Diabetes Division, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284
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ABSTRACT |
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To investigate the effect
of elevated plasma free fatty acid (FFA) concentrations on splanchnic
glucose uptake (SGU), we measured SGU in nine healthy subjects (age,
44 ± 4 yr; body mass index, 27.4 ± 1.2 kg/m2;
fasting plasma glucose, 5.2 ± 0.1 mmol/l) during an
Intralipid-heparin (LIP) infusion and during a saline (Sal)
infusion. SGU was estimated by the oral glucose load
(OGL)-insulin clamp method: subjects received a 7-h euglycemic insulin
(100 mU · m2 · min
1) clamp,
and a 75-g OGL was ingested 3 h after the insulin clamp was
started. After glucose ingestion, the steady-state glucose infusion
rate (GIR) during the insulin clamp was decreased to maintain
euglycemia. SGU was calculated by subtracting the integrated decrease
in GIR during the period after glucose ingestion from the ingested
glucose load. [3-3H]glucose was infused during the
initial 3 h of the insulin clamp to determine rates of endogenous
glucose production (EGP) and glucose disappearance (Rd).
During the 3-h euglycemic insulin clamp before glucose ingestion,
Rd was decreased (8.8 ± 0.5 vs. 7.6 ± 0.5 mg · kg
1 · min
1,
P < 0.01), and suppression of EGP was impaired
(0.2 ± 0.04 vs. 0.07 ± 0.03 mg · kg
1 · min
1,
P < 0.01). During the 4-h period after glucose
ingestion, SGU was significantly increased during the LIP vs. Sal
infusion study (30 ± 2 vs. 20 ± 2%, P < 0.005). In conclusion, an elevation in plasma FFA concentration impairs
whole body glucose Rd and insulin-mediated suppression of
EGP in healthy subjects but augments SGU.
liver; oral glucose; skeletal muscle
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INTRODUCTION |
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SPLANCHNIC GLUCOSE UPTAKE (SGU) accounts for the disposal of approximately one-third of an oral glucose load (18, 24, 26). Hyperglycemia per se enhances SGU in proportion to the increase in plasma glucose concentration, and this mass-action effect of hyperglycemia to augment SGU is dependent upon maintained portal insulin levels (11). Insulin per se, even when administered in pharmacological doses, does not increase SGU in the absence of hyperglycemia (11-13). Similarly, changes in plasma glucagon concentrations do not alter SGU in humans (11). Studies by DeFronzo et al. (12) and Adkins et al. (1) have shown that the gastrointestinal route of glucose administration has a specific enhancing effect on SGU and that after glucose ingestion the uptake of glucose by the splanchnic tissues is significantly greater than the combined effects of hyperinsulinemia plus hyperglycemia created by intravenous glucose/insulin administration (1, 11, 12, 30). Pagliassotti et al. (31) have demonstrated that there is a strong correlation in dogs between SGU and the hepatic portal-arterial glucose concentration difference, implicating a "portal signal" (dependent on the glucose concentration gradient) in the enhancement of SGU after oral glucose administration. The effect of this portal signal is not restricted to the liver but extends to nonhepatic tissues, including skeletal muscle (29). Thus, after glucose ingestion the portal signal, which is responsible for the augmentation of SGU, is communicated to peripheral tissues and leads to a reduction in muscle glucose uptake (29). This "cross talk" provides a mechanism for coordinating the disposition of an oral glucose load between the liver and the peripheral tissues, primarily muscle. At present, no study has examined whether this cross talk exists in normal glucose-tolerant, insulin-sensitive subjects or whether it is preserved in insulin-resistant states such as obesity and type 2 diabetes.
Obese nondiabetic individuals, the offspring of parents with type 2 diabetes mellitus, individuals with impaired glucose tolerance, and type 2 diabetic patients are characterized by insulin resistance, accelerated rates of lipolysis (10, 20, 21, 34), and day-long increased plasma free fatty acid (FFA) levels (34). Elevated plasma FFA concentrations have been shown to impair glucose metabolism by competing with glucose as an oxidative fuel in the muscle, by inhibiting the more proximal steps of insulin action in muscle (3, 4, 15, 33, 34, 36, 43), by augmenting basal hepatic gluconeogenesis (37), and by impairing the suppression of hepatic glucose production by insulin (4, 7, 16). In contrast to their action on muscle glucose uptake and hepatic glucose production/gluconeogenesis, very little is known about the effect of elevated plasma FFA levels on splanchnic (hepatic) glucose uptake in humans in vivo.
