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Original Studies |
Metabolism Unit of the CNR Institute of Clinical Physiology and the Department of Internal Medicine, University of Pisa, Pisa, Italy
Address all correspondence and requests for reprints to: Dr. E. Ferrannini, CNR Institute of Clinical Physiology, Via Savi 8, 56126 Pisa, Italy.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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15%),
insulin sensitivity improved in proportion to the weight reduction,
whereas insulin hypersecretion and high energy expenditure persisted.
In contrast, all hemodynamic changes reverted to normal. We conclude
that in moderate obesity, the metabolic and cardiovascular
abnormalities are largely independent of one another; accordingly,
weight loss affects them differentially. Partial weight normalization
may provide sufficient cardiovascular protection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several studies have documented that weight loss is associated with an improvement in insulin sensitivity (12, 13, 14, 15, 16). There is also evidence that weight reduction is followed by reversal of the hemodynamic abnormalities (12, 17, 18). An important issue that seems to be unresolved is whether the insulin resistance and hemodynamic changes regress in parallel and in quantitative proportion to the amount of weight lost. As a return of the obese subject to "normal" body weight is not easily achieved and is rarely maintained, a relevant clinical question is what extent of weight loss is sufficient to normalize which abnormalities of the obese state. In the present study in moderately obese nondiabetic subjects, multiple metabolic and hemodynamic measurements were obtained at baseline and after an average weight loss of 15%, i.e. a therapeutic effect that has reasonable chances of being achieved and maintained in clinical practice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Eleven obese subjects (7 women and 4 men) and 12 lean control
subjects (7 women and 5 men) were studied. By self-report, in the obese
patients the duration of obesity ranged between 1.5–28.5 yr. None of
the subjects had lost weight or changed dietary habits during the 6
months preceding the initial study. The anthropometric characteristics
are given in Table 1
. All subjects had
normal glucose tolerance on the oral glucose tolerance test (OGTT) by
the National Diabetes Data Group criteria (19) and normal resting
arterial blood pressure levels according to the JNC V (systolic, <140
mm Hg; diastolic, <90 mm Hg) (20). None was taking any medication. All
subjects had normal liver and renal function tests. The investigation
was approved by the institutional review board of the CNR Institute of
Clinical Physiology, and all subjects gave informed consent before the
study began.
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Experimental protocol
Body composition was evaluated by electrical bioimpedance (21); the waist and hip circumferences were measured by the same physician. Each subject received an OGTT and a euglycemic insulin clamp on different days approximately 1 week apart. For the OGTT, 40 g/m2 glucose were ingested over 5 min, and venous blood was sampled at 30-min intervals for 2 h for plasma glucose and insulin measurements. The clamp study, which was carried out after an overnight (12–14 h) fast, consisted of 2 h of euglycemic insulin infusion (at a rate of 7 pmol/min·kg BW) (22). A 20-gauge catheter was inserted into an antecubital vein for the infusion of test substances. Another catheter was threaded into a wrist vein retrogradely, and the hand was placed in a heated box for the sampling of arterialized blood (23). After this procedure, the patients rested at least 30 min in the supine position. The subsequent 2 h before the start of insulin infusion constituted the baseline period. At baseline and during the insulin clamp, the following data were obtained: 1) arterial blood pressure, which was measured by mercury sphygmomanometry at 20-min intervals (in obese individuals a large cuff was used); 2) circulating hormone concentrations (cortisol, GH, PRL, TSH, T3, T4, free T3, free T4, epinephrine, and norepinephrine), which were sampled twice at the end of the 2-h baseline period and twice at the end of the insulin clamp; 3) cardiac output, which was determined noninvasively by two-dimensional echocardiography (24) at the end of the basal and clamp periods by the same physician; 4) endogenous glucose production (EGP), which was determined with the use of the [6H3]glucose technique (25); and 5) indirect calorimetry, using a computerized, continuous, open circuit system with a canopy (Metabolic Measurement Cart Horizon, SensorMedics, CA) (26). Throughout the study, the patency of the sampling catheter was maintained by injecting 1 mL saline after each blood draw. Furthermore, the blood loss due to the sampling was replaced by iv saline, whereas the urine loss was empirically replaced by 150 mL water ingested at the beginning of the basal and clamp periods (urine output averaged 2.6 ± 0.3 before and 2.1 ± 0.2 mL/min at the end of the baseline and clamp periods, respectively). In all subjects, sodium excretion was measured in a 24-h urine sample.
