Departments of 1 Medicine and 2 Physiology and Pharmacology, University of Rochester School of Medicine, Rochester, New York 14642
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ABSTRACT |
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To characterize postprandial glucose disposal more completely, we used the tritiated water technique, a triple-isotope approach (intravenous [3-H3]glucose and [14C]bicarbonate and oral [6,6-2H2]glucose) and indirect calorimetry to assess splanchnic and peripheral glucose disposal, direct and indirect glucose storage, oxidative and nonoxidative glycolysis, and the glucose entering plasma via gluconeogenesis after ingestion of a meal in 11 normal volunteers. During a 6-h postprandial period, a total of ~98 g of glucose were disposed of. This was more than the glucose contained in the meal (~78 g) due to persistent endogenous glucose release (~21 g): splanchnic tissues initially took up ~23 g, and an additional ~75 g were removed from the systemic circulation. Direct glucose storage accounted for ~32 g and glycolysis for ~66 g (oxidative ~43 g and nonoxidative ~23 g). About 11 g of glucose appeared in plasma as a result of gluconeogenesis. If these carbons were wholly from glucose undergoing glycolysis, only ~12 g would be available for indirect pathway glycogen formation. Our results thus indicate that glycolysis is the main initial postprandial fate of glucose, accounting for ~66% of overall disposal; oxidation and storage each account for ~45%. The majority of glycogen is formed via the direct pathway (~73%).
postprandial; glycolysis; gluconeogenesis; glycogen; carbohydrate oxidation
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INTRODUCTION |
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STUDIES OF GLUCOSE HOMEOSTASIS in humans have generally dealt with the postabsorptive state, i.e., 12-14 h after an overnight fast. However, people usually eat at least three times a day, and assimilation of ingested nutrients takes ~5-6 h (38). The majority of the day, therefore, is spent in the postprandial state. This consideration and data suggesting that postprandial hyperglycemia is an important risk factor for cardiovascular disease (24) have made the postprandial state a subject of considerable interest.
Most studies evaluating postprandial glucose homeostasis have used an oral glucose load (14). However, metabolic responses to oral glucose may differ from those of a meal (7, 15, 26, 58, 59). The few studies that have assessed the disposal of a meal (5, 6, 29, 38, 39, 45, 58, 59) have measured net organ glucose balances, net hepatic and muscle glycogen accumulation, whole body carbohydrate oxidation, and isotopically determined glucose uptake by splanchnic and peripheral tissues. None, however, has examined glycolysis, an important route for glucose disposal (19).
Because the pentose phosphate shunt is a minor pathway
(25), glucose taken up by tissues postprandially can be
considered either to be immediately stored or to undergo glycolysis
(Fig. 1). Therefore, direct storage of
glucose (e.g., glucose glucose 6-phosphate
glycogen)
can be calculated as the difference between whole body glucose uptake
and whole body glycolysis. Virtually all of this storage should
represent glycogen formation, since postprandial de novo lipogenesis
and adipose tissue glucose storage are negligible in humans (21,
37). Of the glucose undergoing glycolysis, some will be
oxidized; the remainder will undergo nonoxidative glycolysis leading to
the formation of lactate, pyruvate, and alanine. These 3-carbon
compounds will then be available to undergo gluconeogenesis and either
be stored in glycogen via the indirect pathway or be released into
plasma as glucose.
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In studies reported to date (21, 22, 28, 38, 51), whole body glucose storage after ingestion of a meal or a glucose load has been calculated as the difference between plasma glucose disposal and whole body glucose oxidation rather than whole body glucose disposal minus whole body glycolysis. This could lead to an overestimation of postprandial glucose storage, because whole body glucose oxidation represents only a portion of whole body glycolysis. The magnitude of this is unclear, since the proportion of glucose undergoing oxidative and nonoxidative glycolysis has not as yet been determined. Moreover in previous studies (5, 6, 17, 18, 22, 29, 30, 38, 39, 42, 43, 45), whole body glucose disposal has been equated with the isotopically determined amount of glucose removed from the systemic circulation; the amount of glucose not reaching the systemic circulation because of disposal in splanchnic tissues has not been taken into consideration. Use of plasma glucose disposal rather than whole body glucose disposal could lead to an underestimation of postprandial glucose storage.
