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Original Studies |
Division of Endocrinology and Metabolism (Mi.K., Ma.K., P.N., D.W., M.B., H.S., C.F., W.W., M.R.), Department of Internal Medicine III, and Institute of Medical Physics (S.G., V.M.), University of Vienna Medical School, A-1090 Vienna, Austria
Address all correspondence and requests for reprints to: Michael Roden, M.D., Division of Endocrinology and Metabolism, Department of Internal Medicine III, University of Vienna Medical School, Währinger Gürtel 18-20, A-1090 Vienna, Austria. E-mail: michael.roden{at}akh-wien ac.at.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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G6P167–180 min:
-22 ± 7 vs. +24 ± 7 µmol/L,
P < 0.05) and hyperglycemic periods
(G6P287–300 min: -7 ± 9 vs.
+28 ± 7 µmol/L, P < 0.05). Changes in
intracellular inorganic phosphate exhibited a similar pattern, whereas
FFA did not affect phosphocreatine, ADP, pH, and intramyocellular lipid
contents. In conclusion, the lack of an increase in muscular G6P along
with reduction of whole body glucose clearance indicates that FFA might
directly inhibit glucose transport/phosphorylation in skeletal muscle. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Although such mechanisms may operate in rodent muscle (15, 16), studies in man revealed controversial results (3). Recently, it was demonstrated that plasma FFA elevation inhibits the insulin-dependent rise of intracellular G6P in human calf muscle during euglycemic-hyperinsulinemia (10). This effect is followed by marked reduction in glucose oxidation, glycogen synthesis, and whole body glucose uptake (9, 10) and is detectable even in the presence of physiological plasma FFA concentrations (9), suggesting an alternative mechanism for FFA-induced insulin resistance in man. Because the intracellular concentration of free glucose also declines under comparable experimental conditions, FFAs most likely induce a defect at the glucose transport step (7). It is of note that those studies were performed in the presence of hyperinsulinemia and that plasma FFA elevation reduces tyrosine phosphorylation of the insulin receptor substrate-1 (7), supporting evidence for an interaction of FFA with insulin-stimulated glucose transport. Thus, these findings do not exclude that Randle’s hypothesis is still valid in the postabsorptive state, which might favor the intracellular substrate competition between glucose and FFA.
Therefore, the present study was designed to determine the effects of FFA on the time course of intramuscular G6P concentrations and allosteric mediators of glucose metabolism such as inorganic phosphate (Pi), phosphocreatinine (PCr), ADP, and pH using 31P nuclear magnetic resonance (NMR) spectroscopy during basal (fasting) peripheral insulinemia-euglycemia. To examine the interaction of FFA with glucose-stimulated glucose uptake, plasma glucose concentrations were raised to approximately 10 mmol/L in the second part of the protocol. In addition, noninvasive 1H NMR spectroscopy was used to test the hypothesis (17) that FFAs increase the intramyocellular lipid content (IMCL), which inversely correlates with insulin sensitivity (1, 18, 19, 20).
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Seven healthy male volunteers (26 ± 2 yr, body mass index: 22.3 ± 1.0 kg/m2) without family history of diabetes mellitus, dyslipidemia, or bleeding disorders were included in this study. None were glucose intolerant, suffering from conditions related to insulin resistance, or taking any medication on a regular basis. Rates of glucose turnover were measured in 5 of these subjects (28 ± 2 yr, body mass index: 22.1 ± 0.6 kg/m2) in a similar supplementary protocol after the initial study. The different study days were separated by intervals of 7–56 days. The protocol was reviewed and approved by the local ethical board, and informed consent was obtained from all subjects after the nature and possible consequences of the procedures had been explained to them.
