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Dose-Dependent Effects of Recombinant Human Interleukin-6 on Glucose Regulation

Developmental Endocrinology Branch (C.T., D.A.P., R.D., C.S.M., G.P.C.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; and Hellenic National Center for Research, Prevention and Treatment of Diabetes Mellitus and its Complications (C.T., I.K.), Athens 106 75, Greece

Address all correspondence and requests for reprints to: Constantine Tsigos, M.D., Ph.D., Hellenic National Diabetes Center, 3 Ploutarchou Street, 106 75 Athens, Greece.

	Abstract

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Inflammatory cytokines have metabolic actions that probably contribute to the general adaptation of the organism during infectious or inflammatory stress. To examine the effects of interleukin 6 (IL-6), the main circulating cytokine, on glucose metabolism in man, we performed dose-response studies of recombinant human IL-6 in normal volunteers. Increasing single doses of IL-6 (0.1, 0.3, 1.0, 3.0, and 10.0 mg/Kg BW) were injected sc in 15 healthy male volunteers (3 in each dose) after a 12-h fast. All IL-6 doses were tolerated well and produced no significant adverse effects. We measured the circulating levels of glucose, insulin, C-peptide, and glucagon at baseline and half-hourly over 4 h after the IL-6 injection. Mean peak plasma levels of IL-6 were achieved between 120 and 240 min and were 8, 22, 65, 290, and 4050 pg/mL, respectively, for the 5 doses. After administration of the 2 smaller IL-6 doses, we observed no significant changes in plasma glucose levels, which, because of continued fasting, decreased slightly over time. By 60 min after the 3 higher IL-6 doses, however, the decline in fasting blood glucose was arrested, and glucose levels increased in a dose-dependent fashion. The concurrent levels of plasma insulin and C-peptide were not affected by any IL-6 dose. In contrast, IL-6 caused significant increases in plasma glucagon levels, which peaked between 120 and 150 min after the IL-6 injection. In conclusion, sc IL-6 administration induced dose-dependent increases in fasting blood glucose, probably by stimulating glucagon release and other counteregulatory hormones and/or by inducing peripheral resistance to insulin action.

	Introduction

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INTERLEUKIN-6 (IL-6), together with tumor necrosis factor- (TNF-) and IL-1, takes part in the inflammatory cascade (1). Typically, TNF- is produced first at the site of inflammation, followed temporally by IL-1 and IL-6. In addition to their local autocrine and paracrine actions, the inflammatory cytokines, and mainly IL-6, are released in the circulation and act as hormones to regulate the acute phase reaction and influence the major endocrine axes and the intermediary metabolism (2, 3, 4, 5). More specifically, IL-6 profoundly stimulates the hypothalamic-pituitary-adrenal axis and GH secretion, whereas it suppresses TSH secretion (6, 7, 8, 9). There is little data, however, on the metabolic responses to IL-6 in man. One earlier study was performed in cancer patients, who are known to commonly have abnormal glucose tolerance (9).

We have recently demonstrated that, unlike TNF and IL-1, sc administration of IL-6, at doses that potently stimulated the acute phase reaction, had very modest toxicity and no hypotensive effect in cancer patients (7). The good safety profile of IL-6 allowed us to explore further the actions of IL-6 in normal volunteers. Here we report a dose-response study of single sc injections of recombinant human (rh) IL-6 on plasma glucose and its regulatory hormones, insulin, and glucagon in normal volunteers. We started from the extremely low dose of 0.1 mg/kg of BW and increased to a maximum of 10.0 mg/kg. Our purpose was to cover the concentration range of circulating IL-6 that occurs in common inflammatory or other stress (10, 11, 12).

	Subjects and Methods

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Subjects

The study was performed in 15 normal volunteers and consisted of a dose-response to 0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg of rhIL-6 (Sandoz Pharmaceuticals Co., East Hanover, NJ), given as a single sc injection (Table 1). The study was approved by the National Institutes of Health Clinical Center Investigation Review Board. An Investigational New Drug license for the use of rhIL-6 in normal volunteers was obtained by the Food and Drug Administration. We recruited 15 male volunteers, 20–38 yr of age, who gave informed consent. None of the volunteers had a history of autoimmune, cardiovascular, endocrine, or hematopoietic disease, and they were all screened for normal liver, kidney, and thyroid function. None was taking any medications. Successive cohorts of 3 volunteers each were studied at each escalating IL-6 dose.

