OF APPLIED PHYSIOLOGY VoI. 38, No. 2, February 1975.

&URNAL

Glucose

Printed

in U.S.A.

metabolism

normal

in thyroidectomized

dogs during PAVLE lh’vision

PAUL, MAUREEN of Research, Lankenau

rest and acute DONOHUE, AND WILLIAM Hosfx’tal, Philadelphia, Pennsylvania

and cold exposure

L. HOLMES ~9~5~

for substrate mobilization and utilization PAUL,PAVLE,MAUREENDONOHUE, AND WILLIAM L. HOLMES. when the demand Glucose metabolism in thyroidectomized and normal dogs during resf and increases. Our studies were designed to investigate glucose acute cold e+~osure. J. Appl. Physiol. 38(2): 236-240. 1975.metabolism in normal and thyroxine-deficient dogs during Uniformly labeled [14C]gl ucose was infused iv at a constant rate rest and during the increased energy expenditure caused by into unanesthetized surgically thyroidectomized (THY) and acute cold exposure. These studies were planned to denormal dogs during the basal state at 22°C and during cold termine: a) glucose levels and corresponding glucose turnexposure at 4-5’C. 02 uptake, COP output, and plasma glucose over and oxidation rates in normal and thyroidectornized levels were determined; from these the rates of glucose turnover (THY) dogs in the basal state and during acute cold exand oxidation were calculated. Comparison of THY with normal posure; and b) the differences among these results and to dogs shows that at a mean plasma glucose level of 103 mg/I 00 ml, what extent glucose is participating as an energy substrate a significantly lower glucose turnover rate was observed in THY dogs on the basis of kg body weight, body surface area (m2), but during acute cold exposure (shivering thermogenesis). not per cal BMR, The same percentage of glucose turnover was immediately oxidized in THY and normal dogs, accounting for METHODS 16 and 1575 of the total caloric expenditure, respectively. Acute Eleven normal dogs wgighing 10-l 7 kg (avg 14.3 kg) were cold exposure increased energy expenditure in both THY and normal dogs without a change in glucose level or turnover rate. surgically thyroidectomized 6-l 5 wk prior to the experiHowever, the percentage of glucose turnover which was immements. Completeness of the surgical procedure was judged diately oxidized as well as the amount of glucose oxidized increased by excessive gain in body weight, decrease in BMR, insignificantly and proportionally to the increase in energy expendicrease in plasma cholesterol level above 300 mg/ 100 ml, ture so that the percent of calories derived from plasma glucose and marked increase in the concentration of low density oxidation remained the same as that observed during the control lipoproteins (LDLP) in plasma. They were maintained on period. plasma glucose; ized and normal

metabolism of plasma dogs; energy I expenditure

glucose and

in thyroidectomcold exposure

LIPIDS are important energy substrates and during physiological stress of long duration they provide the major portion of energy substrate requirements ( 1, 2, 8, 12, 18, 19). The importance of plasma glucose as substrate is obvious under various metabolic conditions since the percentage of calories it contributes to total energy expenditure is relatively constant (3, 14, 20, 22). Depocas (3) and Depocas and Masironi (4) showed in rats exposed to termperatures of 30°C and 6°C that there were no changes in glucose level or the percent of CO2 derived from glucose, while the percent of glucose turnover immediately oxidized PLASMA

and with

the amount of glucose cold exposure. The

oxidized

increased

significantly

recent work of Pernod et al. (23) and Minaire et al. (17) sh owed that exposure of dogs to temperatures of - 25 “C did not change the plasma glucose concentration but increased glucose mobilization and oxidation, while the participation of plasma glucose in total energy expenditure decreased. In the absence of the thyroid hormone glucose oxidation is decreased (5, 7, 9, 15) - The role of thyroid hormone in glucose metabolism should be clearer under stress conditions