The current study was designed to determine the effect of an elevation in plasma FFA concentration on SGU after glucose ingestion in healthy nondiabetic human subjects. To quantitate SGU, we employed a combined euglycemic insulin clamp-oral glucose load technique (OGL-clamp) developed in our laboratory (12, 18) and subsequently modified by Ludvik et al. (26).
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METHODS |
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Subjects. Nine healthy nondiabetic subjects with a mean body weight of 74.5 ± 4 kg participated in the study. There were 4 males and 5 females with a mean age of 44 ± 4 yr and body mass index of 27.4 ± 1.2 kg/m2. The fasting plasma glucose concentration and HbA1c were 5.2 ± 0.1 mmol/l and 4.9 ± 0.1%, respectively. All subjects had a normal 2-h oral glucose (75 g) tolerance test. The plasma lipid levels were as follows: total cholesterol = 192 ± 10 mg/dl, low-density lipoprotein cholesterol = 119 ± 11 mg/dl, high-density lipoprotein cholesterol = 55 ± 2 mg/dl, and triglycerides 121 ± 12 mg/dl. None of the subjects had any significant medical problems, and their weight was stable for at least 3 mo before the study. None of the subjects was taking any medications known to affect glucose metabolism. Subjects were instructed to maintain their usual diet and not to engage in vigorous exercise for at least 3 days before the study. The purpose, nature, and potential risks of the study were explained to all subjects, and written consent was obtained before their participation. The protocol was approved by the Institutional Review Board of the University of Texas Health Science Center at San Antonio.
Study design.
Subjects were admitted to the General Clinical Research Center at 1800 on the evening before the study, and a standard, weight-maintaining meal (55% carbohydrate, 30% fat, and 15% protein) was ingested between 1830 and 1900. After 2000, subjects refrained from eating or
drinking anything except water. At 0600 on the next day, a catheter was
placed in an antecubital vein, and subjects received an infusion of:
1) 20% Intralipid (0.2 ml · m2 · min
1) with
heparin (0.2 U · kg
1 · min
1) or
2) normal saline (0.2 ml · m
2 ·min
1). The
Intralipid and saline studies were performed in random order within a
7- to 10-day interval. At 0600, a second catheter was inserted
retrogradely in a vein on the dorsum of the hand for blood sampling,
and the hand was placed in a heated box (60°C) for the duration of
the study. Two hours after the start of Intralipid/heparin or saline
infusion (0800), a euglycemic insulin (100 mU · m
2 · min
1) clamp was
begun and continued for 7 h. Arterialized blood samples were
collected every 5 min for plasma glucose determination, and a 20%
glucose infusion was adjusted to maintain the plasma glucose concentration at ~5.5 mmol/l (9). During the first 180 min of the euglycemic insulin clamp, a primed (25 µCi)-continuous (0.25 µCi/min) infusion of [3-3H]glucose was given to
measure endogenous glucose production (EGP). The tritiated glucose
infusion was discontinued after 180 min, at the time when the glucose
load was ingested. Insulin, glucose, [3-3H]glucose, and
Intralipid/heparin were infused via the antecubital vein. Plasma
samples for determination of plasma insulin and FFA concentration were
obtained every 15-30 min throughout the study. Plasma samples for
the determination of [3-3H]glucose specific activity were
obtained every 5-10 min during the 150- to 180-min period of the
euglycemic insulin clamp (Fig. 1). During
the 150- to 180-min time period of the insulin clamp, the exogenous
glucose infusion rate required to maintain euglycemia was constant
(Fig. 2). Three hours after start of the
insulin clamp (at 1100), subjects ingested 75 g of glucose over a
5-min period. As the oral glucose was absorbed, the exogenous
intravenous glucose infusion rate was reduced appropriately to maintain
euglycemia (Fig. 2). Within 3-3.5 h after glucose ingestion, the
glucose infusion rate returned to or exceeded the rate at 180 min,
indicating that the absorption of the oral glucose load was complete
(Fig. 2).
