Effects of Hepatic Glycogen Content on Hepatic Insulin Action in ...

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0021-972X/97/$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1997 by The Endocrine Society

Vol. 82, No. 6 Printed in U.S.A.

Effects of Hepatic Glycogen Content on Hepatic Insulin Action in Humans: Alteration in the Relative Contributions of Glycogenolysis and Gluconeogenesis to Endogenous Glucose Production* STEVEN WISE, MICHAEL NIELSEN,

AND

ROBERT RIZZA

Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota 55905 ABSTRACT Hepatic glycogen content varies by almost 2-fold during the day, generally increasing from a nadir before breakfast to a peak 4 –5 h after supper. To determine whether differences in hepatic glycogen content of this magnitude alter hepatic insulin action, nine subjects were studied on two occasions. On one occasion saline was infused, whereas on the other occasion an infusion of glucose [16.4 mmol/kg lean body mass (-lbm)zmin] was started immediately after supper and continued throughout the night so as to spare hepatic glycogen. The nocturnal glucose infusion resulted in higher (P , 0.05) plasma glucose (6.0 6 0.1 vs. 5.1 6 0.1 mmol/L) and insulin (127 6 38 vs. 49 6 9 pmol/L) concentrations, and lower (P , 0.05) plasma glucagon concentrations (74 6 11 vs. 97 6 20 pg/mL) than did saline infusion. As anticipated, endogenous glucose production (EGP) was substantially lower (P , 0.001) during the glucose than during the saline infusion (7.0 6 0.9 vs. 19.4 6 1.3 mmol/kg-lbmzmin). After discontin-

uation of the glucose infusion, glucose and insulin concentrations fell to levels that no longer differed from those observed during the saline infusion. In contrast, EGP increased to rates that were higher (P , 0.05) than those observed over the same interval after overnight saline infusion (19.2 6 1.2 vs. 16.5 6 0.7 mmol/kg-lbmzmin). Despite higher EGP, the rate of incorporation of 14CO2 into glucose was lower (P , 0.001) after glucose than that after saline infusion (9.8 6 1.2% vs. 24.4 6 3.0%), implying a reciprocal relationship between hepatic glycogen content and gluconeogenesis. On the other hand, when differences in basal rates were taken into account, insulin-induced suppression of both EGP and incorporation of 14CO2 into glucose did not differ on the two occasions. Thus, whereas hepatic glycogen content influences both the absolute rate of EGP and the percent contribution of gluconeogenesis to EGP, it does not alter hepatic insulin action. (J Clin Endocrinol Metab 82: 1828 –1833, 1997)

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hand, Clore et al. overfed normal human volunteers an excess of 1000 Cal/day for 5 days in an effort to increase hepatic glycogen content (12). Overfeeding resulted in an increase in endogenous glucose production (EGP) and a decrease in the rate of alanine gluconeogenesis. As the increase in EGP occurred in the face of increased fasting plasma insulin concentrations, these results implied the presence of hepatic insulin resistance (12). However, insulin action was not directly measured in those experiments. Furthermore, subjects were fed excess amounts of fat and protein, which also may have influenced hepatic substrate metabolism. The present experiments, therefore, were undertaken to determine whether a difference in hepatic glycogen content alters hepatic insulin action. To do so, we examined insulininduced suppression of EGP after overnight infusion of glucose or saline. Glucose was infused at a rate of 16.4 mmol/kg lean body mass (-lbm)zmin (equal to ;2 mg/kg total BWzmin) so as to suppress nocturnal glucose release and thereby maintain hepatic glycogen stores nearer fed than overnight fasted levels. EGP, the rate of incorporation of 14 CO2 into glucose (an index of gluconeogenesis), as well as the response to insulin were measured immediately after discontinuation of the glucose or saline infusions when differences in hepatic glycogen were anticipated to be the greatest. We report that although an increase in hepatic glycogen increases the overall rate of EGP and decreases the relative contribution of gluconeogenesis to the released glucose, it does not alter hepatic insulin action.

