(Hypertension. 1996;28:120-126.)
© 1996 American Heart Association, Inc.
Articles |
Insulin-Resistant Lipolysis in Abdominally Obese Hypertensive Individuals
Role of the Renin-Angiotensin System
the Department of Medicine and the Clinical Research Center, Medical College of Wisconsin, Milwaukee (M.M.I.H., I.M.O., T.M.K., A.H.K.); Departments of Pharmacology and Medicine, Medical University of South Carolina, Charleston (B.M.E.); and Merck & Co, Inc, West Point, Pa (P.L.).
Correspondence to Ahmed H. Kissebah, MD, PhD, Department of Medicine, Froedtert Memorial Lutheran Hospital, 9200 W Wisconsin Ave, Milwaukee, WI 53226.
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Abstract |
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Resistance to the capacity of insulin to suppress lipolysis may be an important link in the association between abdominal obesity and hypertension. Furthermore, a more active renin-angiotensin system in adipose tissue may contribute to insulin-resistant lipolysis in abdominally obese hypertensive subjects. We determined nonesterified fatty acid concentrations and turnover as well as lipid oxidation under basal conditions and during steady-state euglycemia with two levels of insulinemia (72 and 287 pmol/L) in lean normotensive, abdominally obese normotensive, and abdominally obese hypertensive subjects. To assess the role of the renin-angiotensin system in determining nonesterified fatty acid turnover, we repeated studies in the abdominally obese hypertensive subjects after double-blind random assignment to placebo or enalapril for 1 month each. The main findings were the following: (1) Nonesterified fatty acid flux was significantly higher in abdominally obese hypertensive subjects at both levels of insulinemia than in either abdominally obese normotensive or lean normotensive subjects and correlated significantly with both mean blood pressure and total systemic resistance during the higher level of insulinemia. (2) Enalapril significantly improved insulin-resistant lipolysis in the abdominally obese hypertensive subjects. The improvement in insulin suppressibility of nonesterified fatty acid flux at the high hormonal concentrations correlated positively with the magnitude of reduction in blood pressure. (3) Basal lipid oxidation and suppression in response to insulin were similarly impaired in both obese groups. Resistance to the antilipolytic actions of insulin is thus a characteristic feature in abdominally obese hypertensive subjects and may be linked to the elevated blood pressure in these individuals. A more active renin-angiotensin system may partly explain the insulin-resistant lipolysis in this form of hypertension.
Key Words: obesity • insulin resistance • fatty acids • calorimetry, indirect • renin-angiotensin system
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Introduction |
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Abdominal obesity is associated with a cluster of cardiovascular risk factors, including glucose intolerance, hyperinsulinemia, dyslipidemia, and hypertension.1 The search for a pathogenetic link between abdominal obesity and hypertension has generated evidence implicating resistance to the glucoregulatory effects of insulin and consequently hyperinsulinemia as primary factors.2 3 Other reports, however, were unable to identify an association between hypertension and hyperinsulinemia or resistance to insulin-mediated glucose disposal.4 5 6
The metabolic abnormalities of central obesity are not restricted to carbohydrate metabolism. Elevated NEFA concentration and turnover were reported in individuals with this form of obesity.7 NEFAs can reduce hepatic insulin clearance,8 9 enhance hepatic glucose production,10 decrease skeletal muscle glucose utilization,11 and increase very-low-density lipoprotein synthesis.12 In addition, NEFA metabolism has been linked to hypertension via several mechanisms. Fatty acids have been reported to raise vascular resistance and BP13 14 and enhance local vascular tone15 and 
-adrenoceptor sensitivity.16 Oleic acid inhibits nitric oxide synthase activity and impairs endothelium-dependent vasodilation in aortic rings.17 Oleic acid also has a mitogenic effect in human aortic smooth muscle cells.18 Thus, resistance to the capacity of insulin to suppress lipolysis might be an important link in the association between abdominal obesity and hypertension.
