Glucoregulation during moderate exercise in insulin treated diabetics.

Glucoregulation During Moderate Exercise in Insulin Treated Diabetics BERNARD ZINMAN, FREDERICK T. MURRAY, MLADEN VRANIC, A. MICHAEL ALBISSER, BERNARD S. LEIBEL, PATRICIA A. Me CLEAN, AND ERROL B. MARLISS The Endocrine-Metabolic and Respiratory Divisions, Department of Medicine, Toronto General Hospital, the Research Institute, Hospital for Sick Children, and the Department of Physiology, University of Toronto, Toronto, Ontario, Canada ABSTRACT. To characterize glucoregulation during exercise in insulin treated non-obese diabetics, the response to controlled exercise after an overnight fast was compared to that of normal controls. The diabetics were divided into two groups: ten received insulin by continuous iv infusion while nine received one-third their usual intermediate acting insulin by so injection in the thigh 1 h prior to exercise. Exercise was on a bicycle ergometer for 45 min at 50% maximum O2 consumption. In the sc insulin group glucose was 227 ± 16 mg/dl at rest and exercise induced a progressive fall to 156 ± 18 mg/dl at the end of the exercise period. In both insulininfused diabetic subjects and normal controls exercise did not affect plasma glucose. Glucose turnover was measured by a method employing 3-3H-glucose by primed infusion. Glucose production in the normal controls increased approximately two-fold with exercise and glucose disap-

pearance paralleled production. Similarly, in the normoglycemic insulin-infused diabetics, glucose production and disappearance increased synchronously. By contrast, in the sc insulin diabetics, there was decreased glucose production despite increased disappearance, accounting for the fall in plasma glucose. Plasma immunoreactive insulin (IRI) increased during exercise when insulin was administered by subcutaneous injection. These studies demonstrate: a) moderate exercise in diabetics receiving sc insulin is associated with a rapid fall in plasma glucose; b) plasma glucose in diabetics receiving insulin by constant iv infusion is unaffected by exercise; c) the fall in plasma glucose during exercise in sc treated diabetics is the result of decreased glucose production, perhaps related to insulin mobilization from the sc depot injection site. (J Clin Endocrinol Metab 45: 641, 1977)

E

XERCISE has been accepted as an im- anticipation of increased exercise. The portant component in improving dia- phenomenon of exercise induced hypobetic control in insulin treated diabetics glycemia has been reproduced and char(1-3). However, during and after periods of acterized in depancreatized dogs given exercise insulin treated diabetics can ex- protamine zinc insulin sc (4,5) and apperience severe hypoglycemia and thus fre- pears to be associated with increased mobilquently modify their insulin dosage or in- ization of subcutaneous depot insulin. This crease their carbohydrate consumption in has not been shown to be a mechanism operative in man. Indeed, the metabolic effects of exercise on diabetes are not Received February 9, 1977. Supported by grants from the Juvenile Diabetes uniform (6-8). Marble (2) as early as 1936 Foundation, the Juvenile Diabetes Research Founda- showed that exercise in patients severely tion, the Medical Research Council of Canada, the insulin deficient resulted in an increase in Toronto General Hospital Foundation and the Norman blood glucose. Urquhart Fund of the Toronto General Hospital. The metabolic response to exercise in diaPresented in part at the Eastern Section of the betics receiving insulin by constant iv American Federation for Clinical Research in Boston, infusion has not been studied. This is of Mass. January 9, 1976 (Clin Res 23: 575, 1976, Abstract) and the 36th Annual Meeting of the American particular interest in the studies of glucose Diabetes Association June 23, 1976, San Francisco, regulation by the artificial endocrine panCalifornia (Diabetes 25: 333, (Suppl 1) 1976, Abstract). creas. As previously shown (9,10) this instruAddress correspondence to: Dr. B. Zinman, Clinical ment can be programmed to normalize the Investigation Unit, Toronto General Hospital, 101 Colglycemic response to meals and snacks in lege Street, Toronto, Ontario, Canada M5G 1L7. 641

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642

ZINMANETAL.

human insulin-dependent diabetics. The need for additional control parameters for insulin delivery by the artificial pancreas in patients receiving insulin by infusion during exercise has not been investigated. The present study was undertaken to compare the effects of controlled exercise in post-absorptive diabetics receiving sc intermediate acting insulin with those in diabetics receiving insulin by iv infusion. Nondiabetics of equivalent age, sex and physical fitness were studied as controls. In addition glucose turnover measurements were made to enable a dynamic interpretation of our observations. A concurrent report (11) deals with respiratory gas exchange, the concentration of circulating energy substrates and the glucoregulatory hormones measured in these studies.

