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Université Paris 7 Centre National de la Recherche Scientifique ESA 7059 (C.M., C.C., L.C., M.V., A.K.), 75251 Paris cedex 05, France; Groupe Hospitalier Necker-Enfants-Malades (INSERM CIC 9303) (N.B., J.-L.B.), Laboratoire de Pharmacologie-Néphrologie (A.G., J.-L.E.), Hôpital Necker, INSERM U 342 (G.V.), Hôpital St Vincent de Paul, 75743 Paris Cedex 15, France; Lipha Merck (P.A., M.K.), 91475 Chilly-Mazarin Chilly-Mazarin, France
Address all correspondence and requests for reprints to: Christophe Magnan, Université Paris 7, Centre National de la Recherche Scientifique ESA 7059, Case 7126, 2 place Jussieu, 75251 Paris cedex 05, France. E-mail: magnan{at}paris7.jussieu.fr
Abstract
We investigated the effect of a 48 h triglyceride infusion on the subsequent insulin secretion in response to glucose in healthy men. We measured the variations in plasma concentration and urinary excretion of catecholamines as an indirect estimation of sympathetic tone. For 48 h, 20 volunteers received a triglyceride/heparin or a saline solution, separated by a 1-month interval. At time 48 h, insulin secretion in response to glucose was investigated by a single iv glucose injection (0.5 g/kg-1) followed by an hyperglycemic clamp (10 mg·kg-1·min-1, during 50 min). The triglyceride infusion resulted in a 3-fold elevation in plasma free fatty acids and an increase in insulin and C-peptide plasma concentrations (1.5- and 2.5-fold, respectively, P < 0.05), compared with saline. At time 48 h of lipid infusion, plasma norepinephrine (NE) concentration and urinary excretion levels were lowered compared with saline (plasma NE: 0.65 ± 0.08 vs. 0.42 ± 0.06 ng/ml, P < 0.05; urinary excretion: 800 ± 70 vs. 620 ± 25 nmol/24 h, P < 0.05). In response to glucose loading, insulin and C-peptide plasma concentrations were higher in lipid compared with saline infusion (plasma insulin: 600 ± 98 vs. 310 ± 45 pM, P < 0.05; plasma C-peptide 3.5 ± 0.2 vs. 1.7 ± 0.2 nM, P < 0.05). In conclusion, in healthy subjects, a 48-h lipid infusion induces basal hyperinsulinemia and exaggerated insulin secretion in response to glucose which may be partly related to a decrease in sympathetic tone.
HIGH PLASMA FREE FFA concentration is supposed to predict the development of type 2 diabetes mellitus (1, 2, 3). Our current knowledge is that plasma FFA levels are often elevated in obesity (4) and such elevation is responsible in part for peripheral insulin resistance. On one hand, increased FFA portal concentration could lead to increase hepatic glucose production (5). On the other hand, skeletal muscle insensitivity to insulin is largely related to intramyocellular lipid accumulation and local supplies of triglycerides (6, 7, 8). Moreover, there is increasing amount of evidence that exaggerated plasma FFAs not only impair insulin action but also contribute to the deterioration of pancreatic B-cell function (reviewed in Ref. 9). For example, the high intraislet lipid content is an important component of impaired insulin secretion in Zucker diabetic fatty rats (reviewed in Ref. 10). Finally, The combination of insulin resistance and the impairment of insulin secretion leads finally to chronic hyperglycemia (11, 12).
