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Supraphysiological Hyperinsulinemia Acutely Increases Hypothalamic-Pituitary-Adrenal Secretory Activity in Humans

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

Address all correspondence and requests for reprints to: Bernd Fruehwald-Schultes, M.D., Medical University Luebeck Department of Internal Medicine I, Ratzeburger Allee 160, D-23538 Luebeck, Germany. E-mail: fruehwal{at}kfg.mu-luebeck.de

	Abstract

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Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in association with hyperinsulinemia is frequently found in patients with type 1 and type 2 diabetes mellitus and in subjects with abdominal adiposity. We questioned whether insulin could cause HPA axis activation and, if so, whether this insulin action may arise at the adrenal level or at a central (i.e. hypothalamic-pituitary) level. Experiments lasting for 6 h each were done in 30 lean healthy men. In 15 men, insulin was infused at a rate of 1.5 mU min^-1kg^-1. Plasma glucose concentration was held constant during an euglycemic clamp session and was decreased stepwise in a hypoglycemic clamp session. The sequence of the 2 clamp sessions was random, and a 4-weeks recovery period was allowed between the two sessions. The protocol was essentially the same in another 15 men, with the exception that insulin was infused at a rate of 15.0 mU min^-1kg^-1. During the euglycemic clamp sessions, we found plasma ACTH levels to increase only in the high-, but not in the low-insulin group (group by time interaction, P < 0.01); serum cortisol levels were greater in the high than in the low-insulin group (P < 0.02). In the hypoglycemic clamp sessions, plasma ACTH levels increased in the same pattern in the 2 groups; serum cortisol was greater in the high than in the low-insulin group at the beginning of the clamp (plasma glucose 4.1 mmol/L; P < 0.05). Our results demonstrate that insulin acutely stimulates the HPA secretory activity in humans. The pattern suggests an effect of insulin at both peripheral and central levels of the HPA axis.

	Introduction

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HYPERACTIVITY of the hypothalamic-pituitary-adrenal (HPA) axis and hyperinsulinemia are frequently observed in patients with type 1 and type 2 diabetes (1, 2, 3, 4, 5, 6, 7), as well as in patients with abdominal adiposity (8, 9, 10, 11). Although hyperinsulinemia is secondary to exogenous insulin administration (12) or peripheral insulin resistance (13, 14), the causes of HPA hyperactivity in those subjects remain obscure. It has been well established that hypercortisolism, e.g. in Cushing’s syndrome, induces insulin resistance and compensatory hyperinsulinemia (15). However, it remains unclear as to whether hyperinsulinemia induces secretory activation of the HPA axis. Here, the question has been posed as to whether insulin stimulates the HPA axis, and if so, whether this stimulation is caused by a central or a peripheral mechanism. In an attempt to answer these questions, euglycemic and hypoglycemic clamp experiments were performed, at respective intervals of at least 4 weeks, on each of 30 healthy young males, subdivided into 2 groups according to the rate of insulin infusion. Plasma concentrations of ACTH and cortisol were measured every 30 min, over a 6-h period. The approach of inducing different levels of hyperinsulinemia has previously been used to assess dose-dependent effects of insulin on several parameters, such as glucose uptake (16, 17). Here, we used the same approach to assess dose-dependent effects of insulin on HPA secretory activity.

	Subjects and Methods

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Subjects

Thirty young, healthy men participated in the experiments. Exclusion criteria were chronic or acute illness, current medication of any kind, smoking, alcohol or drug abuse, adiposity, and diabetes or hypertension in first-degree relatives. Each volunteer gave written informed consent, and the study was approved by the local ethics committee.

