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Original Studies |
Medical Research Council Trauma Group, North West Injury Research Center, University of Manchester, Hope Hospital, Salford, United Kingdom M6 8HD
Address all correspondence and requests for reprints to: Dr. Gordon L. Carlson, Medical Research Council Trauma Group, Clinical Sciences Building, Hope Hospital, Salford, United Kingdom M6 8HD. E-mail: gcarlson{at}fs1.ho.man.ac.uk
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Studies of glucose metabolism in critical illness have generally compared patients with healthy control subjects, but the resulting data are difficult to interpret because of confounding factors in patients, such as age (4), malignant disease (5), nutritional deprivation and immobility (6), and drug treatment (7), which may be impossible to control for. A human model of acute insulin resistance that could be applied to healthy volunteers would therefore be of potential interest for exploration of the underlying mechanisms.
Administration of Gram-negative bacterial lipopolysaccharide (LPS) has been used as a model of severe infection in man and has been shown to reliably induce a febrile systemic inflammatory response with associated hormonal and cytokine changes (8, 9). Conflicting data exist, however, on the effect of LPS on insulin sensitivity. Although the administration of high dose LPS to animals results in insulin resistance (10), other animal studies have shown LPS to induce severe and progressive hypoglycemia (11), and it has been suggested that LPS might either increase insulin sensitivity or possess insulin-like effects (12). The effect of LPS on insulin sensitivity in man has not been studied. Furthermore, although LPS induces a stress hormone response, and prolonged infusion of stress hormones in pharmacological doses has been shown to induce insulin resistance in healthy volunteers (13), patients undergoing major abdominal surgery develop prolonged postoperative insulin resistance in the absence of significant or prolonged changes in plasma stress hormone concentrations (14). It is unclear whether the endogenous production of stress hormones at the physiological levels seen after LPS administration might be associated with impaired insulin sensitivity.
The aim of this study was therefore to determine the nature and time course of the effect of LPS on insulin sensitivity in man and to relate changes in insulin-mediated glucose disposal to the other features of this model of infection.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Six subjects [four men and two women; aged 33.7 ± 1.7 yr (range, 24–39 yr); body surface area, 1.84 ± 0.06 m2 (range, 1.82–2.01 m2)] were admitted to the clinical investigation facility of Hope Hospital (Salford, UK). Before the study all subjects were screened by history, physical examination, and electrocardiogram. No subject had a prior history of cardiorespiratory disease or diabetes mellitus, and none was receiving any medication. The study was approved by the local research ethics committee of Salford and Trafford Health Authority, and informed consent was obtained in writing from each subject before enrolment in the study.
Study protocol
Each subject was studied on two occasions, 14–21 days apart, in random order, with half of the subjects receiving endotoxin first and half saline. In between studies subjects consumed a weight-maintaining diet providing at least 200 g carbohydrate each day. All subjects were studied at 0830 h after an overnight fast and refrained from smoking or caffeine-containing beverages for 24 h before the study. After voiding, subjects were weighed to the nearest 0.1 kg using an Avery beam balance (Seca Ltd., Birmingham, UK) and were measured to the nearest 1 cm using a calibrated scale (Seca Ltd.). The subjects, lightly clothed, then rested quietly in a supine position for the remainder of the study. Catheters (Venflon, Helsingborg, Sweden) were inserted into an antecubital fossa vein of the right arm (for infusion) and retrogradely into a vein on the dorsum of the left hand (for sampling). The sampling hand was then placed in a hot box (air temperature, 60 C) to produce arterialization of venous blood. Hand skin temperature was maintained at 42 C and was monitored continuously with a thermistor taped to the dorsum (Vickers Medical Ltd., Hampshire, UK). All catheters were kept patent with heparinized saline (Weddel Pharma, Wrexham, UK; 50 U heparin in 150 mmol/L sodium chloride) when not in use. After a 30-min rest period, a 10-h period of euglycemic hyperinsulinemia was commenced, and 120 min later the subjects received either an iv injection of 20 U/kg National Reference Bacterial Endotoxin (lot EC-6, prepared from Escherichia coli 0113, USPC, Inc., Rockville, MD) or an equivalent volume of saline over a 5-min period. Repeated measurements of substrate utilization, hormone, substrate, and cytokine concentrations were performed over the following 8 h as outlined below. At the end of each study, subjects voided again, and urine volume was measured. A 10-mL aliquot was stored at -4 C for later analysis of urinary nitrogen content.
