Differences Between Prebreakfast and Late Afternoon ... - Diabetes Care

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Morey W. Haymond, MD. Philip E. Cryer, MD. Robert A. Rizza, MD. John M. Miles, MD. Little information is available regarding the optimal timing of exercise in ...
Differences Between Prebreakfast and Late Afternoon Glycemic Responses to Exercise in IDDM Patients

Little information is available regarding the optimal timing of exercise in insulin-dependent diabetes mellitus (IDDM) patients. In this study, six IDDM patients receiving ultralente-based intensive insulin therapy were studied during 30 min of exercise (—60% Vo2max), before breakfast, and at 1600. On two other occasions, they were studied at rest. Plasma glucose increased from 6.7 ± 0.4 to 9.1 ± 0.4 mM during morning exercise (P < 0.01). In contrast, mean plasma glucose did not change during afternoon exercise (A = 0.3 ± 0.5 mM, NS); however, there was a 0.3- to 1.0-mM decrease in three subjects. The observed difference in the glycemic response to exercise could not be explained on the basis of changes in plasma glucagon, growth hormone, norepinephrine, or epinephrine. Plasma cortisol was higher (P < 0.02) in the morning than in the afternoon, and plasma free-insulin concentrations were lower (P < 0.05). These data indicate that the risk of exerciseinduced hypoglycemia is lowest before breakfast. The reason for the divergent glycemic responses to exercise is not entirely clear but may be related to the observed differences in free-insulin concentrations. Because of the lower risk of hypoglycemia, our results suggest prebreakfast exercise may be preferable for some IDDM patients receiving intensive insulin therapy. Whether these findings are relevant to patients receiving other types of insulin therapy will require further investigation. Diabetes Care 13:104-10, 1990

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abitual exercise training improves physical work capacity, reduces cardiovascular risk, and may improve longevity in healthy individuals (1). Although the same benefits may apply to individuals with insulin-dependent diabetes mellitus (IDDM), acute exercise often lowers plasma glucose in these pa-

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|. Jeffrey Ruegemer, MD Ray W. Squires, PhD Harold M. Marsh, MD Morey W. Haymond, MD Philip E. Cryer, MD Robert A. Rizza, MD John M. Miles, MD

tients, and symptomatic hypoglycemia is not unusual (2). Accelerated insulin absorption, failure of insulin levels to decrease with exercise because of continued absorption from a subcutaneous depot, and hyperinsulinemia have all been implicated in exercise-induced hypoglycemia in IDDM (3-5). In recent years, intensive insulin therapy, usually consisting of continuous subcutaneous insulin infusion (CSII) or an ultralente-based multiple injection program, has become popular (6). Both older (7) and more recent (8) studies indicate that exercise-induced hypoglycemia tends to be a feature of well-controlled but not poorly controlled IDDM. Many reports have described a hypoglycemic response to exercise in patients receiving CSII, and it appears that intensive therapy, independent of exercise, may increase the severity and frequency of hypoglycemia (9). Although the glycemic response to exercise may depend on several factors, the major determinant of the response is probably insulin availability (5). Free-insulin concentrations in patients receiving CSII or ultralentebased intensive therapy tend to be lower before breakfast than before subsequent meals or bedtime (10). Thus, less hypoglycemia in response to exercise before breakfast when compared with late afternoon exercise might be expected. These studies were conducted to test this hypothesis.

From the Endocrine Research Unit, Departments of Internal Medicine and Anesthesiology, Mayo Clinic, Rochester, Minnesota; and the Metabolism Division, Washington University School of Medicine, St. Louis, Missouri. Address correspondence and reprint requests to John M. Miles, MD, Endocrinology and Internal Medicine, Mayo Clinic, Rochester, MN 55905. Received for publication 9 January 1989 and accepted in revised form 13 September 1989.