JCE & M • 1977 Vol 45 • No 4

Protocol All studies were performed in the morning after a 12-14 h fast. The subjects were divided into three groups; three of the diabetic subjects were studied on more than one occasion, as detailed in Table 1. 1. Insulin subcutaneous Ten diabetics received one-third of their total daily intermediate acting insulin (NPH or Lente insulin) sc in the right thigh 1 h before exercise without prior alteration of insulin treatment. 2. Insulin infused

Ten diabetics received an iv insulin infusion of 8 - 20 mU/min in 0.9% saline for 12-14 h overnight, which was continued during the experiment. The infusion rate was initially adjusted for each subject according to glycemia, and then maintained constant throughout the study (rest, exercise and recovery periods). For Materials and Methods 48 h prior to the start of the infusion, these subjects received crystalline zinc insulin four Subjects studied times daily in accordance with glycemia to ensure complete absence of intermediate acting insulin Sixteen insulin-dependent diabetics and seven at the time of study. The insulin-infused group control subjects were studied in the Clinical was subdivided into 7 subjects who were Investigation Unit and Respiratory Research maintained normoglycemia and 3 subjects who Laboratory of the Toronto General Hospital. The were maintained hyperglycemic prior to and 10 male and 6 female subjects were non-obese, during the experiment. actively employed and had diabetes from 0.2 to 39 years' duration. They were in good nutritional 3. Normal controls balance and were on a weight-maintaining diet (40% carbohydrate, 40% fat and 20% protein). No exogenous insulin was administered. There was no clinical or laboratory evidence of On the day prior to study, the maximum work diabetic complications (except for Grade II capacity (12) of each subject was estimated as folretinopathy in No. 3) and hepatic, renal, cardiac lows. The subjects were exercised on a bicycle and circulatory function were normal. A normal ergometer at two different work loads, during exercise electrocardiogram was a prerequisite to which heart rate and oxygen uptake were participation in the study. One patient (No. 1) measured. After correcting for age, standardizing had been on replacement L-thyroxine for one for weight, and grading for cardiovascular fitness, year and this was continued. The control group the level of exercise giving a predicted maximum comprised 5 males and 2 females, all healthy oxygen uptake was determined (13,14). and non-obese. Anthropomorphic data on all subThe morning of the experiment the subjects jects and details of their diabetic history as were transferred to the exercise laboratory. An 18 well as data on physical fitness are given in gauge catheter (Argyle Medicut, Aloe Medical Table 1. Variable athletic abilities and participa- Company, St. Louis, Missouri) was" introduced tion in competitive sports were present in both into an antecubital vein for sampling of blood for groups. The nature, purpose and possible risks glucose, insulin and 3-3H-glucose. Patency of the involved in the study were explained and in- catheter was assured by a slow infusion of 0.45% formed consent was obtained. saline between sampling intervals. In an ipsilat-


643

EXERCISE IN INSULIN TREATED DIABETICS TABLE 1. Anthropomorphic data for diabetics and controls

(yrs)

Sex

1

30

M

185

79.0

2

23 24

M F

176

3 4

23

M

181

110.5 52.3 75.5

Average Good

13 3

5

22

M

182

83.6

Average

4

Subject *

>

•

Fitness*

Insulin (type)

Dose (U/d)

Study!

