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Am J Physiol Endocrinol Metab 290: E1331-E1338, 2006. First published January 31, 2006; doi:10.1152/ajpendo.00283.2005
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Acute, same-day effects of antecedent exercise on counterregulatory responses to subsequent hypoglycemia in type 1 diabetes mellitus

Darleen A. Sandoval,1 Deanna L. Aftab Guy,2 M. Antoinette Richardson,1 Andrew C. Ertl,1 and Stephen N. Davis1,3

Departments of 1Medicine and 2Pediatrics, Vanderbilt University School of Medicine; and 3Nashville Veterans Affairs Medical Center, Nashville, Tennessee

Submitted 23 June 2005 ; accepted in final form 24 January 2006


   ABSTRACT
TOP
 ABSTRACT
RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Exercise-induced hypoglycemia can occur within hours after exercise in type 1 diabetes mellitus (T1DM) patients. This study tested the hypothesis that an acute exercise bout causes (within hours) blunted autonomic and metabolic responses to subsequent hypoglycemia in patients with T1DM. Twelve T1DM patients (3 W/9 M) were studied during a single-step, 2-h hyperinsulinemic (572 ± 4 pmol/l) hypoglycemic (2.8 ± 0.1 mmol/l) clamp 2 h after either a hyperinsulinemic euglycemic (AM EUG) or hypoglycemic clamp (AM HYPO) or after sitting in a chair with basal insulin infusion (AM CON) or 90 min of moderate-intensity exercise (50% VO2 max, AM EX). Both AM HYPO and AM EX significantly blunted epinephrine responses and muscle sympathetic nerve activity responses to subsequent hypoglycemia compared with both control groups. Endogenous glucose production was significantly lower and the exogenous glucose infusion rate needed to maintain the hypoglycemic level was significantly greater during subsequent hypoglycemia in AM EX vs. CON. Rate of glucose disposal (Rd) was significantly reduced following AM HYPO. In summary, within 2.5 h, both moderate-intensity AM EX and AM HYPO blunted key autonomic counterregulatory responses. Despite this, glucose Rd was reduced during afternoon hypoglycemia following morning hypoglycemia, indicating posthypoglycemic insulin resistance. After morning exercise, endogenous glucose production was blunted, but glucose Rd was maintained during afternoon hypoglycemia, thereby indicating reduced metabolic defenses against hypoglycemia. These data suggest that exercise-induced counterregulatory failure can occur very rapidly, increasing the risk for hypoglycemia in T1DM within hours.

sympathetic nervous system; hormones

ANTECEDENT EPISODES OF HYPOGLYCEMIA occurring 24 h before exercise have been found to blunt autonomic counterregulatory responses to subsequent prolonged moderate-intensity exercise (90 min at 50% VO2 max) by ~50% in both nondiabetic (8) and type 1 diabetes mellitus (T1DM) (19) individuals. In fact, it seems that this relationship is reciprocal; that is, recent antecedent episodes of prolonged moderate-intensity exercise have also been found to blunt autonomic counterregulatory responses during subsequent hypoglycemia occurring 24 h later in healthy (17, 30) and T1DM subjects (33). However, clinically, exercise-induced hypoglycemia has been reported to occur within 2 h after exercise.

Although acute exercise-induced hypoglycemia in T1DM may at least partially stem from iatrogenic causes (i.e., in balance of subcutaneous insulin and metabolic needs), we (13) have demonstrated that morning hypoglycemia could acutely reduce neuroendocrine and symptom responses to subsequent, same-day, afternoon hypoglycemia in nondiabetic individuals. Despite the blunted neuroendocrine responses, the morning hypoglycemia caused an insulin-resistant state in the afternoon that resulted in significantly reduced rates of glucose oxidation and glucose flux. The increased insulin resistance in the afternoon appeared to offset and partially compensate for the blunted neuroendocrine response by limiting increases in glucose utilization during afternoon hypoglycemia. However, it remains unknown whether in T1DM blunted counterregulation could also be a mechanism responsible for causing acute (within hours) exercise-induced hypoglycemia. Furthermore, the effects of morning exercise on metabolic counterregulatory responses occurring during same-day hypoglycemia in T1DM are unknown. Antecedent exercise may be additionally problematic, as exercise is known to acutely increase insulin sensitivity. Thus the scenario could arise in T1DM that hypoglycemia occurring after exercise could be characterized not only by blunted neuroendocrine responses but also by the ablation of the protective effect of posthypoglycemic insulin resistance. This would result in increased glucose utilization during the subsequent hypoglycemia and consequently cause lower glycemic levels. Thus the aim of this study was to determine the acute effects of morning exercise or moderate hypoglycemia (2.9 mmol/l) on autonomic, neuroendocrine, and metabolic responses during same-day, subsequent afternoon hypoglycemia in T1DM patients.