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Analytical determinations. Plasma glucose concentration was measured by the glucose oxidase method (Beckman Instruments, Fullerton, CA). Plasma insulin (Diagnostic Products, Los Angeles, CA) and C-peptide (Diagnostic Systems, Webster, TX) concentrations were measured by RIA. Tritiated glucose specific activity was determined on deproteinized barium/zinc plasma samples, as previously described (20). Plasma FFA concentration was determined by an enzymatic colorimetric quantification method (Wako Chemicals, Nuess, Germany). Although blood samples were immediately placed on ice and spun in a refrigerated centrifuge within 15-20 min, it is possible that in vitro lipolysis resulted in an overestimation of the plasma FFA concentration in vivo.
Calculations. During the euglycemic hyperinsulinemic clamp before the ingestion of glucose (0-180 min), the rate of total body glucose appearance (Ra) was calculated using Steele's equation (42) and a distribution volume of 250 ml/kg. EGP was calculated by subtracting the exogenous glucose infusion rate from Ra. The rate of insulin-mediated total body glucose disposal (Rd) was determined by adding the rate of EGP to the exogenous glucose infusion rate. The tritiated glucose infusion was discontinued at 180 min, and EGP was not determined during the 180- to 420-min time period after the ingestion of glucose.
The amount of glucose that escaped splanchnic uptake was calculated as follows: the average glucose infusion rate between 180 and 380 min was subtracted from the reference glucose infusion rate to obtain the integrated decrement in the glucose infusion rate. The integrated decrement in the exogenous glucose infusion rate after glucose ingestion was multiplied by the subject's body weight and time to obtain the amount of glucose escaping the splanchnic bed. The reference glucose infusion rate was calculated as the mean glucose infusion rate obtained by drawing a line between the 180- and 380-min time points. The amount of glucose escaping the splanchnic bed was subtracted from the oral glucose load (75 g) to calculate the SGU. Previous studies (25, 26) have shown that glucose absorption from the gastrointestinal tract after glucose ingestion is complete within 3-3.5 h, and this was confirmed in the present study by the sharp rise in the exogenous glucose infusion rate in all subjects to or above the pre-OGL rate (150-180 min) by 380 min. The calculation of SGU assumes that residual EGP during the combined OGL-100 mU · mStatistical analysis. Statistical calculations were performed with StatView for Windows, version 5.0 (SAS Institute, Cary, NC). Changes from baseline within a group were evaluated using the paired Student's t-test. Differences between the Intralipid and saline infusion studies were evaluated by ANOVA. Significant differences between the two studies were confirmed by the Bonferroni test. Pearson correlation coefficients were used for correlation analysis. Data are presented as means ± SE. A P value <0.05 was considered to be statistically significant.
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RESULTS |
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Plasma glucose, insulin, C-peptide, and FFA concentrations.
During the initial 3 h of the euglycemic insulin clamp, the plasma
glucose concentrations were similar during the Intralipid and saline
studies (5.5 ± 0.1 vs. 5.5 ± 0.1 mmol/l). After glucose ingestion, there was a very small increase in the plasma glucose concentration (5.7 ± 0.2 vs. 5.7 ± 0.2 mmol/l,
P = not significant) in both studies during the 180- to
300-min time period (Fig. 3). From 300 to
420 min the plasma glucose concentration remained constant in both the
Intralipid and saline studies (5.4 ± 0.1 vs. 5.4 ± 0.1 mmol/l; Fig. 3).
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Glucose infusion rate.
The time course of the exogenous intravenous glucose infusion rate is
shown in Fig. 2. The mean glucose infusion rate increased steadily
during the initial 150 min of the insulin clamp with both saline and
Intralipid infusion and reached a plateau from 150 to 180 min in both
studies. The glucose infusion rate required to maintain euglycemia was
significantly reduced from 150 to 180 min in the Intralipid vs. saline
infusion (7.4 ± 0.5 vs. 8.7 ± 0.5 mg · kg1 · min
1,
P < 0.01). After glucose ingestion, there was an
abrupt decline in the glucose infusion rate required to maintain
euglycemia in both the Intralipid and saline studies (Fig. 2). By 380 min the glucose infusion rate returned to the pre-OGL value in all
subjects, indicating that the absorption of the oral glucose load was
complete. EGP, determined during the 150- to 180-min period of the
euglycemic insulin clamp, was suppressed by >90% during both the
lipid and saline infusion studies but was significantly higher in the
Intralipid vs. saline infusion study (0.2 ± 0.04 vs. 0.07 ± 0.03 mg · kg
1 · min
1,
respectively, P < 0.01). The whole body Rd
was significantly reduced from 150 to 180 min in the Intralipid vs.
saline infusion (7.6 ± 0.5 vs. 8.8 ± 0.5 mg · kg
1 · min
1,
P < 0.01).