Ultralente Regular Lente Lente Lente Regular Lente Regular Lente Semilente Regular Lente Regular

51 18

I.V..S.C. (x2)

Diabetics

6

4

Weight (kg)

Duration of diabetes (yrs)

Height (cm)

Age

35

F

155

170

51.5

20

Fair Low

6

Fail-

7

45

F

161

50.2

Average

39

8

31

F

161

56.0

Average

5

9

41

F

10

25

F

155 164

11

43

M

177

12

24

iVI

185

13 14

44

M

170

24

M

15

22

M

178 170

16

23

56.0 62.3

Fair Average

81.0 99.5

FailAverage

58.0 71.0 67.0

High Good Fair

M

156

47.0

Average

71.0 47.7 79.5 61.4 79.1 77.3 88.2

Average Average Fair Average Average Good Fair

5 2 6 6

12 20 20 0.2

90

66 40 6 38 14 25 10

I.V. I.V., S.C. T \7 I.V.

TV J..

V . j

O

sr

,\_>.

I.V.

45 12 10

NPH

25

Regular Lente Lente Regular Lente Lente Semilente Lente

25

T V I.V. T V I.V.

26 22 16

I.V.

18

S.C.

32 40

S.C.

24

NPH

30

Ultralente Semilente Lente Regular

32 16 16 10

T V

I.V.

S.C. S.C. S.C. S.C.

f Controls

>

17

54

M

179

18

27

152

19 20

34 27

21

44

22

51

23

32

F M F M M M

185 173 183 183

183

* As defined in Materials and Methods. f S.C. = insulin subcutaneous, I.V. = insulin-infused.

eral forearm vein a double lumen catheter (15) (Abjad Industries, Willowdale, Ontario) was inserted into a 20 gauge catheter for continuous blood glucose sampling. Infusion of a dilute heparin-saline solution (50 units/ml) through the outer lumen at half the continuous withdrawal rate through the inner lumen assured anticoagulation of the blood in the catheter without

introduction of anticoagulant into the patient. Blood withdrawal rate was 0.05 ml/min. A third catheter (18 gauge) was introduced into the contralateral forearm and connected to three Lambda pumps (Harvard Apparatus Co., Millis, Mass.) through a triple input coupling adapter located near the veni-puncture site. Through this system insulin was delivered at a constant rate


644

ZINMAN ET AL.

(8-20 mU/min in the insulin-infused group only), saline 0.45% at 0.5 ml/min to assure delivery of the insulin, and 3-3Hglucose for the measurement of glucose turnover. A 30-100 min period of rest during which steady state glycemia obtained was followed by 45 min of exercise on a vertical bicycle ergometer (Siemens Elema model 380, Stockholm, Sweden) at a work load calculated to result in pulmonary oxygen uptake of 50% of the previously estimated maximum value. A recovery period of 60 min followed. Electrocardiographs monitoring of heart rate was made at rest, at 5,15,30 and 45 min of exercise and at 15 and 30 min of recover)'. Tracer method turnover

and calculation

of glucose

For experiments in which glucose turnover was measured a priming bolus (22 /xCi) of 3-3Hglucose (New England Nuclear, Boston, Mass.) was injected iv at the beginning of the rest period and a continuous infusion (2 jtxCi/ml 0.9% saline) of labeled glucose was infused through the Lambda pump previously described, at a rate of 0.109 ml/min throughout rest, exercise and recovery. The specific activity of plasma glucose did not reach a plateau until approximately 60 min and therefore data from the last 30 min of the rest period were used for the calculation of the baseline turnover values. The rate of production and rate of disappearance of endogenous glucose were determined by the method of primed tracer infusion (16) as modified previously (17,18). Radziuk et at. (19) have validated that glucose turnover can be predicted with accuracy under both steady state and rapidly changing nonsteady state conditions using this method. Analytical samples

methods and processing of blood

The continuous monitoring of plasma glucose was performed as previously reported (20) using a Technicon auto-analyzer (Technicon Instalment Corp., Tarrytown, New York) with a glucose oxidase technique modified such as to have a 90 sec delay between the sampling and display of the results on the strip chart recorder. The instrument was standardized internally with glucose solutions and externally by calibrating with at least two simultaneously obtained plasma samples analyzed using a glucose analyzer