Recent studies indicate that components of the RAS are expressed and produced by adipose tissue.19 20 Furthermore, AOHT with the cardiovascular risk cluster exhibit a more active RAS.21 Since the local release of RAS components could influence adipose tissue perfusion and hormonal exposure, overactivity of this system might play a role in the predisposition to insulin-resistant lipolysis.
The objectives of the present study were (1) to determine whether AOHT express greater abnormalities of NEFA metabolism than AONT or LNT (protocol A), and (2) to assess the effects of an ACE inhibitor, enalapril, on insulin suppressibility of NEFA turnover in AOHT (protocol B).
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Methods |
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Subjects
Volunteers were recruited from the Hypertension Clinic and by advertisement. Study participants, all white, signed a written consent approved by the Human Research Review Committee and the General Clinical Research Center (CRC) Advisory Committee. Subjects who qualified for the study had an oral glucose tolerance test after an overnight fast to exclude individuals with overt diabetes.22 Twelve volunteers (45±2 years of age; 8 men and 4 women), were AOHT, as defined by a BMI greater than 27 kg/m2, WHR greater than 0.85 for women and greater than 0.90 for men, and on three separate visits the mean of three BP measurements greater than 140 mm Hg systolic and/or greater than 90 mm Hg diastolic while off all medications. Six male subjects (43±3 years of age) were AONT as defined by the above criteria, and all had BP less than 140/90 mm Hg. Seven volunteers (6 men and 1 woman, 42±2 years of age) were LNT, defined as BMI less than 25.5 kg/m2 and all BP values less than 140/90 mm Hg.
Height and weight were obtained when volunteers were lightly clothed and without shoes. WHR was calculated from the waist and hip circumferences measured with subjects standing.23 Percent body fat was determined by bioelectric impedance. BP was measured in triplicate with a mercury sphygmomanometer and an appropriately sized cuff after subjects had rested for 5 minutes in the seated position.
Descriptive data for the three groups of subjects are shown in Table 1
. The two obese subgroups did not differ significantly in weight, BMI, WHR, or percent body fat. However, these values were all significantly lower in LNT. Systolic, diastolic, and mean BPs were all significantly higher in the hypertensive group compared with the two normotensive groups.
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Subject Preparation and Dietary Control
All volunteers followed a standardized isocaloric diet as described.6 The diet was controlled for sodium (2000 mg/d), potassium (2500 mg/d), calcium (800 mg/d), and magnesium (300 mg/d). The caloric composition of the diet followed the guidelines for the American Heart Association phase I diet of 55% carbohydrate, 30% fat, and 15% protein. Subjects were seen weekly, and the caloric intake was adjusted to maintain body weight within 1.5% of baseline. Subjects followed this diet for 1 month before admission to the CRC. To enhance compliance, volunteers received all food and beverages from the CRC kitchen for 1 week before admission. A spot urine test was performed every time the subjects came to pick up their meals, and a 24-hour urine sample was collected just before admission to confirm compliance. Subjects were also asked to keep a food record throughout the study. Analysis of these records with the Nutritionist III diet-analysis software (N-Squared Computing) showed no differences in total daily caloric intake between AOHT and AONT.
Experimental Protocols
Protocol A
Seven LNT, 6 AONT, and 10 AOHT (7 men and 3 women) participated in the inpatient CRC protocol A.
Euglycemic hyperinsulinemic clamp
In brief, two sequential euglycemic hyperinsulinemic clamps were performed as described.6 24 25 During the basal period and the two sequential clamp studies, NEFA turnover was monitored with [14C]palmitate (New England Nuclear), prepared for infusion as described by Jensen and coworkers.26 At the beginning of the study (0 minute), a bolus injection of [14C]palmitate (30 µCi) was given, followed by a continuous infusion (0.3 µCi/min) for the 6-hour duration of the study. Blood samples were obtained at 10-minute intervals during the last 30 minutes of the 2-hour basal, level 1 (72 pmol insulin/m2 per minute), and level 2 (287 pmol insulin/m2 per minute) clamp periods. For NEFA determination, blood was collected in tubes containing EDTA. All samples were kept on ice until the plasma was separated and stored at -70°C for later assay of plasma insulin and NEFA concentrations and specific activity.