HE HEPATIC GLYCOGEN content in nondiabetic humans varies considerably during the day, increasing from a nadir of ;75 g before breakfast to a peak of ;115 g 4 –5 h after the last meal of day (1, 2). Hepatic glycogen content also may be altered by physiological (e.g. exercise) and pathophysiological (e.g. diabetes mellitus) processes (3–7) in fasted-refed rats and in humans. It currently is not known whether hepatic insulin action is influenced by hepatic glycogen content. Such a possibility is supported by experiments which have shown that the activities of glycogen synthetase and glycogen phosphorylase are regulated by glycogen content (8 –10) in transgenic mice and humans. An increase in either hepatic or muscle glycogen inhibits glycogen synthetase and activates glycogen phosphorylase (8 – 10). Several recent studies suggest that such effects also may occur in vivo. Munger et al. reported that an increase in human muscle glycogen produced by a glucose-insulin infusion is accompanied by a decrease in muscle glycogen synthetase and an increase in muscle glycogen phosphorylase activity (11). Effects on liver glycogen synthesis and breakdown were not examined in those studies. On the other Received December 17, 1996. Revision received February 5, 1997. Accepted February 19, 1997. Address all correspondence and requests for reprints to: Robert A. Rizza, M.D., Mayo Clinic and Foundation, The Endocrine Research Unit, 200 First Street SW, 5–164 West Joseph, Rochester, Minnesota 55905. E-mail: [email protected] * This work was supported by the USPHS (Grants DK-29953 and RR-00585) and the Mayo Foundation.

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HEPATIC GLYCOGEN AND INSULIN ACTION Subjects and Methods Subjects After approval from the Mayo institutional review board, nine healthy, obese, nondiabetic volunteers (four men and five women; height, 1.68 6 0.04 m; weight, 89 6 5 kg; lean body mass, 50 6 4 kg) gave informed written consent to participate in the study. Volunteers had normal fasting glucose concentrations and no first degree relatives with a history of diabetes mellitus. Medications (naproxen, trazodone, and fluoxetine in one subject each) other than thyroid hormone (two subjects) were discontinued at least 3 weeks before the initial study.

Experimental design All subjects were studied on two occasions separated by at least 10 days. On each occasion, subjects were admitted to the General Clinical Research Center on the evening before the study. After placement of an 18-gauge catheter in a forearm vein, each subject ingested a standard mixed meal (15.2 Cal-lbm/kg, 55% carbohydrate, 30% fat, and 15% protein) between 1800 –1830 h. An infusion of either glucose (16.4 mmol/ kg-lbmzmin) or saline was started at the beginning of supper and continued throughout the night. Additional carbohydrate-containing snacks (4.18 Cal/kg each) were ingested at 2200 and 2400 h. As lean body mass averaged ;50 kg, the total carbohydrate ingested averaged ;245 g carbohydrate. The order of the study was random. An 18-gauge catheter was placed in a retrograde manner in a dorsal hand vein at 0600 h on the following morning, and the hand was placed in a heated unit to provide arterialized venous blood samples. Immediately thereafter, primed continuous infusions of NaH14CO3 (100 mCi; 1 mCi/min; New England Nuclear, Boston, MA) and [6,6-2H2]glucose (3 mg/kg-lbm; 0.03 mg/kg-lbmzmin; Cambridge Isotope Laboratories, Andover, MA) were started and continued for the remainder of each experiment. The overnight infusions of glucose or saline were discontinued at 0830 h, which is referred to as time zero in the figures and text. Ninety minutes were then allowed for subjects to reach a new steady state, after which an unprimed continuous infusion of insulin (Humulin R, Eli Lilly Co., Indianapolis, IN) was initiated at a rate of 0.8 mU/kglbmzmin and continued for the next 300 min. Insulin was mixed in 0.9% normal saline with 0.1% human serum albumin (Miles, Elkhart, IN). Euglycemia was maintained with a variable glucose infusion (13). To maintain plasma enrichment constant, all infused glucose was enriched to 1% with [6,6-2H2]glucose, and the continuous infusion of [6,62 H2]glucose was decreased so as to approximate the anticipated rate of fall in EGP (14). This approach maintained plasma [6,6-2H2]glucose atom percent enrichment during the hyperinsulinemic clamp at 0.011 6 0.000, which differed minimally from the enrichment of 0.010 6 0.000 present before initiation of the insulin infusion. Blood and expired air were collected at regular intervals as previously described (15). Urinary nitrogen excretion was measured in eight of the nine subjects during the hyperinsulinemic clamp and was used to calculate carbohydrate and fat oxidation (16). The urine sample was lost in the ninth subject, and therefore, oxidation rates were not calculated in that subject.