JCE & M • 1977 Vol 45 • No 4

(Beckman Instruments, Inc., Fullerton, California). Samples for glucose turnover determination were obtained at the times indicated on Fig. 2 and placed into tubes which contained heparin and sodium fluoride. The plasma was separated by * centrifugation and then deproteinized with a mixture of equal volumes of zinc sulfate (5% W/V) and barium hydroxide (0.3 normal). An aliquot of the supernatant was evaporated to remove tritiated water (21). The precipitate was redissolved in 1 ml distilled water and mixed with 4 10 ml aquasol scintillation mixture (New England Nuclear, Boston, Mass.). The activity of labeled glucose in the samples was measured by liquid scintillation counting and the concentration of unlabeled glucose was detennined using a glucose analyzer (Beckman Instruments, Inc., Fullerton, California). Specific activity of plasma *• glucose (DPM//xg) was calculated as a ratio between concentrations of labeled (DPM/ /xl) and unlabeled glucose (/xg/ixl). Since it has been reported (21) that 3-3H-glucose does not recycle into circulating metabolites the present method does not require that glucose be isolated from plasma by ion exchange chromatography. Samples for insulin assay were centrifuged with minimal delay at 4 C and supernatants frozen at —20 C until assay. Immunoreactive insulin (IRI) was determined using an anti-beef insulin anti-serum (supplied by Dr. Peter Wright, Minneapolis, Minnesota) purified human insulin standard (25.7 /xU/ng), 125I-labeled pork insulin (Novo Research Inst, Copenhagen, Denmark) y and a dextran-coated charcoal separation of free from bound hormone (22). For respiratory measurements the subjects breathed through a two-way, low-resistance, lowdead-space (9 cc) pulmonary function laboratory breathing valve (W. E. Collins, Boston, Mass.) < into a system fitted with a fan to ensure complete mixing of the expired gases. Respiratory gas concentrations were measured with rapid response CO2 (LB-2) and O2 (OM-11) analyzers (Beckman Instruments Inc., Palo Alto, California). After thorough flushing of the dead space of the breathing valve, tubing and Tissot gas meter, two 2-min collections of expired gas were made at rest. Upon commencement of exercise 1 min collections were made at 5, 15, 30 and 45 min and during recovery at 15 and 30 min. The mixed expired gases were analyzed for oxygen and CO2 concentrations.


645

EXERCISE IN INSULIN TREATED DIABETICS Standard statistical methods were employed with Student's paired t test being used to examine for the significance of changes during exercise and recovery compared with rest and the unpaired t test to compare the diabetic groups with the normal controls.

Results

•

Respiratory data, work performed and heart rate

In Table 2 the mean pulmonary oxygen uptake (VO2) at rest and 45 min exercise, the work load expressed as watts, the per cent maximum oxygen uptake, and the heart rate at rest and at the end of 45 min of A exercise are shown for the normal controls and diabetics receiving insulin by infusion or sc. The pulmonary oxygen uptake was similar for all three groups at rest. During exercise, there was a similar increase in VO2 of four to five-fold in each group. The - work load, although different for each group, was similar for relative work loads achieved as a per cent maximum oxygen uptake. The heart rate at rest was similar for all three groups. However, at the end of exercise the heart rate of both the insulin-infused and insulin-sc subjects was significantly higher than normal controls. Glycemic response to exercise In Fig. 1 glycemia during rest, exercise and recovery is shown for the controls, insulin-infused (normoglycemic and hyper• glycemic) and insulin-sc subjects. Glycemia at rest in the insulin-sc group was constant at 227 ± 16 mg/dl and exercise induced a progressive fall significant at 15 min (P < 0.05) and continuing until the exercise was terminated. Glycemia was constant in , the recovery period at 156 ± 18 mg/dl. Glycemia at rest in the insulin-infused hyperglycemic and normoglycemic subjects was 224 ± 2 8 and 110 ± 9 mg/dl, respectively. When insulin was administered by constant rate iv infusion, irrespective of whether the glucose concentration at the

TABLE 2. Respiratory data, work performed and cardiac response to exercise Normal control VO2t at rest ml/kg/min VO2 at 45 min exercise ml/kg/min Work load watts % Max O2 uptake H.R.f at rest beats/min H.R. at 45 min exercise beats/min