Indirect calorimetry
Oxygen consumption (VO2) and carbon dioxide production (VCO2) were determined during the last 30 minutes of the basal and each of the clamp periods.6 A one-way non-rebreathing valve was placed in the subject's mouth, and his/her nose was closed with a nose clip. Expired air was continuously sampled and analyzed for oxygen and carbon dioxide with an on-line open-circuit metabolic measurement system (Medical Graphics CPX). These measurements were summarized at 1-minute intervals. Data were collected during the middle 15 minutes of each measurement period. A 24-hour urine sample was obtained for measurement of urinary nitrogen and calculation of the nonprotein respiratory quotient.27
Systemic hemodynamic measurements
Stroke volume (milliliters) was measured by thoracic impedance as described.28 Cardiac output (liters per minute) was calculated as Stroke Volume/1000xHeart Rate (beats per minute). Mean BP, measured with the Dinamap 1846SX (Critikon, Inc), was obtained during each measurement of cardiac output for calculation of total systemic vascular resistance as Mean BP/Cardiac Output (millimeters of mercury per liter per minute).
Protocol B
After undergoing protocol A, all 12 AOHT participated in protocol B. Subjects were randomized to receive either enalapril (20 mg daily) or matching placebo (graciously supplied by Merck & Co, Inc) for 4 weeks, and the studies described in protocol A were repeated. During the final 4 weeks, subjects received the alternate treatment and all the studies were repeated.
Analytic Procedures
Serum insulin was measured in triplicate with a solid-phase 125I-radioimmunoassay (Coat-a-Count Insulin, Diagnostic Products Corp), and plasma glucose was measured with a glucose analyzer (Beckman Instruments) as described.24
Plasma NEFA concentrations and specific radioactivity were determined with a high-performance liquid chromatograph (model 1050, Hewlett-Packard) and the procedure described by Miles and coworkers.29 Briefly, phenacyl derivatives of the NEFAs were prepared and resuspended in a solution of acetonitrile/water (83:17). Samples were injected into a 5-µm (4.5x250 mm) reversed-phase octadecyl silica column and eluted with acetonitrile/water (83:17) at a rate of 2 mL/min. External standards containing stearic, elaidic, oleic, palmitic, linoleic, arachidonic, palmitoleic, myristic, and linolenic acids were included with each run for calculation of individual NEFA concentrations. An internal standard (2H31-palmitate) was added to the samples and standards for assessment of recovery. 2H31-Palmitate elutes as a separate identifiable peak approximately 2 minutes before natural palmitate. The effluent was passed through a variable-wavelength detector (254 nm) and then to a fraction collector containing scintillation vials. The fraction containing the radioactive palmitate tracer was collected, dried under nitrogen, and resuspended in scintillation fluid (Biosafe II, Research Products International). Radioactivity was quantified in a scintillation counter (Packard Tri-Carb). Data were collected, integrated, and stored with the Hewlett-Packard Chemstation software program. Total NEFA was defined as the sum of stearic, elaidic, oleic, palmitic, linoleic, arachidonic, palmitoleic, myristic, and linolenic acid concentrations.
Calculations
NEFA kinetic data were analyzed with the use of steady-state equations described by Miles and coworkers.29 Physiological steady state was maintained during the basal period, as there was no exogenous glucose infusion. Isotopic equilibrium was reached 30 minutes after the isotope infusion was started. Although the physiological and isotopic steady states were disrupted with the start of each clamp, they were reestablished within 45 to 60 minutes. The means of four samples obtained during the last 30 minutes of each 2-hour study phase were used for calculation of palmitate specific radioactivity and total NEFA concentration and flux rate. Palmitic acid was used as a paradigm for all NEFAs because it constitutes approximately 30% of the human plasma NEFA pool and its flux accurately monitors total flux. Total NEFA flux rates were calculated with the formula [(Palmitate Specific Radioactivity)(Palmitate Concentration)]/(Total NEFA Concentration).