However, the precise effects of FFA on pancreatic B-cell remain controversial in healthy subjects. On the basis of experiments with lipid infusion, the insulin secretory response to glucose was reported to be increased (13), unchanged (14), or decreased (15). Different mechanisms could be involved to explain these discrepancies. The insulinotropic potency of fatty acids is influenced by chain length and degree of saturation (16). Moreover, the duration of lipid infusion seems also crucial because a study showed opposite effects of short-term (6 h) and long-term (24 h) triglyceride infusion on insulin secretion (15). These studies further pointed out the importance of the glucose administration protocol for challenge of pancreatic function (13, 14, 15). Finally, another important point to consider is the possible interference of variations in sympathetic nervous system tone. On the one hand, neuronal inputs of the pancreas are involved in the control of insulin secretion (17) and, on the other, clinical and epidemiological studies showed that reduced autonomic activity, especially the sympathetic one, might be involved in the onset of obesity (18, 19). Moreover, some data suggest that increase in body fat could impair autonomic nervous system activity in humans (20, 21).
In a previous study in normal rats, we showed that a chronic elevation of plasma FFA levels during 48 h lowered sympathetic activity, which in turn led to increased B-cell responsiveness to glucose in vivo (22). Insulin oversecretion in vivo may therefore partly be due to a FFA-induced decrease in sympathetic tone.
Considering all these points, we examined glucoseinduced insulin secretion after a 48-h lipid infusion period in healthy subjects using a protocol designed to achieve a rapid and sustained increase in plasma glucose concentration. Concomitantly, we measured plasma catecholamine concentration and urinary catecholamine excretion, an indirect estimation of sympathetic tone (19), to evaluate the possible involvement of sympathetic activity in the alteration of pancreatic ß-cell response to glucose.
Subjects and Methods
Subjects
Twelve Caucasian, healthy men without any family history of diabetes, obesity, or hypertension volunteered for the study. They were 25 ± 1 yr old (height 178 ± 1 cm; weight 69 ± 2 kg; BMI 22 ± 1 kg/m2). None took any drug in the last 4 wk preceding the study, and none were smokers. The experimental protocol was approved by the Institutional Ethical Committee (CCPPRB Paris-Necker), and all subjects provided an informed, written consent after explanation of the nature, purpose, and potential risks of this study.
During the study, subjects were fed normally. All subjects consumed three meals a day (0900 h, 1300 h, and 1900 h) and only drank tap water. They received a normal diet, prepared by the dietetic services and providing 50% and 38% of their total energy intake as carbohydrate and fat, respectively. The diet was designed to supply 1.5 times the BMR, calculated according to the Schofield formula (23). The same diet was provided during either saline or lipid infusions.
Experimental design
After an overnight fast, subjects were admitted to the Center d’Investigation Clinique (INSERM CIC 9303) at Hôpital Necker-Enfants Malades (Paris, France) at 0800 h. An indwelling polyethylene catheter was inserted into an antecubital vein for infusions. A second catheter was also inserted into a contralateral forearm vein for blood sampling.
For 48 h, each subject received, in a randomized crossover design, a triglyceride emulsion with heparin or a saline solution (Chaix et Du Marais, Paris, France), 1-month apart. The triglyceride emulsion (Intralipid 20%, Fresenius Kabi, Sèvres, France), was infused at a rate of 0.1 g·kg-1·h-1, together with heparin (24 U·kg-1·h-1 Sanofi Pharmaceuticals, Inc., Gentilly, France), to increase lipoprotein lipase activity. Saline solution was infused at the same rate.
During the infusion period, blood samples were collected every 4 h for the measurement of substrates (FFA, glycerol, glucose, ketone bodies, triglycerides). Heparin was added into tubes for glucose, ketone bodies, and triglycerides. Hormones were also measured (insulin, C-peptide, glucagon, leptin, and cortisol). Heparin was added into tube for insulin and C-peptide and EDTA for leptin. Aprotinine was used as preservatives for glucagon. At time 48 h of infusion, additional samples were taken for the determination of catecholamine concentration. Urine was collected during the last 24 h of infusion to measure catecholamine renal excretion, an index of sympathetic nervous system activity (24). During collection of samples for epinephrine and norepinephrine determination, glutathione was added to prevent oxidation of the catecholamines.
