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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 6 2775-2783
Copyright © 2003 by The Endocrine Society

Insulin Secretion and Cellular Glucose Metabolism after Prolonged Low-Grade Intralipid Infusion in Young Men

Christine B. Jensen, Heidi Storgaard, Jens J. Holst, Flemming Dela, Sten Madsbad and Allan A. Vaag

Department of Endocrinology and Clinical Research Unit (C.B.J., H.S., S.M., A.A.V.), Hvidovre University Hospital, 2650 Hvidovre, Denmark; Steno Diabetes Center (H.S., A.A.V.), 2820 Gentofte, Denmark; Department of Medical Physiology (J.J.H., F.D.), Panum Institute, 2200 Copenhagen N, Denmark; and Copenhagen Muscle Research Centre (F.D.), Rigshospitalet, DK-2100 Copenhagen, Denmark

Address all correspondence and requests for reprints to: Christine B. Jensen, Joslin Diabetes Center, Cellular and Molecular Physiology, One Joslin Place, Boston, Massachusetts 02215. E-mail: cbjensen{at}dadlnet.dk or christine.jensen{at}joslin.harvard.edu.

Abstract

We examined the simultaneous effects of a 24-h low-grade Intralipid infusion on peripheral glucose disposal, intracellular glucose partitioning and insulin secretion rates in twenty young men, by 2-step hyperinsulinemic euglycemic clamp [low insulin clamp (LI), 10 mU/m2·min; high insulin clamp (HI), 40 mU/m2·min], 3-3H-glucose, indirect calorimetry, and iv glucose tolerance test. Free fatty acid concentrations were similar during basal steady state but 3.7- to 13-fold higher during clamps. P-glucagon increased and the insulin/glucagon ratio decreased at both LI and HI during Intralipid infusion. At LI, glucose oxidation decreased by 10%, whereas glucose disposal, glycolytic flux, glucose storage, and glucose production were not significantly altered. At HI, glucose disposal, and glucose oxidation decreased by 12% and 24%, respectively, during Intralipid infusion. Glycolytic flux, glucose storage, and glucose production were unchanged. Insulin secretion rates increased in response to Intralipid infusion, but disposition indices (DI = insulin action·insulin secretion) were unchanged. In conclusion, a 24-h low-grade Intralipid infusion caused insulin resistance in the oxidative (but not in the nonoxidative) glucose metabolism in young healthy men. Moreover, insulin hypersecretion perfectly countered the free-fatty acid-induced insulin resistance. Future studies are needed to determine the role of a prolonged moderate lipid load in subjects at increased risk of developing diabetes.

LARGE-SCALE EPIDEMIOLOGICAL STUDIES have demonstrated that a high plasma free fatty acid (FFA) concentration is an independent risk marker for deterioration of glucose tolerance from both normal glucose tolerance and impaired glucose tolerance (1, 2). A relationship between glucose and FFA metabolism has been known since Randle’s first description, in 1963, of a glucose-fatty acid cycle in perfused rat hearts and diaphragms (3). Randle postulated a substrate competition between FFA and glucose, in which an increased FFA oxidation inhibited glucose uptake and oxidation, explaining the insulin resistance of subjects with noninsulin-dependent diabetes mellitus (NIDDM). Subsequent clinical studies have shown that short-term (-6 h) infusion of triglyceride emulsions (Intralipid) causes a decrease in both insulin-stimulated oxidative (4, 5, 6) and nonoxidative (7, 8) glucose metabolism. There is evidence to suggest that this effect is exerted in a time-dependent manner (7, 9, 10, 11).

Recently, the effects of FFAs on insulin secretion have been the focus of extensive investigation. Acutely, FFAs stimulate glucose-induced insulin secretion both in vitro (12, 13) and in vivo (14, 15, 16), and it is also now recognized that FFAs play an important role in the maintenance of basal and glucose-stimulated insulin secretion in the fasted (but not in the fed) state (16, 17, 18, 19). The effects of a more prolonged (>24 h) exposure to an elevation of FFAs in vivo, however, are conflicting. Supraphysiological FFA concentrations had toxic effects in studies in isolated rodent (20, 21, 22) and human islets (23) and in the perfused rat pancreas (24), whereas both stimulatory (25) and inhibitory (15, 26) effects on ß-cell function were seen in humans after prolonged in vivo FFA elevation.

