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Glucose Metabolism Rather Than Insulin Is a Main Determinant of Leptin Secretion in Humans

Departments of Internal Medicine I (P.W., B.F.-S., W.K., D.D., H.L.F., A.P.) and Clinical Neuroendocrinology (J.B.), University of Lubeck, 23538 Lubeck; and Department of Diabetes and Metabolical Disorders, Klinikum Karlsburg (W.K.), Karlsburg 17495, Germany

Address all correspondence and requests for reprints to: Peter Wellhoener, M.D., Medical University Lubeck, Department of Internal Medicine I, 23538 Lubeck, Germany.

	Abstract

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Circulating plasma insulin and glucose levels are thought to be major regulators of leptin secretion. There is evidence from in vitro and animal experiments that glucose metabolism rather than insulin alone is a main determinant of leptin expression. Here, we tested the hypothesis that in humans also leptin secretion is primarily regulated by glucose uptake and only secondarily by plasma insulin and glucose. In 30 lean and healthy men we induced 4 experimental conditions by using the blood glucose clamp technique. A total of 60 hypoglycemic and euglycemic clamps, lasting 6 h each, were performed. During these clamps insulin was infused at either high (15.0 mU/min·kg) or low (1.5 mU/min·kg) rates, resulting in low-insulin-hypo, high-insulin-hypo, low-insulin-eu, and high-insulin-eu conditions. Serum leptin increased from 0–360 min by 20.5 ± 4.1% in the low-insulin-hypo, 33.6 ± 7.6% in the high-insulin-hypo, 39.6 ± 6.0% in the low-insulin-eu, and 60.4 ± 7.6% in the high-insulin-eu condition. Multiple regression analysis revealed a significant effect of circulating insulin (low vs. high insulin; P = 0.001) and blood glucose (hypoglycemia vs. euglycemia; P = 0.001) on the rise of serum leptin. However, when the total amount of dextrose infused during the clamp (grams of dextrose per kg BW) was included into the regression model, this variable was significantly related to the changes in serum leptin (P = 0.001), whereas circulating insulin and glucose had no additional effect. These findings in humans support previous in vitro data that leptin secretion is mainly related to glucose metabolism.

	Introduction

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LEPTIN, A PEPTIDE secreted by adipose tissue, is considered an important hormone of energy balance. The diurnal rhythm of plasma leptin is entrained to meal timing (1), suggesting that the meal-related increase in plasma insulin or glucose could be a major stimulus for leptin secretion. In fact, leptin levels have been shown to increase during euglycemic hyperinsulinemic clamp experiments (2). The changes in leptin levels during euglycemic clamps depend on the rate of insulin infusion, indicating a dose-dependent stimulatory effect of insulin on leptin secretion (3). However, using the same rate of insulin infusion, during hypoglycemic clamps the rise of leptin was attenuated compared to that during euglycemic clamps (4). In this context, it should be pointed out that during such clamp experiments the rate of insulin infusion and the target blood glucose level determine the glucose disposal rate, reflecting whole body glucose uptake.

There is evidence from in vitro and animal experiments that glucose metabolism rather than insulin alone is a main determinant for leptin expression (5, 6, 7). Mueller et al. demonstrated that a competitive inhibition of glucose transport by 2 deoxy-D-glucose, phloretin, and cytochalasin dose dependently decreased leptin secretion and messenger ribonucleic acid (RNA) content in cultured rat adipocytes (7). These researchers concluded that stimulation of leptin secretion by insulin is probably not due to a direct effect of insulin, but is secondary to its effect to stimulate glucose uptake in adipocytes. Furthermore, Mizuno et al. were able to show that plasma glucose significantly correlated with leptin messenger RNA in lean mice and that glucose and insulin enhanced leptin messenger RNA in lean animals (6). On this background, we hypothesized that in humans also primarily glucose uptake regulates leptin secretion and that insulin only serves as a permissive factor facilitating glucose uptake.

	Subjects and Methods

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Subjects

Experiments were carried out in 30 lean healthy men [mean ± SEM age, 25.7 ± 0.8 yr; range, 22–32 yr; body mass index (BMI), 22.9 ± 0.4 kg/m²; range, 18.6–26.0 kg/m²]. Exclusion criteria were chronic or acute illness, current medication of any kind, smoking, alcohol or drug abuse, and diabetes or hypertension in first degree relatives. Each volunteer gave written informed consent, and the study was approved by the local ethics committee.