Insulin response to glucose
At time 48 h of infusion, after the overnight fast, insulin secretion in response to glucose was investigated. Briefly, a single iv glucose injection (0.5 g·kg-1) was first administrated and 10 min later a glucose infusion was started (10 mg·kg-1·min-) for a period of 40 min. The triglyceride/heparin or saline infusion lasted throughout the test. Blood samples were drawn at time -5, 0, 1, 3, 5, and 10 min following glucose injection and 10, 20, 30, and 40 min during subsequent glucose infusion.
Insulin secretion rate (ISR)
ISR was calculated during the last 30 min of glucose infusion Briefly, it was derived by deconvolution of the plasma C-peptide concentration (25) using version 3.4a of the ISEC software (26). Individual kinetic parameters of C-peptide clearance are computed by ISEC from standard kinetic parameters (27), taking into account the age, sex, and body surface area of the subject.
Insulin sensitivity index (ISI)
Value of glucose infusion rate and average values of plasma glucose and insulin during the last 30 min of the iv glucose tolerance test were used in the calculations. Glucose clearance was computed by dividing the glucose infusion rate (mmol/kg BW per min) by the average plasma glucose concentration (28). Insulin sensitivity was expressed as an ISI computed as the ratio glucose clearance/plasma insulin concentration, multiplied by 106 (µl/kg BW per min per pM insulin).
Analytical procedure
Glucose was assayed enzymatically using an YSI, Inc. 2300 STAT plus analyzer (YSI, Inc.., San Diego, CA). All hormones (insulin, C-peptide, glucagon, leptin, and cortisol) were assayed by RIA kits. Insulin, C peptide, and cortisol kits were supplied by DiaSorin, Inc. (Antony, France). Coefficients of variations within and between-assay were 7.2 and 8.4%, for insulin, 3.2, and 14.2% for C-peptide, and 6.2 and 10.7%, for cortisol, respectively. Plasma glucagon RIA kit was supplied by Pharmacia (Saint Quentin en Yvelines, France). The within and between-assay coefficients of variation were 8.7 and 8.6%, respectively. Leptin was determined by RIA with a kit from Linco Research, Inc. (St. Charles, MO).
Plasma FFA concentration was measured by a colorimetric method (NEFA C, Wako Industrials, Osaka, Japan). Plasma triglyceride, ßhydroxybutyrate, and glycerol concentrations were measured with enzymatic colorimetric kits (Roche Molecular Biochemicals, Mannhein, Germany).
Plasma and urinary catecholamine levels were determined by high performance liquid chromatography with a C18 reversed-phase material (150 x 2 mm Beckman column packed with Ultrasphere ODS C; 18.5 µm average particle size) and electrochemical detection (Kontron 402, Kontron, München, Germany) after alumina extraction. Calibration curves were made with spiked plasma or homogenate. Recoveries were calculated on the basis of peak heights measured by an integrator (Shimazu system, Yakatape, Japan).
Statistical analysis
All data are expressed as means ± SE. ANOVA with repeated measures was used to determine differences in all parameters during triglyceride and saline infusion across all time points.
Correlations between catecholamine urinary excretion and plasma insulin concentration were Pearson’s product-moment coefficients. Insulin concentration was normalized by using a logarithm transformation.
Results
Substrates
Plasma triglycerides, FFA, and glycerol concentrations are shown
in Table 1
. Compared with saline
infusion, lipid infusion caused a 3-fold rise in plasma triglyceride
concentration in the first 8 h. During interval 8–16 h, there was
a slight decrease (from 3.03 ± 0.4 to 1.53 ± 0.13
mM), but plasma triglyceride concentration remained
significantly higher compared with saline values until the end of
infusion (time 48 h: saline infusion; 0.95 ± 0.10; lipid
infusion; 1.94 ± 0.27 mM, P < 0.05,
Table 1). Plasma FFA concentration rose progressively by about 5-fold
during the first 8 h of lipid infusion, and then remained stable
until the end of infusion (time 48 h: saline infusion; 250 ±
31 mM; lipid infusion; 1305 ± 174
mM, P < 0.05, Table 1).
|
).