Insu lin— infused

Insulin— Subcutaneous

3.7 ± 0.2

3.7 ±

0.3

17.5 ± 1.3

17.5 ±

1.6

72.9 ± 8.4

64.5 ± 12.0

53

±3

58

± 6

58

± 3

72

±5

81

± 5

81

± 9

121

±4

149* ± 5

3.6 ± 0.2

20.3 ±

1.6

92.5 ± 12.0

140* ± 4

* P < 0.01 as compared to nor mal controls. \ VO2 = Oxygen uptake 1 H.R. = Heart: rate.

start of exercise was normal or elevated, there was no significant change during exercise or in the recovery period. Glycemia in the normal controls at rest was 90 ± 6 mg/ dl and did not change with exercise. Glycemia in the insulin-infused group maintained normoglycemic was slightly higher than normal controls and was significantly different (P

0

••

;

•-

15

30 45

-

•

60

••

: -

75

Minutes

FIG. 1. The effect of exercise (shaded area) on plasma glucose (mean ± SEM) in fasting post-absorptive diabetics given one-third their usual insulin subcutaneously 1 h prior to exercise (upper panel), maintained hyperglycemic (2nd panel) or normoglycemic (3rd panel) by constant iv insulin infusion, and normal controls (lower panel).

However, in comparing the glucose turnover in the normal controls (Fig. 2) with the insulin-infused diabetics (Fig. 3), it is apparent that glucose production at rest in the insulin-infused diabetics was 25% higher than in the normals (P < 0.05). The increment in glucose production induced by exercise in the normal controls was 1.62 ± 0.22 mg/kg/min as compared to 1.02 ± 0.19 mg/kg/min in the insulin-infused subjects. However, this increment in glucose production observed in the normals was not significantly greater. Glucose turnover measured in 4 of the subjects receiving insulin sc (Fig. 4) demon-

Minutes

FIG. 2. Glucose turnover—normal controls: Plasma glucose concentration, glucose production and glucose disappearance at rest, during exercise (shaded area) and recovery in 5 normal controls.


647

EXERCISE IN INSULIN TREATED DIABETICS centrations of plasma IRI were assessed. In most of the diabetic subjects studied insulin measurement was precluded by the presence of insulin antibodies. However, in two subjects (No. 13 and No. 16) insulin therapy was recently initiated and IRI measurements were possible. The results in IRI measurements at rest, exercise and recovery for normals and two diabetic subjects, who received sc insulin 1 h prior to exercise, are shown in Fig. 5. In the normal controls IRI during rest was 0.44 ± 0.03 ng/ml and decreased significantly during the exercise period (P < 0.01). It rose during recovery but showed a secondary significant fall at 60 min (P < 0.01). In the diabetic subjects IRI in REST

EXERCISE

REST

EXERCISE

RECOVERY (n=4) 234±26mg/dl

RECOVERY (n=4)

4

I

\

3 \

/

100

200

300

Minutes

FIG. 4. Glucose turnover—sc-insulin treated diabetics: Plasma glucose concentration, glucose production and glucose disappearance at rest, during exercise (shaded area) and recovery in 4 diabetics given insulin sc 1 h prior to exercise.

Minutes

FIG. 3. Glucose turnover—insulin-infused diabetics: Plasma glucose concentration, glucose production and glucose disappearance at rest, during exercise (shaded area) and recovery in 4 diabetics maintained normoglycemic by a constant intravenous insulin infusion.

the rest period was 0.28 and 0.78 ng/ml and rose linearly during exercise to 1.05 and 1.48 ng/ml, respectively. In the post-exercise period the insulin concentration decreased toward control values. In both diabetic subjects plasma glucose characteristically fell during exercise. Thus, unlike the normal controls, in whom exercise resulted in de-


648

ZINMANETAL. 1.7

REST

EXERCISE

JCE& M i 1977 Vol45 No 4

RECOVERY • Controls n=7 • S-Aicct 13 lCuL-.(nH! i . C .

1.5 1.3 1.1

FIG. 5. Plasma immunoreactive insulin at rest, during exercise and recovery in 7 controls and two diabetic subjects given sc insulin 1 h prior to exercise.

