patients with essential hypertension.^{1 2} This association is partly explained by a higher prevalence of overweight, impaired glucose tolerance, and diabetes among hypertensive individuals as well as by the adverse effect on insulin sensitivity of some antihypertensive agents.^{3 4 5} When these factors are taken into account, essential hypertensive patients as a group still consistently show a reduction in insulin-mediated glucose disposal compared with matched normotensive control subjects.⁶ It has been estimated that this abnormality is present in approximately 40% of nonobese subjects with untreated essential hypertension.⁷

It is a time-honored notion that the natural history of hypertensive disease is variable, with BP values or other major risk factors explaining only a portion of this variability. It has been hypothesized that at least part of the unexplained variability may be accounted for by the cluster of cardiovascular risk predictors known as the insulin resistance syndrome.^{8 9} Thus, particular attention is currently being devoted to the study of insulin resistance and its associated metabolic and hemodynamic disorders. Insulin resistance has been described in association with the presence of lower limb atherosclerosis,¹⁰ smoking,¹¹ dyslipidemia,¹² enhanced sodium-lithium countertransport,¹³ abnormal platelet function,¹⁴ and hyperuricemia.¹⁵

In population-based studies increased urinary AER has been shown to cluster with cardiovascular risk predictors^{16 17} and to be associated with increased cardiovascular morbidity in both diabetic¹⁸ and nondiabetic¹⁹ individuals. In addition, in patients with NIDDM the presence of microalbuminuria signals a higher degree of peripheral insulin resistance.^{20 21}

We have recently reported that the prevalence of microalbuminuria among essential hypertensive patients is considerably high (approximately 30%²² ) and that microalbuminuria is associated with high serum Lp(a) concentrations, an abnormal circadian BP profile, and a hyperinsulinemic response to oral glucose ingestion.²³ In the present study we set forth to directly measure insulin sensitivity and to characterize sites and involved pathways in carefully selected groups of untreated hypertensive patients with different AERs.

	Methods

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Patient Selection
Patients attending the Hypertension Clinic at the Livorno Hospital routinely have their AER measured on three 24-hour urine samples (after an adequate washout period if on treatment). Microalbuminuria was defined as an average AER greater than 30 mg · d^-1 in the absence of urinary infection on three consecutive 24-hour urine samples. We screened 64 consecutive patients with essential hypertension meeting the following criteria: (1) office diastolic BP values greater than or equal to 95 but less than 110 mm Hg in the absence of antihypertensive therapy; (2) normal routine blood chemistry, lipid profile, and urinalysis; (3) normal fundus, electrocardiogram, and abdominal ultrasound examinations; (4) normal catecholamine, aldosterone, renin, and plasma cortisol values; (5) BMI less than 30 kg · m^-2; (6) no protracted drug use except for antihypertensive therapy; and (7) acceptance of the study protocol. Over a period of 12 months 17 patients with microalbuminuria (microA patients) and 15 without microalbuminuria (normoA patients) with similar clinical characteristics (sex distribution, age, BMI, waist-to-hip ratio, family history of diabetes or hypertension, smoking habits, hypertension duration, and ambulatory BP) were enrolled and completed the study. Careful one-to-one matching of the clinical characteristics produced two groups of 10 patients each segregated by the presence of microalbuminuria. The study protocol was approved by the Institutional Ethics Committee. Each subject gave his or her consent after the nature, purpose, and potential risks of the procedures were fully explained.