   RESEARCH DESIGN AND METHODS
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Subjects

We studied 12 patients with T1DM (9 male/3 female; age 30 ± 2 yr; body mass index 25 ± 1 kg/m2; HB A1c 8 ± 0%, normal range 4.0–6.5%) and duration of diabetes (18 ± 3 yr). None of the patients reported a history of hypoglycemic unawareness, and all received insulin as their only medication. No patient had any clinical evidence of autonomic neuropathy or any other tissue specific complication of diabetes. All patients had normal blood count, plasma electrolytes, and liver and renal function. Studies were approved by the Vanderbilt University Human Subjects Institutional Review Board, and all subjects gave informed written and verbal consent.

Preliminary Exercise Testing

At least 2 wk before the initial study, subjects performed an incremental exercise test on a stationary cycle ergometer to determine maximum oxygen consumption (VO2 max). Expired gases were collected and analyzed using computerized open-circuit indirect calorimetry (ParvoMedics, Sandy, UT). VO2 max was determined when at least two of the following three criteria were met: 1) the subject was too tired to continue, 2) the respiratory exchange ratio was greater than 1.0, or 3) the oxygen consumption plateaued with an increase in workloads. Subjects studied ranged from sedentary to recreationally active (average VO2 max 31 ± 3 ml·kg–1·min–1, range 18–48 ml·kg–1·min–1).

Experimental Design

Subjects underwent randomized, single-blind studies consisting of one episode of hyperinsulinemic (9 pmol·kg–1·min–1) hypoglycemia (2.8 ± 0.1 mmol/l) 2 h after either a hyperinsulinemic euglycemic clamp (AM EUG) or a hyperinsulinemic hypoglycemia clamp (AM HYPO) or sitting in a chair with basal insulin infusion (1 U/h; AM CON) or after 90 min of moderate-intensity exercise (50% VO2 max, AM EX). All study patients were asked to avoid any exercise and consume their usual weight-maintaining diet for 3 days before each study. All patients performed intensive home blood glucose monitoring (before each meal, at bedtime, and on two occasions at 3:00 AM) for 2 wk before a study. An experiment was not conducted if blood glucose readings fell below 3.9 mmol/l. On the day preceding an experiment, intermediate or long-acting insulin was discontinued and replaced by injections of regular insulin before breakfast and lunch. Each subject was admitted to the Vanderbilt General Clinical Research Center (GCRC) at 5:00 PM on the evening before an experiment. At that time, two intravenous cannulae were inserted under 1% Lidocaine as a local anesthesia. One cannula was placed in a retrograde fashion into a vein on the back of the hand. This hand was placed in a heated box (55–60°C) so that arterialized blood could be obtained (1); the other cannula was placed in the contralateral arm for infusions. Patients then received an evening meal, and a continuous low-dose infusion of insulin was started to normalize plasma glucose. The insulin infusion was adjusted overnight to maintain blood glucose between 4.4 and 7.2 mmol/l.

After an overnight 10-h fast, at ~10:00 AM and after a 30 min basal period, subjects were randomized to be studied under one of the four protocols (AM EUG, AM HYPO, AM CON, or AM EX). The AM EUG and AM HYPO clamp experiments involved a standardized hyperinsulinemic euglycemic or hypoglycemic glucose clamp. An insulin infusion solution was prepared with normal saline containing 3% (vol/vol) of the subject's own plasma. At time 120 min, a primed constant (9.0 pmol·kg–1·min–1) infusion of insulin (Eli Lilly, Indianapolis, IN) was started via a precalibrated infusion pump (Harvard Apparatus, South Natick, MA) and continued until 240 min. The rate of fall of glucose was controlled (0.06 mmol/min), and for AM HYPO the glucose nadir (2.9 mmol/l) was achieved using a modification of the glucose clamp technique (14). During the clamp periods, plasma glucose was measured every 5 min, and a 20% dextrose infusion was adjusted so that plasma glucose levels were held constant (5.1 ± 0.1 mmol/l for EUG and 2.8 ± 0.1 mmol/l for HYPO). Potassium chloride (20 mmol/l) was infused during the clamp to reduce insulin-induced hypokalemia.