I ~DO

0.9

£

0.7 0.5 0.3 0.1

. I -30

-80

I 0

j 20

i.i. _i 40 60

J 80

L L_ 100 120

Minutes EXERCISE ' Subcutaneous Insulin :

Th-gh

creased IRI, the subjects receiving sc insulin demonstrated a two to four-fold increase in IRI and a marked reduction in glycemia associated with exercise. Exercise hypoglycemia as related to insulin injection site

I

l._ " I ....I.-J

l_i L _ l _ !

i

Subcutaneous Insulin Thigh No Exercise

Subcutaneous Insulin Arm

40

60

80

100

120

Minutes FIG. 6. Glycemic response to exercise in one subject studied on three separate occasions. 1) Insulin sc in an exercising thigh (upper panel). 2) Insulin sc in the thigh without exercise (middle panel). 3) Insulin injected sc into an immobilized arm during exercise (lower panel).

In all the experiments reported above insulin was injected sc in a leg which subsequently underwent active exercise. To determine if the site of insulin injection affected the response to exercise on the bicycle ergometer one subject was studied on three separate occasions (Fig. 6). The glycemic response to sc insulin administered in the thigh was a reduction in glycemia of 100 mg/dl. When sc insulin was administered in the thigh but without exercise only a slight decrease in glycemia occurred. On a third occasion the same dose of insulin was administered sc in the left arm which was immobilized prior to and during exercise. Under these conditions exercise was without effect in lowering plasma glucose. Discussion The metabolic response to exercise in normals and juvenile-onset diabetics is deter-


EXERCISE IN INSULIN TREATED DIABETICS mined by many variables including their physical fitness, the work load imposed and the duration of exercise (23,24). In this study care was taken to assess the physical fitness of each subject prior to study and exercise for a defined period of time was estimated to be approximately 50% maximal capacity. The physical fitness of the diabetic subjects and the controls was similar (Table 1). The work load varied from group to group > depending on anthropomorphic measurements but the relative work performed in terms of per cent of maximum oxygen uptake was similar for all three groups. Oxygen uptake at rest (Table 2) was similar in all three groups and increased approxi^ mately four to five-fold by the end of the exercise period. The intergroup uniformity is further evident in that the three diabetic subjects who participated in both studies (insulin-sc and insulin-infused) did so at the same work load and demonstrated responses typical of those observed for the other subjects in both groups. In contrast to previous studies performed with 16-24 h between the last insulin administration and the onset of exercise (7,23,24) the present study examined the effect of different routes of insulin administration in close temporal relation to exercise. The ' results demonstrated that the glucose lowering effect of exercise is dependent on the route of insulin delivery. Post-absorptive diabetics given one-third their usual insulin characteristically showed a fall in plasma glucose beginning 10 min after the start of - exercise, progressing at a constant rate throughout exercise, and stopping abruptly with the cessation of exercise. In contrast diabetics maintained normoglycemic by a constant rate iv infusion of insulin did not show a significant change in plasma glucose during exercise. To determine whether the glucose lowering effect of exercise in the sc group was related to the elevation of plasma glucose at the start of exercise, 3 diabetic subjects maintained hyperglycemic by insulin infusion were studied. As observed in the normoglycemic insulin-in-

649

fused subjects, no fall in plasma glucose occurred during exercise in these 3 subjects. The glucose lowering effect of exercise in diabetics receiving sc insulin has similarly been shown for milder exercise (4 mph 21/2° and 5° slope) (3) as well as for strenuous exercise in depancreatized dogs (4). Vranic et al. (25) demonstrated that strenuous exercise in depancreatized dogs receiving insulin by constant portal infusion did not result in a fall in plasma glucose. Thus, the fall in plasma glucose associated with exercise in insulin treated diabetes appears to be a phenomenon characteristic of sc insulin administration. To define the dynamics of glucose regulation during exercise glucose turnover was measured in the three groups studied by the method of primed tracer infusion. The use of this method to measure nonsteady-state glucose turnover in exercising normal and diabetic humans complements the previous observations in normal and depancreatized dogs (4-6). The technique of glucose turnover measurement for steady-state conditions has been well established (26), and Radziuk et al. (19) have recently validated the primed tracer infusion method for nonsteady-state applications for the inulin and glucose systems. In the normal controls and insulin-infused diabetics (Figs. 2,3) glucose production and glucose disappearance rose synchronously during exercise and thus no change in plasma glucose concentration was observed. In this respect the normals and diabetics maintained normoglycemic by insulin infusion were similar. However, basal glucose production rate in the insulin-infused group compared to the normal controls was significantly elevated (P < 0.05) and probably reflected mild underinsulinization. This inference as to insulinization is supported by the levels of other metabolites in these subjects (11). Interestingly, production rose to the same absolute levels as in the normals, in whom insulin levels fell characteristically. The rise to normal in such infused subjects may have been possible due to the presence of