Study protocol
The participants were randomly assigned to either triglyceride emulsion/heparin or glycerol infusion, and crossed over to the other treatment on the second study day. After an overnight fast of 12 h, studies were begun at 0700 h (-120 min) with the insertion of catheters (Vasofix; Braun, Melsungen, Germany) into one antecubital vein of the left and right arms for blood sampling and infusions, respectively. D-[6,6-2H2]glucose (98% enrichment; Cambridge Isotope Laboratories, Andover, MA) was infused (bolus, 6.6 µmol/kg; continuous infusion, 0.08 µmol/kg·min) for determination of endogenous glucose production (EGP) from -120 to +300 min. To maintain fasting peripheral insulinemia, somatostatin (UCB Pharma, Vienna, Austria) was infused at a rate of 0.1 µU/kg·min (-5–300 min) and insulin (Actrapid; Novo Nordisk, Bagsvaerd, Denmark) was replaced from 0 to 300 min at a rate of 0.1 mU/kg·min (21). Because acute deficiency of human GH does not affect carbohydrate and lipid metabolism in the presence of basal insulinemia, human GH was not replaced (6, 22). To avoid a potential FFA-dependent rise in EGP with subsequent increase of plasma glucose during the euglycemic clamp period (6, 8), glucagon was not replaced in this study. Plasma glucose was maintained at approximately 5 mM from 0 to 180 min (euglycemic period) and thereafter at approximately 10 mM from 180 to 300 min (hyperglycemic period) using a variable infusion of 20% dextrose. On one day (LIP), plasma FFA concentrations were raised by combined infusion (0–300 min) of a triglyceride emulsion (1.5 mL/min; Intralipid 20%, Pharmacia & Upjohn, Inc., Vienna, Austria) and heparin (0.2 IU/kg·min; Immuno AG, Vienna, Austria) as described previously (6, 9, 10). During control studies (CON), glycerol was infused (0.95 mg/kg·min) to match the rise in plasma glycerol concentrations observed during lipid/heparin infusion. Blood samples were drawn in timed intervals, immediately cooled, centrifuged and stored at -80 C to avoid further lipolysis.
Because stable plasma tracer enrichments were not achieved during the hyperglycemic period of this protocol, a variable labeled glucose infusion (hot-GINF protocol) was used in a supplementary study to determine glucose turnover rates (7, 23). Five of the 7 subjects were studied again during lipid/heparin and glycerol infusion under otherwise identical conditions. Beginning at 0700 h (-120 min), D-[6,6-2H2]glucose (98% enrichment; Cambridge Isotope Laboratories) was infused (bolus, 22.2 µmol/kg; continuous infusion, 0.22 µmol/kg·min) from -120 to +300 min and the variable glucose infusion was enriched to 2.5% with D-[6,6-2H2]glucose. Blood samples for measurement of D-[6,6-2H2]glucose enrichments were drawn at timed intervals.
In vivo NMR spectroscopy
31P NMR spectroscopy. Intracellular concentrations of G6P, Pi, and PCr in the medial head of the gastrocnemius muscle were quantified using a 3-T magnetic resonance spectrometer (Medspec S300-DBX; Bruker, Ettlingen, Germany) as described previously (9). During acquisition of spectra, subjects remained in the supine position in the spectrometer with the calf muscle of their right leg positioned over the surface coil. The magnetic field was shimmed on the global water signal (usual bandwidth, approximately 35 Hz). Changes of G6P, Pi, and PCr from baseline values were determined noninvasively from difference spectra obtained every 7-min (0–100 min and 166–300 min) during the studies. Intracellular pH was calculated from the difference of the chemical shift between Pi and PCr (24, 25). ADP concentrations were calculated according to the equation for the equilibrium constant for the creatine kinase reaction (25, 26). The mean intrasubject coefficient of variation for measurement of G6P concentrations in our laboratory is 19.8% (9).
1H NMR spectroscopy. The IMCL was measured noninvasively in the soleus muscle of the right leg before and after 330 min of lipid/heparin or glycerol infusion. Localized 1H NMR spectra were acquired using a birdcage resonator with a diameter of 25 cm. The magnetic field was shimmed on the localized water signal (usual bandwidth, approximately 15 Hz). Scout images were acquired to position the volume of interest. The stimulated echo acquisition mode sequence (27) with chemical shift selective water suppression (echo time, 20 ms; repetition time, 6 s; 64 averages, 2048 data points) was used on the volume of 1.5 x 1.5 x 1.5 cm3 positioned in the soleus muscle. Spectra were line-broadened and phase- and baseline-corrected, and the resonances of interest were quantified using a line-fitting procedure using the MacNuts-PPC software package (AcornNMR Inc., Livermore, CA). After T2 relaxation correction, the IMCL was assessed from the intensity of the (CH2)n = resonance (1.25 parts per million), which was compared with the water resonance intensity obtained from spectra without water suppression (1). The IMCL is expressed as the percentage of the intensity of the water resonance. This method has been extensively validated (20, 28). In addition, we checked the precision of our measurements by comparing 4 consecutive spectra from each of five subjects, which gave a mean intrasubject coefficient of variation of 23.3%.