Lipid oxidation rates were determined from continuous gaseous exchange measurements according to the equations described by Frayn.27 Lipid oxidation was expressed as micromoles NEFA equivalents (using the molecular weight of tripalmitein, 861) for easier comparison with the flux data.
Statistical Analysis
Statistical analyses were performed with StatView 4.0 software for a Macintosh computer. Values of P
.05 were accepted as statistically significant. Data are reported as mean±SE. Metabolic data are expressed per meter squared of body surface area because it represents the metabolically active body mass. In protocol A, the power of the study to detect a difference of 50 µmol/m2 per minute in NEFA flux was 0.94. Comparisons of differences in NEFA metabolism among the three groups were made with two-factor repeated measures ANOVA with Fisher's protected least significant difference. ANCOVA was also performed comparing NEFA flux and concentrations during both clamp levels adjusting for the baseline differences among the three groups. Pearson correlation coefficients were used for determination of the relationship between NEFA flux and hemodynamic measures. Paired two-tailed t test was used for examination of within-group effects of the clamp on NEFA concentrations and flux. In protocol B, the power of the study to detect a difference of 10 mm Hg in systolic or diastolic BP was 0.92. The effects of enalapril on the hemodynamic and metabolic parameters were determined by paired two-tailed t test. Repeated measures ANOVA was also used to test the adequacy of the crossover design. There was no significant order effect (placebo versus enalapril) on either mean BP (P=.43) or NEFA flux (P=.26).
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Results |
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Protocol A: NEFA Metabolism and Its Relationship to Hemodynamics
Baseline Fasting Values
Fig 1
shows mean plasma NEFA concentrations obtained during the basal period and the last 30 minutes of each level of insulinemia. Baseline NEFA concentrations were significantly higher in AOHT than LNT. The differences between AONT and LNT were not significant. Despite higher basal insulin levels (122±22 pmol/L for AOHT, 172±50 pmol/L for AONT compared with 57±7 pmol/L for LNT), mean NEFA flux rates were significantly higher in the two obese groups. No significant differences in baseline NEFA concentration or flux were observed between AOHT and AONT.
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, n=7), AONT (
, n=6), and AOHT (
, n=10). *P<.0001 vs LNT; 
P<.005 vs AONT.
Euglycemic Hyperinsulinemia
As shown in Fig 1
, plasma NEFAs in all three groups decreased significantly during both levels of insulinemia compared with basal values. At both clamp levels, plasma NEFAs were higher in the AOHT group compared with either the LNT (P<.0001) or AONT (P<.005). In AONT, NEFA levels and turnover during both levels of insulinemia were not significantly different from those observed in LNT.
Fig 1 also shows the insulin dose-response curves for suppression of NEFA flux in the three subject groups. When plasma insulin was raised approximately 150 pmol/L above basal in clamp level 1, NEFA flux rates were decreased by 50% in both groups of normotensive subjects. However, a much smaller suppression (28%) was observed in the AOHT group. When plasma insulin was increased 600 pmol/L above basal in clamp level 2, NEFA flux rates were further suppressed in all three groups. Nevertheless, during both levels of euglycemic hyperinsulinemia, mean NEFA flux rate remained significantly higher in AOHT than LNT (P<.001) and AONT (P<.05). ANCOVA, with adjustment for the mean basal values of both NEFA concentrations and flux, verified this conclusion. AOHT had significantly higher concentrations compared with LNT (P=.005) and AONT (P=.007) as well as significantly higher flux rates compared with LNT (P=.002) and AONT (P=.0002) during the higher insulin clamp. However, NEFA levels and flux rates did not differ significantly between LNT and AONT during the insulin clamp.