The objective of the present study was to examine the simultaneous effects of prolonged low-grade Intralipid infusion on glucose uptake, endogenous glucose production (EGP), intracellular glucose metabolism, and glucose-induced insulin secretion in young nondiabetic men; Insulin secretion was expressed as a disposition index, thereby adjusting for the ambient degree of insulin resistance.

Subjects and Methods

Subjects

Twenty healthy male volunteers (mean age, 19 yr; BMI, 22.6 ± 0.8 kg/m2; total fat mass, 15.6 ± 1.5 kg; lean body mass, 56.9 ± 1.6 kg (dual-energy x-ray absorptiometry scan); VO2max, 3.5 ± 0.2 l/min) participated in the study. All participants had normal glucose tolerance after a standard 75-g oral glucose tolerance test (World Health Organization criteria), and none had known systemic illness or were taking medication that could affect glucose or lipid homeostasis. Informed written consent was obtained from all study subjects before participation. The protocol was approved by the regional ethical committee, and procedures were performed according to the principles of The Helsinki Declaration.

Experimental protocol (Fig. 1Go)

Each subject was studied on two occasions (3–5 wk apart), preceded, in randomized order, by a 24-h Intralipid or saline infusion. No changes in diet, weight, or lifestyle were recorded from the time of recruitment until the completion of both studies. For at least 48 h before the experiment, the participants were instructed to consume a diet rich in carbohydrate and to refrain from alcohol ingestion and strenuous physical activity. The study subjects reported to the laboratory at 0800 h, after a 10-h overnight fast (d -1). A polyethylene catheter was placed in the antecubital vein for test infusions (Intralipid: Intralipid (20%), 0.4 ml/kg·h; Heparin (200 U) (bolus), 0.2 U/kg·h; or saline: NaCl 9 g/liter, 0.4 ml/kg·h). The test substances were infused for 24 h and continued throughout the iv glucose tolerance test (IVGTT) and clamp studies (in total, 301/2 h). A second catheter was placed in a dorsal hand vein of the contralateral arm, for blood sampling. The hand was placed in a heated Plexiglas box to ensure arterialization of the venous sample. Standardized meals were served at +15 min (breakfast); +3 h, 15 min (lunch); +9 h (dinner); +12 h, 30 min (sandwich). A standardized 15-min light exercise on a bicycle was performed at +2 h and +5 h after initiation of the study. The following day (study day), after a 10-h fast, a primed-continuous infusion of [3-3H]-tritiated glucose (bolus, 10.9 µCi, 0.109 µCi/min) was initiated at 0 h and continued throughout the 2-h basal period (0–120 min), 30-min IVGTT (+120–150 min), and clamp studies (+150–390 min). A 1-min iv-glucose bolus (0.3 g/kg body weight) was given immediately after the 2-h basal period (+120 min). Blood samples for analysis of glucose, insulin, and C-peptide were drawn at 0, 2, 4, 6, 8, 10, 15, 20, and 30 min. A primed-continuous insulin infusion (square wave bolus, 2 U, 10 mU/m2·min) was begun at +150 min, continued for 120 min during the low physiological insulin clamp (LI: +150–270 min), and was raised to 40 mU/m2·min during the 120-min high physiological insulin clamp (HI: +270–390 min). Steady state was defined as the last 30 min of each 2-h basal, LI, and HI clamp period, respectively, when tracer equilibrium (i.e. constant specific activity) was anticipated. Indirect calorimetry was performed, during all three steady state periods, using a computerized flow-through canopy gas analyzer system (Deltatrac; Datex, Helsinki, Finland) as previously described (27). Variable infusion of so-called cold glucose (180 g/liter) enriched with tritiated glucose (hot-GINF) [13.75 µCi/500 ml (10 mU/m2·min), 55 µCi/500 ml (40 mU/m2·min)] maintained euglycemia during insulin infusion. Plasma glucose concentration was monitored every 5–10 min during basal and insulin-stimulated steady state periods. Blood samples for analysis of plasma insulin, C-peptide, glucagon, and FFAs were drawn every 30 min; for tritiated glucose/water, every 10 min, during steadystate periods; and every 30 min for the rest of the study period.



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  		Figure 1. Study design. Day -1: M, meals; S, blood sampling; E, exercise; SS, steady state period. For blood sampling time points on study day, please refer to Experimental protocol.