Analytical procedures
Plasma glucose was measured by the glucose oxidase technique on a Beckman Glucose Analyzer (Beckman, Fullerton, CA). Plasma concentrations of insulin (InsKit, Sorin, Saluggia, Italy) and cortisol (Sorin) were measured by RIA, whereas GH (Hybritech, San Diego, CA), TSH (Sorin), and PRL (Hybritech, San Diego, CA) were measured by immunoradiometric assay. Plasma catecholamine concentrations were assayed by high performance liquid chromatography (on an HLC 725 apparatus) using electrochemical detection (Eurogenetics, Tessenderlo, Belgium). Plasma uric acid and triglycerides were assayed spectrophotometrically, in duplicate, on an Eris Analyzer 6170 (Eppendorf Geratebau, Hamburg, Germany). Serum free fatty acids were measured spectrophotometrically (Wako, Neuss, Germany).
Data analysis
Fat-free mass was calculated as the difference between body weight and fat mass. Whole body glucose utilization (or the M value) was calculated from the infusion rate of exogenous glucose during the second hour of the insulin clamp period after correction for changes in glucose levels in a distribution volume of 250 mL/kg. The M value was normalized by kilograms of fat-free mass (micromoles per min/kg FFM). An index of insulin sensitivity was calculated as the ratio of insulin-mediated glucose clearance rate (M divided by the steady state plasma glucose level) to the steady state plasma insulin concentration (log transformed) (27). Under the steady state conditions prevailing in the fasting state, the glucose rate of appearance (Ra) is calculated as the ratio between the tracer infusion rate and the basal glucose specific activity (SA). During insulin infusion, the estimation of changes in glucose Ra can be optimized by minimizing the changes in plasma glucose SA (28). To approximate a clamp of glucose SA, the basal tracer glucose infusion rate was halved every 15 min after the start of insulin infusion until 45 min into the clamp, when it was stopped. At the same time, the exogenous glucose infused during the clamp was enriched with 150 µCi [6H3]glucose. This level of enrichment was chosen on the basis of previous experiments so as to match the steady state plasma glucose SA prevailing during the basal state (25). Nonsteady state glucose Ra values were calculated from the isotopic data by a two-compartment model with an ad-hoc computer program (28). EGP was calculated as the difference between Ra and the exogenous glucose infusion rate. Areas under the OGTT time-concentration curves were calculated by the trapezium rule. As exogenous hyperinsulinemia suppresses fasting endogenous insulin release by about 50% (29), the posthepatic insulin clearance rate was calculated as the ratio of the insulin infusion rate to the difference between the steady state plasma insulin concentration and half the fasting insulin level (29, 30). The fasting posthepatic insulin delivery rate was then obtained as the product of posthepatic insulin clearance by the fasting plasma insulin concentration (30). Post-OGTT posthepatic insulin delivery was calculated as the product of insulin clearance and the OGTT insulin area under curve on the assumption that posthepatic insulin clearance is unchanged during glucose absorption (31).
Mean arterial blood pressure was calculated as the diastolic blood pressure plus one third of the pulse pressure. Cardiac output was estimated by measuring left ventricular outflow tract diameter by two-dimensional echocardiography in the parasternal, long axis view, and stroke volume was determined by continuous wave Doppler left ventricular outflow tract samples from the apical long axis view. Total peripheral vascular resistance was calculated as the mean arterial blood pressure divided by cardiac output.
Statistical analysis
All data are given as the mean ± SEM. Means
comparison was performed by paired or unpaired t test, as
appropriate. Simple and multiple linear regression analysis was carried
out using standard techniques. P 
0.05 was considered
statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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)
Although by selection all study subjects had normal glucose
tolerance, plasma glucose and insulin levels during the OGTT were
significantly higher in the obese than in the lean group at several
points (Fig. 1). Both in the fasting
state and during the clamp, serum free fatty acid levels did not differ
between lean and obese subjects. Serum triglyceride, but not total, low
density lipoprotein, or high density lipoprotein cholesterol,
concentrations were significantly higher in obese than in lean
individuals.