Basal lipid oxidation rates, expressed as NEFA equivalents (micromoles per meter squared per minute), were not different among the three groups, averaging 94±17 in AOHT, 94±15 in AONT, and 95±16 in LNT. Fig 2 shows the suppressibility of total body lipid oxidation during the hyperinsulinemic euglycemic clamps. Since the initial fasting values were not significantly different among the three groups, data were expressed as percentages of basal values. In LNT, lipid oxidation was suppressed by 90% during the level 1 insulin clamp, when insulin levels were increased by 150 pmol/L above basal values. During the level 2 insulin clamp, total lipid oxidation was almost completely suppressed in LNT. In contrast, total body lipid oxidation was not suppressed to the same extent in either abdominally obese group. At both levels of insulinemia, lipid oxidation was higher in both obese groups (P<.05), and the suppressibility of lipid oxidation by insulin was equally impaired in the two obese groups.
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As noted above, the mean NEFA flux rate was markedly more resistant to suppression by insulin in AOHT than in the two normotensive groups, even at higher levels of insulinemia. Therefore, we examined potential relationships between NEFA flux and systemic hemodynamic measurements at clamp level 2. As shown in Fig 3, NEFA flux correlated significantly with mean BP (r=.61, P=.001). The correlation of NEFA flux to BP appeared to be mediated more by a relationship to total systemic resistance (r=.48, P=.02) than to cardiac output (r=-.26, P=.22).
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Protocol B: Effects of Enalapril on Insulin-Resistant Lipolysis in AOHT
Data on BP and NEFA metabolism in AOHT during the placebo and enalapril phases are shown in Table 2. As expected, both systolic and diastolic BPs were significantly lower during the enalapril phase. Both NEFA concentration and flux tended to be lower during double-blind random assignment to enalapril than during placebo. More importantly, however, the resistance of NEFA turnover to suppression by insulin during the higher insulin infusion was significantly improved by enalapril (251±21 versus 343±31 µmol/m2 per minute, P<.01). As shown in Fig 4, this improvement in the ability of insulin to suppress NEFA flux during the high insulin clamp correlated positively with the magnitude of the enalapril-induced reduction in mean BP (r=.73, P<.005).
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Discussion |
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Although the incidence of hypertension in upper-body obesity is well established, the mechanisms responsible for this association are unclear. We have used palmitate tracers and indirect calorimetry to examine the role of NEFA metabolism in the pathogenesis of hypertension accompanying abdominal obesity. We then assessed the effects of the ACE inhibitor enalapril on insulin suppressibility of NEFA turnover. This study shows for the first time that AOHT are distinguished from AONT or LNT by greater resistance to the antilipolytic action of insulin. This abnormality of NEFA metabolism may be linked to BP homeostasis, as suggested by the strongly positive correlation during the higher insulin clamp level between NEFA flux rates and mean BP as well as total systemic resistance. Enalapril was associated with an improvement, yet not normalization, of the severe insulin-resistant lipolysis in AOHT, suggesting a role for the RAS in the regulation of adipose tissue lipolysis and insulin action. The strong correlation between the improvement of insulin-resistant lipolysis and the reduction of BP during ACE inhibition provides further evidence for an association between NEFA metabolism and BP. Finally, we have demonstrated similar lipid oxidation defects in both AOHT and AONT. These included failure to augment basal oxidation in the face of enhanced flux as well as resistance to suppression during euglycemic hyperinsulinemia.