650

ZINMAN ETAL.

minimal underinsulinization, though similar increases occurred in two of the four subjects who were clearly normoglycemic. Glucose production at rest in the subcutaneous insulin group was more than double (P < 0.005) that of the normal controls reflecting enhanced glucose production by the liver as a result of insulin deficiency. Unlike the normals and insulininfused diabetics in whom exercise induced an increase in glucose production, the diabetics receiving sc insulin demonstrated a decrease in glucose production. Concurrent with a fall in glucose production glucose disappearance increased with exercise in these subjects and thus a fall in plasma glucose occurred. Of interest is that the increment in glucose disappearance was of the same magnitude as in the other groups, though beginning at a higher level. Depancreatized dogs maintained on protamine zinc insulin showed similar changes in glucose turnover during strenuous exercise (5). The measurement of glucose production in post-absorptive normals at rest in this study, expressed as mmol/min, was 0.83 and is in agreement with previous studies (0.91 (27), 0.77 (28), 0.61 (29), and 0.71 (30)) using isotope dilution methods as well as measurements made using the technique of arteriovenous difference multiplied by blood flow (0.61 (7), 0.95 (31) and 1.12 (32)) by other investigators. However, less agreement exists as to the contribution of increased glucose production to hyperglycemia in post-absorptive diabetics. Our measurements demonstrating increased glucose production in the sc insulin group (mean glucose 234 mg/dl) as compared to normals is in accordance with other studies (28,33) in which a two to three-fold increase in glucose production was measured in post-absorptive diabetics of similar glycemia using glucose tracer methods. Other investigators (31,32) using the hepatic venous catheter technique failed to show a significant difference in glucose production in diabetics of similar glycemia as compared to normals. As suggested by Bowen and Moorhouse (33)

JCE & M • 1977 Vol 45 • No 4

this diversity offindingsmay have been due to nonrecognition of a circadian cycle in glucose turnover, more marked in diabetes. As well, non-tracer techniques determine net glucose production across the splanchnic bed, whereas isotope studies estimate absolute glucose production. In contrast to the significant fall in IRI measured in normal subjects during exercise a two to four-fold increase was demonstrated in two sc insulin subjects in whom insulin could be measured. Depancreatized dogs (5) given protamine zinc insulin sc similarly demonstrated an increase in IRI associated with exercise. These observations are consistent with the hypothesis that exercise results in mobilization of subcutaneous depot insulin. This increase in IRI is sufficient to inhibit glucose production by the liver and concurrent with enhanced glucose utilization by muscle during exercise a fall in plasma glucose occurs. As well, FFA failed to rise with exercise and glycerol and ketone body increments were small further supporting the observation of increased insulin effect during exercise in the insulin-sc group (11). Of interest, the increment in glucose utilization with exercise observed in the sc insulin group was the same as for the normal controls despite increased IRI. Thus, it appears that al- ^ though enhanced glucose utilization by muscle during exercise is dependent on a small amount of insulin being present (34) it is not of greater magnitude when excess insulin is mobilized during exercise. Preliminary studies in one subject re- < ceiving insulin at different injection sites suggested that mobilization of insulin may be variable as to the site of injection and the degree of local muscular exertion perha s related to blood or lymph flow. These observations may have clinical relevance < with respect to selection of the site of insulin administration prior to planned exercise. The cardiac response to exercise was different in diabetics as compared to normal controls (Table 2). The heart rate of both