Indirect calorimetry
Open circuit indirect calorimetry was commenced 1 h before the clamp and was then performed for the last 30 min of each of the following 10 h. The calorimeter (Deltratrac, Datex, Helsinki, Finland) was calibrated before and after each measurement with the manufacturer’s recommended gases, having previously been validated by alcohol combustion and shown to deliver values within 98% of those predicted.
Euglycemic hyperinsulinemic clamp
A primed, continuous, 80 mU/m2·min insulin infusion (Humulin S, Eli Lilly & Co., Basingstoke, UK) was continued for a 10-h period, during which euglycemia (5 mmol/L) was maintained by a variable infusion of aqueous glucose (B.P. 20% glucose, Steriflex, Boots Hospital Products, Nottingham, UK). The concentration of glucose in arterialized venous plasma was monitored at 5-min intervals using an automated glucose oxidase-based glucose analyzer, (Beckman Coulter, Inc., Fullerton, CA). The rate of glucose infusion was adjusted according to the plasma glucose concentration using a computer program run on a laptop computer at the bedside.
Substrate utilization
For each subject, VO2 and VCO2 were averaged for each measurement period, and the values were used in subsequent calculations. Glucose and lipid oxidation rates were calculated from the calorimetry data, adjusting for urinary nitrogen output averaged over the entire 10-h study period (15). Negative values for net lipid oxidation were assumed to reflect net lipid synthesis. Glucose storage was assumed to equate with nonoxidative disposal and was calculated each hour by subtracting net glucose oxidation rate, after adjusting for net lipid synthesis, where appropriate (15), from the glucose infusion rate (GIR) for that hour.
Sample collection
Arterialized venous blood samples were taken hourly for
measurements of hormone, substrate, and cytokine concentrations.
Samples for interleukin-6 (IL-6) and tumor necrosis factor-
(TNF)
assays were taken into EDTA. The sample for glucagon assay was taken
into aprotinin (Trasylol, Bayer Corp.,
Newbury, UK) in lithium heparin, and all other samples were taken into
lithium heparin alone. Samples were centrifuged, and the plasma was
separated and stored immediately at -20 C, except for glucagon,
catecholamine, and cytokine samples, which were stored at -80 C
pending analysis.
Biochemical analysis
Substrate concentrations. Plasma glucose and lactate concentrations were measured spectrophotometrically using a Cobas Bio Centrifugal analyzer (Roche, Welwyn Garden City, UK). The plasma free fatty acid (FFA) concentration was also measured spectrophotometrically with a NEFA C kit (Wako Chemicals, Alpha Laboratories, Hampshire UK). Urinary nitrogen content was analyzed using a micro-Kjeldahl technique (Foss Electric, Copenhagen, Denmark). No correction was made for unsensible losses of nitrogen.
Hormones. Commercially available RIA kits were used for the measurement of plasma insulin (Pharmacia Biotech, Milton Keynes, UK), glucagon (Linco Research, Inc., St. Charles, MO), and cortisol (Wallac Oy, Turku, Finland) concentrations. GH concentrations were measured by a two-site immunoenzymometric assay (coefficient of variation, 3.5%). Plasma concentrations of epinephrine and norepinephrine were measured by reverse phase high pressure liquid chromatography and electrochemical detection (16). The MCR for insulin was calculated by dividing the increase above basal in mean steady state plasma insulin concentration between 0–480 min by the rate of insulin infusion (1).
Cytokines. Plasma TNF and IL-6 concentrations were both
measured by immunoenzymometric assay (Medgenix Europe, Fleurus,
Belgium). Detection limits for TNF and IL-6 were 3 and 2 pg/mL,
respectively.
Temperature, pulse, and blood pressure measurement
Tympanic membrane temperature was measured at 30-min intervals using an infrared probe (Genius, Sherwood Medical, Crawley, UK). Pulse rate and mean arterial pressure (MAP) were measured automatically every 30 min using an electronic electrocardiographic and sphygmomanometric monitor (Marquette, Milwaukee, WI). In each case the mean of three measurements taken over a 5-min period was used.
Statistical analysis
ANOVA for repeated measures was used to assess time effects and treatment-time interactions (LPS vs. saline). When this revealed a significant treatment-time interaction, post-hoc pairwise comparison between LPS and saline groups was made using Student’s t test with correction for multiple comparisons where appropriate. All calculations were performed using Statistical Package for the Social Sciences computer software (SPSS, Inc., Chertsey, UK).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The subjects’ weights did not significantly change between the two studies (72.7 ± 4.9 vs. 72.5 ± 5.2 kg, control vs. LPS, respectively). Mean BSA (1.84 ± 0.06 m2) was identical on the two occasions.