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RESEARCH DESIGN AND METHODS All studies were conducted in the Mayo Clinic General Clinical Research Center. After approval by the Mayo Institutional Review Board, informed written consent was obtained from six volunteer subjects with IDDM aged 30 ± 4 yr (3 men, 3 women) with a duration of diabetes of 6 ± 2 yr. Glycosylated hemoglobin levels were 7.5 ± 0.6% (normal range 4.0-7.0%). The subjects were at 98 ± 2% of ideal body weight and taking 0.7 ± 0.2 U insulin • kg" 1 • day"1. All subjects were accustomed to moderate erratic exercise, but none engaged in a regular exercise program; all subjects were taking three preprandial injections of soluble human insulin together with an injection of beef-pork ultralente insulin before the evening meal for at least 2 yr. None had proliferative retinopathy, proteinuria, significant peripheral neuropathy, or known cardiac or peripheral vascular disease. Each subject was studied on four occasions over a period of 3-4 mo continuing his/her usual diet over this period. One week before the first study, maximum O2 uptake (Vo2max) was determined for each subject with a graded exercise protocol with a Schwinn Air-Dyne mechanically braked cycle ergometer, a multiple-lead ECG, and a Horizon Sensormedics metabolic measurement cart for expired gas analysis (11). Vo2max was 34 ± 3 ml • kg" 1 • min" 1 in six subjects. On two occasions, patients were admitted to the Clinical Research Center at 1030 and given a standard meal at noon, and the study was begun at 1600. On the other two occasions, patients were admitted at 1700 and given a meal at 1800 and a bedtime snack at 2200 and were studied the next morning at 0700. Meals were individualized according to diet history. Meals on control days were identical to those given on exercise days. Each subject performed an exercise bout for one morning and one evening study and was studied at rest on the other two occasions. The exercise studies were conducted in random order. Thirty minutes before each meal (but not the bedtime snack), the patient's usual insulin dose, supplemented with a standard algorithm based on the prevailing blood glucose, was administered (6). All insulin injections were administered in the abdomen. Forty minutes before blood sampling, a 19-gauge butterfly needle was placed in a dorsal hand vein in retrograde fashion. The hand was maintained in a warming box to provide arterialized venous blood, and the needle was maintained patent by a controlled (10-ml/h) infusion of 0.9% saline (12). A plasma glucose determination was performed (glucose analyzer YSI, Yellow Springs, OH) to ensure that the patients' plasma glucose was between 4.4 and 8.3 mM. On two occasions, studies were rescheduled because the plasma glucose was not in this range. For the two exercise studies, each subject exercised on the cycle ergometer for 30 min at an intensity of ~60% of Vo2max. The appropriate exercise intensity was achieved and maintained for each subject by measure-

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ment of O2 uptake every 5 min with the Sensormedics cart. In the second exercise study in each subject, Vo2max was matched with the first study. Blood samples were obtained at - 2 0 , - 1 0 , 0, 15, 30, 45, 60, 75, 90, 120, 180, 240, 300, and 360 min for determination of plasma glucose, lactate, acetoacetate, (3-hydroxybutyrate, free fatty acids, human growth hormone, cortisol, glucagon, free insulin, epinephrine, and norepinephrine (13-20). Sixty minutes after completion of exercise, the subjects' usual premeal insulin dose was given, again supplemented according to blood glucose, followed by a meal 30 min later. Statistical analysis. A paired t test was used to compare morning and afternoon data with the Bonferroni correction for multiple comparisons when appropriate (21). Exercise and control phases were compared in a similar fashion as the response to exercise, except that data were expressed as a change from baseline. Data are expressed as means ± SE.

RESULTS The six subjects exercised at an average intensity of 63 ± 0.9% of Vo2max in the morning and 63 ± 0.6% of Vo2max in the afternoon. Figure 1 shows plasma glucose concentrations during morning and afternoon studies on the control (rest) and exercise days. During morning exercise, the mean plasma glucose increased from

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Minutes FIG. 1. Plasma glucose concentrations before, during, and after exercise. • , Morning exercise; O, morning control period; A, afternoon exercise; A, afternoon control period. Values are means ± SE; n = 6.