equal amounts of Wayne dog food mixed with Laddie Boy horse meat chunks- Normal dogs of both sexes weighing 1 l-20 kg (avg 15.2 kg) were used as controls in this study. All animals were trained to lie quietly on a table during the experimental period. Two days before an experiment, under light morphine-Pentothal anesthesia, indwelling polyethylene catheters (P&240, Intramedic, Clay-Adams, New York City) were placed into the right carotid artery and the jugular vein. The catheters were filled with physiological saline and kept tightly plugged (no anticoagulant was used). All experiments were carried out after 24 h of fasting. were conducted Experimental procedure. The experiments in a ventilated room (climatic chamber). After the dog had a resting period of 120 min at a temperature of 22”C, the room temperature was decreased over a period of 60-90 min to a new level of 4-5% which was maintained for an additional 120 min. During this latter period the animals shivered constantly; this part of the experiment is designated steady-state shivering or shivering. A recovery period of 60 min followed, during which time the dogs were covered with blankets and the room temperature was increased to 16-18°C. labeled [U-14C]glucose After a priming dose, uniformly (specific activity (SA) approximately 5 mCi/mol; New England Nuclear Corp., Boston, Mass.) was infused iv at a constant rate throughout the experiment. The ratio be-

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GLUCOSE

METABOLISM

Gl”c0s&“C

DT, RING

(UL) 46 mpclkg P/////////i CONTROL

COLD

I3

A min

44

mpc/kg

min

20

%CO, plasma

from glucose

,5 10 I

Glucose turnover pmolefkg

Glucose wcfm

H

min

SA ale

‘8 14

120 Plasma glucose mg/lOOml

100 80

Energy expenditure kcal/m2min

5

14.5

9

/?L 9.6%

237

EXPOSURE

10.7%

FIG. 1. Effect of acute cold exposure on the rates of uptake and oxidation of plasma glucose in normal dog A and thyroidectomized dog B. A priming dose of [W] glucose was given at t = 0 followed by a constant infusion. Thatched areas: upper, rate of oxidation of plasma glucose and percentage of turnover oxidized; lower, energy expenditure provided by plasma glucose and percentage of total energy expenditure.

tween priming dose (nCi) and infusion rate (nCi/min) was approximately f 00 : 1. During the experimental period a plastic hood with a rubber collar was placed over the head of the animal and an accurately measured airflow through the hood was maintained by a pump (10). During the basal state, airflow through the hood was 20-30 liters/min according to the body weight of the animal; it was increased to 30-40 liters/ min during acute cold exposure. At the time intervals shown in Fig. 1, samples of the diluted expired air were collected for 4 min in a Douglas bag by means of a second pump and analyzed for 0 2 and CO2 content by a calibrated Noyons diaferometer (12). Arterial blood samples were taken immediately following collection of air and analyzed for plasma glucose. Measurements. The SA of 14C02 was measured according to the method of Fredrickson and Ono (6) adapted to our experimental conditions (16) - Arterial blood samples were analyzed for plasma glucose by the Glucostat method (Glureagent, Worthington Biochemical Corp., costat “special” Freehold, N. J .). The SA of plasma glucose was determined as described previously (13) - All radioactivity was counted in a Packard Tri-Carb liquid scintillation counter at 2°C. Cdculations. In the steady state, when the plasma glucose

level is reasonably constant, the rate of glucose release from the depots is equal to the rate of its removal by the tissues; hence the term turnover is appropriate. Glucose turnover was calculated according to the isotope-dilution method, i.e., the infusion rate of the tracer (nCi/kg . min) divided by the average SA of the substrate (nCi/pmol glucose) which represents the rate at which the unlabeled substrate enters the circulation. Since there was no difference in the plasma glucose levels during rest and acute cold exposure, the average glucose SA during these two periods was used to calculate glucose turnover rate. During the constant-rate infusion of tracer, the SA of exhaled CO:! ( n C’/1 mmol) rises in the form of an exponential curve approaching an asymptotic value. Infusion of ~%aH~~C03 in normal and THY dogs showed a difference in these two groups with respect to 14C02 excretion during the resting period (2 1). The asymptotic COzSAtzcc for normal dogs was calculated according to Steele et al. (24, 25) and the calculation of the asymptotic value for THY dogs was corrected accordingly. Increased energy expenditure, which does not increase blood lactate, provides a steady state in which 14C02 output is essentially the same as the infusion rate of NaH14C03 . Due to the increased rate of exchange of the fractional turnover rate of the bicarbonate pool, no correction for asyxnptote is necessary as was found in the case of exercise (22) or acute cold exposure of normal or THY dogs (2 1). The asymptotic CO2 SAL=, during rest or CO2 SA during acute cold exposure was divided by the plasma SA and multiplied by 6 (6 CO2 from the glucose) to obtain the percentage of CO2 derived from the immediate oxidation of plasma-glucose. The percentage of CO:! from plasma glucose and the respiratory CO2 output were used to calculate the rate of plasma glucose oxidation. The body surface area was estimated according to the formula: area in m1-3= 0.112 wt0-667. BMR and energy expenditure in kcal/min during rest and acute cold exposure were calculated from 02 uptake and respiratory quotient (RQ). The caloric value of glucose oxidized (0.74 kcal/ mmol) was used to calculate its participation in the total energy expenditure. In each experiment the values reported for each period are the means of three-tofive separate measurements. During cold exposure, the values taken at temperatures of 4-5°C were used for further evaluation. The means of these values were used to calculate the group average presented in the tables. RESULTS