 
Analytical procedures

Plasma glucose was measured at bedside by an automated glucose oxidase method (Glucose Analyzer 2; Beckman Instruments, Inc./Hybritech, Fullerton, CA). Plasma insulin, C-peptide, and glucagon blood samples were centrifuged immediately at 4 C and stored at -80 C for later analysis. Plasma insulin and C-peptide concentrations were determined by a 1235 AutoDELPHIA automatic immunoassay system (Wallac, Oy, Turku, Finland). The plasma insulin assay had a detection limit of approximately 3 pM. Cross-reactivity with intact proinsulin was 0.1%, 0.4% with 32–33 split proinsulin, and 66% with 64–65 split proinsulin intraassay coefficient of variation, 4.5%; and interassay variation, 7%. The detection limit of the C-peptide assay was 5 pM. Cross-reactivity with intact proinsulin was 51%, 35% with 32–33 split proinsulin, and 92% with 64–64 split proinsulin (no detectable cross-reactivity with insulin), intraassay variation, 5%; and interassay variation, 8%. The glucagon assay (28) is directed against the COOH-terminus of the glucagon molecule (antibody code no. 4305) and measures glucagon of mainly pancreatic origin. Plasma was extracted with ethanol (final concentration, 70%, vol/vol) before analysis. The detection limit and intraassay coefficient of variation of the assay used were 1 pM, and less than 6%, respectively. Tritiated glucose and water was measured as described by Hother-Nielsen and Beck Nielsen (29). Plasma FFAs were quantified by an enzymatic colorimetric method (Wako Pure Chemical Industries Ltd., Neuss, Germany). Lipoprotein lipase inhibitor was not added; and hence, the true FFA concentrations may be slightly lower. Plasma lactate was quantified on an automatic lactate analyzer (YSI 23AM; YSI, Inc., Yellow Springs, OH), whereas concentrations of alanine, D-ß-hydroxybutyrate, and glycerol were measured by the fluorometric method.

Calculations

Basal and insulin-stimulated glucose turnover rates. Rates of appearance (Ra), disposal (Rd), and EGP were calculated at 10-min intervals during steady state, using Steele’s nonsteady state equations (30). In the calculations, distribution vol of glucose was 200 ml per kilogram of body weight; and the pool fraction, 0.65. Rates of whole-body glycolysis (GF) were estimated from the increment per unit time in tritiated water [(cpm per ml per min)·total body water mass (ml)/[3-3H] glucose specific activity (cpm per mmol)] (31). Plasma water was estimated as 93% of total plasma volume, and total body water mass was assumed to be 65% of the body mass (32). EGP was calculated by subtracting the exogenous glucose infusion rate from the rate of appearance of [3-H3] glucose; exogenous glucose storage (EGS), as Rd minus GF [the term: "exogenous" used in "exogenous glycolytic flux (GF)" and in "EGS" is used to emphasize that the calculated turnover rates are based on flux of the infused glucose tracer]; Glucose turnover rates were expressed as mg/kg fat free mass (FFM)/min and are presented throughout the paper as mean values of the 30-min steady state periods. The sensitivity index (SiRd) (33) represents the net increase in glucose disposal above basal per unit change in plasma insulin concentration during hyperinsulinemia (40 mU/m2·min), adjusted for mean steady state glucose concentrations [(Rd40mU-Rdbasal)/(p-insulin40mU–p-insulinbasal)·(p-glucose40mU)] (mg·kg FFM-1·min-1·pM insulin-1·mM gluc-1). Lipid oxidation (LIPOX) rates were derived from the indirect calorimetry, as described in Ref.27 .

IVGTT. Prehepatic insulin secretion rates (ISR) were calculated by deconvolution of peripheral C-peptide concentrations, using a two-compartment model of C-peptide kinetics (34, 35) and population-based C-peptide kinetic parameters (36). The population-based parameters are derived from analysis of a large number of individual kinetic parameters, allowing adjustment for clinical status (normal, obese, or type 2 diabetes), age, and body surface (36). Calculations were based on the assumption that only hepatic clearance of insulin and not C-peptide was affected by Intralipid infusion. The total and incremental areas under the curve (AUC) for glucose (mM·min), insulin (pM·min), C-peptide (pM·min) and ISR (pM·kg-1) were calculated by means of the trapezoidal rule, from 0–10 min during the IVGTT. The disposition indices DI1 and DI2 were calculated as the product of SiRd and incremental AUCinsulin (mg glucose·kg FFM-1·min-1·kg-1·mM gluc-1), and SiRd and incremental AUCISR (mg glucose·pmol insulin·kg FFM-1·L-1), respectively.