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baseline values of 6.7 ± 0.4 to 9.1 ± 0.4 mM at 60 min (A = 2.4 ± 0.3 mM, P < 0.01). In contrast, preexercise plasma glucose was 4.6 ± 0.2 mM for the afternoon study (P < 0.01 vs. corresponding morning value) and did not change in response to exercise (A = 0.3 ± 0.5 mM at 60 min, NS). Although there was no change in mean plasma glucose during afternoon exercise, plasma glucose concentrations decreased by 0.3 to 1.0 mM in three subjects and increased by 0.3 to 1.6 mM in three subjects; no symptomatic hypoglycemia occurred. In contrast, a hyperglycemic response to morning exercise was observed in all subjects. The exercise-induced change in plasma glucose was lower for afternoon versus morning exercise whether expressed as peak increment (0.4 ± 0.4 vs. 2.5 ± 0.3 mM, P < 0.01; data not shown) or 90-min integrated response (area under curve; 11 ± 28 vs. 161 ± 17 mM/1.5 hr 1 , P < 0.01). In contrast, no significant change in plasma glucose occurred from baseline during the 90-min preprandial period of either control study (4 ± 12 and - 32 ± 20 mM/ 1.5 h 1 in morning and afternoon control studies, respectively). The integrated glycemic response to morning exercise was greater than the response in both control studies (P < 0.05). Baseline plasma free insulin concentrations decreased significantly from ~ 108 to ~65 pM during the two afternoon studies (both P < 0.05), whereas no change occurred in plasma free insulin during the morning studies (Fig. 2). When expressed as area under the curve, free insulin levels were higher during afternoon studies than during the morning exercise study (6.3 ± 0.4 vs. 3.9 ± 0.3 mM/1.5 h ', P < 0.05). Figure 3 shows plasma glucose concentrations in response to a meal on the four study days. Before the meal, plasma glucose concentrations were higher after morning exercise than on the other three study days (P < 0.05). However, there were no differences among any of the groups 4 h after the meal. Despite higher (P < 0.05) postprandial insulin levels in the afternoon versus morning exercise studies (data not shown), the postprandial rise in plasma glucose expressed as peak increment was greater in the afternoon than morning (6.8 ± 0.6 vs. 5.6 ± 0.5 mM, P = 0.05; data not shown). There were no differences in incremental postprandial rise in plasma glucose between control and exercise studies. Glucagon concentrations were higher in the preexercise period of the afternoon study than the morning study (287 ± 41 vs. 237 ± 30 ng/L, P < 0.05) and were similar thereafter. Plasma growth hormone concentrations tended to increase with exercise and decrease after exercise, but none of the observed changes were statistically significant (data not shown). Plasma cortisol values were higher before, during, and after the morning exercise study compared with the afternoon exercise study (600-775 vs. 330-470 mM, P < 0.02) when compared by area under the curve analysis. Baseline plasma epinephrine levels (Fig. 4) were higher in the afternoon than in the morning (P < 0.05) in both exercise and control studies, whereas there was no difference in norepineph106

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Minutes FIG. 2. Plasma free-insulin concentrations before, during, and after exercise. • , Morning exercise; O, morning control period; A, afternoon exercise; A, afternoon control period. Values are means ± SE; n = 6.

rine levels. Plasma epinephrine and norepinephrine levels increased to similar levels during the two exercise periods (Fig. 4), whether calculated as integrated response (area under the curve) or peak increment. Plasma lactate, total ketone body (acetoacetate plus (3-hydroxybutyrate), and free-fatty acid concentrations are shown in Table 1. Plasma lactate increased significantly from - 1 . 5 to ~9 mM (P < 0.01) at 15 min of exercise and returned to baseline values by 90 min. Plasma free-fatty acid levels increased significantly (P < 0.05) from - 0 . 5 to ~1.3 mM at 45 min and returned to baseline thereafter in both exercise studies. Plasma ketone body concentrations decreased slightly with both morning and afternoon exercise and increased to levels significantly above baseline (P < 0.05) in the postexercise period. There were no differences between morning and afternoon studies in any of the substrate responses to exercise. Plasma ketone body and freefatty acid concentrations were significantly higher than baseline at 90 min of the afternoon control study.

DISCUSSION

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his study demonstrates that moderate exercise before breakfast is associated with a significant increase in plasma glucose in patients with wellcontrolled IDDM receiving intensive insulin therapy, whereas this mild hyperglycemic effect is absent in DIABETES CARE, VOL. 13, N O . 2, FEBRUARY 1990

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INSULIN MEAL

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FIG. 3. Plasma glucose concentrations before, during, and after mixed meal. • , Morning exercise; O, morning control period; A, afternoon exercise; A, afternoon control period. Values are means ± SE; n - 6.

response to late-afternoon exercise. The increase in plasma glucose after morning exercise (together with slightly elevated preexercise ketone body concentrations) suggests slightly low basal free-insulin concentrations and the absence of an effect on absorption of insulin from the ultralente depot. The reduced glycemic excursion during afternoon exercise was consistent with higher circulating free-insulin concentrations due to ongoing absorption of soluble insulin from the midday injection. These results are at variance with previous studies that suggest exercise has a hypoglycemic effect in IDDM (2,7) unless undertaken under conditions of severe hyperglycemia and ketosis (8) and many studies in which a hypoglycemic response to exercise was observed in patients receiving CSII (22-28). The differences in glycemic response in this study may be explained, at least in part, by differences in antecedent insulin concentrations. Some of the studies that demonstrate a lowering of plasma glucose during exercise have examined patients taking intermediate-acting insulin (8,24,28,29), and in other studies of patients receiving intensive insulin therapy, exercise was performed within a few hours of a meal preceded by an insulin injection (23,24,26,2931). Our patients exercised when their insulin concentrations were at basal (prebreakfast) or near-basal (late afternoon) levels. Differences in the intensity and/or duration of exercise may also influence the glycemic response to exerDIABETES CARE, VOL. 13, N O . 2, FEBRUARY 1990