Experimental design

Each subject underwent a hyperinsulinemic hypoglycemic clamp experiment and a hyperinsulinemic euglycemic clamp experiment, separated by an interval of at least 4 weeks. The order of conditions was balanced across subjects, and experiments were performed in a single-blind fashion. The 30 subjects were randomly assigned to 2 different groups of 15 subjects each. In the first group, insulin was infused at a rate of 1.5 mU min^-1kg^-1 during both clamp sessions (low-insulin group), whereas in the second group, insulin was infused at a rate of 15.0 mU min^-1 kg^-1 during both clamp sessions (high-insulin group). The low-insulin group had a mean age (± SEM) of 26.0 ± 1.0 yr (range, 22–32 yr) and a mean BMI of 22.5 ± 0.6 kg m^-2 (18.6–25.5 kg m^-2); the high-insulin group had a mean age of 25.4 ± 0.6 yr (23–29 yr), and a mean BMI of 23.2 ± 0.5 kg m^-2 (19.9–26.0 kg m^-2).

All subjects were requested to abstain from alcohol, not to perform any kind of exhausting physical activity, and to go to bed no later than 2100 h on the day preceding the study. On the day of the study, subjects came to the medical research unit at 0800 h, after an overnight fast of at least 10 h. The experiments took place in a sound-attenuated room with the subjects sitting with their trunk in an almost upright position (about 60 degrees) and their legs in a horizontal position on the bed. A cannula was inserted into a vein on the back of the hand, which was placed in a heated box (50–55 C) to obtain arterialized venous blood. A second cannula was inserted into an antecubital vein of the contralateral arm. Both cannulas were connected to long thin tubes, which enabled blood sampling and adjustment of the rate of dextrose infusion from an adjacent room without the knowledge of the subject. After a 1-h baseline period, insulin (H-insulin, Hoechst Marion Roussel, Inc., Frankfurt, Germany) was infused at a continuous rate of either 1.5 mU min^-1kg^-1 or 15.0 mU min^-1kg^-1, respectively, depending upon the group. A 20% dextrose solution was simultaneously infused at a variable rate to control plasma glucose levels. Arterialized blood was drawn at 5-min intervals to measure plasma glucose concentration (Glucose Analyser, Beckman Coulter, Inc., Munich, Germany). In euglycemic clamp sessions, plasma glucose was held stable between 5.0 and 5.5 mmol/L. In hypoglycemic clamp sessions, plasma glucose levels were reduced, in a stepwise manner, to achieve four respective plateaus of 4.1, 3.6, 3.1, and 2.6 mmol/L. Each plateau was maintained for a 45-min period, and the next lower plateau was induced gradually within the next 45 min. Blood samples for determination of plasma or serum levels of insulin, cortisol, and ACTH were collected every 30 min. During high-dose insulin infusion, potassium concentrations were monitored at 30-min intervals, and substitution was given whenever the level fell below 4.0 mmol L^-1.

Analytical methods

All blood samples were immediately centrifuged, and the supernatants were stored at -24 C until assay. Serum insulin was measured by RIA (Pharmacia Insulin RIA 100, Pharmacia Diagnostics, Uppsala, Sweden) with an interassay coefficient of variation (CV) < 5.8% and an intraassay CV < 5.4%. Serum cortisol was measured by enzyme-linked immunosorbent assay (Enzymun-Test Cortisol, Roche Molecular Biochemicals Immundiagnostica, Mannhein, Germany) with an interassay CV < 3.0% and an intraassay CV < 4.2%. Plasma ACTH was measured by immunoluminometric assay (LUMI test ACTH, Brahms Diagnostica, Berlin, Germany) with an interassay CV < 12% and an intraassay CV < 8%.

Statistical methods

All values are presented as means ± SEM. Statistical analysis was based on analyses of covariance (ANCOVAs) for repeated measurements, including the factors group (low vs. high insulin) and time (duration of the clamp), with baseline values (0 min) serving as the covariate. The interaction effect of these two factors were termed: group by time. Serum insulin concentrations were compared using the unpaired Student’s t test. A P-value < 0.05 was considered statistically significant.