Study design

To achieve 4 experimental conditions with different glucose disposal rates, i.e. whole body glucose uptake, we varied either the rate of insulin infusion (high insulin vs. low insulin) or the target blood glucose (euglycemic vs. hypoglycemic) in a total of 60 clamp experiments. Experiments lasting 6 h each were carried out in 30 healthy men randomly assigned to 2 different groups (each of 15 persons). Every subject participated in a series of 2 clamp sessions that differed in glucose target levels (hypoglycemia and euglycemia), with the order of sessions balanced across subjects. Both clamp sessions were separated by at least 4 weeks. Insulin infusion rate during the clamps was 1.5 mU/min·kg (low) in 1 group of 15 subjects and 15.0 mU/min·kg (high) in another group of 15 subjects. Thus, the 4 conditions included a hypoglycemic clamp with a low rate of insulin infusion (low-insulin-hypo), a hypoglycemic clamp with a high rate of insulin infusion (high-insulin-hypo), an euglycemic clamp with a low rate of insulin infusion (low-insulin-eu), and an euglycemic clamp with a high rate of insulin infusion (high-insulin-eu).

Clamp procedure

After a 10-h overnight fast subjects arrived at our medical research unit at 0800 h. They were seated in a comfortable position, and a venous cannula was inserted into a vein on the back of the right hand. This hand was kept in a heated box (50–55 C) to obtain arterialized blood. After a 1-h baseline period, insulin (Hoechst, Frankfurt, Germany) was infused via a second cannula in the left antecubital vein at a continuous flow of either 1.5 or 15.0 mU/min·kg depending on the experimental condition. Simultaneously a 20% dextrose solution was infused at variable rates to control serum glucose. Arterialized blood was drawn every 5 min to measure blood glucose (Beckman glucose analyzer, Munich, Germany). During euglycemic clamps serum glucose was held stable at 5.0–5.5 mmol/L. During the stepwise hypoglycemic clamps we reduced serum glucose to achieve plateaus of 4.2, 3.7, 3.0, and 2.3 mmol/L. Plateaus were held for 45 min; the time to achieve the next lower plateau was set at 45 min.

Measurements

Blood for leptin and insulin determinations was collected every 30 min. Serum was kept at -20 C until analysis. In the high insulin group potassium was controlled every 30 min and substituted orally when below 4.0 mmol/L. The glucose infusion rate was integrated over time to calculate the total amount of dextrose infused (in grams per kg BW). RIAs were used to measure insulin [Pharmacia Biotech, Uppsala, Sweden; interassay coefficient of variation (CV), 7.5%; intraassay CV, 5.4%] and leptin (Linco Research, Inc., St. Louis, MO; interassay CV, 6.1%; intraassay CV, 5.4%).

Statistical analysis

Data are reported as the mean ± SEM. P < 0.05 was considered significant. Because of greater interindividual variability in baseline leptin levels, changes in serum leptin during the clamp were expressed as leptin (%). leptin (%) was calculated as the difference between the levels at 360 and 0 min divided by the level at 0 min. ANOVA for repeated measures on the changes in serum leptin were performed across all four conditions, including the factors insulin (high vs. low insulin infusion rate) and blood glucose (euglycemic vs. hypoglycemic condition). We also calculated the ratio between the changes in serum leptin from 0–360 min (percentage) and the total amount of dextrose (grams per kg) that was infused during the whole clamp. ANOVA for repeated measures performed on these ratios was also performed across all four conditions. For further analysis we applied multiple linear regression of serum leptin at 360 min to the total amount of infused dextrose and covariates. Leptin at baseline (0 min) was included regardless of statistical significance. The variables insulin (high vs. low insulin infusion rate), blood glucose (euglycemic vs. hypoglycemic condition), BMI, and insulin resistance were conditionally selected in a forward stepwise procedure (inclusion criteria, P < 0.05). Insulin resistance was calculated using the homeostasis model assessment (HOMA) of fasting insulin and glucose levels (8). Data were analyzed using the SPSS, Inc. statistical program (version 6.1, SSPS, Inc., Chicago, IL).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Figure 1 shows blood glucose and insulin levels during hypoglycemic and euglycemic clamps. Blood glucose concentrations were equal in the low and high insulin conditions throughout all sessions. In the high insulin condition, however, serum insulin concentrations 60 min after the clamps were started were approximately 40-fold higher than those in the low insulin condition. They were 622 ± 32 pmol/L in the low-insulin-hypo, 23,624 ± 1,587 pmol/L in the high-insulin-hypo, 543 ± 34 pmol/L in the low-insulin-eu, and 24,029 ± 1,595 pmol/L in the high-insulin-eu condition. The total amount of dextrose per kg BW infused during the clamps was 2.00 ± 0.17 g/kg in the low-insulin-hypo, 3.05 ± 0.13 g/kg in the high-insulin-hypo, 3.66 ± 0.17 g/kg in the low-insulin-eu, and 4.61 ± 0.12 g/kg in the high-insulin-eu condition.

View larger version (20K): [in this window] [in a new window]   Figure 1. Serum insulin levels and blood glucose during hypoglycemic and euglycemic clamp experiments. The insulin infusion rate in the low insulin group was 1.5 mU/min·kg; that in the high insulin group was 15.0 mU/min·kg. Open symbols represent clamps with low insulin infusion rates; solid symbols represent clamps with high insulin infusion rates. Triangles are hypoglycemic clamp conditions; circles are euglycemic clamp conditions.