Plasma ketone bodies concentration progressively rose during the first
16 h of lipid infusion (from 0.12 ± 0.01 to 0.22 ±
0.05 mM, P < 0.05) and then returned to
basal value until the end of infusion (Table 1).
Plasma glucose concentrations were similar with both treatments, except
a transient and slight increase during lipid infusion at time 12 and
36–40 h (Fig. 1A).
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Hormones
Time course of plasma hormone concentrations is shown in Table 2. In response to lipid-infusion, there
was a marked increase in plasma insulin concentration during the first
8 h (from 57 ± 6 to 185 ± 12 pM,
P > 0.05, Fig. 1B); thereafter, plasma insulin levels
remained significantly higher compared with saline infusion, except at
time interval 24–36 h. Changes in plasma C-peptide concentration was
similar to plasma insulin (Fig. 1C). Neither glucagon nor cortisol
levels were modified by lipid infusion (Table 2). Plasma leptin
concentration remained similar in both groups except a transient
increase during lipid infusion period at time 16 h.
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At time 48 h of infusion, plasma norepinephrine concentration
was significantly decreased during lipid compared with saline infusion
(0.66 ± 0.04 vs. 0.42 ± 0.03 ng/ml,
P < 0.05, Fig. 2A). In
contrast epinephrine plasma concentrations was unaffected by lipid
infusion (Fig. 2A).
|
), whereas epinephrine excretion was
similar in both groups (Fig. 2B). Insulin response to glucose
In response to glucose challenge, the increase in plasma glucose
concentration was similar with both treatments (lipid infusion: from
4.8 ± 0.4 to 18.2 ± 1.2 mM; saline infusion;
from 4.7 ± 0.5 to 16.3 ± 2.6; Fig. 3A). Hyperinsulinemia was more pronounced
during lipid than saline infusion (600 ± 98 vs.
310 ± 45 pM, P < 0.05,
Fig. 3B). Plasma C-peptide concentration was also higher during
lipid-infusion (mean value 3.5 ± 0.2 vs. 1.7 ±
0.2 nM, P < 0.05, Fig. 3C).
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As shown in Fig. 4A, time course of
ISR was similar in both infusion studies. However, ISR during the first
phase of insulin secretion was significantly increased during lipid
infusion compared with saline infusion. The second phase was also
markedly increased during the lipid study.
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, P < 0.05). There was a significant negative correlation between urinary catecholamine excretion (24–48 h) and the logarithm of insulin concentration at 48 h (r =-0.59; F = 10.5; P = 0.004).
During glucose challenge, there was a clear tendency to a negative relationship between urinary catecholamine excretion and the log of the maximal insulin concentration but significance was not reached (r = -0.40; F = 3.75; P = 0.067), likely because of an important interindividual variations.
Discussion
The data from this study provide two significant new observations: a marked elevation of plasma FFA concentration during 48 h provokes 1) a dramatic increase in glucose-induced insulin secretion; and 2) a concomitant decrease in norepinephrine release.
As expected in response to triglyceride infusion, there was a significant increase in plasma TG, whereas ketone body levels were poorly affected, except a slight increase during the first 16 h of infusion. As also expected, plasma glycerol and FFA concentrations were increased, as a result of TG hydrolysis, especially a 2.5-fold increase was observed in FFA as early as 8 h after starting infusion.