For the AM CON studies subjects sat in a chair, and for the AM EX studies subjects exercised on an upright cycle ergometer (Medical Graphics, Yorba Linda, CA) and pedaled at 60–70 rpm for 90 min. During exercise and while resting in the chair (control subjects), insulin was infused at 1 U/h, and potassium chloride was infused at a rate of 5 mmol/h. Plasma glucose was measured every 5 min during both exercise and control periods and was maintained at 5.1 ± 0.1 mmol/l with a 20% dextrose infusion.

After the morning procedures, at 240 min (Fig. 1), a primed (18-µCi) infusion (0.18 µCi/min) of HPLC-purified [3-3H]glucose (PerkinElmer Life Sciences, Boston, MA; 11.5 mCi·mmol–1·l–1) was administered via a precalibrated infusion pump (Harvard Apparatus). Also at that time, the microneurography procedure (described below) was started. At 360 min, a hyperinsulinemic hypoglycemic clamp (using identical clamping procedures described above) was performed on all subjects.


Figure 1
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  		Fig. 1. Diagrammatic timeline of experimental protocols. The 4 groups were AM EUG, hyperinsulinemic euglycemia; AM HYPO, hypoglycemia; AM CON, control; AM EX, moderate-intensity exercise in the morning.

 
Direct Measurement of Muscle Sympathetic Nerve Activity

Muscle sympathetic nerve activity (MSNA) was recorded in the present study, as this has been demonstrated to reflect increased sympathetic activity during insulin-induced hypoglycemia (9, 10, 12, 17, 18). MSNA was measured from the peroneal nerve at the level of the fibular head or popliteal fossa, and the data were processed as described previously (32).

Tracer Calculations

Rates of glucose appearance (Ra), endogenous glucose production (EGP), and glucose utilization were calculated according to the methods of Wall et al. (35). EGP was calculated by determining the total Ra (this comprises both EGP and any exogenous glucose infused to maintain the desired hypoglycemia) and subtracting it from the amount of exogenous glucose infused. It is now recognized that this approach is not fully quantitative, because underestimates of total Ra and rate of glucose disposal (Rd) can be obtained. The use of a highly purified tracer and taking measurements under steady-state conditions (i.e., constant specific activity) in the presence of low glucose flux eliminates most, if not all, of the problems. In addition, to maintain a constant specific activity, isotope delivery was increased commensurate with increases in exogenous glucose infusion. During this study, only glucose flux results from the steady-state basal and the final 30-min periods of the hypoglycemic clamps are reported.

Analytical Methods

Plasma glucose concentrations were measured in triplicate using the glucose oxidase method with a glucose analyzer (Beckman, Fullerton, CA). Blood for hormones and intermediary metabolites was drawn twice during the control period and every 15 min during the experimental period. Catecholamines were determined by HPLC (4) with an interassay coefficient of variation (CV) of 12% for both epinephrine and norepinephrine. We made two modifications to the procedure for catecholamine determination: 1) we used a five-point rather than a one-point standard calibration curve; and 2) we spiked the initial and final samples of plasma with known amounts of epinephrine and norepinephrine so that accurate identification of the relevant catecholamine peaks could be made. Insulin (36) (CV = 11%), cortisol (Clinical Assays Gamma Coat Radioimmunoassay Kit; interassay CV = 6%), growth hormone (25) (interassay CV = 8%), pancreatic polypeptide (23) (interassay CV = 8%), and glucagon (Linco Research, St. Louis, MO; interassay CV = 15%) were all measured using radioimmunoassay techniques. Lactate, glycerol, alanine, and beta-hydroxybutyrate were measured on deproteinized whole blood, using the method of Lloyd et al. (29). Nonesterified fatty acids (NEFA) were measured using the WAKO kit adopted for use on a centrifugal analyzer (24).

Cardiovascular parameters (heart rate and systolic, diastolic, and mean arterial pressure) were assessed every 10 min and measured manually during exercise and control periods and noninvasively by a Dinamap during all hyperinsulinemic clamp periods (Critikon, Tampa, FL). Symptoms of hypoglycemia were assessed every 15 min during the hypoglycemic clamps by use of a previously validated semiquantitative questionnaire (6). Each subject was asked to rate symptoms of tiredness, confusion, hunger, dizziness, difficulty thinking, blurred vision, sweatiness, tremor, agitation, heat/thirst, and palpitations. The score for the first six symptoms was summed for neuroglycopenic and for the last five symptoms for autonomic symptom scores.

Expired gases were collected and analyzed during the basal period and the final 15 min of each experimental period (morning and afternoon) using computerized open-circuit indirect calorimetry (TrueOne 2400; ParvoMedics, Sandy, UT). Whole body fat and carbohydrate oxidation was calculated using the equations of Frayn (16) after correction for protein oxidation. Nonoxidated glucose disposal was calculated by subtracting oxidative glucose disposal from glucose Rd.