Nearly 10 years ago, Rossetti and colleagues (52, 53) validated a method using generation of tritiated water from infused tritiated glucose to measure glycolysis of plasma glucose. Féry et al. (19) have used this approach to compare glycolysis of intraduodenally and intravenously infused glucose in normal volunteers and the effect of metformin on the disposal of an oral glucose load in patients with type 2 diabetes (20). In the present studies, we used the tritiated water technique to assess glycolysis after ingestion of a meal in normal human volunteers. Additionally, using indirect calorimetry and isotopic measurements of glucose taken up by splanchnic and peripheral tissues as well as glucose entering plasma via gluconeogenesis, we estimated postprandial whole body direct and indirect glucose storage and partitioned postprandial glycolysis into oxidative and nonoxidative components.
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METHODS |
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Subjects.
Informed written consent was obtained from 11 healthy volunteers after
the protocol had been approved by the University of Rochester
Institutional Review Board. The subjects (5 men and 6 women 47 ± 4 yr of age, body weight 87 ± 6 kg, %body fat 25 ± 2) had
normal physical examinations, routine laboratory tests, and glucose
tolerance (World Health Organization criteria) (62), as
well as no family history of diabetes mellitus. For 3 days before the
study, all had been on a weight-maintaining diet containing 200 g of
carbohydrate and had abstained from alcohol and exercise.
Protocol. Subjects were admitted to the University of Rochester General Clinical Research Center between 6:00 and 7:00 PM the evening before experiments, consumed a standard meal between 6:30 and 8:00 PM, and fasted thereafter.
A 12-h overnight urine collection was started at 8:00 PM for measurement of urea nitrogen excretion to be used to estimate protein oxidation for indirect calorimetry calculations. Urine was also collected during the 6-h postprandial period. At 4:00 AM, a primed (~20 µCi) continuous (~0.20 µCi/min) infusion of [3-H3]glucose and [14C]NaHCO2 (100 µCi, 1.1 µCi/min) was started in a forearm vein for measurement of plasma glucose turnover and gluconeogenesis. Five hours were allowed for isotope equilibration. At ~8:00 AM, an infusion of p-aminohippuric acid (12 mg/min) was started for determination of renal blood flow (4) for calculation of renal glucose uptake and release, which will be reported separately. In 8 of the 11 subjects, a renal vein was catheterized between 8:00 and 9:00 AM. At ~9:00 AM, a dorsal hand vein was cannulated and kept in a thermoregulated Plexiglas box at 65°C for sampling arterialized venous blood. About 1 h later, simultaneous blood sampling was started from the dorsal hand vein and the renal vein at 30-min intervals for the next 7 h. Whole body glucose and lipid oxidation was determined over 20-min intervals three times during the baseline period and hourly thereafter during the remainder of the experiment by use of a canopy indirect calorimetry system (Delta Trac, Anaheim, CA) (28). To allow for equilibration within the canopy, only data during the last 10 min were used for analysis. Throughout the experiment, arterialized samples were collected at 30-min intervals for measurements of glucose, free fatty acids (FFA), insulin, glucagon, lactate, glycerol, and alanine levels, glucose specific activities, and glucose enrichments. Breath samples for 14CO2 specific activities were collected at 30-min intervals beginning atAnalytical procedures. Blood samples were collected for glucose, lactate, alanine, and glycerol concentrations, [3H]- and [14C]glucose specific activities, [6,6-2H2]glucose enrichments, and tritiated water in oxalate-fluoride tubes for FFA concentrations in EDTA tubes and for insulin and glucagon concentrations in EDTA tubes containing a protease inhibitor. Samples were immediately placed in a 4°C ice bath, and plasma was separated within 30 min by centrifugation at 4°C. Plasma glucose was determined in triplicate with a glucose analyzer (Yellow Springs Instrument, Yellow Springs, OH).