SGU.
SGU during the OGL-insulin clamp performed with Intralipid (22.5 ± 1.5 g) was significantly higher (P < 0.005)
compared with the saline study (15.3 ± 1.5 g). The
percentage of the oral glucose taken up by the splanchnic tissues also
was significantly higher (Fig. 4) during
the Intralipid vs. saline study (30 ± 2 vs. 20 ± 2%,
P < 0.005). The Intralipid-induced decrement in whole
body Rd during the insulin clamp study correlated
positively with the increase in SGU (r2 = 0.55, P = 0.02), i.e., subjects with the greatest
decrease in Rd during the Intralipid infusion study
demonstrated the greatest increase in SGU (Fig.
5).
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DISCUSSION |
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In the present study we have employed the OGL-insulin clamp technique (12, 18, 26) to examine the effect of an increase in the plasma FFA concentration on net SGU in healthy nondiabetic human subjects with normal glucose tolerance. Our results demonstrate that elevation of the plasma FFA concentration by an Intralipid infusion resulted in a decrease in whole body glucose uptake, which primarily reflects muscle glucose uptake (10), and a reciprocal increase (Fig. 5) in SGU by 47% (15.3 to 22.5 g) after glucose ingestion. As previously shown by us and others (4, 16, 43), the elevation in plasma FFA concentration during Intralipid infusion impaired the suppression of EGP by insulin, although the magnitude of the impairment was small because the high insulin infusion rate caused a >90% suppression of EGP in both groups.
Although we did not measure SGU before glucose ingestion, previous
studies from our laboratory have demonstrated that SGU under basal
conditions is small and varies little from person to person
(11-13, 18). During the 3.5-h period after glucose ingestion, the mean rate of glucose uptake by the splanchnic tissues was 1.01 ± 0.10 mg · kg1 · min
1 during the
saline infusion. This rate of SGU was two times that observed with
comparable levels of hyperglycemia plus hyperinsulinemia created by
intravenous glucose/insulin administration (12, 18). These
results are consistent with our previous observations in humans
(12, 18) and with those of Adkins et al. (1)
and Cherrington (8) in dogs and demonstrate that the oral
route of glucose administration has a specific effect to enhance SGU. Pagliassotti et al. (31) have demonstrated in dogs that a
portal signal, generated by the glucose gradient between the portal
vein and hepatic artery, is responsible for the greater increase in splanchnic (hepatic) glucose uptake after oral compared with
intravenous glucose administration. The partitioning of an oral glucose
load among the tissues is also regulated by the portal signal. Thus Moore et al. (29) in conscious dogs have shown that
the increase in hepatic glucose uptake after glucose ingestion
is associated with a reciprocal decrease in peripheral (primarily
muscle) glucose uptake. Furthermore, Galassetti et al.
