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Original Studies |
Department of Pediatrics (R.A., G.L., L.U., P.S.), University of Tennessee, Graduate School of Medicine, Knoxville, Tennessee 37920; and Department of Pediatrics (A.E.S.), Northshore University Hospital-New York University, School of Medicine, Manhasset, New York 11030
Address all correspondence and requests for reprints to: Ramin Alemzadeh, M.D., Division of Pediatric Endocrinology, Metabolism and Nutrition, University of Tennessee Medical Center, 1924 Alcoa Highway, U-113, Knoxville, Tennessee 37920. E-mail: ralemzad{at}mc.utmck.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In obese individuals, sensitivity to insulin’s antilipolytic action is maintained, in contrast to the development of resistance to insulin’s glucoregulatroy action, as demonstrated by forearm perfusion studies (7) and euglycemic clamp studies (8). This concept is supported by the observation that adipocytes from lean and obese individuals show little resistance to insulin inhibition of lipolysis (9). These findings suggest that persistence of the hyperinsulinemic state maintains obesity, whereas decreasing hyperinsulinemia would be expected to reverse obesity. We previously demonstrated that attenuation of hyperinsulinemia by diazoxide (DZ), a K+[ATP] channel agonist, resulted in decreased weight gain, increased insulin sensitivity (SI), and improved glucose tolerance in obese Zucker rats (10, 11). Theoretically, if DZ can inhibit insulin secretion and concurrently enhance SI in humans, a method of decreasing lipogenesis without inducing hyperglycemia may be achieved. To test this hypothesis, a double-blind placebo-controlled trial was undertaken in which DZ was administered to a group of hyperinsulinemic obese adults over an 8-week period.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects consisted of 24 moderate-to-morbidly obese adults with
a body mass index (BMI) greater than 30 kg/m2. Subjects
with history of glucose intolerance, diabetes, cardiovascular disease,
renal disorder, and/or other endocrine problems, as well as those with
fasting plasma glucose greater than 120 mg/dL and/or glycohemoglobin of
7.0% or higher were excluded. Each subject underwent a complete
physical examination at the initial evaluation, body weight being
measured on a standard electronic scale (Seca delta, model 707). All
women of childbearing age were advised to use barrier contraceptive
methods during the study. Subjects provided informed consent according
to guidelines approved by the University of Tennessee Institutional
Review Board. Table 1
summarizes the
clinical characteristics of the 2 groups of subjects participating in
the study.
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Twenty-four-hour dietary recall was obtained from each subject. The
dietary recalls were analyzed using a standard computer software
program (Nutritionist IV, N-Squared Computing, Salem, OR). The mean
reported caloric intake was comparable between the groups (Table 1
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All subjects were placed on a hypocaloric diet, supplying 1260 kcal/day
for females and 1570 kcal/day for males, comprised of liquid shakes
(160 kcal/packet) and nutrition bars (150 kcal/bar, Optifast, Sandoz)
for 6 days and then, on the seventh day, eating a regular diet from a
corresponding hypocaloric Optimealplan (Optifast Encore Program,
Sandoz). The subjects were instructed to keep a food diary for day 7 to
ensure compliance with their meal plan and were requested not to change
exercise or activity level.
Methods
Before commencing, and after completion of the study, the following laboratory tests were obtained: fasting plasma glucose, insulin, cholesterol, triglycerides, free fatty acids (FFA), and glycohemoglobin. Additionally, routine chemistry profiles and fasting plasma glucose were obtained weekly to identify those subjects with evidence of glucose intolerance and/or electrolyte abnormalities. Glucose was analyzed in plasma, by the glucose oxidase method (Sigma Chemical, St Louis, MO). Insulin concentration was determined by RIA using a double-antibody kit (ICN Pharmaceuticals, Inc, Costa Mesa, CA). Cholesterol and triglyceride concentrations were measured by an enzymatic method (Sigma Diagnostics, St Louis, MO). Plama FFA was determined by an enzymatic colorimetric method (Wako Chemicals, Richmond, VA).