Statistical Analysis

Data are expressed as means ± SE and were analyzed using standard parametric, two-way analysis of variance (ANOVA) and with repeated measures where appropriate. A Tukey's post hoc analysis was used to delineate statistical significance. P < 0.05 was accepted as statistical significance.


   RESULTS
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
AM Results

Subjects performed a relative exercise intensity of 54 ± 1% VO2 max for the AM EX group. Exercise caused heart rate to increase from 76 ± 2 to 130 ± 7 beats/min and systolic blood pressure to increase from 108 ± 3 to 134 ± 6 mmHg, whereas diastolic blood pressure did not change. During morning hypoglycemia, heart rate increased by 12 ± 6 beats/min and systolic blood pressure increased by 6 ± 3 mmHg, whereas diastolic blood pressure did not change. There were no significant cardiovascular changes during morning procedures in the AM EUG or AM CON groups.

Morning glucose levels were similar to baseline during the final 30 min of the exercise (5.2 ± 0.1 mmol/l), control (5.2 ± 0.2 mmol/l), and euglycemic clamp (5.1 ± 0.1 mmol/l) periods and reached a nadir of 2.8 ± 0.1 mmol/l during morning hypoglycemia (Fig. 2). Similarly, morning insulin levels were similar to baseline (64 ± 10 pmol/l) during the final 30 min of the AM EX (75 ± 6 pmol/l) and CON (70 ± 11 pmol/l; Fig. 2). Insulin levels reached 573 ± 49 pmol/l during AM EUG and 574 ± 31 pmol/l during AM HYPO (Fig. 2).


Figure 2
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  		Fig. 2. Glucose and insulin levels during morning and afternoon studies in type 1 diabetic (T1DM) AM EUG, AM HYPO, AM CON, and AM EX subjects. Values are means ± SE. Levels were similar during morning and afternoon studies, respectively, among all 4 groups.

 
Epinephrine responses were lower (928 ± 144 vs. 1,538 ± 146 pmol/l, P < 0.05) and norepinephrine responses were higher (4.7 ± 0.6 vs. 1.5 ± 0.2 pmol/l, P < 0.05) during the final 30 min of the morning exercise bout compared with the morning hypoglycemic clamp. Plasma cortisol increased by similar amounts by the final 30 min of exercise and hypoglycemia (649 ± 88 and 742 ± 206 nmol/l, respectively). Lactate increase with morning exercise was significantly greater than with morning hypoglycemia (1.6 ± 0.2 vs. 1.2 ± 0.1 mmol/l, P < 0.05). beta-Hydroxybutyrate did not increase significantly during morning procedures in any group. None of the counterregulatory hormones or metabolites increased over baseline in either the AM EUG or AM CON groups during the morning experimental periods.

PM Results

Glucose and insulin levels. During the afternoon hypoglycemic clamp, steady-state plasma glucose (2.8 ± 0.1, 2.8 ± 0.1, 2.7 ± 0.1, and 2.8 ± 0.1 mmol/l) and insulin levels (571 ± 43, 579 ± 43, 557 ± 84, and 597 ± 57 pmol/l) were similar between the AM EUG, AM HYPO, AM CON, and AM EX groups, respectively (Fig. 2).

Counterregulatory hormone levels. Epinephrine response to hypoglycemia was significantly lower in AM HYPO and AM EX vs. AM EUG and AM CON (1,719 ± 247 and 1,528 ± 424 vs. 2,278 + 191 and 1,959 ± 533 pmol/l, P < 0.05, respectively; Fig. 3). Norepinephrine (Fig. 3), pancreatic polypeptide, growth hormone, cortisol, and glucagon responses to hypoglycemia were similar between the four groups (Table 1).


Figure 3
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  		Fig. 3. Epinephrine and norepinephrine responses to hyperinsulinemic (9 pmol·kg–1·min–1) hypoglycemia in T1DM subjects who underwent a hyperinsulinemic euglycemia (AM EUG), hypoglycemia (AM HYPO), control (AM CON), or moderate-intensity exercise (AM EX) in the morning. Values are means ± SE. *P < 0.05; AM EX and AM HYPO are significantly reduced vs. AM CON and AM EUG groups.

