Diabetes Care 28:1225-1227, 2005
© 2005 by the American Diabetes Association, Inc.
Metabolic Syndrome/Insulin Resistance Syndrome/Pre-Diabetes
Brief Report |
Glucose-Induced Insulin Secretion in Dyslipidemic and Normolipidemic Patients With Normal Glucose Tolerance
Christophe Binnert, PHD1,
Myriam Genoud, MD2,
Gérald Seematter, MD1,
Assia Fekirini, MD1,
Vincent Mooser, MD, PHD3,
Gérard Waeber, MD, PHD2 and
Luc Tappy, MD1,4
1 Department of Physiology, Medical School, University of Lausanne, Lausanne, Switzerland
2 Department of Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland
3 GlaxoSmithKline, Collegeville, Pennsylvania
4 Division of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital, Lausanne, Switzerland
Address correspondence and reprint requests to Prof. L. Tappy, Département de physiologie, 7 rue du Bugnon, 1005 Lausanne, Switzerland. E-mail: luc.tappy{at}unil.ch
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INTRODUCTION
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The metabolic syndrome is highly prevalent in industrialized countries, where it represents a major public health burden due to the associated high risk of diabetes and cardiovascular disorders (1,2). High plasma triglyceride and low HDL cholesterol are prominent features of this syndrome (2,3). Large epidemiological studies have shown associations with both insulin resistance and low insulin secretion (4). The aim of this study was to evaluate whether the alterations of blood lipid, observed in the metabolic syndrome, are associated with alterations of insulin sensitivity or secretion in subjects with normal glucose tolerance. Glucose homeostasis was evaluated during a two-step hyperglycemic clamp in a group of dyslipidemic patients and in a group of normolipemic subjects of similar age and body weight. Subjects were studied after short-term administration of dexamethasone to evaluate reciprocal changes in insulin secretion and insulin sensitivity (5,6,7,8).
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RESEARCH DESIGN AND METHODS
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Twenty dyslipidemic subjects (13 men and 7 women) with BMI >27 kg/m2 but having normal glucose tolerance, as documented by a standard oral glucose tolerance test (fasting glycemia 94 ± 7 mg/dl, 2-h glycemia 95 ± 17 mg/dl) (9), were selected for the study. They had a mean (±SD) age of 46.6 ± 7.6 years, body weight of 85.4 ± 10.3 kg, height of 173.2 ± 9.2 cm, BMI of 28.6 ± 4.1 kg/m2, waist circumference of 98.9 ± 11.0 cm, waist-to-hip ratio of 0.91 ± 0.08, fasting plasma triglyceride concentration of 2.25 ± 0.84 mmol/l, fasting total plasma cholesterol concentration of 5.66 ± 1.04 mmol/l, fasting HDL cholesterol concentration of 1.06 ± 0.11 mmol/l, and blood pressure of 123 ± 13/78 ± 8 mmHg. They were compared with a group of 20 normolipemic subjects (18 men and 2 women) with normal glucose tolerance (fasting glycemia 96 ± 7 mg/dl, 2-h glycemia 95 ± 22 mg/dl) and similar age (52.6 ± 6.3 years), body weight (91.8 ± 17.2 kg), height (176 ± 10 cm), BMI (29.6 ± 3.9), waist circumference (99.6 ± 12.2 cm), waist-to-hip ratio (0.91 ± 0.07), and blood pressure (126 ± 11/80 ± 7 mmHg) but had normal triglyceride (0.80 ± 0.21 mmol/l), total cholesterol (5.03 ± 0.91 mmol/l), and HDL cholesterol (1.71 ± 0.27 mmol/l) concentrations. All subjects were recruited from the GEMS (Genetic Epidemiology of Metabolic Syndrome) project study population (10). Fourteen dyslipidemic and no normolipemic patients fulfilled the criteria for the metabolic syndrome (2). Six dyslipidemic and three normolipemic subjects were receiving treatment for high blood pressure, and two dyslipidemic patients were being treated with statins.