Metabolic Studies
Six of 10 patients in each group had never been on antihypertensive treatment. The remaining 8 patients were currently treated with angiotensin-converting enzyme inhibitors or calcium antagonists and were therefore studied after a washout period of 4 weeks. All studies were performed with patients in the postabsorptive state. All patients underwent a standard oral glucose tolerance test (75 g), with blood samples collected every 30 minutes for determination of plasma glucose and insulin levels. Before glucose ingestion an additional blood sample was collected for measurement of serum triglycerides, total cholesterol, high-density lipoprotein cholesterol, and Lp(a) concentrations. Patients were then referred to the Metabolism Unit in Pisa, where insulin sensitivity was measured by the euglycemic insulin clamp technique. The investigators in Livorno and Pisa were cross-blinded to AER and insulin sensitivity results. Studies began at 8 AM, with patients supine. A polyethylene catheter was inserted retrogradely into a dorsal vein of the wrist, and another catheter was inserted into an antecubital vein of the same arm. The patients drank 300 mL water and were then invited to void before start of the basal urine collection, which lasted at least 2 hours. The hand was kept in a heated box (60°C) to ensure arterialization of the blood sampled from the wrist vein; the antecubital vein was used for infusion of test substances. During the last 60 minutes of the 2-hour baseline period three blood samples were collected at 20-minute intervals for insulin, electrolyte, and metabolite determinations. The patient’s head was then placed in a ventilated Plexiglas hood for measurement of respiratory gas exchanges (Metabolic Measurements Chart System 2900, Sensormedics). Before each blood sampling arterial BP was measured by mercury sphygmomanometry, and forearm blood flow and heart rate were measured with a strain-gauge plethysmograph (Vasculab SPG 16, Medasonics Inc) on the contralateral arm. Each determination was the mean of three consecutive readings. At the end of the baseline period patients were again invited to void; urine volume was recorded; and a sample was stored for subsequent electrolyte, nitrogen, and creatinine determinations.

At time 0 a bolus (approximately 40 µCi) of [³H-6]glucose was injected simultaneously with the start of the euglycemic insulin clamp (primed-continuous insulin infusion rate of 7 pmol · min^-1 · kg^-1), and fasting plasma glucose levels were clamped by infusion of a 20% glucose solution enriched with approximately 200 µCi of [³H-6]glucose. The measured specific activity of the glucose solutions averaged 2024±106 disintegrations per minute per milligram. During the second hour of the clamp arterialized blood was sampled four times at 20-minute intervals, and BP, heart rate, forearm blood flow, and respiratory gas exchange were measured. In addition, at 20, 40, 60, 80, 90, 100, 110, and 120 minutes blood samples were obtained for measurement of [³H-6]glucose specific activity. At the end of the 2-hour clamp urine output was again measured and another urine sample collected. To avoid hemodynamic perturbation caused by blood loss (approximately 200 mL over 3 hours), we replaced the volume of each blood sample with an equal amount of a plasma expander (Haemagel, Bhering).

Twenty-Four-Hour BP Monitoring
All patients underwent ambulatory BP monitoring on an outpatient basis during a habitual working day, supplemented with a diary for reporting of significant episodes. The instrument (model TM-2420, Takeda) was calibrated with a mercury sphygmomanometer before each recording. Left arm readings were taken with a standard-size cuff from 9 AM to 9 PM. Measurements were made every 20 minutes from 7 AM to 10 PM (daytime period) and every 30 minutes from 10 PM to 7 AM (nighttime period).

Exercise Testing
All patients eventually included in the present study were invited to return to the clinic to undergo a bicycle exercise stress test (Cardioline ECT WS 2000 Stress Testing System). Oxygen consumption during the exercise was measured every 20 seconds with a computerized system (TT-Oxycon Champion, Erich Jaeger GmbH & Co). The patients were invited to sit on the bicycle and rest for 10 minutes to adapt to the mask from which the expired air flow was continuously measured and sampled. After a basal (5-minute) period patients were invited to bicycle at a constant rate (55 Hz); the workload increased automatically in a stepwise fashion (by 25 W every 3 minutes) until the patients stopped because of exhaustion. Twelve-lead electrocardiographic traces were recorded continuously, and BP was measured with a mercury sphygmomanometer throughout the test. Maximal oxygen consumption was measured as the average of the three maximal values and expressed in milliliters per minute per kilogram of body weight.