Insulin clearance. On d -1, a measure of insulin clearance was derived from the ratio between the 24-h AUC for C-peptide and the 24-h AUC for insulin (pM C-peptide·pM insulin-1); whereas, on the study day, insulin clearance was calculated as the insulin infusion rate (LI: 10 mU/m2·min or HI: 40 mU/m2·min) divided by the mean steady state plasma insulin concentration (liter·m-2·min-1·pmol-1).

Data analysis and statistics. Nonparametrical Wilcoxon test for paired data, Spearman’s {rho} for correlation analysis, and Friedman’s test (ANOVA for repeated measurements, nonparametrical data) were employed in the data analysis. Calculations were performed with Instat software (Instat Statistical Package; GraphPad Software, Inc., San Diego, CA). Data are presented as mean ± SEM. P < 0.05 was considered significant in two-tailed analysis.

Results

Plasma glucose, insulin, C-peptide, glucagon, and FFA concentrations on d -1 (Fig. 2Go)

Baseline plasma glucose, insulin, C-peptide, glucagon, and FFA concentrations were similar in the Intralipid and control studies. Intralipid infusion maintained a mean 24-h plasma FFA concentration at approximately fasting level (~0.5 mM), with minor meal-related excursions, as opposed to sufficient meal-induced FFA suppression and, on average, 60% lower plasma FFA concentrations in the control study (AUCFFA: 13.68 ± 1.18 vs. 7.62 ± 0.45 mM·h, P < 0.0001; Fig. 1EGo). Plasma FFA values leveled toward the end of the 24-h period [+19–24 h, not significant (NS)]. Despite a significant increase in plasma insulin and C-peptide concentrations (AUCinsulin: 2011.2 ± 128.7 vs. 2651.6 ± 178.6, P < 0.0001; AUCC-peptide: 22104.4 ± 1102.3 vs. 25607.9 ± 1191.8 pM·h, P = 0.001; Fig. 1Go, B and C), Intralipid infusion caused a small (but statistically significant) increase in plasma glucose levels (Fig. 1AGo) after breakfast (+1:45 h: 5.5 ± 0.2 vs. 6.3 ± 0.3 mM, P < 0.002; +2:45 h: 5.9 ± 0.2 vs. 6.3 ± 0.2 mM, P < 0.02) and in the early morning (+19.00 h: 5.7 ± 0.1 vs. 6.0 ± 0.1 mM, P < 0.05). Plasma glucagon concentrations (Fig. 1DGo) were unaffected by Intralipid infusion. Insulin clearance decreased by 12% (11.5 ± 0.6 vs. 10.1 ± 0.5 pM C-peptide·pM insulin-1, P = 0.007).



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  		Figure 2. Twenty-four-hour profiles for plasma glucose (A), insulin (B), C-peptide (C), glucagon (D), and FFA (E) on d -1 of the Intralipid ({square}) and control ({blacksquare}) study. Data are mean ± SEM. *, P < 0.05; ¤, P < 0.001.

 
Plasma glucose, insulin, C-peptide, glucagon, FFA, glycerol, D-ß-hydroxybutyrate, alanine, and lactate concentrations during basal and insulin-stimulated steady state periods (Table 1Go)