Basal NEFA levels and flux were greater in AOHT and AONT than in LNT. These data are consistent with previous reports that the abdominal fat pattern and not BP per se explains the higher basal NEFA flux.7 The preponderance of ß-adrenoceptors compared to -adrenoceptors and the greater blood flow in abdominal fat may contribute to a highly sensitive and active site for mobilization of fatty acids. Since fatty acid turnover at the basal state was not significantly different between AOHT and AONT, it is unlikely that these measures of fatty acid metabolism account for the BP differences between these two groups under basal conditions. NEFA flux was suppressed to a variable degree at both levels of insulinemia in all three subject groups. In the AOHT, however, NEFA concentrations and flux were more resistant to suppression by insulin than in the AONT or LNT. Although AOHT were slightly heavier than AONT, WHR was virtually identical in the two groups. Furthermore, previous studies have shown that the effect of BMI on insulin sensitivity is less pronounced than the effect of body fat distribution.1 2 It is therefore unlikely that the difference in adipose tissue insulin sensitivity could be due to differences in BMI. These data support the notion that insulin-resistant lipolysis and NEFA flux might be pathogenetically linked to BP in abdominal obesity.
We previously examined interactions between abdominal obesity, hypertension, and the insulin resistance of stimulated peripheral glucose uptake in the same subject groups.6 Our results with NEFA metabolism contrast with those observed with glucose metabolism. The coexistence of hypertension and upper-body obesity did not worsen the defect in insulin-mediated glucose metabolism associated with abdominal obesity without hypertension. The marked differences in NEFA concentrations and turnover suppressibility by insulin in AOHT compared with AONT suggest that the link between insulin resistance and hypertension may be confined to the effects on NEFA metabolism. These findings thus suggest that the insulin-resistant fatty acid metabolism and adipose tissue lipolysis might be involved in the pathogenesis of hypertension, whereas the resistance to the glucoregulatory response of insulin and skeletal muscle glucose uptake are not.
One of the main findings of this study was the link between BP and the suppressibility of NEFA flux by insulin. This is supported by the positive correlation between these two variables. This relationship is further emphasized by the observed correlation between the magnitude of the BP reduction and improvement of the antilipolytic action of insulin by enalapril. New evidence suggests that NEFAs might contribute to the vascular abnormalities in obese hypertensive individuals. For instance, overweight subjects with elevated BP have increased vascular -adrenergic tone,30 31 which is not explained by an impairment of the capacity of insulin to antagonize forearm vascular response to locally injected norepinephrine.28 Studies in minipigs have also shown that elevating systemic free fatty acid concentrations increased vascular resistance in most tissue beds in addition to increasing BP.14 Fatty acids may also elevate BP by inhibiting Na+,K+-ATPase activity,32 enhancing calcium influx,33 or activating protein kinase C.34 Recently, it has also been shown that raising fatty acids locally increases vascular tone15 and selectively augments vascular 1-adrenoceptor responses in vivo.16 Increased fatty acid levels thereby could stimulate vasoconstriction and contribute to increased neurovascular tone in obese hypertensive subjects. Furthermore, oleate has been found to inhibit nitric oxide synthesis and impair endothelium-dependent vasodilation in aortic rings.17 Oleate also induces mitogenesis in human aortic smooth muscle cells.18 Thus, multiple actions and effects of NEFAs may contribute to vascular dysfunction in obese hypertensive subjects.
Our study did not show significant relationships between basal NEFA levels or flux and BP. Furthermore, enalapril had no significant effects on basal levels of NEFA, and only its potentiation of the suppressibility of NEFA flux by insulin at the higher insulin levels correlated with the improvement in BP. These data might argue against the hypothesis that NEFA levels, flux, or both are directly involved in the pathogenesis of the increased BP. Previous studies, however, have shown that basal NEFA flux is representative only of the overnight condition, whereas the postprandial flux represents the daytime exposure.35 Of importance in this regard is the fact that the plasma insulin levels achieved during the clamp procedures were similar to those observed during the postprandial state in lean normotensive subjects and substantially lower than those expected in the majority of abdominally obese individuals.1 Thus, our data clearly show significant links between hypertension and insulin regulation of NEFA metabolism although the potential mechanisms mediating these links remain uncertain.