EXERCISE IN INSULIN TREATED DIABETICS diabetic groups was significantly higher than normal controls at the end of the exercise period by a mean of 19 to 28 beats per minute. Wahren et at. (7) made the identical observation in diabetics studied under similar conditions with comparable work loads. The present data do not explain this observation. The possibility exists, however, that the greater increase in heart rate with exercise is the result of autonomic nervous system dysfunction (denervation hypersensitivity to circulating catecholamines released during exercise) or perhaps secondary to microvascular disease (basement membrane thickening). The observation that plasma glucose in diabetic subjects receiving insulin by constant rate iv infusion does not fall with exercise is of particular relevance to the development of an artificial pancreas which delivers insulin iv. It implies that special control parameters for the adjustment of the rate of insulin infusion during exercise will not be required to assure the absence of hypoglycemia during glycemic control by such an instrument. However, complete normalization of the metabolic response to exercise apart from glycemia (glucose turnover, flux of other substrates), may require more sophisticated control parameters. Acknowledgments The authors gratefully acknowledge the enthusiastic technical assistance of Dr. A. Denoga, Mrs. Katarina Thumm, Mrs. N. Kovacevic, Miss M. Young and Mr. Ting-Po Kam. The active participation by the nursing and dietetic staff of the Clinical Investigation Unit of the Toronto General Hospital is sincerely appreciated. The excellent secretarial assistance of Mrs. Dinah Oakley is gratefully acknowledged. We thank Drs. M. Mihic, B. Hazlett and G. Steiner for referral of subjects for study.

4.

5.

6. 7.

8. 9.

10. 11.

12. 13.

14.

15.

16.

17.

References 1. Lawrence, R. D., The effect of exercise on insulin action in diabetes, Br Med J 1: 648, 1926. 2. Marble, A., and R. M. Smith, Exercise in diabetes mellitus, Arch Intern Med 58: 577, 1936. 3. Klachko, D. M., T. H. Lie, E. J. Cunningham, G. R. Chase, and T. W. Burns, Blood glucose

18.

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Hypoglycemia during hemodialysis in diabetics treated with insulin.

Role of FFA-glucose cycle in glucoregulation during exercise in total absence of insulin.

Exercise-induced fall of blood glucose in insulin-treated diabetics unrelated to alteration of insulin mobilization.

Unrecognised nocturnal hypoglycaemia in insulin-treated diabetics.

Serum IRI in insulin-treated diabetics during a 24-hour period.

Soluble immune complexes in the sera of newly diagnosed insulin-dependent diabetics and in treated diabetics.

Glucoregulation and hormonal responses to maximal exercise in non-insulin-dependent diabetes.

Insulin antibodies and clinical complications in diabetics treated for five years with lente or sulfated insulin.

Determination of free and total insulin and C-peptide in insulin-treated diabetics.

The relationship between circulating free and bound insulin, insulin antibodies, insulin dosage and diabetic control in insulin treated diabetics.

Plasma volume shifts during moderate exercise in splenectomized greyhounds.

Concentration of porcine proinsulin-like material in plasma of insulin-treated diabetics in relation to purity of insulin preparations.

Effect of the alpha-glucosidase-inhibitor BAY-g-5421 on blood glucose control of sulphonylurea-treated diabetics and insulin-treated diabetics.

Emotional attitudes in adult insulin-dependent diabetics.

Tolbutamide-induced insulin release in pregnant diabetics.

Auditory feedback improves heart rate moderation during moderate-intensity exercise.

Exercise in type 1 (insulin-dependent) diabetic patients treated with continuous subcutaneous insulin infusion. Prevention of exercise induced hypoglycaemia.

Exercise training enhances insulin-stimulated nerve arterial vasodilation in rats with insulin-treated experimental diabetes.

Normalization of insulin delivery to diabetics by pulsed insulin infusion.

High-carbohydrate diets and insulin-dependent diabetics.

High-carbohydrate diets and insulin-dependent diabetics.

Continuous electrocardiographic recording during exercise in young male diabetics. A computer study.

High-carbohydrate diets and insulin-dependent diabetics.

Unawareness of hypoglycemia by insulin-dependent diabetics.