Analytical techniques Arterialized blood was placed on ice, centrifuged at 4 C, separated, and stored at 220 C until assay. The glucose concentration was measured using the glucose oxidase method (Yellow Springs Instrument Co., Yellow Springs, OH). Plasma insulin, C peptide, and glucagon concentrations were measured by RIA (Linco Research, St. Louis, MO). GH concentration was measured by RIA using a kit from ICN Biomedicals (Costa Mesa, CA). Lactate concentrations were measured using the lactate oxidase method (Yellow Springs Instrument Co.). Plasma free fatty acid concentrations were measured using a colorimetric assay (Wako Pure Chemical Industries, Osaka, Japan). Indirect calorimetry was performed with a Deltatrac Metabolic Monitor (SensorMedics, Corp., Yorba Linda, CA), and rates of carbohydrate and fat oxidation were calculated using the equations of Frayn (17). Lean body mass and percent body fat were measured by dual photon absorptiometry (Hologic, Waltham, MA). Plasma [6,6-2H2]glucose was measured using gas chromatometric mass spectrometry (18). The plasma [14C]glucose specific activity was measured using liquid scintillation counting as previously described (19).

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Calculations The plasma atom percent enrichment of [6,6-2H2]glucose and specific activity of [14C]glucose were smoothed using the optimal segments program of Bradley et al. (20). Glucose appearance and disappearance were calculated using the equations of Steele (21). The volume of distribution of glucose was assumed to equal 200 mL/kg, with a pool correction factor of 0.65. The percentage of glucose derived from 14CO2 was calculated by dividing the specific activity of [14C]glucose in plasma by the specific activity of 14CO2 in breath as previously described (15). The advantages and limitations of this method in the estimation of gluconeogenesis have been discussed in detail previously (15, 22–24).

Statistical analysis All data are expressed as the mean 6 sem. Rates of infusion and turnover in the figures and text are expressed per kg lean body mass/ min. Values during the 30 min before the start of the hyperinsulinemic glucose clamp (i.e. 60 –90 min) were meaned and considered as basal. Integrated responses below basal were calculated using the trapezoidal rule. The relative rates of suppression of both EGP and incorporation of 14 CO2 into glucose were determined for each individual by first setting the basal value of each parameter equal to 100% and then expressing each subsequent value as a percentage of the basal value. Statistical analysis was performed using Student’s two-tailed paired t test. P , 0.05 was considered statistically significant.

Results Glucose, insulin, C peptide, and glucagon concentrations

Overnight glucose infusion resulted in higher (P , 0.001) plasma glucose concentrations than did overnight saline infusion (5.99 6 0.12 vs. 5.09 6 0.06 mmol/L). When the glucose infusion was discontinued at time zero, glucose concentrations promptly decreased to values that no longer differed from those observed after overnight saline (Fig. 1, upper panel). Glucose concentrations also did not differ during the hyperinsulinemic clamp (i.e. from 90 min onward) in the overnight glucose- and saline-treated groups (5.44 6 0.05 vs. 5.40 6 0.05 mmol/L). Plasma insulin (127 6 37 vs. 49 6 8 pmol/L) and C peptide (1.00 6 0.15 vs. 0.58 6 0.11 mmol/L) concentrations were higher (P , 0.03) after overnight glucose than after overnight saline (Fig. 1, middle panels). Upon discontinuation of the glucose infusion, insulin concentrations promptly fell to values that no longer differed from those after overnight saline. However, due at least in part to its longer half-life, the C peptide concentration remained slightly, but significantly, higher (P , 0.01) after the overnight glucose infusion. Upon initiation of the insulin infusion at 90 min, plasma insulin concentrations increased (to 248 6 30 vs. 262 6 38 pmol/L) and C peptide concentrations decreased (to 0.63 6 0.09 vs. 0.58 6 0.11 mmol/L) equally in the overnight glucose and saline infusion groups. As anticipated, plasma glucagon concentrations were lower (P , 0.05) after overnight infusion of glucose than after overnight infusion of saline (74 6 11 vs. 97 6 20 pg/mL). Somewhat surprisingly, glucagon concentrations did not increase upon discontinuation of the glucose infusion at time zero (Fig. 1, lower panel). Glucagon concentrations fell slightly, but comparably, in both groups during the hyperinsulinemic clamp. GH concentrations did not differ during or after discontinuation of the glucose and saline infusions or during the hyperinsulinemic clamps (data not shown).