0L -20

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Minutes FIG. 4. Plasma norepinephrine {A) and epinephrine (B) in 4 studies. • , Morning exercise; O, morning control period; A, afternoon exercise; A, afternoon control period. Values are means ± SE; n - 6.

cise. Brief intense exercise tends to induce mild hyperglycemia, whereas moderate prolonged exercise can result in hypoglycemia, both in diabetic patients in whom circulating insulin levels are fixed and in nondiabetic individuals in whom circulating insulin levels can change (28,32-34). The duration of exercise in studies in subjects with IDDM has varied from 10 min to 4 h (31,32). Exercise intensity has also varied; moreover, many studies have estimated relative work load by extrapolation from heart rate, a method that is imprecise (22,24,27,29,35-37). In this study, relative work load was precisely quantified by measurement of oxygen uptake. It is important to note that mild hyperglycemia (A = 0.7-2.2 mM) has been reported in three studies of IDDM patients receiving CSII who exercised after an overnight fast at an intensity comparable to or greater than that chosen for this study (32,35,36). Our results indicate that prebreakfast exercise should 107

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TABLE 1 Plasma lactate, free-fatty acid, and ketone body concentrations

Lactate (mM) Morning study Exercise Control Afternoon study Exercise Control Free fatty acids (mM) Morning study Exercise Control Afternoon Exercise Control Ketone bodies (mM) Morning study Exercise Control Afternoon study Exercise Control

Baseline

15

30

45

1.3 ±0.1 1.4 ±0.1

9.2 ± 1 . 1 * 1.3 ± O.It

8.1 ±1.2* 1.4 ± O.It

4.2 ± 0.7* 1.4±0.2t

2.6 ± 0.3* 1.4 ±0.2

1.6 ±0.1 1.5 ±0.2

1.6 + 0.1 1.5 ±0.1

9.7 ± 0.7*

8.4 ± 0.8* 1.3 ±0.1+

4.2 ± 0.5* 1.4 ±0.2+

2.7 ± 0.3

1.4 ± O.It

1.3 ±0.2+

1.6 ±0.5 1.3 ±0.1

0.53 ± 0.07 0.47 ±0.12

0.52 ± 0.08 0.55 ± 0.12

0.76 ± 0.08* 0.52 ±0.11

1.33 ±0.13* 0.55 ± 0.14+-

1.00 ± 0 . 1 1 * 0.56 ± 0.16

0.73 ± 0.12 0.56 ± 0.12

0.50 ± 0.20 0.30 ± 0.07

0.43 ±0.13 0.48 ± 0.10

0.63 ± 0.21 0.56 ± 0.18

1.18 ±0.39* 0.62 ± 0.21

1.02 ±0.32* 0.61 ±0.17

0.81 ± 0.13 0.68 ± 0.10*

0.58 ± 0.09 0.31 ±0.10

0.30 ± 0.02* 0.34 ± 0.10

0.28 ± 0.02* 0.36 ± 0.10

0.60 ± 0.06 0.36 ± 0.10

0.79 ± 0.09* 0.39 ± 0 . 1 1 *

0.80 ±0.11* 0.39 ± 0.13*

0.27 ± 0.09 0.18 ± 0.04

0.20 ± 0.05 0.26 ± 0.07

0.20 ± 0.03* 0.35 ± 0.09

0.36 ± 0.08** 0.40 ± 0.12

0.49 ± 0.12** 0.46 ±0.13

0.61 ± 0.13* 0.58 ± 0.16*

60

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*P < 0.05 compared with baseline. +P < 0.01 compared with morning exercise. *P < 0.05 compared with morning exercise.

carry a lower risk of hypoglycemia for patients receiving ultralente-based intensive insulin therapy than nonfasting exercise, and that prebreakfast exercise may therefore be preferable for such patients. Although mean plasma glucose did not change during afternoon exercise, there was a mild hypoglycemic response in three of six patients. Had our patients exercised at a lower intensity for a longer period of time (e.g., 60 min at 50% of Vo2max), we might have observed a hypoglycemic response in the afternoon and little or no glycemic change in the morning. Although it is difficult to compare intensity of exercise among published reports because few studies have used relative oxygen uptake as a reference, the fact that our patients achieved higher plasma lactate concentrations than most other studies (8,22,26,28,37) suggests that the exercise was more intense. Exercise of such duration and intensity is nonetheless similar to exercise typically undertaken to improve cardiovascular health (38). It cannot be determined from this study whether the hyperglycemia observed during morning exercise was primarily due to greater hepatic glucose production or a relative impairment of peripheral glucose uptake. It is probable that the hyperglycemia during morning exercise was entirely related to lower free-insulin levels before breakfast than before the evening meal; other studies have shown that free-insulin concentrations remain above basal levels ^ 4 h after preprandial injections of soluble insulin, even when the injections are administered in the abdomen (10). The higher plasma cortisol