The profile of pancreatic hormones in response to plasma FFA increase was very different. Plasma glucagon concentration was unchanged during lipid compared with saline infusion. In contrast, lipid infusion markedly altered insulin metabolism, as reflected by a dramatic hyperinsulinemia that occurred in the absence of any significant change in glycemia according to treatment except a slight hyperglycemia after meals. This situation strongly suggests insulin resistance. It is now well established that elevated FFA levels impair insulin-mediated glucose utilization in peripheral tissues, thus participating to insulin resistance (11). Intramuscular lipid pools that are present in both rodent and human skeletal muscles (7, 8) lead to local supply of lipids that has been clearly associated with impairment in insulin-stimulated glucose metabolism within the muscle (6). In addition, as shown by Randle and co-workers(29), glucose utilization by the muscle is inhibited by FFA, mainly via citrate overproduction that inhibits phosphofructokinase-1 and perhaps, as recently proposed by induction of UCP3 expression, which in turn accelerates FFA oxidation by the muscle (30). Hyperinsulinemia during lipid infusion could be considered as an adaptative response to FFA-induced insulin resistance. As previously showed, this could be partly related to an increase in FFA portal concentration, which could lead to increase hepatic glucose production (5). However, this does not exclude that FFA may directly alter insulin secretion and/or insulin clearance.
The dramatic increase in the insulin response to the glucose challenge in the lipid experiment compared with the saline one clearly demonstrates that there was a compensatory insulin secretion that overcame the decrease in sensitivity. Note that plasma glucose remained similar during glucose infusion in the saline and the lipid study. Also note that insulin resistance was clearly evidenced by the significant reduction of ISI after lipid infusion. Because FFAs per se alter hepatic and splanchnic insulin uptake and degradation (31), it cannot be excluded that the high hyperinsulinemia observed after a glucose challenge was partly related to a decrease in insulin clearance. However, the data rather suggest insulin oversecretion, at least after a glucose challenge, in the lipid study. Indeed, 1) plasma C-peptide concentration was increased in a similar extent as plasma insulin concentration; and 2) after glucose loading, ISR was increased by approximately 2-fold in lipid compared with saline study. Such a result is at variance with a previous study by Carpentier et al. (14) showing a similar response in ISR with glucose infusion following a 48-h lipid or saline infusion. In this study, because ISI was concurrently decreased, it was argued that the ISR should have been increased, and that an unaltered response reflecting inadequate adjustment of insulin secretion was observed. The discrepancy could be related to protocol differences, especially glucose administration. Indeed in our study, glycemia rose from 5–20 mM within 3 min and was maintained at this level during 50 min. In contrast, in Carpentier’s study, a two-step hyperglycemic clamp was performed (10 and 20 mM) and glycemia rose to 20 mM at time 150 min. Another study also showed a lack of high ISR in response to glucose when there was a sudden and transient rise in glycemia performed by (15). In contrast, when sustained hyperglycemia was maintained, insulin hypersecretion was observed (13).
The possibility that the overstimulation of insulin secretion in our study was caused by substances other than FFAs was unlikely. Plasma TG and glycerol concentrations significantly rose during lipid infusion study, but none is considered as an insulin secretagogue (32). Furthermore, despite an increase during the first 16 h of infusion, ß-hydroxybutyrate, which is a weak insulin secretagogue (32), probably poorly contributed to insulin oversecretion. Indeed, its plasma concentration was similar in both studies during the last 24 h of infusion. Plasma cortisol levels, which are often elevated in hyperlipidemia (33) and could influence insulin secretion (33) remained similar during both treatments. Finally, increased insulin secretion was probably not related to variations in plasma leptin because, except for a transient and mild increase at time 16 h of lipid infusion, leptin level was similar in saline and lipid infusions. Anyway, leptin was recently reported to inhibit (34) or being ineffective on insulin secretion (35).