SI was assessed by an iv glucose tolerance test (IVGTT) using the modified minimal model (12). After an overnight fast, a glucose bolus (300 mg/kg) was administered iv, followed (20 min later) by a bolus of insulin (Humulin R 0.03 U/kg, Eli Lily, Indianapolis, IN). Blood for determination of glucose and insulin was obtained from a contra lateral vein at -30, -15, 0, 2, 3, 4, 5, 6, 8, 10, 19, 22, 25, 30, 40, 50, 70, 100, 140, and 180 min. SI and glucose effectiveness (SG) were calculated using Bergman’s modified minimal-model computer program before and after the completion of the study. Acute insulin response to glucose (AIRg) was determined over the first 19 min of the IVGTT, and the glucose disappearance rate (Kg) was determined from 8–19 min of the IVGTT.
Body composition was measured by bioelectrical impedance using the Valhalla 1990B bioresistance body composition analyzer (San Diego, CA) before and at the completion of the study. Resting energy expenditure (REE) was measured by indirect calorimetry, using a Deltatrac Metabolic Monitor, after an overnight 12-h fast, with subjects lying supine for a period of 30 min. Urine was collected over the corresponding 24 h, for measurement of total nitrogen and determination of substrate use, before and after the study.
Statistical analysis
The reported values represent the mean ± SE. The change in measurements (i.e. weight, lipids, body fat (BF), fat-free mass (FFM), REE, SI, and SG) from the lead-in period to the end of study for the DZ group were compared with those of the placebo group, using a paired Student’s t test. P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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).
After 8 weeks, some weight loss was observed in both the placebo group
and the DZ group. However, weight loss was significantly greater in the
DZ group (9.8 ± 1.0 kg) than in the placebo group (5.0 ±
1.0 kg, P < 0.01) and was about twice that of the
placebo group at the completion of the study (9.5 ± 0.69%
vs. 4.6 ± 0.61%, P < 0.001) (Fig. 1). The weight loss was associated with
significantly greater loss in BF in the DZ group than in the placebo
group (-9.3 ± 1.0 kg vs. -3.6 ± 0.9 kg,
P < 0.01), whereas the FFM loss was similar in both
groups (-1.3 ± 0.3 vs. -1.9 ± 0.5 kg;
P, not significant), resulting in a greater increase in the
FFM/BF ratio in the DZ group than the placebo group (P
< 0.01). The weight loss in the DZ group may have been even greater
than recorded, because there was a greater increase in body water in
this group, when compared with the placebo group (P <
0.05). There were no significant changes in the REE values of either
group. Substrate use, as derived from indirect calorimetry, did not
reveal any significant change in carbohydrate or fat metabolism in
either group (data not shown).
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documents fasting plasma
concentrations of glucose, insulin, cholesterol, triglycerides, and
FFA, after 8 weeks therapy. There were no significant differences in
glucose, insulin, and lipids between the two groups at the beginning of
the study. After treatment, the decrease in fasting insulin was greater
in the DZ group than in the placebo group (P < 0.01),
without a significant change in fasting glucose concentrations in
either group.
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). Acute plasma insulin responses to
glucose (AIRg) were similar in DZ and placebo subjects
before treatment. DZ treatment resulted in a marked decrease in the
(AIRg), as compared with control subjects
(P < 0.01), without a significant change in
Kg (8–19 min). Furthermore, there was no significant
change observed in the SI, SG, and
glycohemoglobin after therapy.