Each participant took part in a two-step hyperglycemic clamp (target glycemia of 135 mg/dl during 60 min and of 180 mg/dl during the next 60 min) to simultaneously evaluate glucose-induced insulin secretion and glucose/insulin-mediated glucose disposal. Participants received 2 mg/day dexamethasone during the 2 days preceding the clamp procedure and 0.5 mg on the morning of the procedure. [6,6-2H2]glucose (bolus 2 mg/kg, continuous infusion 20 µg/kg/min for 60 min before the clamp, then exogenous glucose labeled with 1.25% [6,6-2H2]glucose [hot infusate approach] [11]) was used to calculate whole-body glucose kinetics. The results obtained were compared by means of unpaired t tests.
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RESULTS
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At their inclusion in the study, dyslipidemic and normolipemic subjects had similar fasting plasma glucose (94 ± 7 vs. 97 ± 7 mg/dl) and insulin (31.5 ± 4.9 vs. 31.7 ± 7.4 mU/l). After administration of dexamethasone for 2 days (Table 1), dyslipidemic subjects had fasting glucose and insulin concentrations that were not significantly different from those of normolipemic subjects. During the clamp procedure, similar rates of exogenous glucose infusion were necessary to maintain target glycemia (Table 1). However, the rates of exogenous infusion divided by steady-state plasma insulin concentration were lower in dyslipidemic than in normolipemic subjects, indicating impaired glucose/insulin-induced glucose metabolism. Compared with normolipemic subjects, dyslipidemic subjects had 41 and 74% higher plasma insulin concentrations during the low and high plateaus of glycemia, respectively. Basal endogenous glucose production and its suppression at both plateaus of glycemia were similar in dyslipidemic and normolipemic subjects.
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Table 1— Parameters of glucose metabolism during the two-step hyperglycemic clamp procedure in dyslipidemic and normolipemic overweight subjects with normal glucose tolerance
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CONCLUSIONS
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This study focused on dyslipidemic patients free of any disorder of glucose homeostasis. Such patients offer the possibility to investigate the contribution of insulin sensitivity and/or secretion in the pathogenesis of dyslipidemia. Glucose homeostasis was evaluated by a two-step hyperglycemic clamp after administration of dexamethasone, a procedure aimed at decreasing insulin sensitivity with compensatory hyperinsulinemia. The rate of exogenous glucose infusion divided by plasma insulin concentration was lower in dyslipidemic than in normolipemic subjects, indicating a lower insulin- and glucose-induced glucose disposal. Although this protocol was not performed without dexamethasone administration, these results are consistent with some degree of insulin resistance in dyslipidemic subjects. Dyslipidemic subjects also had significantly higher plasma insulin concentration at each plateau of glycemia, consistent with impaired insulin sensitivity, but this also indicates that their glucose-induced insulin secretion was not decreased. This hyperinsulinemia cannot be attributed to differences in BMI or body fat distribution, since dyslipidemic and normolipemic patients had similar characteristics. Since both groups had similar plasma glucose and insulin concentrations before dexamethasone, we propose that short-term dexamethasone administration offers a way to detect subclinical insulin resistance in dyslipidemic patients.
In conclusion, our results indicate that dyslipidemic, glucose-tolerant patients have increased glucose-induced insulin secretion to compensate for impaired insulin sensitivity. We propose that these alterations are indicative of insulin resistance in dyslipidemic patients. The chronic hyperinsulinemia consecutive to insulin resistance may possibly contribute to increase plasma triglyceride concentrations by stimulation of hepatic de novo lipogenesis and secretion of VLDL lipoproteins (12,13). Conversely, it is also possible that primary alterations of hepatic lipid metabolism, leading to hypertriglyceridemia and low HDL levels may in the long-term contribute to the development of insulin resistance and hyperinsulinemia (14,15). Only prospective studies in individuals at risk for the metabolic syndrome will provide clarification between these two hypotheses.
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Acknowledgments
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This study was funded by a grant (3200-067787) from the Swiss National Science Foundation.
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Footnotes
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A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
Received for publication December 9, 2004.
Accepted for publication February 8, 2005.
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References
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INTRODUCTION
RESEARCH DESIGN AND METHODS