Two experiments, A in normal and B in THY dog, during rest and acute cold exposure are shown in Fig. 1. The average caloric expenditure of normal dog was 0.64 kcal/m2 min in basal state and 1.1. kcal/m2* min during shivering. In the basal state, the plasma glucose level was 100 mg/ 100 ml. Of the glucose turnover rate of 19.5 prnol/kg min, 28 G-/o was immediately oxidized, accounting for 14.5 L/t of the total caloric expenditure. During cold exposure, a slight decrease in glucose level (96 mg/ 100 ml) and glucose turnover rate (17.4 pmol/kg*min) were observed. In contrast, the percentage of glucose turnover immediately oxidized rose to 41 ‘%. In spite of this, the percentage of caloric expenditure derived from plasma glucose oxidation decreased l

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238

PAUL,

to 9.6 o/;;,during the same period. The percentage of CO2 from plasma glucose and the RQ decreased during acute cold exposure when compared to the control period. In THY dog B, caloric expenditure during rest was 0.47 kcal/ m2. min which increased to 1.00 kcal/m2. min during cold exposure. The plasma glucose level of 109 mg/ 100 ml at rest did not change during the course of the experiment. However, even though the glucose turnover during the control and shivering periods was the same, it was substantially lower (15.0 pmol/kg min) than that observed in normal dogs. The percentage of the glucose turnover which is immediately oxidized rose from 26 % at rest to 51 % during shivering. Of the total caloric expenditure there was only a slight decrease in calories derived from plasma glucose. A slight decrease in the percentage of CO2 from plasma glucose and a decrease in RQ were found. During recovery, in both dogs the caloric expenditure decreased toward the control values. Glucose level and turnover rate remained practically unchanged, while the percent of glucose turnover which is immediately oxidized reached its control valParthpation

1.

Energy Expenditure, kcaI/m2- min

Qo2

Thyroidectomized dogs (n = 12)

P values Values TABLE

HOLMES

of ghcose in energy metabolism during rest

ml/kg*

Normal dogs (n = 23)

AND

ues. The percentage of calories derived from plasma glucose oxidation remained lower than that found during the control period in both dogs. The results of 23 experiments in normal dogs and 12 experiments in THY dogs during rest are summarized in Table 1. A significantly lower 02 consumption and energy expenditure, as expected, were found in THY dogs. The plasma glucose level was the same in both groups, but a significantly lower glucose turnover rate, calculated on the basis of either body weight or body surface area, shows that glucose mobilization was lower in THY than in normal dogs. However, when the glucose turnover rate was expressed as mmol/cal BMR, a significantly higher amount of energy delivered in the form of glucose per calorie expenditure was found in THY dogs. No significant differences were found in percentage of glucose turnover immediately oxidized, percent CO2 from plasma glucose, or percent of kcal from glucose in these two groups, although significantly less glucose was oxidized in THY dogs; a significantly higher RQ was found in THY dogs.

l

TABLE

DONOHUE,

&in

6.83 =t= 0.22

It

4.39 =t= 0.22

0.48 A 0.02

Glucose metabolism in thyroidectomized and normal dogs during rest and acute cold exposure.

Uniformly labeled (14C)glucose was infused iv at a constant rate into unanesthetized surgically thyroidectomized (THY) and normal dogs during the basa...
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