Analytic Procedures
Albumin concentration in fresh 24-hour urine samples was measured by an immunoturbidimetric method.²⁴ Plasma insulin was measured by radioimmunoassay (Insk 5, Sorin Biomedica). Plasma glucose was assayed by the glucose oxidase method (Glucose Analyzer, Beckman Instruments). Plasma creatinine, free fatty acids, total cholesterol, and triglycerides were measured by an enzymatic-spectrophotometric method (Eris Analyzer 6170, Eppendorph Geratebau). Plasma Lp(a) was measured by enzyme-immunoassay [Immunozym Lp(a), Immuno]. Plasma and urinary sodium and potassium levels were assayed in duplicate immediately after blood withdrawal by an ion-selective electrode method (Mycrolytes 6, Kone Instruments). Urinary nonprotein nitrogen concentrations were measured by the Kieldhal method.²⁵ [³H-6]Glucose concentrations were measured on the supernatants of Somogyi [1N ZnSO₄ plus 1N Ba(OH)₂] precipitates of plasma samples. Five diluted aliquots of the glucose containing [³H-6]glucose were also processed in the same way as plasma samples for precise determination of the tracer infusion rate. On the same Somogyi supernatants, "cold" glucose concentration was also measured with an enzymatic-spectrophotometric method (Eris Analyzer 6170, Eppendorph Geratebau) for calculation of tracer specific activity.

Data Analysis
Oxygen consumption, carbon dioxide release, and urinary nitrogen excretion were used for calculation of substrate oxidation and energy expenditure rates according to equations described elsewhere.²⁶ To minimize the amount of radioactivity administered to patients, we measured hepatic glucose production only during the clamp by the primed-variable [³H-6]glucose infusion as described above. During the final 40 minutes of the clamp the tracer specific activity was extremely stable, with a within-patient mean coefficient of variation of 8±2%. Since the exogenous glucose infusion rates and plasma glucose levels of the last 40 minutes also were relatively stable (coefficient of variation, 9±2% and 5±2%, respectively), whole-body glucose appearance rate was calculated as the ratio of the mean tracer infusion rate of the last 40 minutes to the corresponding mean tracer specific activity, according to the principles of the tracer dilution theory at steady state.²⁷ Hepatic glucose production was then calculated as the difference between the whole-body glucose appearance rate and mean exogenous glucose infusion rate. The insulin sensitivity value was calculated as the exogenous glucose infusion rate corrected for plasma glucose changes (considering 250 mL · kg^-1 as the volume of glucose distribution). Nonoxidative glucose disposal, which largely coincides with glycogen synthesis, was calculated as the difference between whole-body glucose uptake and net glucose oxidation.

All data are expressed as mean±SEM. Areas under time–concentration curves were calculated by the trapezoidal rule. Creatinine clearance and electrolyte fractional excretion rates were calculated by standard formulas. Between-group differences in mean values were analyzed by unpaired t test. A two-way ANOVA for singly repeated measures over time was used to simultaneously test the effect of the microalbuminuria and the effect of the experimental procedure (within-subject repeated measures) as well as their interaction.

	Results

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Except for a higher prevalence of smoking in the microA group, the study groups were well matched on all other variables (Table 1). Of note is the fact that duration and degree of hypertension, as assessed by office BP measurements, also were similar. The serum lipid profile was superimposable in the two groups (normoA versus microA: triglycerides, 1.04±0.14 versus 1.14±0.13 mol · L^-1; total cholesterol, 5.17±0.29 versus 4.99±0.18 mol · L^-1; high-density lipoprotein cholesterol, 1.35±0.10 versus 1.14±0.13 mol · L^-1; low-density lipoprotein cholesterol, 3.35±0.26 versus 3.33±0.13 mol · L^-1). MicroA patients showed higher plasma Lp(a) levels (43±12 versus 18±5 mg · dL^-1, P<.05). Both systolic and diastolic 24-hour BP tended to be higher in microA than normoA patients (157±6/97±4 versus 146±3/92±3 mm Hg). The difference was more accentuated for nighttime values (145±8/95±5 versus 140±5/86±4 mm Hg, P=.1 for both) as normoA showed a larger nocturnal dip, particularly in diastolic BP (-11±2 versus -5±3 mm Hg, P<.10).

View this table: [in this window] [in a new window]   Table 1. Characteristics of the Study Population

Fasting plasma glucose and insulin concentrations were not significantly different between normoA and microA groups (4.67±0.11 versus 5.00±0.17 mmol · L^-1 and 78±12 versus 114±18 pmol · L^-1, respectively). As depicted in Fig 1, after glucose ingestion plasma glucose levels were slightly but consistently higher in microA than normoA patients. Thus, the glucose area under the curve was significantly larger in the microA group (928±43 versus 784±19 mmol·L^-1·2 h^-1, P<.02). On the other hand, the plasma insulin response to oral glucose was twice as high in microA than normoA patients (49.8±3.7 versus 26.8±3.3 µmol·L^-1·2 h^-1, P<.001) (Fig 1).