View larger version (15K): [in this window] [in a new window]   Figure 2. Scatterplot with bidirectional error bars. The leptin (%) at time t vs. the total amount of infused dextrose during the experiment until time t. Open symbols represent clamps with low insulin concentrations; solid symbols represent clamps with high insulin concentrations. Triangles are hypoglycemic clamp conditions; circles are euglycemic clamp conditions. The relations of leptin (%) vs. infused dextrose are virtually identical despite different insulin concentrations and different levels of glycemia.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

We designed our study to detect insulin effects on serum leptin by using different levels of hyperinsulinemia. Increasing insulin levels to 500 pmol/L, as we did in the low insulin group, will virtually eliminate hepatic glucose production (10). Given an inhibited glucose production by the liver the dextrose infusion rate in our experiments approximately reflects the whole body glucose uptake. Although at this level of hyperinsulinemia the effect on glucose production is complete, glucose utilization is not saturated. It takes a high arterial plasma insulin over 2500 pmol/L to saturate glucose uptake under euglycemic conditions (11). To examine insulin effects under conditions of a complete blockade of hepatic glucose output, we compared two levels of hyperinsulinemia, i.e. approximately 500 and 25,000 pmol/L. To detect an insulin dose-response relationship on receptor and postreceptor effects, Koltermann et al. used the hyperinsulinemic clamp technique in humans with high doses of hyperinsulinemia (12, 13). Here we used the same method with similar doses of insulin to study a dose-response relationship on serum leptin concentrations. The dose-response relationship between the serum insulin level and whole body glucose uptake is a sigmoid curve. Thus, an effect of changes in insulin in the lower range can be expected to be more pronounced than the effect we observed here with high concentrations. To be able to detect smaller effects, a larger sample (including a total of 60 clamp sessions) of a homogeneous group was investigated.

During the hypoglycemic clamps, the counterregulatory increase in cortisol and epinephrine levels could potentially have influenced leptin secretion. For instance, epinephrine has been shown to inhibit leptin secretion (14, 15, 16), whereas glucocorticoids, e.g. dexamethasone, have been shown to stimulate leptin secretion in humans (17, 18, 19). However, compared to the euglycemic clamps, the increase in leptin levels during the hypoglycemic clamps was already blunted after 120 min, i.e. when blood glucose was approximately 4.0 mmol/L. As this level of blood glucose was unlikely to have stimulated epinephrine and cortisol secretion (20), an effect of these counterregulatory hormones on the early differences in leptin levels between the hypoglycemic and euglycemic clamp conditions can be excluded.

Glucose uptake by skeletal muscles and adipose tissue decreases by 60–70% during insulin-induced hypoglycemia. This decline is a counterregulatory mechanism that allows shunting of glucose to more important organs, e.g. the brain (21, 22). As shown in Fig. 2, the relation between serum leptin and the amount of dextrose infused was virtually identical during hypoglycemic and euglycemic clamp conditions. Thus, it is unlikely that the counterregulatory hormones have exerted a major effect on serum leptin that has not been mediated by glucose uptake.

In interpreting the results one limitation of our study is that two of the experimental conditions (low-insulin-hypo and high-insulin-hypo) were not strictly at steady state, so the glucose infusion rate may not have accurately reflected whole body glucose disposal or glucose utilization. A second limitation was that we did not directly measure glucose uptake into adipose tissue, which is known to be the major source of leptin production. It seems reasonable, however, to assume that during hyperinsulinemic clamps in healthy individuals glucose uptake into adipose tissue will parallel whole body glucose uptake.

One potential mechanism by which glucose uptake could regulate leptin secretion has been identified by Wang et al., showing that increased tissue concentrations of the end product of the hexosamine biosynthetic pathway, UDP-N-acetylglucosamine, results in rapid and marked increases in leptin messenger RNA and protein levels (23). The hexosamine biosynthetic pathway is a cellular sensor of energy availability and mediates the effect of glucose on the expression of several gene products (24, 25). Thus, it seems possible that in the present study infusion of insulin and glucose have increased glucose uptake into the adipose tissue, causing an accumulation of UDP-N-acetylglucosamine, which then stimulated leptin secretion.

In summary, the amount of infused dextrose closely paralleled the rise of serum leptin in all experiments. Throughout all conditions, the increase in leptin per amount of infused dextrose was constant and independent of blood glucose and insulin levels. Therefore, our findings in humans support previous data from in vitro and animal experiments that leptin secretion is mainly related to glucose metabolism.

	Acknowledgments

 
We thank Christiane Zinke and Steffi Baxmann for their expert and invaluable laboratory assistance, and Anja Otterbein for her organizational work. We gratefully thank Dr. Thomas Kohlmann for his methodological advice.

Received August 11, 1999.

Revised November 19, 1999.

Accepted December 6, 1999.

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