The IL-6 injection was given between 0800 h and 0900 h, after an overnight fast. All subjects remained in the hospital for monitoring after the IL-6 injection and were discharged the following morning (at 24 h). They were subsequently reevaluated as outpatients clinically and biochemically at 48 h and 7 days.

Blood for glucose, insulin, C-peptide, and glucagon was drawn at 0, 15, 30, 60, 90, 120, 150, 180, and 240 min after the IL-6 injection. Vital signs were monitored half-hourly during the test and then two-hourly up to 10 PM. No medications were administered during the test.

Hormone assays

Plasma IL-6 concentrations were measured by enzyme-linked immunosorbent assay kit (Quantikine, R & D Systems, Minneapolis, MN). The sensitivity of the assay was 0.7 pg/mL, and the intra- and interassay coefficients of variation (CVs) were 3.6% and 4.4%, respectively.

Serum insulin was measured by an automated enzyme immunoassay (TOSOH Medics Inc., Foster City, CA). The sensitivity was 2.0 mU/mL, and intra- and interassay CVs were, respectively, 5% and 10%. Serum C-peptide was measured by RIA (Incstar, Stillwater, Minnesota) using a highly specific antibody to human C-peptide of insulin (residues 33–63 of the human proinsulin molecule). The sensitivity of the assay was 0.1 ng/mL, and the intra- and interassay CVs were 6% and 14%, respectively.

Plasma glucagon was measured by RIA kit (Linco Research, Inc., St. Charles, MO), which uses a specific antibody for pancreatic glucagon, with less than 0.1% crossreactivity to oxyntomodulin, the primary gut glucagon. The sensitivity and the intra- and interassay CVs were, respectively, 20 pg/mL, 7%, and 10%.

Statistical analysis

Comparison between peak and basal levels within the groups was performed by the paired t test. Correlations between peak plasma IL-6 levels and peak glucose and hormonal responses were performed by Spearman’s rank correlation coefficient. A P value of less than 0.05 defined statistical significance. All values in the text are presented as mean ± SEM.

	Results

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IL-6 levels

Acute elevations in plasma IL-6 levels were observed within 15 min after the IL-6 injection, slowly increasing thereafter to reach a peak between 120 and 240 min (at 8 ± 1, 22 ± 5, 65 ± 22, 290 ± 38, and 4050 ± 149 pg/mL, respectively, for the five doses) and plateauing, in every case, by the end of the 4-h sampling time (Fig. 1). By the next morning, plasma IL-6 concentrations had returned to baseline in all five groups.

View larger version (24K): [in this window] [in a new window]   Figure 1. Mean IL-6 levels in the circulation achieved after escalating single sc injections of rhIL6. Y axis is in log scale.

No hypotension, heart rate abnormalities, nor any other severe side effects occurred during the inpatient and outpatient follow-up of the subjects. All volunteers who received the two higher IL-6 doses experienced moderate tympanic temperature elevations (not exceeding 38.5 C), which started between 2–4 h and peaked between 10–12 h after the IL-6 injection (Fig. 2). Most of these subjects also developed mild to moderate malaise and intermittent headache. Four of the other nine volunteers who received lower IL-6 doses also experienced similar but milder symptoms. In all cases, symptoms resolved by 24 h. Transient borderline bilirubin increases above the normal range were observed in five subjects receiving the higher IL-6 doses, which returned to normal by 48 h. Finally, two subjects, one from each of the higher IL-6 doses, developed a trace of proteinuria at 24 h, which also disappeared by 48 h.

View larger version (22K): [in this window] [in a new window]   Figure 2. Tympanic temperature monitoring during the 24-h period after the IL-6 injection. In no case did temperature rise above 38.5 C.

After the two smaller IL-6 doses, we observed no significant changes in plasma glucose levels, which, presumably because of continued fasting, decreased slightly over time (Fig. 3, Table 1). After the three higher IL-6 doses, the normal decline in fasting blood glucose was arrested by 60 min and followed by dose-related increases in plasma glucose levels over time (Fig. 3).