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FIG. 1. Glucose, insulin, C peptide, and glucagon concentrations. The overnight glucose and saline infusions were stopped at time zero (dashed line), and an insulin infusion was started at 90 minutes (dotted line).

EGP and the rate of incorporation of

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CO2 into glucose

Overnight infusion of glucose resulted in suppression (P , 0.001) of EGP (Fig. 2, upper panel) relative to that observed after overnight infusion of saline (7.0 6 0.9 vs. 19.4 6 1.3 mmol/kglbmzmin). Upon discontinuation of the glucose infusion, EGP rose to rates that exceeded (P , 0.05) those observed over the same interval after overnight infusion of saline (19.2 6 1.2 vs. 16.5 6 0.7 mmol/kg-lbmzmin). Suppression of EGP during the hyperinsulinemic clamp was equal on both study days, whether analyzed as the area below basal (Fig. 2, upper panel) or as a percentage of basal (Fig. 3, upper panel). Because of the longer time required for tracer equilibration (24, 25), the first measurement of the rate of incorporation of 14 CO2 into glucose was obtained 1 h after discontinuation of the overnight glucose infusion. At that time, despite higher rates of EGP, the rate of incorporation of 14CO2 into glucose was lower (P , 0.001) after overnight glucose infusion than after overnight saline infusion (9.8 6 1.2% vs. 24.4 6 3.0%). The rate of incorporation of 14CO2 into glucose was promptly suppressed during the hyperinsulinemic clamp on both study days (Fig. 2, lower panel). As basal rates were lower after overnight glucose than after saline infusion, the degree of suppression when expressed as the area below basal also was lower (P , 0.001). However, when baseline differences were taken into account by expressing the data as a percentage of basal, the response to insulin did not differ on the 2 study days (Fig. 3, bottom panel).

FIG. 2. Rates of EGP and incorporation of 14CO2 into glucose. The overnight glucose and saline infusions were stopped at time zero (dashed line), and an insulin infusion was started at 90 min (dotted line).

Rate of glucose disappearance, glucose oxidation, and nonoxidative storage

Glucose disappearance was higher (P , 0.01) after overnight glucose infusion than after overnight saline infusion (23.3 6 1.1 vs. 19.5 6 1.4 mmol/kg-lbmzmin). After discontinuation of the glucose infusion, concomitant with the fall in glucose and insulin concentrations, glucose disappearance fell to rates that no longer differed (P 5 0.09) from those seen after saline infusion. Insulin infusion resulted in an equivalent increase in glucose disappearance on both study days (Fig. 4, upper panels). Glucose oxidation and nonoxidative storage also did not differ on the 2 study days (Fig. 4, lower panels). Free fatty acid concentrations and rates of lipid oxidation

After discontinuation of the glucose infusion, free fatty acid concentrations did not differ on the two occasions (Fig. 5). Insulin-induced suppression of both free fatty acid concentrations and lipid oxidation was the same on the 2 study days. In addition, plasma lactate concentrations did not differ during or after discontinuation of the glucose and saline infusions or during the hyperinsulinemic clamps (data not shown). Discussion

The present experiments sought to determine whether insulin action is influenced by hepatic glycogen content. We report that hepatic insulin action, assessed after overnight infusion of saline when hepatic glycogen stores were permitted to decrease to normal postabsorptive levels, did not

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FIG. 3. Effects of insulin on the rate of EGP and the rate of incorporation of 14CO2 into glucose observed after an overnight infusion of either glucose or saline. Data are expressed as a percentage of the basal value, which was defined as the mean of rates observed from 60 –90 min.