Plasma glucose 14C and 3H specific activity and breath 14CO2 specific activities and plasma dideuterated glucose enrichments were measured by previously described methods (10, 55). Plasma tritiated water specific activity was measured as follows. Protein-free filtrates of plasma were passed over ion exchange columns, and the resultant eluate (3H2O + [3-3H]glucose) was divided. One aliquot was evaporated to remove 3H2O and represented disintegrations per minute (dpm) only in glucose; this was resuspended and counted as well as the other aliquot representing 3H2O plus [3-3H]glucose (53). The difference between the two represents the counts in 3H2O. Plasma lactate, alanine, glycerol, and FFA concentrations were determined by standard microfluorometric assays (32, 40, 60). Plasma insulin and glucagon were determined by standard radioimmunoassays as previously described (57). Plasma p-aminohippuric acid concentrations were determined by a colorimetric method (4).Calculations.
Systemic release and uptake of glucose were determined with
steady-state equations before meal ingestion (61) and
subsequently after meal ingestion with non-steady-state equations of
DeBodo et al. (11) by use of a pool fraction of 0.65 and a
volume of distribution of 200 ml/kg. The rate of appearance of the oral glucose in the systemic circulation was calculated from
[6,6-2H2]glucose data with the equation of
Chiasson et al. (8; see also Ref.
28). The proportion of systemic glucose uptake
attributable to glucose originating in the meal was calculated as the
product of plasma glucose disappearance and the ratio of the rate of
appearance of the ingested glucose in plasma to overall plasma glucose
appearance (28). Endogenous glucose release was calculated
as the difference between the overall rate of plasma glucose appearance
and the rate of appearance of exogenous glucose (28, 42).
Glucose entering plasma via gluconeogenesis was calculated from the
incorporation of 14C into plasma glucose from
[14C]NaHCO2 by modifications of the
aforementioned equations for the postabsorptive and postprandial states
(16, 38). In the postabsorptive steady state, it was
calculated as Ra × SAg/SACO2, where Ra is the overall rate of plasma glucose appearance,
SAg is the 14C plasma glucose specific activity
(dpm/µmol), and SACO2 is the 14C specific
activity of CO2 in exhaled breath (dpm/µmol). After meal
ingestion, the non-steady-state equation was used
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Statistical analysis. Unless stated otherwise, data are expressed as means ± SE. Paired two-tailed Student's t-tests were used to compare the mean baseline data with the mean data obtained after oral glucose ingestion. A P value <0.05 was considered statistically significant.
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RESULTS |
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Substrate and hormone concentrations.
As shown in Fig. 2, After meal
ingestion, arterial glucose increased from 4.6 ± 0.1 mM to a
maximum of 8.1 ± 0.4 mM at 60 min and returned to near basal
values by 240 min. Plasma insulin followed a similar pattern. Plasma
glucagon decreased to nadir at 90 min and subsequently increased to
values that were greater than baseline values at the end of the
experiment (P = 0.03). Plasma lactate increased
transiently to maximum at 90 min and returned to basal values by 180 min. Plasma alanine followed a similar pattern to lactate (data not
shown). Plasma FFA decreased to nadir at 120 min and thereafter
progressively increased to values above baseline at the end of the
experiment (P = 0.05). Plasma glycerol followed a
similar pattern to FFA (data not shown).
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Rates of total, meal, and endogenous plasma glucose appearance and
gluconeogenesis.
Plasma glucose and breath bicarbonate specific activities and plasma
glucose enrichments are given in Table 1.
After meal ingestion, total plasma glucose appearance (endogenous plus
ingested) increased almost threefold to a maximum at 30 min and
subsequently decreased, reaching basal rates by 240 min. During the
entire 6-h postprandial period, a total of 75.7 ± 7.6 g of
glucose entered the systemic circulation. The rate of appearance in
plasma of glucose from the meal followed a pattern similar to that of
total plasma glucose appearance. During the 6-h postprandial period, a
total of 54.8 ± 5.1 g of glucose from the meal entered the
systemic circulation. Endogenous glucose release decreased from a
basal rate of 8.8 ± 0.6 µmol · kg1 · min
1
to a nadir of 2.3 ± 0.4 µmol · kg
1 · min
1
at 180 min and subsequently returned toward basal rates. During the 6-h
postprandial period, endogenous glucose release was 20.9 ± 3.3 g. This represented 27.6 ± 2.1% of all glucose entering the systemic circulation and a 58.3 ± 4.2% suppression compared with the amount of glucose that would have entered the circulation if
basal rates of endogenous glucose release had remained constant (P < 0.001) (Fig. 3).