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)
The whole body glucose Ra in response to insulin was lower in
obese than in lean subjects at all time points (Fig. 2). Thus, insulin sensitivity was
significantly impaired in the obese in terms of both the M value and
the insulin sensitivity index (ratio of glucose clearance to steady
state plasma insulin level). Posthepatic insulin clearance was similar
in obese and lean subjects, whereas posthepatic insulin delivery was
greater in the former than in the latter both in the fasting state and
after glucose ingestion. Resting energy expenditure (REE) was
significantly increased in the obese. REE was strongly related to
fat-free mass (r = 0.71; P < 0.0001); therefore,
when REE was expressed per kg fat-free mass, the difference between
obese and lean subjects was canceled out (81 ± 4 vs.
81 ± 3 J/min·kg FFM; P = NS).
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and overall (by 84 ± 2% vs. 83 ± 4%, lean
vs. obese, average value during the 2 h of the
clamp).
Cardiovascular parameters (Table 4)
The obese patients had higher systolic and mean blood pressure values and higher stroke volume and cardiac output values. Total peripheral vascular resistance tended to be lower in the obese group, although this difference did not reach statistical significance. Urinary sodium excretion was similar in lean and obese subjects.
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)Fasting levels of all measured hormones did not differ significantly between obese and lean subjects.
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)
Weight reduction consisted of loss of both fat-free mass and fat
mass, so that overall body composition was unchanged; the waist/hip
ratio, however, was significantly reduced. Weight loss was also
accompanied by a 12% improvement in oral glucose tolerance
(glucose area) and by significant decrements in serum triglyceride and
uric acid levels. During the clamp, insulin sensitivity was improved by
about 25% when the effect of insulin was judged by the M value. In
contrast, total insulin-mediated glucose disposal was only improved by
8%, on the average, and this change did not reach statistical
significance. Likewise, there was no significant change in REE in
absolute terms, and there was only a marginal improvement (to 91
± 4 J/min·kg FFM; P = 0.07) when REE was expressed
as kilograms of fat-free mass. Fasting EGP was not affected by weight
loss, and its suppression by insulin was improved minimally (Fig. 2).
Both fasting and post-OGTT insulin deliveries were reduced after weight
loss, but neither of these changes reached statistical significance.
With regard to hemodynamics, systolic blood pressure, stroke volume,
and cardiac output had all returned to normal after weight loss
(P = NS vs. the lean group); total
peripheral vascular resistance, however, was significantly increased
compared to the baseline value. These changes were accompanied by
slight, but significant, decrements in the circulating levels of
thyroid hormones, whereas all other hormones were unchanged.
On the pooled data from all study subjects (n = 23), there was no
relationship between insulin sensitivity and any of the hemodynamic
variables. Insulin sensitivity and body mass were reciprocally related
(r = 0.61; P < 0.002); after weight loss, the
obese group appeared to regress along the same line (Fig. 3). Insulin delivery was related to
insulin sensitivity by an inverse hyperbolic function, which was still
statistically significant after adjustment by the body mass index (BMI;
multiple r = 0.80; P < 0.0001); after weight
loss, this relationship appeared to be maintained (Fig. 4).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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For the hemodynamic parameters, our obese subjects had clear evidence of a high output, low resistance state, resulting in slightly elevated arterial blood pressure levels even within the normotensive range. In the study group as a whole, there was no quantitative relationship between the hemodynamic and metabolic parameters that resisted adjustment for BMI. This suggests that the two sets of abnormalities are parallel consequences of overweight, although we cannot rule out that some weight-independent association would emerge in a larger sample.
Caloric restriction reduced the body weight of the obese patients to a level intermediate between their baseline and the value of the control group. This change was the result of loss of both lean and fat mass, with a predominance of the former. Although weight reduction is known to be accompanied by loss of lean mass, the proportion seen in the present study is somewhat higher than that reported by others (36). This difference may be due to the small numbers of subjects in this and other studies, or it may reflect the fact that our obese patients made no attempt to preserve lean mass during dieting by increasing physical activity.