View larger version (20K): [in this window] [in a new window]   Figure 3. Mean plasma glucose levels in response to the five doses of sc rhIL-6 administration.

View larger version (29K): [in this window] [in a new window]   Figure 4. Mean insulin (upper panel) and C-peptide (lower panel) responses to sc rhIL-6 administration.

View larger version (20K): [in this window] [in a new window]   Figure 5. Mean plasma glucagon responses to sc rhIL-6 administration.

	Discussion

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Escalating administration of rhIL-6 caused dose-dependent increases in plasma IL-6 concentrations, which peaked, in all cases, between 3 and 4 h after the injection. All IL-6 doses employed were well tolerated and did not cause any significant side effects, other than short-lived moderate temperature elevations, malaise, and occasional headache. Dose-dependent stimulation of acute phase reactants by IL-6 occurred, even at small doses (0.3 and 1.0 mg/kg), that had no appreciable metabolic effects. Interestingly, the acute phase reaction took more than 4 h to develop and peaked between 24 h and 48 h.

The acute metabolic responses to IL-6 required elevations of IL-6 in the circulation to levels higher than 25–65 pg/mL, which were consistently achieved only with the 3.0- and 10.0-µg/kg IL-6 doses. Interestingly, these IL-6 levels were in the range previously reported in septic patients or during acute trauma and surgery (10, 13, 14). This suggests that our results represent the effects of clinically relevant concentrations of IL-6.

In response to the higher doses of IL-6, the normal small decline in fasting blood glucose, over time, was arrested by the end of the first hour, followed by progressive, small, and dose-dependent glucose increases over the next 3 h. The relative contribution of increased endogenous glucose production and/or altered peripheral glucose metabolism to the changes of observed glucose concentrations remains unclear. The IL-6-induced glucagon release could have increased hepatic glycogenolysis and, thus, could have contributed to the blood glucose elevations that ensued temporally. This is in agreement with a previous report that showed increased rates of glucose appearance after an rhIL-6 infusion in cancer patients (9).

In addition to glucagon, rhIL-6 has been shown to actually stimulate the other principal glucose counteregulatory hormones (cortisol, GH, and catecholamines), which also may play a role in the observed glucose changes (6, 9). In vitro data have suggested that IL-6 also may have a direct stimulatory effect on hepatic glucose release from glycogen pools by inhibiting glycogen synthase (15). However, this direct effect of IL-6 on hepatocytes does not appear before at least several hours and, thus, is unlikely to have contributed significantly to the acute glucose changes seen in our study.

Another plausible mechanism for the effects of IL-6 on glucose metabolism might be via induction of peripheral insulin resistance. This could be partly mediated by the IL-6-induced increases of cortisol, GH, and catecholamine concentrations, although a direct effect of IL-6 on the insulin signal cascade in target tissues, as is the case for TNF-induced insulin resistance (16, 17), cannot be excluded. A putative IL-6 effect on insulin resistance, however, might be expected to require longer to manifest than the 4-h observation period of our study. It might well be that glucose levels increased further after the 4 h, as would probably be expected, given the more pronounced responses of glucagon and of the other counteregulatory hormones to IL-6 (6).

Despite the increases in blood glucose concentrations, the insulin and C-peptide levels did not change appreciably after the IL-6 injection in the normal volunteers. This could be explained by IL-6-mediated inhibition of glucose-stimulated insulin secretion, as previously suggested by in vitro studies in cultured rat islets of Langerhans (18, 19).

In conclusion, sc IL-6 administration induced small dose-dependent increases in blood glucose, probably by stimulating glucagon and other counteregulatory hormone secretion and/or by directly or indirectly inducing peripheral resistance to insulin action. IL-6 seems to be important in the metabolic adaptation of the organism to stress. The increased production of IL-6 in inflammatory or severe noninflammatory stress may contribute to the glucose increases and insulin resistance that accompanies these conditions. This would be adaptive for limited periods of time because it would direct energy to defense rather than to growth or energy storage.

Received June 12, 1997.

Revised August 6, 1997.

Accepted August 20, 1997.

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