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Plasma glucose disposal, glycolysis and direct storage. After meal ingestion, plasma glucose disposal increased to maximum at 120 min and returned to values not significantly different from baseline at 270 min (P = 0.26). During the 6-h postprandial period, 75.4 ± 7.5 g of glucose were removed from the systemic circulation. Of these, 54.8 ± 5.1 g represented glucose from the meal and 20.8 ± 3.3 g from residual endogenous glucose release.
As shown in Fig. 4, the tritiated water content of plasma increased progressively during the entire experimental period as expected (19, 27). Glycolysis from plasma glucose (Fig. 5), calculated from the increases in plasma tritiated water, followed a pattern similar to that of disposal, returning to baseline values at 6 h. During the 6-h postprandial period, a total of 50.2 ± 3.9 g of plasma glucose underwent glycolysis, accounting for 66.5 ± 3.5% of plasma glucose disposal.
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Whole body glucose disposal, glycolysis, oxidation and storage. The meal that our subjects consumed contained an average of 77.8 ± 5.0 g of glucose. Of these, only 54.8 ± 5.1 g entered the systemic circulation. Because all of the glucose in the meal should have been absorbed from or metabolized by the gastrointestinal tract by the end of the 6-h postprandial period (49), the 22.9 ± 2.6 g of the glucose in the meal that did not enter the systemic circulation must have been disposed of by splanchnic tissues. Accordingly, total body glucose disposal, the sum of plasma glucose disposal (75.4 ± 7.5 g) and splanchnic glucose disposal (22.9 ± 2.6 g), was 98.3 ± 6.9 g.
Whole body glycolysis, calculated similarly as the sum of splanchnic glycolysis (16.0 ± 2.1 g) and plasma glycolysis (50.2 ± 3.9 g), totaled 66.2 ± 2.9 g over the 6-h postprandial period. Whole body direct glucose storage, calculated as the difference between whole body disposal and whole body glycolysis totaled 32.1 ± 5.8 g over the 6-h postprandial period. ![]() |
DISCUSSION |
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The present studies were undertaken to characterize postprandial glucose homeostasis more completely. For this purpose, we used a combination of isotopic techniques and indirect calorimetry to assess routes of glucose disposal after ingestion of a meal by healthy volunteers. Included among these routes was the proportion of postprandial glucose disposal attributable to glycolysis that had not been hitherto examined and that would allow one to calculate postprandial glucose storage more accurately.
During the 6-h interval following ingestion of a meal that contained on
average ~78 g of glucose, a total of ~98 g was disposed of (~75 g
of glucose that had entered the systemic circulation plus ~23 g of
glucose disposed of by splanchnic tissues; Fig. 6). The reason that total glucose
disposal was greater than the amount of glucose ingested can be readily
attributed to the fact that endogenous glucose release was found to be
suppressed only ~60%, as has been previously observed
(14). Indeed, the sum of the ingested glucose and the
endogenous glucose disposed of (98 g) equaled the sum of splanchnic
glucose and plasma glucose disposal (98 g).
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Using the generation of tritiated water to estimate glycolysis from plasma glucose, we found that ~66% of plasma glucose disposal was initially attributable to glycolysis. As indicated above, however, plasma glucose disposal represents only ~80% of total body postprandial glucose disposal. Nevertheless, even if no glycolysis had occurred in splanchnic tissues, glycolysis from plasma glucose would still initially account for ~50% of whole body postprandial glucose disposal. This must, however, be considered a minimal estimate, since there is evidence for appreciable postprandial glycolysis in splanchnic tissues (2, 41, 44).