Analytical methods
Metabolites and hormones. Plasma glucose concentrations were measured by the glucose oxidase method (Glucose analyzer II; Beckman Coulter, Inc. Fullerton, CA). Plasma FFA concentrations were determined using a microfluorimetric method (Wako Chem USA Inc., Richmond, VA). Plasma triglycerides were hydrolyzed by lipase and the released glycerol was measured by a peroxidase-coupled colorimetric assay (Roche, Vienna, Austria). Plasma glycerol, lactate, and ß-hydroxy-butyrate concentrations were determined using enzymatic methods (Roche). Plasma-immunoreactive insulin was measured by commercially available RIAs (Pharmacia, Uppsala, Sweden).
Gas chromatography-mass spectrometry. Blood samples for the determination of atom percent 2H enrichments (APEs) in glucose were drawn at defined time points at baseline and at the end of the euglycemic period. Plasma glucose was derivatized to the aldonitrile-pentaacetate after deproteinization with 70% acetone in H2O with [1,2,3,4,5,6,6-2H7]- glucose (Cambridge Isotope Laboratories) added as an internal standard. All analyses were carried out on a Hewlett-Packard Co. 5890 gas chromatograph (Hewlett-Packard Co., Palo Alto, CA) equipped with a 25-m CP-Sil5 capillary column (0.2 mm i.d., 0.12-µm film thickness; Chrompack, Middelburg, The Netherlands) and interfaced to a Hewlett-Packard Co. 5971A mass selective detector. The programmed column temperatures were: 80 C for 30 s, followed by a rise to 140 C within 2 min, and then increased by 10 C/min to 230 C and by 5 C/min to 255 C. The mass spectrometer was operated in the electron ionization mode. Selected ion monitoring was used to determine enrichments in various molecular mass ion fragments. 2H enrichments in glucose were determined from the mass-to-charge ratio of 189–187 of the fragment consisting of C3 to C6 (29).
Calculations and statistical evaluation
Basal rates of glucose appearance (Ra) were calculated by dividing the tracer ([6,6-2H2]-glucose) infusion rate times tracer enrichment by the percent of tracer enrichment in plasma and subtracting the tracer infusion rate (30, 31). Ra and rates of glucose disappearance (Rd) during the clamp tests were calculated using Steele‘s non-steady state equations (23). EGP was calculated from the difference between Ra in plasma and the glucose infusion rates (GIRs).
All data are given as means ± SEM. Statistical comparisons between glycerol and triglyceride/heparin infusion studies were performed using the paired Student’s t test. Data within a group were compared by repeated measurements ANOVA and Dunnett‘s post hoc testing. Differences were considered statistically significant at P values less than 0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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). Plasma insulin
concentrations were maintained at approximately 50 pmol/L in both
studies (Fig. 1B). Plasma FFA concentrations increased
during lipid/heparin infusion (P < 0.001
vs. CON), but slightly decreased during glycerol infusion
(Fig. 1C). Plasma triglycerides rose only during lipid/heparin infusion
(CON, 1.2 ± 0.32 mmol/L; LIP, 3.4 ± 0.32 mmol/L;
P < 0.001 vs. CON). Plasma glycerol
concentrations similarly increased during both studies
(P < 0.01) without differences between the two
protocols (Fig. 1D).
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). During lipid/heparin infusion,
plasma lactate decreased to be lower than in the glycerol protocol
(P < 0.05; Fig. 2B).
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.
During lipid/heparin infusion GIRs started to be lower
(P < 0.05) at 100–120 min and were reduced by
approximately 80% (P < 0.01) and approximately 68%
(P < 0.001) compared with glycerol infusion studies at
167–180 min and 287–300 min, respectively.
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. APEs remained stable despite
rapid elevation of plasma glucose between 180 and 210 min, and were not
different between the two protocols (Fig. 4A). GIRs behaved similar as
in the initial study (Fig. 4B). Rates of glucose disappearance,
Rd, were lower during lipid/heparin infusion
compared with glycerol infusion at the end of the euglycemic period
(150–180 min) and during hyperglycemia (210–300 min; Fig. 4D).