Pulse, blood pressure, and temperature
A single iv dose of LPS produced significant pyrexia in all
volunteers (F = 7.0; P < 0.001; 15 df). This was
first apparent 120 min after LPS administration (Table 1
) and peaked with a mean increment of
1.1 ± 0.28 C at 180 min. Subjects remained significantly pyrexial
for the remainder of the study period. LPS also induced significant
tachycardia (F = 4.1; P < 0.001; 15 df), with a
mean peak increment in heart rate of 28.1 ± 4.5 beats/min with a
time course similar to that of pyrexia (Table 1). MAP fell 270 min
after LPS treatment (F = 2.7; P < 0.001; 15 df),
with a mean depression of MAP by 10.5 ± 1.1 mm Hg between
360–480 min (Table 1).
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The glucose infusion rate (M) varied considerably among
individuals, although no significant differences were observed in the
same individuals in the two arms of the study before LPS
administration. As a result of the basal interindividual variability in
insulin sensitivity, changes in M were therefore expressed as the
percent change in M from the basal period of -30 to 0 min for each
clamp before LPS or saline administration (Fig. 1).
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The glucose oxidation rate increased progressively throughout the
period of euglycemic hyperinsulinemia (Fig. 2A). Although a slightly higher plateau
for glucose oxidation rate was observed after LPS (129.0 ± 4.5
mg/m2·min) than in the controls (105.1 ±
5.0 mg/m2·min), the difference narrowly failed
to achieve statistical significance (F = 3.5; P =
0.09).
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). In control studies, nonoxidative glucose disposal rose to a
plateau of 257.0 ± 13.6 mg/m2·min by 300
min after the start of the euglycemic clamp. LPS administration
significantly altered this pattern of glucose disposal (F = 26.2;
P < 0.001). The glucose storage rate increased
abruptly after LPS compared with that in the control study at 120 min,
to 330.9 ± 48.1 mg/m2·min
(P < 0.01). The glucose storage rate then declined
progressively, until it was significantly less after LPS treatment
compared with the control value at 420 min (176.2 ± 56.7
mg/m2·min; P < 0.01) and 480
min (130.5 ± 43.8 mg/m2·min;
P < 0.02).
Euglycemic hyperinsulinemia was associated with a progressive reduction
in the net lipid oxidation rate after both LPS and saline
administration (Fig. 2C). By 300 min after the start of the clamp,
however, net lipid synthesis had occurred in control studies, whereas
after LPS administration, net lipid oxidation continued (F = 2.4;
P < 0.05) despite infusion of glucose and insulin. The
mean urinary nitrogen output was unaffected by LPS administration
(0.6 ± 0.3 vs. 0.5 ± 0.2 g/h, LPS vs.
control; P > 0.3).
Hormone, metabolite, and cytokine concentrations
In all studies stable conditions of glycemia and hyperinsulinemia
were observed (Table 2). Mean plasma
glucose concentrations during euglycemic hyperinsulinemia were not
significantly affected by the administration of LPS (5.1 mmol/L for
both control and LPS), and the stability of glycemia during the studies
was indicated by relatively low mean coefficients of variation for both
control (7.1%) and LPS studies (9.9%). Mean plasma insulin
concentrations (Table 2; 979.2 ± 96.6 vs. 907.2
± 76.8 pmol/L, control vs. LPS) and MCR for insulin
(537.0 ± 38.8 vs. 563.8 ± 38.6
mL/min·m2, control vs. LPS) were
unaffected by the administration of LPS.
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) did not change significantly
in control studies, but a modest rise was observed after LPS (F =
3.15; P < 0.01). This was attributable to a transient,
but statistically significant, increase between 300 and 360 min, and
lactate concentrations had begun to return to normal by the end of the
study.
In contrast, plasma FFA concentrations (Table 2) fell rapidly during
euglycemic hyperinsulinemia in both control (F = 20.3;
P < 0.001) and LPS groups (F = 13.1;
P < 0.001) and were below the threshold of assay
detection by 240 min. This response was not significantly affected by
LPS (F = 0.4; P > 0.9).
LPS produced significant changes in counterregulatory hormone
concentrations. The plasma cortisol concentration began to rise 60–120
min after LPS (Fig. 3A) and reached a
plateau by 240 min (F = 9.42; P < 0.001). Plasma
glucagon rose 120 min after LPS (Fig. 3B) and reached a plateau by 180
min (F = 2.3; P < 0.05), as did plasma GH (Fig. 3C; F = 4.5; P < 0.001). Neither plasma
norepinephrine nor epinephrine changed significantly in response to
LPS. Although modest increments in the plasma concentration were
observed for both catecholamines from 180 min onward, the increases
were highly variable and did not reach statistical significance (Table 2).