FIG. 4. Rates of glucose disappearance, glucose oxidation, and glucose storage observed during the hyperinsulinemic clamp. Results after the overnight glucose infusion are shown as solid bars, and results after the overnight saline infusion are shown as open bars.

differ from that observed when hepatic glycogen stores were preserved by infusing glucose throughout the night. When baseline differences were taken into account, insulininduced suppression of both EGP and the rate of 14CO2 incorporation into glucose were virtually identical on the two occasions. In addition, there were no differences in glucose disappearance, glucose oxidation, or glucose storage. On the other hand, the overnight infusion of glucose and its presumed sparing of hepatic glycogen resulted in an increase in the absolute rate of EGP and a decrease in the relative contribution of gluconeogenesis to the released glucose. These data provide further support for a reciprocal relationship between glycogenolysis and gluconeogenesis (26 –29). However, this autoregulatory process was not complete because an increase in hepatic glycogen content resulted in an increase in the absolute rate of EGP. Thus, the rate of EGP, but not the response to insulin, appears to be modulated by hepatic glycogen content. Hepatic glycogen content was not directly measured in the present studies. Therefore, it is possible that hepatic glycogen content did not differ on the 2 study days. However, we doubt this, as previous studies using nuclear magnetic resonance spectroscopy under similar conditions have shown that hepatic glycogen content peaks at ;115 g 4 –5 h after supper (1). Hepatic glycogen content then falls by ;40 g during the night, reaching a level of ;75 g by the following morning (1). In the present experiments, EGP averaged ;7 mmol/kg-lbmzmin during the final hour of the overnight

glucose infusion and ;19 mmol/kg-lbmzmin during the final hour of the saline infusion. If comparable differences in EGP persisted throughout the night, then ;518 mmol (or ;93 g) less glucose was released during the overnight glucose infusion. If, as suggested by Rothman et al. (30), gluconeogenesis accounts for 50% of the released glucose, then approximately 47.5 g glycogen would have been spared. In this circumstance, hepatic glycogen content would have increased to levels slightly (;7.5 g) greater than those normally present after supper. In the more likely event that gluconeogenesis also was suppressed, and therefore accounted for less than 50% of the glucose released during the night, then the amount of glycogen spared would have been somewhat less. Although recent studies have shown that the kidney also can produce glucose, the amounts are relatively small (31, 32). However, if a portion of the residual EGP observed during glucose infusion was coming from the kidney, then even more hepatic glycogen would have been spared. Although the above calculations are only approximations, they suggest that the overnight glucose infusion resulted in the hepatic glycogen content being maintained near that normally present after the evening meal (33). Considerable attention has been focused on so-called hepatic autoregulation (26 –29). Previous studies have demonstrated that gluconeogenesis can be either enhanced or inhibited without altering EGP (26 –29). The present studies and those reported by Clore et al. (12) indicate that autoregulation appears to be less effective when glycogenolysis,

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FIG. 5. Plasma free fatty acid concentrations and rates of lipid oxidation observed during the hyperinsulinemic clamp. Results after the overnight glucose infusion are shown as solid bars, and results after the overnight saline infusion are shown as open bars.

rather than gluconeogenesis, is stimulated. Clore et al. sought to increase hepatic glycogen stores by feeding volunteers an excess of 1000 Cal/day for 5 days. Based on previous studies by Nilsson et al. (2), such overfeeding was estimated to have increased hepatic glycogen approximately 3-fold relative to postabsorptive levels (1, 2). If so, then hepatic glycogen stores were probably somewhat higher in those experiments than in the present experiments. Nevertheless, the increase in EGP observed after 5 days of overfeeding and that in the present experiments after discontinuation of the nocturnal glucose infusion was virtually identical (i.e. ;3 mmol/kgzmin). Furthermore, although we used the rate of incorporation of 14 CO2 into glucose, whereas Clore et al. (12) used the rate of incorporation of [14C]alanine into glucose to estimate gluconeogenesis, we both found that an increase in EGP occurred despite a 40 –50% decrease in gluconeogenesis. In the present experiments, these changes occurred in the face of comparable glucose, insulin, and free fatty acid concentrations, implying a direct effect of hepatic glycogen content, and its presumed associated increase in glycogenolysis, on the rate of gluconeogenesis. Although glucagon concentrations were statistically lower after the overnight glucose infusion, the magnitude of the difference (;20 pg/mL) was small, and, if anything, would have tended to decrease rather than increase EGP. Insulin-induced suppression of EGP did not differ after the overnight glucose and saline infusions. Although the rate of incorporation of 14CO2 into glucose started out lower after the overnight glucose infusion, when expressed as a percentage of the baseline, the rate of suppression during the hyperinsulinemic clamp was not different from that observed