View larger version (22K): [in this window] [in a new window]   Figure 1. Line graphs show plasma glucose and insulin profiles in normoalbuminuric (normoA) and microalbuminuric (microA) essential hypertensive patients after an oral glucose load (75 g). Inset bar graphs show values of area under the corresponding curves expressed as mmol·L-1·2 h-1 for glucose and nmol·L-1·2 h-1 for insulin. *Statistically significant difference (unpaired t test, P<.05).

During insulin clamp (Fig 2) plasma insulin concentrations rose to similar plateaus in the two groups (332±29 versus 368±41 pmol · L^-1), whereas euglycemia was maintained throughout the study (with a mean intraindividual variability of 5±1%). The exogenous glucose infusion rates required to maintain euglycemia differed significantly between the two groups throughout the clamp (F=6.06, P<.03 by ANOVA). As a result, the total amount of infused glucose was 22% smaller in microA than normoA patients (0.18 versus 0.23 mol, P<.05 by t test).

View larger version (16K): [in this window] [in a new window]   Figure 2. Graphs show plasma insulin, plasma glucose, and glucose infusion rates during the basal period and euglycemic insulin clamp. MicroA indicates microalbuminuric patients; normoA, normoalbuminuric patients.

From the analysis of the tracer specific activity curves (which reached stable values in all patients between 80 and 120 minutes), the rate of whole-body glucose appearance was calculated to be 33.2±2.2 versus 26.5±2.2 µmol · min^-1 · kg^-1 in normoA and microA patients, respectively (P<.05 by t test). During the same time interval hepatic glucose production (ie, the difference between tracer-determined glucose rate of appearance and exogenous glucose infusion rate) was not significantly different from zero in either group (-0.07±0.09 versus 0.23±0.11 µmol · min^-1 · kg^-1, normoA versus microA, P=NS), indicating virtually complete suppression of glucose production by insulin.

The calorimetric data (Table 2) show that at baseline all parameters were similar between the two groups. Insulin stimulated both oxygen consumption (by 4%) and carbon dioxide release (by 12%), whereby the respiratory quotient, resting energy expenditure, and net carbohydrate oxidation increased and lipid oxidation decreased. These responses to insulin were similar in microA and normoA patients. Consequently, insulin-mediated nonoxidative glucose disposal (ie, the difference between total and oxidative glucose utilizations) was 40% lower in the former than the latter patient group.

View this table: [in this window] [in a new window]   Table 2. Indirect Calorimetry Data

Both the hypokalemic and antilipolytic actions of insulin, as assessed by the time-dependent fall of plasma potassium and free fatty acid concentrations during the clamp, were similar in the two groups (Fig 3).

View larger version (16K): [in this window] [in a new window]   Figure 3. Line graphs show free fatty acids and potassium levels during the basal period and euglycemic insulin clamp in normoalbuminuric (dashed line) and microalbuminuric (solid line) essential hypertensive patients.

At baseline, BP (148±7/101±3 versus 151±5/95±2 mm Hg), heart rate (61±2 versus 63±3 beats per minute), and forearm blood flow (3.24±0.47 versus 2.68±0.24 mL · min^-1 · dL^-1 of forearm tissue, in normoA and microA patients, respectively) were similar in the two groups. During the final 40 minutes of the clamp BP tended to decrease (-3%) and heart rate to increase (+4%), but these changes fell short of statistical significance. Forearm blood flow also showed a tendency toward increasing during the clamp (+21±11%), particularly in the microA group (+30±17%); however, ANOVA of the pooled data indicated no difference between the groups (P=.60) and no time-related differences (P=.11) or interactions (P=.30) but only a large interindividual variability (P<.02). This variability was not explained by BMI, age, BP, duration of disease, or glucose disposal rate, with only insulin-stimulated energy expenditure being directly related to the percent change in forearm blood flow (r²=.36, P<.02).