Elevation of plasma glucose concentrations increased glucose use by
approximately 77% (P < 0.01 for values at 150–180
min vs. values at 270–300 min) only during glycerol
infusion. During lipid/heparin infusion Rd
returned to baseline values in the hyperglycemic period (210–300 min;
Fig. 4D). Fasting EGP was comparable between lipid/heparin and glycerol
infusion studies (Fig. 4E). Initiation of the pancreatic clamp tests
rapidly reduced EGP by approximately 46% (P < 0.01
for values at baseline vs. values at 0–30 min) in both
protocols. In the euglycemic period (0–180 min) EGP remained unchanged
during glycerol infusion, but slowly increased during lipid infusion
(Fig. 4E). Elevation of plasma glucose suppressed EGP by approximately
74% (P < 0.01 for values at 150–180 min
vs. values at 270–300 min) only during glycerol infusion.
However, during lipid/heparin infusion, EGP was not significantly
reduced by hyperglycemia.
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G6P and
Pi obtained at the end of the euglycemic (167–180 min) and
hyperglycemic period (167–180 min) during glycerol and lipid infusion
are depicted in Fig. 5. Intramuscular G6P
concentrations were similar at baseline (CON, 76 ± 9 µmol/L;
LIP, 87 ± 11 µmol/L). During lipid/heparin infusion,
intramuscular G6P did not change within the first 100 min, but was
lower compared with baseline values (P < 0.05) and
glycerol infusion studies (P < 0.01) at the end of the
euglycemic period (167–180 min), and did not exceed baseline values
thereafter (Fig. 3B
). In contrast, during glycerol infusion, G6P
concentrations rose (P < 0.01) above baseline, and
were higher (P < 0.05) than during lipid/heparin
infusion from 100 min on. Induction of the hyperglycemic period
(180–190 min) resulted in a small, transient increase of intramuscular
G6P concentrations in both studies (P < 0.01
vs. values at 167–180 min).
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). During glycerol infusion,
intramuscular Pi rose (P < 0.01) above baseline within
174 min, and were higher (P < 0.05) than during
lipid/heparin infusion between 202–260 min. Intramuscular
concentrations of ADP, PCr, and pH at baseline as well as changes
during the clamp tests were not different between both protocols (Table 1).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Under postabsorptive conditions approximately 20% of whole body glucose uptake is directed into the skeletal muscle where glucose is oxidized (35). In the present study, the increase by approximately 33% of intramuscular G6P during glycerol infusion might have resulted from increased glucose uptake, glycogen breakdown, and/or decreased glycolysis. Because GIRs and plasma lactate concentrations were higher during glycerol infusion, a glycerol-induced decrease in glycolysis is unlikely. Employing similar conditions of fasting peripheral insulinemic-hypoglucagonemic-euglycemia, Laurent et al. (36) found no changes in intramuscular glycogen concentrations. Thus, the rise in intramuscular G6P observed in the control study most likely reflects increased muscular glucose uptake, which is in agreement with the increase of the metabolic glucose clearance rate under similar conditions (6). In contrast, no increase in intramuscular G6P was seen during lipid/heparin infusion. Because plasma FFA elevation does not affect intramuscular glycogen concentrations (36) and glycogen synthase activity (37) under postabsorptive conditions, the decrease in G6P is again in keeping with the reduction of glucose clearance (6) and glucose uptake (36) during lipid/heparin infusion. However, according to Randle’s hypothesis the FFA-induced reduction in muscular glucose uptake is mediated by high intracellular G6P concentrations, which allosterically inhibit hexokinase II (13, 14). In contrast to hyperinsulinemia, conditions of fasting peripheral insulinemia are expected to promote the substrate competition between glucose and FFA for mitochondrial oxidation. Nevertheless, intramuscular G6P remained lower during lipid/heparin than during glycerol infusion. Previous biopsy studies failed to demonstrate any difference in G6P between lipid and control conditions (12, 38). This is most likely due to in vitro glycogen breakdown, which may artificially increase intracellular G6P (39) and thereby mask the effect of FFA in biopsy studies. Taken together, these results support the concept that FFAs rather inhibit transmembraneous glucose transport/phosphorylation irrespective of the prevailing insulin concentration.
In contrast to basal insulinemic-euglycemia, hyperglycemia favors by mass action (15, 40) whole body glucose uptake in skeletal muscle where glucose will be metabolized by both oxidative and nonoxidative pathways (35). In the present study, plasma FFA elevation inhibited the hyperglycemia-induced increase in glucose use observed during glycerol infusion. EGP was reduced by approximately 74% by hyperglycemia during glycerol infusion. This is in agreement with previous studies (41, 42). However, plasma FFA elevation prevented this glucose-dependent suppression of EGP.