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after the overnight saline infusion (see Fig. 3). Of note, the time course of the fall in EGP and that of the fall in the incorporation of 14CO2 into glucose closely paralleled one another. These results, which confirm those previously reported by Turk et al. (34), imply concordant inhibition of glycogenolysis and gluconeogenesis. We are unaware of any previous studies examining the effect of hepatic glycogen content on hepatic insulin action. On the other hand, several investigators have observed circadian variations in insulin action in both diabetic and nondiabetic subjects (35–39). Boden et al. recently reported that hepatic insulin action is lowest in subjects with noninsulindependent diabetes mellitus (NIDDM) during the early morning hours (40) when hepatic glycogen content also is the lowest. However, the present data make it unlikely that the changes in hepatic glycogen content per se cause the circadian variation in hepatic insulin action. These data also argue against the possibility that the lower hepatic glycogen content reported to be associated with NIDDM (4) accounts for the impairment in hepatic insulin action that is commonly seen in this disorder (34, 41, 42). On the other hand, the reciprocal relationship between hepatic glycogen content and gluconeogenesis observed in the present experiments and those of Clore et al. (12) leads to the interesting speculation that lower hepatic glycogen content, rather than a primary defect in hepatic glucose metabolism, results in the well described increase in gluconeogenesis in NIDDM (4, 43, 44). Plasma insulin concentrations were approximately 2-fold higher after overnight infusion of glucose than after treatment with saline. An increase in insulin concentration of this magnitude is similar to levels that we and others observed after overnight infusion of insulin in people with NIDDM (14, 45– 48). Overnight infusion of insulin was used in those experiments to match the glucose concentrations in the diabetic subjects to those observed in the nondiabetic control group. One of the problems with this approach is the possibility that the resultant hyperinsulinemia causes insulin resistance (49 –51). It is, therefore, reassuring that the nocturnal hyperinsulinemia that accompanied the overnight glucose infusion did not alter either insulin-induced stimulation of glucose disappearance or suppression of free fatty acid concentrations. Similarly, stimulation of carbohydrate oxidation and nonoxidative storage as well as suppression of lipid oxidation were equal on the two occasions. Thus, although sustained hyperinsulinemia clearly can cause insulin resistance (49 –51), an increase in insulin of the magnitude and duration (i.e. overnight) found in the present experiments does not. In summary, infusion of glucose during the night at a rate designed to suppress hepatic glucose release and, therefore, spare hepatic glycogen results in an increase in the absolute rate of EGP the following morning. In contrast, the rate of incorporation of 14CO2 into glucose was lower after glucose than after saline infusion, implying a reciprocal relationship between glycogenolysis and gluconeogenesis. However, when differences in basal rates were taken into account, insulin-induced suppression of both glucose production and the rate of incorporation of 14CO2 into glucose was virtually identical on the two occasions, as was insulin-induced stimulation of glucose uptake and glucose oxidation. We, therefore, conclude that although the differences in hepatic gly-

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cogen content that normally occur under the conditions of daily living and in various disease states (e.g. diabetes mellitus) may alter the relative contributions of glycogenolysis and gluconeogenesis to EGP, such differences do not alter hepatic or extrahepatic insulin action. Acknowledgments We thank P. Berg, T. Madson, D. Nash, and C. Nordyke for technical assistance; A. Wagner for assistance with preparation of the manuscript, and the staff of the Mayo General Clinical Research Center for their assistance with performing the studies.

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