(19) demonstrated that a negative arterial-portal gradient
decreases skeletal muscle glucose uptake while enhancing hepatic
glucose uptake in dogs. The results of the current study demonstrate,
for the first time in humans, the existence of a similar mechanism in
which cross talk between the liver and the peripheral tissues works in
a coordinated manner to maintain normal glucose tolerance after glucose
ingestion. During the OGL-insulin clamp with saline infusion, 15.3 g (20%) of the 75-g oral glucose load were taken up by the splanchnic tissues (primarily liver), and the remaining 59.7 g of glucose were taken up by extra splanchnic tissues, primarily muscle. During the
last 30 min of the euglycemic insulin clamp performed with Intralipid,
the increase in plasma FFA concentration induced peripheral insulin
resistance and decreased glucose Rd by ~13%. Because the plasma FFA, glucose, and insulin concentrations during the 4-h period
(180-420 min) of the OGL-insulin clamp were virtually identical to
those during the 150- to 180-min period of the euglycemic insulin clamp, one can assume that a similar defect in peripheral glucose disposal would prevail after glucose ingestion and that 13% of 59.7 g, or ~8 g less of the oral glucose, would be taken up by peripheral tissues compared with the saline infusion OGL-insulin clamp
study. SGU during the OGL-insulin clamp with Intralipid was 22.5 ± 1.5 g, which represents an increment of 7.2 ± 1.5 g compared with the saline OGL-insulin clamp study. This amount agrees
quite closely with the expected decrease (~8 g) in peripheral glucose
uptake. Thus, in healthy humans, as in dogs (1, 8), after
glucose ingestion there appears to be a reciprocal relationship between
SGU and peripheral glucose uptake. In a recently published study
(38) using a different experimental design
(hyperinsulinemic hyperglycemic clamp combined with hepatic vein
catheterization), Shah et al. demonstrated that elevated plasma FFA
levels (Intralipid/heparin infusion) significantly impaired leg
(muscle) glucose uptake in healthy nondiabetic human subjects, and
there was a tendency, although not statistically significant, for SGU
to increase. These observations are consistent with those in the
present study. Thus, when peripheral insulin resistance is induced by
Intralipid infusion, the splanchnic (liver) tissues compensate by
augmenting glucose uptake in an attempt to maintain normal oral glucose
tolerance. A similar mechanism can be inferred from the results of
Ludvik et al. (26). These investigators reported that SGU
was increased in obese vs. lean nondiabetic subjects. Because the obese
subjects in this study (26) were resistant to insulin, one
would predict that an intact portal signal would redirect the
disposition of the ingested glucose load from peripheral to splanchnic
tissues, and this is precisely what was observed. Whether the portal
signal remains intact in type 2 diabetic subjects remains to be
determined, but studies by Ferrannini and colleagues (17,
18) suggest that the normal cross talk between peripheral and
hepatic tissues may be disrupted.
The precise mechanisms responsible for the generation of the portal signal have yet to be defined, but neural and humoral mechanisms have been implicated. A role for humoral agents, including the intestinal incretins, has been suggested (14), but definite proof has yet to be forthcoming. Studies performed in animals provide evidence for the role of the autonomic nervous system and hypothalamus in mediating the portal signal. The liver, as the sensor organ, detects the increased glucose concentration gradient between portal vein and the hepatic artery via intrahepatic sensory effector nerves and generates a cholinergic signal that augments hepatic glucose uptake, thus coupling glucose absorption and hepatic glucose uptake (2, 28, 39-41). Adkins-Marshall et al. (2) demonstrated in dogs that the enhancement in hepatic glucose uptake after intraportal glucose infusion was abolished by hepatic denervation. Consistent with these observations, Shiota et al. (41) demonstrated in conscious dogs that portal vein acetylcholine infusion enhanced hepatic glucose uptake of intravenously administered glucose, although adrenergic blockade had no effect on hepatic glucose uptake. These results suggest a role for the parasympathetic nervous system in the generation of the portal signal after portal glucose delivery. Studies by Shimazu et al. (39, 40) and Minokoshi et al. (28) in rats have shown that the lateral and ventromedial hypothalamic nuclei play important roles in the central integration of the parasympathetic stimuli generated by the portal signal and relay the efferent response to the liver and peripheral tissues via sympathetic nerves (28). Matsuhisa et al. (27) have demonstrated in dogs that a reduction in glucose gradient between the brain and the portal vein blunts the enhancement in hepatic glucose uptake (despite the presence of a negative portal-arterial gradient in the liver after intraportal glucose delivery) and completely abolishes the effect of the intraportal glucose infusion to decrease peripheral (muscle) glucose uptake. Thus the hypothalamus and the autonomic (both parasympathetic and sympathetic) nervous system both participate in the regulation of peripheral (muscle) and hepatic glucose uptake, leading to the coordinated disposal of an oral glucose load. However, recent studies by Hsieh and colleagues (22, 23) suggest that the signal that brings about the suppressive effect of portal glucose delivery on peripheral glucose uptake may originate in the liver itself.