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) and reached peak concentrations at
120 min, declining slowly thereafter (F = 20.9; P
< 0.001). In contrast, the rise of plasma IL-6 was delayed (Fig. 4B),
beginning 60–120 min after LPS and reaching a peak concentration at
180 min (F = 11.2; P < 0.001).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Animal studies have also shown that LPS produces an increase in glucose disposal without a significant change in endogenous glucose production, provided euglycemia is maintained by exogenous glucose infusion (21). It seems unlikely that changes in glucose utilization in the present study could be attributed entirely to the hemodynamic effect of LPS. Although the late decline in the glucose infusion rate might be explicable by a reduction in skeletal muscle blood flow associated with the decline in MAP, the minor hemodynamic alterations in the first 2 h of the period after LPS administration seem unlikely to explain the increased glucose utilization. Although more invasive cardiovascular monitoring may have clarified the relationship between hemodynamic responses and changes in glucose utilization, previous human studies using invasive monitoring have failed to demonstrate significant changes in lower extremity blood flow using the same model (9). The initial increase in the glucose infusion rate could indicate an increase in insulin sensitivity, a direct insulin-like action of LPS, the release of other factors with insulin-like effects such as insulin-like growth factor I (IGF-I), or activation of noninsulin-mediated glucose uptake. The failure of glucose oxidation to increase at the same time as GIR suggests that the additional glucose consumed in association with the increased GIR was not oxidized, but was, instead, stored as glycogen or processed by anaerobic glycolysis. Although it has been suggested as a result of animal (22) and in vitro studies (12) that LPS might have direct insulin-like effects, it seems unlikely that LPS would possess sufficient insulin-like activity to exceed that of the high rate of insulin infusion used in the present study. In addition, studies in which LPS has been administered without glucose and insulin infusion have only demonstrated transient and mild hypoglycemia (19). Although other molecules, such as IGF-I, also exert insulin-like effects, LPS has been shown to reduce plasma IGF-I concentrations (23), which does not support a role for IGF-I in this response.
Stimulation of noninsulin-mediated glucose uptake might provide an alternative explanation for the increase in GIR at the onset of constitutional symptoms. The increase in GIR in the present study coincided with the appearance of TNF in plasma, and TNF has been shown to directly increase noninsulin-stimulated basal glucose uptake in vivo (24, 25) and in vitro (26). The effect of LPS on basal glucose uptake was not measured in the present study, but an abrupt increase in noninsulin-mediated glucose uptake could have accounted for the early increase in GIR. Although the majority of glucose infused iv is taken up into skeletal muscle (27), it is unclear whether this is true of the increased GIR seen in the present study in which euglycemia was maintained, as animal studies have shown that hyperglycemia is required for the LPS-induced increase in basal glucose uptake in skeletal muscle (28). As the increased GIR occurred at a time of initiation of the inflammatory response, it is possible that an increase in glucose uptake, channeled into anaerobic glycolysis within the reticuloendothelial system, might account for the enhanced nonoxidative glucose disposal. Animal studies have indicated that LPS induces an increase in glucose uptake principally in macrophage-rich tissues such as spleen and gut (21). The failure of plasma lactate concentrations to increase substantially at this time point does not exclude this hypothesis, as lactate clearance might have increased simultaneously, as has been recently shown in sepsis (29).
Although the length of time that patients remain insulin resistant has been studied after infection (30) and surgery (14), no data are available concerning the onset of insulin resistance in human infection, chiefly because of the unpredictable clinical course of human sepsis. The data presented here are somewhat at variance with reported findings in animals. In the present study insulin resistance was only clearly demonstrable 7 h after LPS administration, whereas animal studies have demonstrated insulin resistance within 3–5 h (10, 31). The reasons for these differences are unclear, but it should be noted that the dose of LPS used in animal studies has been much greater than that used in the present study (10, 21, 31). In addition, we administered LPS after 120 min of euglycemic hyperinsulinemia, whereas previous studies have treated fasted animals with LPS and commenced the clamp subsequently (10, 31). As postoperative insulin resistance can be attenuated by intraoperative glucose/insulin infusion (32), it is possible that the period of euglycemic hyperinsulinemia before LPS might have attenuated or delayed the development of insulin resistance.