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The intake of DZ caused minimal (but reversible) side effects in 5 of 12 subjects. No patient discontinued participation in the study because of side effects. Edema was noted in 4 of the patients; it resolved after the first 2 weeks of therapy. Three patients complained of headaches during the first week of therapy. Two patients experienced mild dyspepsia during the first week, which resolved when DZ suspension was administered after food intake. No patient observed hypertrichosis.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The relation of hyperinsulinemia and insulin resistance to obesity is becoming increasingly apparent, and the findings of the present study support the contention that attenuation of hyperinsulinemia will result in weight reduction in obese subjects. Hyperinsulinemia and insulin resistance are thought to induce preferential shunting of substrates toward adipose tissue, leading to adipocyte hypertrophy, hyperplasia, and conversion of preadipocytes to adipocytes. These are changes that contribute to a persistent lipogenic state and obesity (13). In humans, the pathogenesis and sequence of alterations in insulin secretion and action associated with obesity remain unknown. Previous studies have shown that under basal, fasting conditions, as well as during ingestion of a mixed diet, the hyperinsulinemia of obesity results predominantly from increased insulin secretion (14). Polonsky et al. (15) demonstrated that temporal a pattern of insulin secretion in hyperinsulinemic obese adults was largely normal, which suggests that the functioning ß-cell mass is enhanced but responds to normal regulatory mechanisms. Because hyperinsulinemia has been studied almost exclusively in patients with established, prolonged, and stable obesity (1, 14, 15, 16), at a stage of generalized insulin resistance, it is unclear whether increased insulin secretion is a cause or a consequence of insulin resistance. It is uncertain whether ß-cells already hyperfunction during the early stages of obesity. It has recently been suggested that SI may play a permissive role in BF accretion, such that a minimum value (threshold) is necessary for acute insulin secretion to have any effect on weight gain (6). In the present study, reduction in body weight in DZ-treated subjects was accompanied by marked attenuation of AIRg administration, with a modest but insignificant improvement in SI. This response is similar to that shown in our DZ-treated Obese Zucker rat studies, where the attenuation of hyperinsulinemia was associated not only with marked decrease in weight gain but also caused up-regulation of insulin receptors, enhanced glucose uptake, and decreased SI-to-antilipolytic action of insulin in isolated adipocytes (10, 11). Also, the decrease in BF was significantly greater in the DZ-treated group, with significantly greater body water and FFM/BF ratio than in the placebo group. However, it should be pointed out that the use of bioelectrical impedance has methodological limitations during periods of changing fluid states and possible DZ-induced edema. Therefore, the estimated FFM and body water data should be interpreted cautiously.
It is possible that the antiobesity effect of DZ may be, at least partly, caused by its extrapancreatic effects on adipose tissue and may be independent of its insulin-lowering action. Recent studies suggest that the K+[ATP] channel agonist, DZ, may decrease lipogenesis in primary fat cell culture by decreasing Ca+2 influx (17). It has been previously shown that the product of both the mouse and human agouti gene regulates adipocyte intracellular Ca2+ and stimulates adipocyte lipogenesis via a Ca2+-dependent process regulating fatty acid synthase (FAS) activity (18, 19). Kim et al. (20) have shown that treatment of obese viable yellow (Avy/a) mice with nifedipine, a Ca2+ channel blocker, resulted in significant decrease in fat pad weights and adipose FAS activity. A recent in vitro study, evaluating the direct effect of DZ on 3T3-L1 adipocytes, demonstrated that DZ-induced membrane hyperpolarization resulted in indirect inhibition of Ca2+ influx (17). Furthermore, DZ completely inhibited the 4-fold increase in FAS activity and triglyceride accumulation stimulated by insulin in 3T3-L1 adipocytes (17). In the same study, it was demonstrated that the sulfonylurea K+[ATP] antagonist glibenclamide, which depolarizes ß-cells and thereby stimulates insulin release, also increased intracellular Ca2+ in adipocytes in a dose-responsive fashion. Glibenclamide also caused a commensurate stimulation of adipocyte FAS activity, which was inhibited by DZ and the calcium channel antagonist, nitredipine. Thus, antagonism of K+[ATP] channels stimulates Ca2+ influx and, consequently, lipogenesis, whereas the K+[ATP] channel agonist, DZ, antagonizes these effects and presumably inhibits lipogenesis.
This preliminary study demonstrates that DZ-induced attenuation of hyperinsulinemia in obese individuals results in a significant decrease in BF, presumably caused by a decrease in lipogenesis. These findings suggest that modification of the disturbed insulin metabolism of obesity by DZ may be of potential benefit in achieving weight loss without inducing hyperglycemia. This is the first demonstration that DZ can act as a weight-reducing drug in humans. A number of recently introduced weight-reducing drugs, such as serotonin reuptake inhibitors (dexfenfluramine), and their combination with other appetite-suppressants (fenfluramine/phentermine) looked promising (21). However, serious side effects with these drugs have been reported that may make their routine administration unsafe (22, 23). The mechanism of action of DZ is completely different and is aimed at decreasing the hyperinsulinemia of obesity. DZ has been used for decades, in children and adults, to treat hyperinsulinemia-induced hypoglycemia with the following relatively few and reversible side effects: hypertrichosis, edema, hyperglycemia, hypotension, and hypercuricemia. Larger and long-term studies seem justified to evaluate the therapeutic effect of DZ in the management of obesity.
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Acknowledgments |
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Footnotes |
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Received October 20, 1997.
Accepted February 23, 1998.
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, P < 0.001.