	Results

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Plasma glucose and serum insulin

Table 1 presents the levels of all measurements at baseline and the end of the clamp. Plasma glucose concentrations did not differ between the high- and the low-insulin groups during either the euglycemic (Fig. 1A) or the hypoglycemic (Fig. 2A) clamp sessions. Mean serum insulin concentrations were approximately 40-fold greater in the high- than in the low-insulin group during the euglycemic clamp sessions (543 ± 34 vs. 24,029 ± 1,595 pmol/L; P < 0.0001; Fig. 1B) and during the hypoglycemic clamp sessions (622 ± 32 vs. 23,624 ± 1,587 pmol/L; P < 0.0001; Fig. 2B).

View larger version (21K): [in this window] [in a new window]   Figure 1. Mean (SEM) plasma or serum concentrations of glucose (A), insulin (B), ACTH (C), and cortisol (D) during the euglycemic clamp session of the low-insulin group (; dotted line) and the high-insulin group (•; solid line). Each group consisted of 15 healthy men. SEMs of serum insulin concentrations were smaller than the size of symbols.

View larger version (21K): [in this window] [in a new window]   Figure 2. Mean (SEM) plasma or serum concentrations of glucose (A), insulin (B), ACTH (C), and cortisol (D) during the hypoglycemic clamp session of the low-insulin group (; dotted line) and the high-insulin group (•; solid line). Each group consisted of 15 healthy men. SEMs of serum insulin concentrations were smaller than the size of symbols.

During the euglycemic clamp sessions, plasma ACTH concentrations in the low-insulin group did not essentially change (Fig. 1C), whereas plasma ACTH concentrations in the high-insulin group increased from 4.3 ± 0.3 to 7.6 ± 1.4 pmol/L (group by time, P < 0.01). Serum cortisol concentrations in the low-insulin group gradually decreased, whereas serum cortisol concentrations in the high-insulin group slightly increased (Fig. 1D). ANCOVA revealed a clear difference between the groups in regard to serum cortisol, with higher concentrations in the high-insulin group (effect of group, P < 0.02); this difference increased with duration of the clamp (group by time, P < 0.005).

During the hypoglycemic clamp sessions, plasma levels of ACTH increased in a similar pattern in both groups (Fig. 2C; effect of time, P < 0.0001). Likewise, in both groups, serum levels of cortisol increased to comparable peak values (Table 1; effect of time, P < 0.0001). However, separate analyses of the different hypoglycemic plateaus revealed higher levels of cortisol in the high- than low-insulin group for the first hypoglycemic plateau, i.e. 4.1 mmol/L (240 ± 30 vs. 350 ± 30; P < 0.05).

Dependency of cortisol on ACTH

To determine to what extent the changes in cortisol could be reduced to effects of insulin on plasma ACTH levels, ANCOVAs were performed on cortisol levels (at each point in time) with corresponding ACTH concentrations serving as covariates, i.e. adjusting for ACTH levels. Values of ACTH concentrations were log-transformed before this analysis, taking into account the logarithmic relationship between cortisol release after exogenous ACTH administration found in previous studies (18). The present analyses revealed that cortisol levels during the euglycemic and the hypoglycemic clamp sessions were strongly related to ACTH (with ACTH as covariate at each time point, P < 0.001). At most points in time during the euglycemic and the hypoglycemic clamp sessions, differences in serum cortisol between the two groups were completely explained by differences in plasma ACTH (with residual effects of the group being not significant).

However, the differences in serum cortisol concentrations between the high- and the low-insulin groups during the second hour of the euglycemic (Fig. 1) and the hypoglycemic (Fig. 2) clamp sessions occurred without differences in ACTH levels between the groups. At 90 min, e.g. differences in serum cortisol between the two groups remained significant, even after adjusting for plasma ACTH (effect of group: euglycemia, P < 0.02; hypoglycemia, P < 0.05, respectively).