Hyperglycemia transiently raised intramuscular G6P when compared with the preceding fasting peripheral insulinemic-euglycemic period. No such increase in G6P was found using the muscle biopsy technique, when plasma glucose was increased up to approximately 26 mM and plasma insulin kept at or below approximately 40 pM (43). The rise of intramuscular G6P by approximately 45 µM was markedly lower compared with the approximately 2-fold increase observed during hyperinsulinemic-euglycemia (9, 10, 25). Nevertheless, this expansion of the intracellular G6P pool during hyperglycemia might be sufficient to account for the increase in leg glucose storage by allosteric activation of glycogen synthase as postulated by Mandarino et al. (30).
During plasma FFA elevation, intramuscular G6P remained lower than
during glycerol infusion and did not change from baseline values in the
hyperglycemic state. Considering no alteration of muscular glycogen
synthesis (36) the failure to increase intramuscular G6P
hints at a defect in either glucose transport or glucose
phosphorylation. Because intracellular pH, PCr, and ADP did not change,
allosteric effects of these mediators can be excluded. To the extent
that the observed decrease in intracellular Pi, an allosteric inhibitor
of hexokinase, could have rather stimulated glucose phosphorylation,
plasma FFA elevation most likely interfered with the glucose transport
step. Given the low plasma insulin concentrations, insulin-independent
mechanisms could be responsible for such inhibitory effects of FFA,
which as long-chain fatty acyl CoA may 1) interact with membrane
composition and fluidity (44, 45), 2) directly affect
glucose transporters (46, 47), 3) stimulate hexosamine
formation (48), or 4) increase protein kinase C 
(49) and thereby reduce glucose transport.
Although elevated plasma FFAs do not affect the insulin-stimulated rise in intramuscular Pi (9), they inhibited the increase in Pi during fasting peripheral insulinemia in the present study. Such metabolic behavior relates to stimulation by insulin of Na+-dependent Pi uptake in skeletal muscle (8) and to inhibition by arachidonic acid and other unsaturated fatty acids of epithelial phosphate transport in vitro (50). Thus, the potent insulin-induced stimulation of transcellular Pi uptake might have masked the FFA effect on intracellular Pi during hyperinsulinemic conditions.
This study also measured IMCL using 1H NMR spectroscopy, which allows noninvasive quantification of intramyocellular fat contents (1) and was recently validated using muscle biopsies (20). IMCL did not change between 12 and 18 h of fasting. This is contrast to studies suggesting that intracellular lipid pools contribute to whole body lipid oxidation in the basal state (51), but rather support other findings that intracellular trigycerides do not add quantitatively to lipid oxidation (52). Lipid/heparin infusion also did not affect IMCL in healthy men, whereas muscle triglyceride concentrations were increased in rats under similar conditions (17). However, these results do not exclude that long-term FFA elevation may augment the intracellular lipid pool.
The plasma FFA concentrations achieved in the present study (approximately 2.5 mmol/L) are within the range of those [approximately 0.75 mmol/L (5) to approximately 4.7 mmol/L (53, 54)] reported previously using identical triglyceride/heparin infusions. Because no inhibitor of lipolysis was added to the samples, in vitro lipolysis might have occurred resulting in overestimation of the actual plasma FFA concentrations. Prevention of such in vitro lipolysis will give at least approximately 28% lower estimates of plasma FFA under comparable conditions (55), which, however, should not affect the main conclusions of the present results.
In conclusion, elevation of plasma FFA 1) inhibits the hyperglycemia-induced suppression of EGP, 2) reduces glucose-stimulated glucose uptake, 3) blunts the rise in intramuscular G6P, and 4) inhibits the parallel increase of intramuscular Pi, but 5) does not affect intramyocellular lipid concentrations during basal (fasting) insulinemia. These findings support the hypothesis that in skeletal muscle impaired glucose uptake rates lead to increased fatty acid oxidation, rather than the reverse (47).
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Acknowledgments |
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Footnotes |
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Received November 10, 1999.
Revised March 29, 2000.
Revised April 14, 2000.
Accepted January 28, 2001.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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and alterations in the insulin signaling cascade. Diabetes. 48:1270–1274.[Abstract]
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) or lipid emulsion plus heparin (LIP, •). Data are given as
means ± SEM of seven healthy subjects who underwent
both somatostatin-glucose-insulin clamp tests. +, P
< 0.01; 
, P < 0.001 vs.
LIP.
, 
, •). Data are given as means ±
SEM of seven healthy subjects who underwent both
somatostatin-glucose-insulin clamp tests. *, P <
0.05; +, P < 0.01; 