The mechanisms of the insulin resistance in the present study are unclear. TNF infusion induces insulin resistance in rodents by impairing insulin-mediated glucose disposal (24), and there has been recent evidence to suggest a role for TNF as a mediator of insulin resistance in obesity and diabetes (33). Although in the present study plasma concentrations of TNF and IL-6 were elevated for significantly longer than has previously been reported after LPS treatment (8, 23) and were still significantly elevated when insulin resistance developed, this does not necessarily imply a causal relationship, and peak plasma concentrations of both proinflammatory cytokines did not correlate with either absolute or percent reductions in glucose utilization (data not shown). Furthermore, anti-TNF antibodies have not been shown to prevent LPS-induced changes in glucose metabolism in rats (34), and it is unclear whether IL-6 infusion can induce insulin resistance in man (35).
LPS administration induced significant increases in plasma cortisol and GH concentrations, confirming previous reports (9, 18). Although it has previously been stated that counterregulatory hormones cannot explain the changes in basal glucose metabolism associated with sepsis because their onset of action is too slow (10), the relatively long time course of the onset of insulin resistance in the present study does not rule out a role for cortisol and/or GH. Insulin resistance developed in this study within 6 h of considerably lower endogenous plasma levels of cortisol and glucagon than those shown to induce insulin resistance after exogenous administration for 72 h (13). The plasma cortisol levels observed after LPS in the present study are broadly comparable with those observed in insulin-resistant septic patients (3) and were maintained for at least 6 h. It has been shown that similar levels of plasma cortisol can induce insulin resistance in healthy humans over this time period (36). In addition, mean plasma GH concentrations were above the levels shown to maximally induce insulin resistance (50 mU/L) after 4 h when GH is infused alone (37).
The presence of a glucagon response to LPS was unexpected, because previous studies have failed to demonstrate LPS-induced glucagon release (9, 18). In both of these earlier studies, however, the plasma glucose concentration was not controlled, and mild, but significant, hyperglycemia had occurred by 3 h, suggesting that hyperglycemia in the previous studies might have suppressed the glucagon response to LPS. This is in agreement with the results of a study in which a lethal dose of LPS was shown to induce marked hyperglucagonemia in rodents provided that euglycemia was maintained (21) and is also supported by the demonstration that sepsis-induced hyperglucagonemia can be suppressed by hyperglycemia during prolonged glucose infusion (3, 38). Although glucagon stimulates endogenous glucose production, it is unclear to what extent the glucagon response in the present study contributed to the observed insulin resistance. The level of hyperglucagonemia was modest compared with that recently reported in septic patients, in whom skeletal muscle, rather than hepatic insulin resistance, was observed (3), and LPS reduced hepatocyte responsiveness to glucagon in vitro (39).
In the present study the rates of endogenous glucose production were not measured because of the extremely long study protocol. For this reason, the insulin resistance observed cannot wholly be attributed to impaired storage in skeletal muscle as opposed to increased hepatic endogenous glucose production. It should be emphasized, however, that the levels of hyperinsulinemia achieved in this study have previously been shown to maximally suppress hepatic glucose output even in septic animals, with a 2-fold increase in basal glucose production (40). Animal studies have also indicated that LPS does not prevent insulin-mediated suppression of endogenous glucose production at plasma insulin concentrations considerably lower than those reported in the present study (41), and the rate of glucose appearance has been shown to remain low after LPS administration in man, even in the absence of insulin infusion (19). It thus appears likely that the reduction in GIR observed during the period of insulin resistance at the end of the study was attributable to skeletal muscle as opposed to hepatic insulin resistance. In addition, the failure to demonstrate any defect of glucose oxidation in association with the fall in glucose utilization confirms recent reports of selective impairment of glucose storage as the underlying cause of insulin resistance in sepsis (3, 42).
Increased fatty acid availability has been linked to insulin resistance (43), and LPS administration in man has been shown to increase lipolysis and plasma FFA concentrations (9, 19). The findings of the present study strongly suggest, however, that FFA did not contribute to the observed insulin resistance, as the suppression of lipolysis and resulting low plasma FFA concentrations were not reversed by LPS despite the development of insulin resistance.
In summary, LPS administration in man results in a biphasic response of glucose metabolism, with an initial, possibly cytokine-mediated, transient increase in glucose utilization, followed by the development of insulin resistance. The time course of insulin resistance implies that it arises secondarily to the counterregulatory hormone response. Further studies using this human model of sepsis may be able to address this issue.
Received November 11, 1999.
Revised April 21, 2000.
Accepted June 6, 2000.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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function. Nature. 389:610–614.[CrossRef][Medline]
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; n =
6), and in saline controls (•; n = 6) at 0 min. All values are
the mean ± SE. *, P < 0.05; **,
P < 0.01 (LPS vs. control).