	Discussion

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The present results demonstrate an acute stimulatory effect of supraphysiological levels of insulin on HPA secretory activity in humans. Because plasma ACTH has been found to increase during experiments with a high rate of insulin infusion, as compared with those performed at a low rate of insulin infusion, it is likely that the effects of insulin pertained to the pituitary or central nervous stages of this axis. However, we also found differences in cortisol levels between the high and the low rates of insulin infusion that were not explained by differences in ACTH levels, implying that insulin induces cortisol release additionally via a direct influence on the adrenals. The stimulatory effect of insulin on HPA secretory activity was detected during euglycemia and at low levels (4.1 mmol/L) of hypoglycemia.

The finding that supraphysiological hyperinsulinemia acutely stimulates HPA secretory activity during euglycemia agrees with previous observations that cortisol concentrations increase from baseline during hyperinsulinemic euglycemic clamp experiments in dogs (19) and in humans (20, 21). However, because those studies had no control condition, they did not allow for a straightforward conclusion as to a causative role of insulin for the increased release of cortisol. Other undefined factors, such as experimental stress, also could have caused the increase in cortisol levels of those studies. Here, different supraphysiological degrees of hyperinsulinemia were induced to investigate the effect of insulin per se on plasma concentrations of ACTH and cortisol. This approach seems to be superior to a comparison of the effects of insulin infusion and fasting without insulin infusion, i.e. placebo condition. During fasting, plasma glucose decreases in conjunction with various neuroendocrine changes (22), which may per se act on HPA activity (23), and thereby prevent a clear-cut interpretation of changes after insulin administration. Such metabolic and neuroendocrine changes are absent or attenuated during supraphysiological hyperinsulinemic euglycemic clamps. Moreover, it must be emphasized, in this context, that in the present experiments both low- and high-insulin groups were subjected to exactly the same experimental conditions, concerning potential stress factors, which excludes a confounding influence by these factors.

Insulin seems to be a minor stimulus for HPA activation, as compared with neuroglucopenia, because an additional stimulatory effect of insulin on ACTH/cortisol release was not detectable during more pronounced hypoglycemia, i.e. neuroglucopenia. The strong stimulatory effect of hypoglycemia may have covered the moderate stimulatory effect of insulin on HPA secretory activity. This view seems to be supported by several foregoing studies investigating the effects of hypoglycemic clamps at different levels of hyperinsulinemia in humans, which provided completely inconsistent results. The cortisol response to hypoglycemia in those studies was found to be attenuated (24), not different (25, 26), and amplified (27, 28) by high-dose insulin infusion, as compared with a low-dose insulin infusion. However, a selective increase in the level of insulin in the blood perfusing the brain has been shown to amplify the cortisol response to mild hypoglycemia (3.2 mmol/L) in dogs (29). This experimental data suggests that insulin also increases HPA secretory response to moderate hypoglycemic-stress. In addition, in a recent study (30), we demonstrated a prolonged stimulatory effect of insulin on HPA secretory activity, preventing the development of hypoglycemia-associated counterregulatory failure.

The magnitude of the stimulatory effect of insulin on HPA activity cannot be determined directly from the present results because we compared effects of two different supraphysiological degrees of hyperinsulinemia. However, in the light of findings indicating a sigmoid dose-response relationship for the effects of insulin on various other physiological parameters (31), one may assume that the effects of insulin on HPA activity will follow a similar dose-response curve. Because serum insulin levels were supraphysiological under both sets of experimental conditions, the differences between the effects of the two different degrees of hyperinsulinemia were expected to be small. To detect small differences, the study included a relatively large number of rather homogeneous subjects. Although the magnitude of insulin effect on HPA activity cannot be defined exactly here, the present results provide evidence that insulin is capable of stimulating HPA activity.