Direct stimulatory effects of FFA on the B-cell have been documented elsewhere (38, 39, 40). Briefly, these effects could be related to increased Ca2+ influx, formation of long-chain fatty-acyl CoA esters, generation of metabolic signals, and pancreatic B-cell hyperplasia (reviewed in Ref. 41). In vitro studies showed that, while acute exposure of pancreatic B-cells to FFAs resulted in a stimulatory effect (40, 42), long-term exposure impaired glucoseinduced insulin release (43). Therefore, we hypothesized that the dramatic increase in glucose-induced insulin secretion that we observed after a 48 h infusion with lipids could rather reflect indirect effect of FFA on B-cell activity, involving extrapancreatic factors. A first explanation might be that elevated FFA plasma concentration markedly reduced the inhibitory effect of insulin on hepatic glucose production as shown by Sindelar et al. (5) and then resulted in high glucose release by the liver, which in turn provoked a compensatory insulin oversecretion to maintain euglycemia. An alternative, but not contradictory, explanation is that factors of neural origin may be crucial. On one hand, neural inputs to the pancreas include the parasympathetic and sympathetic system, whose activation results in the stimulation or the inhibition of insulin secretion, respectively (17). On the other hand, we previously showed an interplay between FFA, nervous system and insulin secretion because 48 h lipid infusion decreased sympathetic tone and led to glucose-induced insulin oversecretion in rats (22). In the present study, at time 48 h of lipid infusion, plasma norepinephrine concentration was significantly decreased. Furthermore, norepinephrine urinary excretion was also reduced. These parameters reflect a decrease in sympathetic tone. Indeed, it has been shown in humans that a decrease in plasma norepinephrine concentration and urinary excretion was correlated with a concomitant decrease in muscle sympathetic nerve activity measured by microneurography (19, 44). Dopamine and epinephrine levels were unaffected by lipid infusion, thus reinforcing the conclusion that hyperlipidemia specifically affected the sympathetic pathway. Our present result is in keeping with epidemiological studies showing that hyperlipidemia could impair autonomic nervous system activity in humans (20) and that an increase in body fat mass is associated with a decrease in sympathetic nervous activity (21). However, it must be pointed out that our data are indices of whole body sympathetic nervous activity. It is not necessary indicative of sympathetic input to pancreatic islet. Indeed, as previously showed sympathetic nervous activity can differ regionally including heart, kidney, skeletal muscle (45, 46) and pancreas (47).
FFAs may modify sympathetic neural activity acting at the level of central nervous system, especially hypothalamus (reviewed in Ref. 48). Their effects may involve either neurotransmitter synthesis and release or alteration of receptor binding properties (48). At peripheral level, FFAs may modulate nicotinic acetylcholine receptor function in presynaptic ganglia (49).
In conclusion, in healthy subjects, a 48 h lipid infusion induces basal hyperinsulinemia and exaggerated insulin secretion in response to glucose. Although the concomitance of low norepinephrine levels and high insulin secretion in response to glucose does not necessary imply a cause-and-effect relationship, insulin oversecretion may result in part from a decrease in sympathetic nervous system activity and/or norepinephrine release. Such a conclusion is further supported (but not definitely evidenced) by the clear inverse correlation that we found between urinary catecholamine excretion and plasma insulin concentration at the end of infusions. Low sympathetic nervous system activity has be proposed as one of the metabolic factor predicting body weight gain and development of obesity (50). Furthermore, lower sympathetic activity is a characteristic of Pima Indians, a population with a high prevalence of obesity and type 2 diabetes (19). The present data are compatible with a sequence of events in which the decrease in sympathetic tone could be one of the first steps leading to insulin oversecretion and to progressive ß-cell exhaustion and pancreatic dysfunction, therefore contributing to permanent hyperglycemia in subjects predisposed to type 2 diabetes.
Acknowledgments
We would like to thank the staff of the Center d’Investigation Clinique: Colette Allain, Agnès Antoine, Yvette Quarteron, Isabelle Ratet, Isabelle Singh-Malhi, Nicole Corbel, Philippe Frugier, Isabelle Gaillon, Yvette Sylva (nurses), Violetta Lecoeur and Alexandre Papot (technicians) whose dedication was critical to this work. Special thanks to Christophe "El Che" Helary for his helpful support.
Footnotes
This work was supported by Institut National de la Santé et de la Recherche Médicale Grant No. 297/331020 and by complementary fundings from the Center d’Investigation Clinique.
Abbreviations: ISI, Insulin sensitivity index; ISR, insulin secretion rate.
Received January 19, 2001.
Accepted July 9, 2001.
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