At baseline, urine output, creatinine clearance, and urinary sodium and potassium excretion rates were virtually superimposable in normoA and microA patients (Table 3). Hyperinsulinemia induced a 35% decrease in all urinary parameters (.02>P>.001 by ANOVA), except for creatinine clearance, which remained stable. No difference in insulin action on urinary electrolyte excretion was evident between normoA and microA patients.

View this table: [in this window] [in a new window]   Table 3. Urinary Data

By multiple regression analysis, approximately 42% of the variability of insulin sensitivity was independently explained by BMI and AER (P<.002) (Fig 4). In contrast, no significant correlation was observed between any BP measurement (ambulatory, 24-hour, daytime, or nighttime systolic, diastolic, or mean BP) and insulin sensitivity. AER was also directly related to the insulin area under the curve (r²=.36, P<.001), Lp(a) (r²=.20, P<.02), and 24-hour mean BP (r²=.13, P<.05). By multiple regression, the association of AER with insulin sensitivity was no longer significant, whereas the insulin area under the curve and 24-hour mean BP together explained a large portion of AER variability (r²=.61, P<.001).

View larger version (13K): [in this window] [in a new window]   Figure 4. Scattergram and regression of urinary AER and calculated residuals of insulin sensitivity (M) obtained from simple regression between insulin sensitivity and BMI.

	Discussion

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Insulin sensitivity is affected by a large number of factors, such as degree and distribution of adiposity,²⁸ physical fitness and sex,²⁹ presence of family history of hypertension³⁰ or diabetes,³¹ smoking,¹¹ treatment with some antihypertensive agents,³² and dyslipidemia.¹² Therefore, case-control studies of insulin sensitivity should take into account as many possible confounders as is feasible. In the present study we put much effort into controlling for known confounders when comparing hypertensive patients with or without microalbuminuria. The matching proved particularly difficult as our microA hypertensive population was enriched with obese subjects, smokers, and familial history of diabetes. Whether microalbuminuria in hypertension shows significant clustering with these traits remains to be verified in population-based surveys. In our series, 5 microA compared with 2 normoA patients had one first-degree relative with NIDDM. Although this difference was not significant (because of the small sample size), it is nevertheless possible that in hypertension the insulin resistance associated with microalbuminuria cosegregates with a familial history of diabetes. More studies are needed to elucidate this point. Our study groups also differed in smoking habits (Table 1). However, among the smokers 2 patients smoked less than 5 cigarettes per day, and 2 less than 15; exclusion of these patients did not change the results. Furthermore, smoking is associated with insulin resistance and significant dyslipidemia,¹¹ whereas our hypertensive groups were matched for lipid levels. Therefore, any difference between the study groups is likely to be predominantly related to the presence of microalbuminuria.

Hypertensive patients with abnormal AER showed slightly worse glucose tolerance (albeit within normal limits), a marked hyperinsulinemic response to oral glucose, higher serum Lp(a) levels, and a 35% reduction in insulin-mediated glucose disposal compared with their normoalbuminuric counterparts. The latter change was entirely due to impaired nonoxidative glucose disposal, for the ability of insulin to stimulate glucose oxidation was unaltered. Therefore, the intracellular defect must lie in the glycogen synthesis pathway. Since approximately two thirds of the glucose used under steady-state conditions of euglycemic hyperinsulinemia is taken up by skeletal muscle,³³ such defective glycogen synthesis is likely to be mainly located in skeletal muscle. By analogy with other insulin-resistant states,³⁴ it is conceivable that glycogen synthase, the rate-limiting step in glucose incorporation into glycogen, is resistant to insulin activation. With regard to this, it is of great interest that a polymorphism in the glycogen synthase gene has been reported in association with insulin resistance in diabetic patients with current hypertension and a family history of hypertension.³⁵ Also related to our results is the finding that diabetic patients with microalbuminuria are significantly more insulin resistant than matched diabetics without microalbuminuria.²⁰

The other actions of insulin that we explored were conspicuously normal. Thus, insulin antilipolysis, as judged from the decrease in circulating free fatty acid levels and lipid oxidation rates, was not different between microA and normoA patients and was similar to that observed in healthy subjects.³⁶ Insulin-induced hypokalemia and thermogenesis were unaltered, and hepatic glucose production was normally responsive to the inhibitory action of the hormone. More importantly, the antinatriuretic effect of insulin was similar in the two groups and unrelated to either the degree of insulin sensitivity or microalbuminuria. Therefore, microA patients, by virtue of their hyperinsulinemia (Fig 1) and normal renal insulin sensitivity, are likely to be exposed to a stronger antinatriuretic pressure throughout most of the day. It is conceivable that this might contribute to the maintenance of high BP values, although such a mechanistic connection remains to be proved.