Mean plasma glucose concentrations were similar during basal and HI steady state but slightly higher during LI in the Intralipid study (P = 0.002). Mean plasma insulin concentrations were significantly higher during basal and LI in the Intralipid study but similar at HI. Basal C-peptide concentrations were higher in the Intralipid study (P = 0.002) but similar at LI and HI. Intralipid infusion impaired the suppression of glucagon by insulin at LI (P = 0.003) and HI (P = 0.03), as well as decreased insulin/glucagon ratio (LI: 22.3 ± 2.2 vs. 18.3 ± 1.2, P = 0.03; HI: 108.8 ± 16.6 vs. 75.7 ± 10.5, P = 0.02). Basal FFA concentrations did not differ but remained high (fasting level) during both LI (P < 0.0001) and HI (P < 0.0001) in the Intralipid study. Intralipid infusion caused a significant increase in plasma glycerol concentrations during all three steady state periods (P < 0.0001) and blunted insulin suppression of plasma glycerol (as seen in the control study). Plasma D-ß-hydroxybutyrate concentrations were significantly higher in the Intralipid study at LI and HI (P < 0.0001) but comparably suppressed by insulin in both studies. Plasma lactate was slightly lower only at HI in the Intralipid study, compared with the control study (P < 0.0001), whereas insulin had the same stimulatory effect in both studies. Finally, plasma alanine was decreased at LI and HI in the Intralipid study (P < 0.05, P < 0.0001), and the stimulatory effect of insulin was slightly blunted at HI. Insulin clearance decreased by 10% at LI (0.50 ± 0.02 vs. 0.56 ± 0.02 pM C-peptide·pM insulin-1, P = 0.003) but was unchanged at HI (0.77 ± 0.02 vs. 0.75 ± 0.02 pM C-peptide·pM insulin-1, NS).


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  		Table 1. Plasma concentrations during basal and insulin-stimulated steady states

 
Whole-body glucose disposal (Rd), glucose oxidation (GOX), endogenous EGP, exogenous GF, EGS, and LIPOX (Fig. 3Go)

Tracer equilibrium, i.e. constant specific activity of glucose tracer, was reached in both studies in all three steady state periods (Table 1Go). Mean plasma glucose specific activity was lower at LI in the Intralipid study (P < 0.05, Table 1Go). A linear increase in plasma-tritiated water was observed at LI and HI in both studies (saline: LI: r2 = 0.60 ± 0.07, HI: r2 = 0.75 ± 0.06; Intralipid: LI: r2 = 0.58 ± 0.05, HI: r2 = 0.77 ± 0.05). When plasma insulin concentration was increased from basal to LI, Rd and GOX increased significantly and EGP and LIPOX decreased significantly both in the control and Intralipid studies. EGP was suppressed by approximately 50% in both studies. GF and EGS did not change. Raising plasma insulin further from LI to HI caused significant stimulation of Rd, GF, GOX, and EGS and significant inhibition of LIPOX in both studies. EGP was not further reduced.



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  		Figure 3. Basal and insulin-stimulated glucose and lipid fluxes in the Intralipid ({square}) and control ({blacksquare}) studies. Rates of glucose disposal (Rd) (A), GOX (B), EGP (C), GF (D), EGS (E), and LIPOX (F) are expressed as milligrams per kilogram of fat-free body mass per minute. Data are mean ± SEM. Saline (SAL) vs. Intralipid (LIP): *, P < 0.05; ¤, P < 0.001. For insulin effect (insulin vs. basal), please refer to Results.

 
Intralipid infusion did not interfere with basal (i.e. noninsulin-stimulated) Rd, GOX, EGP, GF, EGS, or LIPOX. At LI, GOX decreased (2.64 ± 0.17 vs. 2.36 ± 0.13 mg·kg FFM-1·min-1, P = 0.005; Fig. 2BGo), LIPOX remained high (0.81 ± 0.06 vs. 1.05 ± 0.04 mg·kg FFM-1·min-1, P = 0.0004; Fig. 2FGo), and there was a borderline significant increase in EGP (1.62 ± 0.16 vs.1.93 ± 0.17 mg·kg FFM-1·min-1, P = 0.076; Fig. 2CGo). All other fluxes were unchanged. At HI, we observed a slight (but significant) reduction in Rd (11.86 ± 0.68 vs.10.42 ± 0.77 mg·kg FFM-1·min-1, P < 0.05; Fig. 2AGo), a decreased GOX (4.82 ± 0.26 vs. 3.68 ± 0.26 mg·kg FFM-1·min-1, P = 0.0003; Fig. 2BGo), and a tendency toward reduction in EGS (6.49 ± 0.64 vs. 5.51 ± 0.65 mg·kg FFM-1·min-1, P = 0.12; Fig. 2CGo). GF and EGP were unaltered; LIPOX remained high (0.11 ± 0.06 vs. 0.72 ± 0.01 mg·kg FFM-1·min-1, P < 0.0001; Fig. 2FGo). There was no correlation between FFA and LIPOX at basal or insulin-stimulated condition (absolute or incremental).