Féry et al. (19) found that virtually identical proportions of intravenously and intraduodenally infused tritiated glucose underwent glycolysis during 180-min experiments in normal volunteers. Therefore, to obtain an estimate of total body glycolysis, we multiplied splanchnic glucose disposal by the fraction of plasma glucose disposal undergoing glycolysis (~66%). The applicability of this approach is further supported by the studies of Radziuk (48), indicating that ~60% of splanchnic glucose uptake is not directly converted to glycogen, i.e., must undergo glycolysis. This approach yielded an estimate of 16.0 ± 2.1 g for postprandial splanchnic glycolysis. Adding this to the amount of plasma glucose undergoing glycolysis (50.2 ± 3.9 g) gives 66.2 ± 2.9 g for whole body glycolysis (Fig. 6).
This amount of glycolysis seems physiologically reasonable when one considers the 3-carbon precursors produced via nonoxidative glycolysis that would be needed for ongoing postprandial gluconeogenesis (see below) and that would be needed to satisfy tissue energy requirements via oxidative glycolysis during postprandial reduction in the availability of FFAs. Oxidative glycolysis, measured independently by indirect calorimetry in the present study, alone accounted for ~65% of whole body glycolysis.
Having an estimate of whole body glycolysis permitted the calculation of whole body direct glucose storage and partition of glycolysis into oxidative and nonoxidative pathways. Subtracting whole body glycolysis from total body glucose disposal (~98 g) yields a value of ~32 g for postprandial whole body direct glucose storage (Fig. 6).
Whole body nonoxidative glycolysis, calculated by subtracting whole body glucose oxidation from whole body glycolysis, amounted to ~23 g and accounted for ~35% of overall glycolysis and ~23% of total body glucose disposal. On the basis of euglycemic hyperinsulinemic clamp experiments, it has been thought that nonoxidative glycolysis accounts for only ~10% of insulin-mediated glucose disposal (12). Although the magnitude of nonoxidative glycolysis found to occur postprandially in the present study is substantially greater than that found in euglycemic clamp experiments (13, 53), it is consistent with the results of previous postprandial studies (9, 19). For example, Consoli et al. (9) found that ~15 g of lactate entered the systemic circulation during a 3-h period following ingestion of 75 g of glucose by normal volunteers. Féry et al. (19) found that, during a 3-h intraduodenal infusion of 92 g of glucose in normal volunteers, ~26 g of glucose were disposed of via nonoxidative glycolysis.
Our value for postprandial nonoxidative glycolysis (~23 g) provides a maximal estimate of carbons derived from glucose that would be available for gluconeogenesis and, hence, for indirect pathway glycogen synthesis. In the present study, ~11 g of glucose appeared in plasma as a result of gluconeogenesis, a value comparable to those found in previous studies using the same 14CO2 technique (5, 22, 38, 39). If all of the carbons used for this gluconeogenetically derived plasma glucose were the result of nonoxidative glycolysis and if all of the remaining carbons generated by nonoxidative glycolysis were used for indirect pathway glycogen formation, this would provide a maximum of ~12 g for indirect pathway glycogen formation. Thus our data suggest that, in humans, the indirect pathway is not the major route for glycogen formation after a meal; i.e., of a possible ~44 g of total glucose storage (32 g direct + 12 g indirect), the indirect pathway would account for ~27%. Previous estimates of indirect pathway glycogen formation in humans have ranged from 23 to 60% (34, 35, 46-48, 50, 54, 58). Our data are compatible with those of Pimenta et al. (47), Peterson et al. (46), and Magnusson et al. (34, 35), who found the indirect pathway to account for 33, 37, 23, and 35%, respectively, of overall glycogen formation.
Parenthetically, had we used only plasma glycolysis (~50 g) and not included estimates of splanchnic glycolysis, this would have left no carbon for indirect pathway glycogen formation after subtracting glucose oxidation (~43 g) and glucose entering plasma via gluconeogenesis (~11 g). This consideration supports our including an estimate for splanchnic glycolysis, since without it an unrealistic estimate for indirect pathway glycogen formation is obtained (34, 35, 46-48, 50, 54, 58).