What links reduced insulin sensitivity and microalbuminuria is not known. In general, the connection, if any, could be either direct or mediated by the compensatory hyperinsulinemia. With regard to this, in our data the insulin area under the curve was more strongly related to 24-hour AER than insulin sensitivity and replaced the latter in a multiple regression model. This would suggest that part of normal insulin action might be to increase AER. Data directly bearing on this possibility are scanty, but it is noteworthy that in both control subjects³⁷ and insulin-dependent diabetics³⁸ short-term insulin administration was shown to increase AER in the absence of plasma glucose changes; and in healthy subjects but not in insulin-dependent diabetics,³⁹ glucose ingestion was associated with an increase in AER, suggesting a direct action of insulin on renal vascular permeability to albumin. A good estimate of vascular (ie, endothelial) permeability to albumin (at the whole-body level) can be obtained from the measurement of the albumin TER. The link between TER and AER is suggested by recent studies that have reported a higher TER in microalbuminuric NIDDM patients compared with normoalbuminuric diabetics.⁴⁰ Of note is the fact that insulin has been found to acutely increase TER in healthy subjects,^{41 42} although negative results have been reported in insulin-dependent diabetics.⁴³ Preliminary results of controlled experiments carried out in our laboratory indicate that insulin administration does not alter TER in healthy volunteers or normoalbuminuric NIDDM subjects (C. Catalano, unpublished data, 1995). If confirmed in patients with essential hypertension this finding would be a clear indication that any effect of insulin on AER is specifically on the kidney rather than generally on vascular permeability. Insulin may operate in concert with other factors active on glomerular hemodynamics or permeability (eg, catecholamines, angiotensin II, glucagon, protein diet, sodium balance). In this regard, it is of note that salt-sensitive hypertensive patients have been shown to have higher AERs than salt-resistant patients.⁴⁴ Furthermore, when salt-sensitive patients are given a high sodium diet they show an increase in filtration fraction, calculated glomerular pressure, and AER.⁴⁵ One could therefore hypothesize that when essential hypertension is associated with insulin resistance and salt sensitivity, the attendant hyperinsulinemia favors renal sodium retention, which in turn confers a higher degree of salt sensitivity to BP control. Therefore, salt sensitivity and insulin may interactively lead to changes in glomerular permeability and hemodynamics both favoring AER.

It has been suggested that endothelial dysfunction may prevent insulin-mediated skeletal muscle vasodilation, thereby compromising the ability of insulin to promote peripheral glucose uptake.⁴⁵ In this view, a single tissue, the endothelium, could explain both microalbuminuria and insulin resistance. However, in the present data insulin-induced forearm vasodilation did not differ between microA and normoA patients. In addition, endothelial function (tested as acetylcholine-induced forearm vasodilation) does not appear to be related to insulin sensitivity in patients with essential hypertension (A.N. et al, unpublished data, 1995) and is not different between microA and normoA hypertensive patients (S. Taddei et al, unpublished data, 1995). Finally, the role of blood flow in modulating insulin-mediated glucose utilization has recently been disputed.^{46 47} Thus, the hypothesis that a primary endothelial dysfunction might generate parallel defects in AER and insulin sensitivity, although of attractive simplicity, remains highly speculative.

	Selected Abbreviations and Acronyms

 

AER = albumin excretion rate BMI = body mass index BP = blood pressure Lp(a) = lipoprotein(a) NIDDM = non–insulin-dependent diabetes mellitus TER = transcapillary escape rate

	Acknowledgments

 
We would like to express our appreciation to Dina Malvaldi, RN, and Silvia Niccolini, RN, and to the ergometry laboratory personnel Guido Nassi and Laura Corelli for their invaluable help.

Received March 1, 1995; first decision April 24, 1995; accepted August 3, 1995.

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