As expected, weight loss improved insulin sensitivity essentially in proportion to the amount of weight lost. The regression of the baseline measurements predicts that halving BMI from 40 to 20 kg/m2 is associated with a doubling of the insulin sensitivity index. However, it is important to note that the total amount of glucose disposed of under the influence of insulin was only 17% lower in the obese than in the lean subjects and increased by only 8% after weight loss; neither difference was statistically significant. Thus, although each unit of lean mass is resistant to insulin action on glucose metabolism, the increased lean mass of the obese provides a compensatory mechanism of glucose utilization. Conversely, the loss of lean mass with weight reduction limits the benefit of improved insulin sensitivity in target tissues. Consistent with this view, glucose tolerance (as the OGTT glucose area) was better related to the absolute M value (r = 0.57; P < 0.005) than to the insulin sensitivity index (r = 0.48; P = 0.02).
Insulin secretion was independently related to the degree of overweight and insulin resistance, indicating that only part of the insulin hypersecretion of the obese is secondary to insulin insensitivity; the remainder is inherent in the obese condition. This quantitative dependence of insulin secretion on insulin sensitivity appeared to be maintained after weight loss. Of interest is that the response of the ß-cell to glucose (as expressed by the insulin/glucose ratio) was significantly enhanced in the obese patients and was little modified by weight loss. This result is compatible with previous evidence that, unlike insulin resistance, the insulin hypersecretion of obesity is corrected by weight reduction in an incomplete (37) or delayed fashion (38).
In contrast to metabolic function, the hemodynamic parameters were fully normalized by the amount of weight reduction experienced by our patients. After weight loss, systolic and mean blood pressure, stroke volume, and cardiac output were no longer different from the values of the lean subjects. At baseline, cardiac output was linearly related to body weight (r = 0.51; P < 0.03); from this relationship, the expected drop in cardiac output for an average weight loss of 11 kg was 0.6 L/min, whereas the observed value was twice as large. Therefore, our results indicate that in moderately obese, normotensive subjects, a modest weight reduction is sufficient to reverse the cardiovascular abnormalities. The reason for such a dissociation between the metabolic and hemodynamic effects of weight reduction cannot be determined from the current data, but may relate to the significant decreases in thyroid hormone levels and adrenergic activity. Thyroid hormones sensitize tissues to the effects of catecholamines (39), and adrenergic tone has been reported to decrease with weight loss (40). Although in our subjects, plasma catecholamine levels and urinary sodium excretion were not detectably different after weight loss, norepinephrine turnover can change in the absence of significant changes in circulating norepinephrine levels (41); natriuresis, on the other hand, is acutely influenced by sympathoexcitation, but in the longer run only reflects sodium intake (42). Thus, reduction of adrenergic activity remains a likely explanation for the cardiovascular changes associated with weight loss (5).
It must be observed that with weight loss peripheral vascular resistance showed an increase rather than a decrease. As previously discussed (43), changes in body mass are accompanied by reciprocal changes in peripheral vascular resistance on a purely hemodynamic basis. Therefore, blood pressure is the result of adaptation of cardiac output to the new resistance regimen. Paradoxically, if cardiac output did not decrease, i.e. if adrenergic drive was persistently high, weight loss would result in hypertension. In line with this interpretation, cardiovascular mortality has been reported to be higher in lean than obese hypertensive subjects even when accounting for potential confounders (44, 45, 46).
A final issue is whether any of the measured parameters was able to predict the observed improvement in insulin resistance. Although the number of subjects is too small to run a complete predictive model, we did find that a larger baseline waist circumference was associated with a greater improvement in insulin resistance even after accounting for the lost weight (multiple r = 0.78; P < 0.03). There was, therefore, a suggestion that individuals with more pronounced abdominal obesity may achieve particular benefit, at least in terms of insulin sensitivity, from losing any amount of excess weight. Clearly, larger databases are necessary before consistent predictors of metabolic and/or hemodynamic changes can be identified.
In conclusion, we have shown that in normotensive, normotolerant patients with moderate obesity (i.e. the prevalent phenotype in our clinics), the metabolic and cardiovascular abnormalities are largely independent of one another; accordingly, weight loss affects them differentially. In these subjects, a modest weight reduction, which has reasonable chances of being achieved and maintained, may provide sufficient cardiovascular protection.
Received March 6, 1997.
Revised May 16, 1997.
Accepted June 5, 1997.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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