Plasma glucose, insulin, C-peptide, and ISR during IVGTT (Fig. 4Go, Table 2Go)

Baseline plasma glucose and C-peptide concentrations were significantly higher in the Intralipid study (P = 0.03; P = 0.01), with a similar trend for plasma insulin (P = 0.14). This was reflected in a higher baseline ISR (P = 0.001). A slight increase (~8%) in total and incremental AUCglucose (P = 0.001) and 25–30% increase in total and incremental AUC for C-peptide and insulin (P = 0.001; P = 0.004), compared with the control study, was seen during Intralipid infusion. The calculated prehepatic total and incremental AUCISR increased by approximately 16% (P < 0.0001). When expressed as a disposition index, an appropriately enhanced insulin secretion countered the Intralipid-induced insulin resistance, i.e. the disposition indices Di1 and Di2 were unchanged.



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  		Figure 4. IVGTT data for plasma glucose (A), insulin (B), and C-peptide (C) in the Intralipid ({square}) and control ({blacksquare}) studies. *, P < 0.05; **, P < 0.01; §, P < 0.005.

 

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  		Table 2. IVGTT

 
Discussion

A number of studies investigated the short-term effects of elevated plasma FFA concentrations on insulin secretion (14, 15, 16, 26) and glucose utilization (4, 5, 6, 7, 8, 9, 10, 11), whereas the impact of a more prolonged lipid exposure remains controversial (15, 26). The majority of both short- and long-term studies used supraphysiological FFA concentrations, and the impairment of glucose uptake in long-term studies has only been documented during hyperglycemia (15, 26). In the present study, healthy young individuals were infused with Intralipid/heparin for 24 h before, and continuously throughout, the 61/2-h study period. Importantly, the FFA concentrations were similar to those seen in type 2 diabetic patients, i.e. marginally higher in the postabsorptive and fasting state but several fold higher during (meals and) insulin stimulation. We found that a 24-h low-grade Intralipid infusion resulted in only modest reduction in insulin-stimulated glucose disposal at HI. Moreover, insulin resistance was observed in the oxidative, but not in the nonoxidative, glucose metabolic pathway. Interestingly, plasma glucagon concentrations were higher, and insulin/glucagon ratio lower, during insulin infusion in the Intralipid study. Although not quite statistically significant, this may have contributed to increased EGP at LI (1.62 ± 0.16 vs. 1.93 ± 0.16 mg/kg FFM/min, P = 0.075). Finally, there was no evidence of a direct inhibitory effect on ß-cell function. In fact, insulin hypersecretion perfectly matched the FFA-induced decline in insulin sensitivity.

Does FFA-induced insulin resistance of glucose metabolism depend on the exposure time? Previous studies have shown that, when lipid infusion was initiated simultaneously with the clamp, impairment of insulin-stimulated glucose uptake and, in particular, nonoxidative glucose metabolism (glycogen synthesis) occurred only after 3–5 h infusion (7, 9, 10, 11). Moreover, this reduction seemed to be dose-dependent, such that the higher FFA concentration, the larger the inhibition of glucose metabolism (10). The time lag has been interpreted as an indirect (rather than direct) effect of FFA, potentially associated with an increase in intramyocellular lipid content (37) or diacylglycerol (38). We were interested to see whether these findings in acute studies, using rather high FFA concentrations, could be extrapolated to a situation of more prolonged (but also more moderate) FFA exposure. Interestingly, when Intralipid was infused for 24 h before and continuously throughout the 61/2-h test period, insulin-stimulated glucose storage (as assessed by the tracer method) was not significantly reduced, despite a significant (although modest) decrease in Rd and immediate and sustained reduction in GOX. Thus, we speculate that the interaction between lipid and glucose may depend not exclusively on the lipid infusion time but also on the prevailing FFA and insulin concentration, the length of the clamp, and (perhaps equally important) the body’s ability to cope with prolonged lipid exposure. The subjects in this study were young, healthy volunteers; prediabetics and/or diabetics may very well react differently to a similar load. Two additional points should be made about the interpretation of our findings. First, although Intralipid/heparin was infused at a constant rate throughout the entire 301/2-h period, FFA concentrations were not significantly different in the early morning or during basal steady state. This was not anticipated, and the reason remains elusive. We speculate that an increased tissue FFA uptake has occurred as a means to maintain metabolic homeostasis. Nevertheless, the fact that the FFA concentration was almost similar for some hours may have tended to underestimate the FFA effect on glucose metabolism (and, by inference, disposition index), especially during the LI. Second, because previous investigators found that induction of insulin resistance by FFAs required 4–6 h of combined hyperinsulinemia and hyperlipidemia, the 2 x 2-h clamp design may also tend to underestimate the impact of FFA. Nevertheless, the target tissue FFA concentration and/or metabolism, rather than the plasma concentration, may be more physiologically relevant.