Because the present study did not include a placebo condition (without insulin infusion), for the above mentioned reasons, it remains unclear whether the low rate of insulin infusion also had a stimulatory effect on HPA secretory activity during the euglycemic clamp. However, the rapid fall in ACTH and cortisol levels, observed during the baseline period, abruptly stopped 30–60 min after starting the low rate of insulin infusion (Fig. 1). This finding may hint at an effect of the low rate of insulin infusion on the diurnal variations of HPA secretory activity, attenuating or delaying the commonly observed decrease in ACTH and cortisol levels throughout daytime. Support for this view derives from a comparison of the present data with those obtained during a previous study (32) investigating the diurnal plasma cortisol pattern in healthy male subjects. In this study, cortisol levels decreased by about 60 nmol/L between 1000 h and 1200 h, whereas in the present study, cortisol levels decreased only by 20 nmol/L during this time interval, i.e. the first 2 h of low-rate insulin infusion.

Interestingly, ACTH levels increased during the high-rate insulin infusion of the euglycemic clamp, whereas cortisol levels essentially did not change (Table 1). Correspondingly, ACTH levels did not change during the low rate of insulin infusion of the euglycemic clamp, whereas cortisol levels decreased. This finding may be explained by the diurnal variations in adrenal sensitivity to the effects of ACTH, which have been demonstrated to be highest during the time of greatest spontaneous HPA secretory activity in rats (33). Furthermore, there is also a diurnal change in ACTH sensitivity to corticosterone feedback (34). Together, these mechanisms may likely explain the changes in the ACTH-to-cortisol relationship observed during the euglycemic clamps.

Because it is well established that insulin crosses the blood-brain barrier (35), the effect of insulin on ACTH release could be exerted at 3 levels, i.e. the hippocampus, the hypothalamus, and the pituitary. The hippocampus is one of the brain regions with the highest density of insulin receptors (36) and a mediator of negative feedback effects of corticosteroids on HPA activity (37). By inhibiting hippocampal activity (36), insulin may impair this feedback regulation, thereby enhancing ACTH and cortisol release. The hypothalamus is another possible site for insulin to exert its effect on ACTH release. Evidence for this view derives from experiments by Grunstein et al. (38), demonstrating, in rats, that hyperinsulinemia suppresses glucose use in the medial basal hypothalamus, accompanied by an increase in serum corticosterone. Thus, even with normal plasma glucose concentration, hyperinsulinemia may induce neuroglucopenia in the medial basal hypothalamus and counterregulatory hormone release. At the pituitary, insulin may directly influence ACTH release, because insulin receptors have been found widely dispersed throughout the pituitary gland (39).

The present data also suggest that insulin activates cortisol release at peripheral sites independently of its effect on ACTH release. This insulin effect could be localized at the adrenals or at extraadrenal sites. The adrenals are a likely site for such an insulin effect, given that Penhoat and colleagues (40) have found and characterized insulin receptors in bovine adrenal fasciculata cells. Furthermore, they demonstrated that insulin enhances the steroidogenic and cAMP response to ACTH, in a series of in vitro experiments. Based on this background, insulin may also, in vivo, enhance adrenocorticotropic action of ACTH. Therefore, the stimulation of cortisol secretion by insulin does not seem to be entirely independent of ACTH release, but rather reflects an increased sensitivity of the adrenals to the action of ACTH.

At extra adrenal sites, insulin may also increase plasma cortisol concentration, considering that Bujalska et al. (41) recently demonstrated that adipose stromal cells from omental fat have a large capacity to convert inactive cortisone to active cortisol through the expression of 11ß-HSD1 (11ß-hydroxysteroid dehydrogenase isoform 1). In vitro, insulin increased the expression and activity of this enzyme (41). This mechanism of converting cortisone to cortisol could be likewise relevant for the in vivo increase in cortisol concentrations after insulin administration.

In summary, this study provides evidence for an acute stimulatory effect of insulin on HPA secretory activity in humans. This finding may explain, at least in part, the frequently found hyperactivity of the HPA axis in hyperinsulinemic subjects, such as patients with diabetes or abdominal adiposity.

	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 and Dr. Carol Falk for her language advice.

Received November 12, 1998.

Revised April 6, 1999.

Accepted May 17, 1999.

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