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concentrations could also contribute to hyperglycemia with morning exercise, although we are not aware of any evidence that differences in cortisol concentrations within the observed range (275-830 mM) can have an effect on glucose metabolism. Preexercise plasma glucagon and epinephrine concentrations were higher in the afternoon than in the morning, presumably due to glucose counterregulation. It is unlikely that the differences in the glycemic response to exercise were mediated by glucagon, growth hormone, or catecholamines because there were no differences between the morning and afternoon concentrations of these hormones during or after exercise. Finally, although differences in lipid fuel availability can influence glucose uptake by peripheral tissues, it is unlikely that this mechanism was operative in this study because there were no significant differences in morning versus afternoon free-fatty acid concentrations (39). Results of this study fail to demonstrate a late hypoglycemic effect of exercise, as has been suggested by others (27). There was no difference between the glycemic response to a meal consumed 90 min after exercise versus a meal consumed without antecedent exercise; similarly, there was no difference in absolute plasma glucose levels 4 h after the meal. It remains possible that late hypoglycemia could occur after exercise of different duration or intensity. It should be emphasized that the observed differences in glycemic response to exercise are not related to the time of day of the exercise but rather the timing of the

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exercise in relation to antecedent meals and, most importantly, antecedent insulin injections. If this interpretation is correct, a hyperglycemic response to late-afternoon but not early-morning exercise would be expected in shift workers with IDDM who sleep during the day and eat their meals during the night, because these individuals would have lower free-insulin concentrations before the evening meal (10-12 h after the last insulin injection) than in the morning (4-6 h after the last insulin injection). Some investigators have suggested that exercise can be a useful means of improving glycemic control in patients with diabetes mellitus (40). Studies that examine this question in patients with IDDM, however, have failed to demonstrate any glycemic improvement associated with an exercise program (41). In fact, the results of most studies indicate that if exercise has an effect, it is to complicate the management of diabetes by inducing either hypoglycemia or hyperglycemia ( 2 2 28,32,35,36). With this in mind, the goals of exercise in patients with IDDM should be viewed as similar to those that obtain with respect to the general population: to improve cardiovascular fitness, to improve sense of well-being, and possibly to promote longevity. The hyperglycemia associated with prebreakfast exercise could be interpreted as an unacceptable consequence of such exercise, because the goal of intensive insulin therapy is near normalization of plasma glucose (6). We believe that this interpretation is unwarranted. The benefits of intensive insulin therapy are theoretical and unproven, whereas the risks of hypoglycemia are tangible and documented (9,42). Moreover, hyperglycemia induced by prebreakfast exercise is mild and shortlived, and thus would likely have a minimal impact on overall glycemic control. Results of this study do not justify a blanket recommendation that all patients receiving ultralente-based intensive insulin therapy confine their exercise to the earlymorning hours. This is not a practical recommendation for high-school and college athletes or others involved in organized sports activities. Moreover, many patients will find that hypoglycemic events can be minimized by reductions in preexercise insulin dose and/or supplemental snacks before or during exercise. However, for the patient engaging in individual exercise later in the day who is troubled by frequent hypoglycemia despite such measures, early-morning exercise would be a logical alternative, based on our data. In summary, this study suggests that the risk of hypoglycemia is lowest with prebreakfast exercise in patients with IDDM receiving ultralente-based intensive insulin therapy, perhaps because of lower plasma free-insulin concentrations at that time of day. Exercise did not have a late hypoglycemic effect, regardless of whether it was performed in the morning or late afternoon. It is likely that these observations would prevail equally in patients receiving CSII because these individuals would have higher plasma free-insulin concentrations in the late afternoon compared with early morning. Whether our

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findings are relevant to patients following intermediate insulin programs will require further investigation.

ACKNOWLEDGMENTS

This work was supported in part by grants for the U.S. Public Health Service (DK-38092,DK-29953, DK-26989, DK-27085, DK-20579, and RR-00036) and the Mayo Foundation. We thank D. Nash, J. Aikens, J. King, V. Heiling, and S. Shah for technical assistance and K. Young and J. Ashenmacher for editorial assistance. Parts of this study were presented in abstract form at the 47th annual meeting of the American Diabetes Association, Indianapolis, Indiana, June 1987.

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