Increased plasma glucagon concentrations and central insulin resistance

It is a matter of debate, whether (prolonged) elevation of FFAs causes central insulin resistance, i.e. interferes with insulin-mediated suppression of EGP. Fasting plasma FFAs correlate with the magnitude of hyperglycemia and EGP in diabetic Pima Indians (39). Under hyperinsulinemic conditions, lipid/heparin infusion either increased (40, 41), or had no effect on, EGP (7, 8, 42). Several studies have shown that insulin suppression of EGP and FFA are well correlated and that preventing the fall in FFA will also prevent the fall in EGP (43, 44, 45). On the other hand, FFAs stimulate insulin secretion, which may tend to suppress EGP (46). Our study is the first to examine the effect of a prolonged low-grade lipid infusion on EGP and plasma glucagon concentrations during a clamp. Basal EGP was not affected, which perhaps is not surprising, in the face of elevated insulin concentrations, a higher insulin/glucagon ratio, and similar (i.e. not elevated) FFA levels. In contrast to findings in short-term experiments (47), prolonged Intralipid infusion increased plasma glucagon concentrations and decreased the insulin/glucagon ratio at LI, in spite of higher plasma insulin and glucose concentrations. This could reflect insulin resistance on the {alpha}-cell and may have contributed to the observed borderline-significant increase in EGP. Plasma glucagon remained elevated at HI, but there was no difference in insulin/glucagon or EGP. Not surprisingly, plasma glycerol and ketones increased, whereas both lactate and alanine concentrations went down during Intralipid infusion. Although gluconeogenesis was not directly measured in this study, we speculate that the drop in plasma lactate and alanine concentrations during Intralipid infusion may reflect an increased utilization of these two substrates for gluconeogenesis. Insulin suppression of EGP was only 50% on both study days, with no additional effect of increasing insulin concentrations from LI to HI. We speculate that this may be attributable, at least in part, to the study design, whereby the combination of hyperglycemia and hyperinsulinemia during the IVGTT may have influenced the liver before the insulin clamps. Overnight infusion of insulin either improved (48), or had no effect on (49), hepatic insulin action in type 2 diabetic subjects. The hepatic glycogen content influences the absolute rate of EGP but does not affect hepatic insulin action (50). In addition, slightly (but significantly higher) insulin levels at the end of the IVGTT in the Intralipid study may have obscured or attenuated any FFA effect on the liver. Nevertheless, in daily life, target tissues such as the liver and muscle are exposed to a combination of hyperglycemia and hyperinsulinemia as insulin secretion rises in response to a meal. A similar design was previously used by our group (51, 52) and others (53, 54).