The OGL-hyperglycemic clamp technique originally was developed in our
laboratory to quantitate SGU (12, 18). More recently, Ludvik et al. (26) modified the OGL-hyperglycemic clamp
technique by administering the oral glucose load during a euglycemic
insulin clamp study. This modification has the advantage of providing more reproducible and constant steady-state plasma insulin
concentrations (Fig. 3), since the arterial plasma glucose
concentration is maintained at euglycemic levels. Thus, after glucose
ingestion at 180 min, the plasma insulin concentrations did not change
significantly from their values during the last 30 min of the
euglycemic insulin clamp (150- to 180-min time period). Furthermore,
the insulin infusion rate (100 mU · m2 · min
1) produced
pharmacological plasma insulin concentrations that caused a nearly
complete suppression (>90%) of EGP during 180 min of both the saline
and Intralipid infusion studies. Moreover, the resultant portal
hyperglycemia (after glucose ingestion) further serves to ensure the
complete suppression of hepatic glucose production. The OGL-insulin
clamp technique has the additional advantages that it is noninvasive
(hepatic vein catheterization not required), can be performed
repetitively to follow changes in SGU, and circumvents the problems of
tracer cycling and non-steady-state conditions that exist with the
double tracer technique. Both the OGL-hyperglycemic clamp and
OGL-insulin clamp techniques have been validated by direct comparison
with the hepatic vein catheter technique (12, 18, 26).
The OGL-insulin clamp technique assumes that the absorption of the oral glucose load is complete (75 g) within 4 h and that EGP is completely or nearly completely suppressed. With respect to the first assumption, previous studies have demonstrated that an oral glucose load, comparable to that employed in the present study, is absorbed within 3-3.5 h (25, 26). This was confirmed in the present study by return of the exogenous glucose infusion rate during the 380- to 420-min time period to values that were equal to or greater than the glucose infusion rate at 180 min, i.e., immediately before ingestion of the glucose load. Because EGP during the saline infusion studies was nearly completely suppressed during the last hour of the euglycemic insulin clamp, and the plasma insulin concentration remained constant after glucose ingestion, one can reasonably assume that EGP remained suppressed during the 4 h after glucose ingestion. Elevated plasma FFA concentrations have been shown to impair insulin-mediated suppression of EGP in prior studies (4, 7, 16), and we observed a similar impairment during the last hour of the euglycemic insulin clamp performed with the Intralipid infusion. However, the slightly higher rate of EGP would only serve to underestimate the magnitude of the increase in SGU that was observed during the Intralipid infusion.
As reported by other investigators (3, 4, 15, 16, 35, 36, 43), we also observed a reduction in whole body glucose Rd by ~13% during the last 30 min of the euglycemic insulin clamp (before glucose ingestion) during Intralipid infusion (compared with saline infusion). Randle and colleagues (32, 33) proposed more than 30 years ago that elevated blood FFA levels contribute to the development of insulin resistance in obesity and type 2 diabetes by decreasing glucose uptake and oxidation in muscle. Consistent with the operation of the Randle cycle, elevated plasma FFA levels in healthy humans have been shown to inhibit insulin-stimulated glucose oxidation within 1-2 h, followed by an inhibition of glucose uptake and glycogen synthesis within 3-4 h (3, 6). Two distinct mechanisms account for this late inhibition of glucose disposal: 1) an inhibition of glucose transport and/or phosphorylation (36) and 2) a decrease in muscle glycogen synthase activity (5).
In summary, an acute elevation in the plasma FFA concentration in healthy subjects impairs whole body glucose disposal and insulin-mediated suppression of EGP, but it augments SGU. These results provide evidence for cross talk (that is independent of hyperglycemia) between peripheral tissues (muscle) and liver in the maintenance of normal glucose homeostasis. Thus the development of insulin resistance in muscle is associated with a "compensatory" increase in SGU, and oral glucose tolerance remains normal. The precise mechanisms responsible for this cross talk remain to be defined. It also is unclear whether this cross talk is disrupted during the diabetic state.
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ACKNOWLEDGEMENTS |
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We thank the nurses at the General Clinical Research Center for diligent care of our patients and especially Patricia Wolff, Norma Diaz, James King, and John Kincade for carrying out the insulin clamp studies. We gratefully acknowledge the technical assistance of Kathy Camp, Cindy Munoz, and Shiela Taylor. Lorrie Albarado and Elva Chapa provided skilled secretarial support in the preparation of this manuscript.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. Bajaj, Diabetes Division, Dept. of Medicine, Univ. of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78284--7886 (E-mail: mandeepbajaj{at}hotmail.com).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
April 9, 2002;10.1152/ajpendo.00329.2001
Received 20 July 2001; accepted in final form 8 April 2002.
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