It is possible, however, that our estimate for splanchnic glycolysis is too low. This would result in an overestimation of direct glucose storage and an underestimation of indirect glucose storage. If glycolysis accounted for all of splanchnic glucose disposal, which is unlikely (48), total body glycolysis would have been ~73 instead of ~66 g, direct glucose storage would have been ~25 instead ~32 g, and indirect pathway glucose storage would have been 19 instead of ~12 g, a value still representing only ~43% of total glucose storage. It is of note that total glucose storage would not have been altered; i.e., it is independent of estimations of splanchnic glycolysis. Had we calculated whole body glucose storage as the difference between plasma glucose disposal and whole body glucose oxidation, as was done in previous studies, whole body glucose storage would have been only 32 g in contrast to the 44 g found in the present study.
The amount of glucose calculated to have been stored postprandially in the present study (~44 g) should represent ~40 g of glycogen, since only 3-5 g would be expected to have been incorporated into adipocyte triglycerides (37). There is evidence that glycogen cycling occurs in humans postprandially (i.e., simultaneous glycogen formation and degradation) (31, 36). Our method mostly measures net storage, i.e., the difference between glycogen formation and degradation, since glycogen broken down and oxidized would have been measured as glucose oxidation by indirect calorimetry. Labeled glycogen that was broken down and underwent glycolysis would have been measured as glycolysis by the tritiated water technique. On the other hand, our method would overestimate net glycogen storage to the extent that either unlabeled ingested glucose that had been directly stored or glycogen formed via the indirect pathway underwent nonoxidative glycolysis. An approximation of this overestimation can be calculated from our data to be ~8 g, assuming 60% glycogen cycling as reported by Magnusson et al. (36) (see APPENDIX). Subtracting these 8 g would yield a value for maximal net glycogen accumulation of ~32 g, ~41% of the ingested glucose. This value is in good agreement with results of studies directly measuring postprandial net glycogen accumulation in liver and muscle (1, 37, 46, 58, 59). These studies indicate that a total of ~40% of ingested glucose maximally accumulates in liver and muscle as glycogen.
In summary, our results indicate that glycolysis is the main initial postprandial fate of glucose after ingestion of a meal, accounting for ~66% of overall glucose disposal; somewhat less is accounted for by oxidation (~44%) and glycogen formation (~45%), of which the majority is via the direct pathway (~73%).
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APPENDIX |
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The amount of glycogen formed via the indirect pathway (12 g) that could undergo nonoxidative glycolysis due to cycling is calculated as 12 g × the rate of cycling (0.6) × the proportion of overall glycolysis that is nonoxidative (0.35) = 2.5 g. Similarly, the amount of glycogen formed via the direct pathway (32 g) from unlabeled glucose that would undergo nonoxidative glycolysis is calculated as 32 g × the rate of cycling (0.6) × the proportion of overall glycolysis that is nonoxidative (0.35) × the proportion of direct storage from the unlabeled glucose (0.8) (the glucose load divided by total glucose disposal) = 5.4 g.
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ACKNOWLEDGEMENTS |
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We thank Mary Little for excellent editorial assistance and the nursing and laboratory staff of the General Clinical Research Center for superb help.
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FOOTNOTES |
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The present work was supported in part by Division of Research Resources-General Clinical Research Center Grant 5M01 RR-00044 and the National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-20411.
H. J. Woerle is now at Ludwig-Maximilians-University of Munich in Munich, Germany. C. Meyer is now at Carl T. Hayden Veterans Affairs Medical Center in Phoenix, AZ. J. Dostou is now at University of North Carolina in Chapel Hill, NC. N. Islam is now at Bangladesh Medical College in Dhaka, Bangladesh. E. Popa is now at Baylor University Medical Center in Dallas, TX.
Address for reprint requests and other correspondence: J. E. Gerich, Univ. of Rochester School of Medicine, 601 Elmwood Ave., Box MED/CRC, Rochester, NY 14642 (E-mail: johngerich{at}compuserve.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.
First published December 10, 2002;10.1152/ajpendo.00365.2002
Received 17 August 2002; accepted in final form 26 November 2002.
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