Insulin secretion increased to match the decline in insulin sensitivity

One of the earliest recognized and perhaps most important defects in insulin secretion in type 2 diabetes is the reduced first-phase insulin response (55). The relationship between insulin sensitivity (Si) and insulin secretion in vivo is hyperbolic, such that the product of Si and insulin secretion, the disposition index, is a constant (33, 56). Most previous studies of the FFA-mediated effects on insulin secretion failed to take into account the decline in insulin sensitivity. In our study, a normal plasma glucose concentration was maintained throughout the 24-h period, at the expense of moderately increased plasma insulin and C-peptide concentrations. Furthermore, an increase of approximately 16% in the calculated prehepatic ISR, during IVGTT, fully compensated the modest FFA-induced insulin resistance (i.e. disposition indices were unchanged). Paolisso et al. (26) found an absolute decrease in the acute insulin response after 24-h 3-fold FFA elevation (1.5 mM) and progressively rising glucose levels in glucose-tolerant men and women. The participants were older (mean age, 36), and had considerably higher 2-h postload plasma glucose (6.9 mM). At approximately the same FFA concentration (1 mM), Carpentier et al. (15) showed decreased glucose-stimulated insulin secretion during graded iv glucose infusion (dose-response test) and 2-step (10 and 20 mM) hyperglycemic clamps, but only after adjusting ISR for the prevailing insulin resistance, as estimated from the glucose infusion rate at each hyperglycemic step. Although it may be that the dynamic insulin response to small changes in glucose and the maximal insulin secretory capacity are affected differently than the first-phase insulin, the direction of change, i.e. inhibition, was similar in both studies and confirms most in vitro studies (20, 21, 23). Boden et al. (25) used a different approach. Plasma glucose was clamped at 8.6 mM to stimulate insulin secretion continuously throughout the 48-h period. Mean FFA concentration was about 10-fold higher than in the control study, which produced insulin resistance after 24 h (that apparently disappeared after 48 h). ISR rose immediately and remained higher throughout the study, although not statistically significant after 24 h. Disposition indices were not calculated but seemed to decline slightly. Although hyperglycemia may have contributed to the stimulatory effect on the ß-cell, the 24-h findings of Boden et al. (25) are similar to ours; and together, the two studies challenge the rather consistent reports of lipotoxicity on the ß-cell after long-term FFA elevation. Our IVGTT data are suggestive of a finely tuned balance between the periphery and the ß-cell, rather than a direct selective lipotoxic effect on the ß-cell. We can only speculate as to the potential mechanisms for the observed parallel increases in insulin resistance and insulin secretion. It is plausible that insulin resistance per se is associated with a slight increase in either plasma glucose or perhaps, on a more chronic basis, some other glucose-independent circulating factor (57), or that excess FFA up-regulates the anaplerosis pathway, as proposed recently (58), as a stimulus to the ß-cell. Alternatively, FFAs may simultaneously and independently affect the periphery and the ß-cell. It has been demonstrated that infusion of Intralipid during a 5-h hyperinsulinemic euglycemic clamp caused a significant increase in intramyocellular lipid content (59) and diacylglycerol (38), both of which were closely and negatively associated with whole-body insulin sensitivity. A parallel lipid accumulation may take place in the islets and stimulate insulin secretion acutely (hours), whereas ß-cell exhaustion seems to be a consequence in the long run (60).

In conclusion, we have tried to mimic the type 2 diabetic condition by maintaining slightly elevated postabsorptive plasma FFA concentrations throughout the Intralipid study. Although our data are consistent with a long-term detrimental effect of FFA on peripheral insulin sensitivity, only one study previously reported a stimulatory effect on the ß-cell, whereas the majority of long-term studies supported a toxic effect. We believe that the rather modest overall impact of lipid infusion in our study should be viewed in the light of considerably higher FFA concentrations and/or sustained hyperglycemia in those previous studies. However, even the rather low FFA concentrations used in our study may, over time, lead to ß-cell exhaustion in the presence of chronic mild insulin resistance in susceptible individuals (genetic predisposition, low birth weight), and there is evidence to suggest that some prediabetics may be even more susceptible to the impairing effect of elevated FFAs than are matched controls (61, 62, 63). Finally, it has not previously been recognized that prolonged FFA infusion impairs the suppression of glucagon by insulin, which may very well contribute to impaired suppression of EGP.

Acknowledgments

We are indebted and most grateful to all who participated in the study. For skillful assistance with clamps and analytical procedures, we thank biomedical assistants Susanne Reimer and Sussi Polmann (Hvidovre Hospital).

Footnotes

This work was supported by grants from The Danish Diabetes Association, Novo Nordisk Research Foundation, H:S Research Foundation, and The Research Fund for Copenhagen, Greenland and The Faeroe Islands. C.B.J. was granted a research fellow scholarship from The Faculty of Medicine, University of Copenhagen, Denmark.

Abbreviations: AUC, Area(s) under the curve; EGP, endogenous glucose production; EGS, exogenous glucose storage; FFA, free fatty acid; FFM, fat free mass; GF, glycolytic flux; GOX, glucose oxidation; HI, high insulin clamp; ISR, insulin secretion rate(s); IVGTT, iv glucose tolerance test; LI, low insulin clamp; LIPOX, lipid oxidation; NIDDM, non-insulin-dependent diabetes mellitus; NS, not significant.

Received September 11, 2002.

Accepted February 27, 2003.

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