The ACE inhibitor enalapril was associated with an improvement in the antilipolytic action of insulin in AOHT at the higher insulin concentration. Despite the improvement of insulin suppressibility of NEFA flux, the absolute amount of fatty acid turnover remained greater in AOHT than in either AONT or LNT at the same insulin infusion rate. Thus, the intake of ACE inhibitor partially improved the insulin-resistant lipolysis characteristic of the AOHT. Abdominally obese subjects with cardiovascular risk factor clustering have greater activity of the components of the renin-angiotensin axis.21 More recently, it has been shown that adipocytes possess local ACE19 and that angiotensin modulates adipocyte function.20 36 Enalapril may thus enhance the antilipolytic actions of circulating insulin by inhibiting angiotensin formation locally, perhaps via changes in adipose tissue blood flow and/or redistribution. Additional studies, however, are required to prove that a reduction of angiotensin, in contrast to an increase of kinins,37 is responsible for the observed changes in insulin-resistant lipolysis and to assess whether these changes reflect hemodynamic and/or cellular responses to this peptide. The antilipolytic action of insulin was improved but not normalized by ACE inhibition, suggesting that factors other than the RAS, probably at the level of the adipocyte, might be involved in influencing insulin resistance.
We have recently reported that although NEFA flux was significantly lowered after enalapril treatment, insulin-stimulated peripheral glucose utilization was not significantly affected by ACE inhibition.38 These observations suggest that insulin sensitivity is augmented to a greater extent in adipocytes than in skeletal muscle after ACE inhibition. Therefore, the greater activity of the adipose tissue RAS might contribute to the marked resistance to the antilipolytic effects of insulin, thus explaining the differential response of lipid and glucose metabolism to ACE inhibition.
Total body lipid oxidation, both in the basal state and in response to euglycemic hyperinsulinemia, was impaired in abdominally obese subjects. The magnitude of this defect was comparable in both obese groups. Despite higher basal NEFA flux relative to that seen in the LNT controls, lipid oxidation rates in the two obese groups were normal. These results suggest a defect in lipid oxidation, since raising circulating levels of NEFA in healthy lean volunteers is associated with enhanced lipid oxidation.39 A similar observation has recently been reported in subjects with non–insulin-dependent diabetes40 and in AONT.41 The sensitivity of LNT to suppression of lipid oxidation by insulin is consistent with the notion that insulin in normotensive subjects markedly inhibits lipid oxidation at the cellular level.42 Although AOHT manifested greater resistance to the antilipolytic effects of insulin than AONT, both obese groups were equally resistant to suppression of fatty acid oxidation by insulin. Since lipid oxidation occurs primarily in skeletal muscle, and given the fact that insulin-mediated glucose disposal is not remarkably different between the two obese groups,6 the association between hypertension and insulin resistance appears to derive from a defect in adipose tissue and not skeletal muscle. The finding that enalapril selectively improved adipose tissue but not skeletal muscle response to insulin further supports this notion.38
We conclude that AOHT are extremely resistant to the antilipolytic action of insulin. This may be explained by increased activity of adipose tissue RAS. This, together with the defect in lipid oxidation, results in diminished suppressibility of regulated NEFA levels and turnover by insulin. Abnormalities in adipose tissue insulin sensitivity may partly account for the pathogenic link between hypertension and insulin resistance in abdominal obesity.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by General Clinical Research Center Grant M01-RR00058, by grant HL-43164 (B.M. Egan), and by grant HL-34989 (A.H. Kissebah) from the National Institutes of Health. This work was also supported in part by a grant from Merck & Co, Inc. We are grateful to our research volunteers for their cooperation during the studies. The excellent technical assistance of the General Clinical Research Center nursing and dietary staff is greatly appreciated, in particular Judit Hudetz, Keryl Jones, Jacqueline Marks, and Joan Pleuss. We also wish to acknowledge Dr Glenn Krakower for his assistance in the preparation of this manuscript.
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Footnotes |
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This work was presented in part at the Central Society for Clinical Research, Chicago, Ill, September 16-18, 1994, and at the American Federation for Clinical Research, San Diego, Calif, May 5-8, 1995.
Received July 5, 1995;
first decision August 16, 1995; first decision February 21, 1996;
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