 

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  		Table 1. Neuroendocrine responses to afternoon hyperinsulinemic hypoglycemia after morning hyperinsulinemic euglycemia (AM EUG), hypoglycemia (AM HYPO), control (AM CON), or exercise of 50% VO2 max (AM EX)

 
Glucose Kinetics

Glucose specific activity (dpm/mmol) did not change significantly during either the control period or the final 30 min of the hypoglycemic clamp (CV = 4 and 5% for basal and final 30 min of hypoglycemia; Table 2). Endogenous glucose production was significantly lower during the final 30 min of hyperinsulinemic hypoglycemia in AM EX compared with AM CON and AM EUG (1.5 ± 0.5 vs. 4.2 ± 1.5 and 3.4 ± 0.7 µmol·kg–1·min–1, P < 0.05; Fig. 4). As a consequence, the exogenous glucose infusion rate needed to maintain the hypoglycemic level of 2.8 mmol/l was significantly greater in AM EX compared with AM CON (20 ± 3 vs. 12 ± 2 µmol·kg–1·min–1, P < 0.05; Fig. 4). Glucose Rd was significantly lower in AM HYPO than in AM EUG, AM CON, and AM EX (12 ± 2 vs. 23 ± 4, 17 ± 2, and 22 ± 2 µmol·kg–1·min–1, respectively, P < 0.05; Fig. 4). Indirect calorimetry data indicated that both the basal and final 30-min (P < 0.05; Table 3) fat oxidation rates were significantly greater in AM EX and AM HYPO compared with AM EUG. Final 30-min nonoxidative glucose disposal rates were also significantly greater in AM EX compared with all other groups (1.6 ± 0.5 vs. 0.7 ± 0.4, 0.3 ± 0.2, and 0.7 ± 0.3 mg·kg–1·min–1 for AM EX vs. AM EUG, AM HYPO, and AM CON, respectively, P < 0.05).


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  		Table 2. Glucose specific activity for basal and final 30-min periods during afternoon hyperinsulinemic hypoglycemia in the 4 experimental groups

 

Figure 4
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  		Fig. 4. Endogenous glucose production, glucose utilization (rate of disappearance), and glucose infusion rate during afternoon 2-h hyperinsulinemic (9 pmol·kg–1·min–1) hypoglycemic T1DM subjects who underwent a hyperinsulinemic euglycemia (AM EUG), hypoglycemia (AM HYPO), control (AM CON), or moderate-intensity exercise (AM EX) in the morning. Values are means ± SE. *P < 0.05, AM EX vs. AM CON and AM EUG groups; {dagger}P < 0.05, AM HYPO vs. AM EUG and AM EX groups; {ddagger}P < 0.05, AM CON and AM HYPO.

 

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  		Table 3. Indirect calorimetry and metabolite responses to afternoon hyperinsulinemic hypoglycemia in the 4 experimental groups

 
Intermediary Metabolism

Basal NEFA (527 ± 66 and 512 ± 113 vs. 200 ± 44 and 202 ± 81 µmol/l, P < 0.05) and glycerol (111 ± 23 and 86 ± 14 vs. 57 ± 11 and 67 ± 14 µmol/l, P < 0.05) levels were significantly greater after AM HYPO and EX compared with both AM EUG and AM CON (Fig. 5). However, by the end of afternoon hypoglycemia, values for both NEFA and glycerol were similar between groups. Lactate levels significantly increased with hyperinsulinemic hypoglycemia similarly among the three groups (Table 4). Basal beta-hydroxybutyrate levels were also greater after AM HYPO and EX compared with AM EUG and CON groups (0.23 ± 0.05 and 0.36 ± 0.08 vs. 0.05 ± 0.01 and 0.10 ± 0.04 mmol/l, P < 0.05; Table 4). However, by the end of the hyperinsulinemic hypoglycemic clamp, beta-hydroxybutyrate levels were similar among the groups. Basal and final 30-min alanine levels during the afternoon hypoglycemic clamp were similar among the groups (Table 4).


Figure 5
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  		Fig. 5. Free fatty acid and glycerol levels during the afternoon hyperinsulinemic (9 pmol·kg–1·min–1) hypoglycemic clamp in T1DM subjects who underwent a hyperinsulinemic euglycemia (AM EUG), hypoglycemia (AM HYPO), control (AM CON), or moderate-intensity exercise (AM EX) in the morning. Values are means ± SE. *P < 0.05, AM HYPO vs. AM EUG and AM EX vs. AM CON.

 

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  		Table 4. Cardiovascular and symptom responses to afternoon hyperinsulinemic hypoglycemia in the 4 experimental groups

 
Cardiovascular and Symptomatic Responses

Heart rate significantly increased with hyperinsulinemic hypoglycemia in all groups (Table 4). However, systolic blood pressure, mean arterial pressure, and diastolic blood pressure did not change with hyperinsulinemic hypoglycemia in any group (Table 4). Total hypoglycemic, autonomic, and neuroglycopenic symptom scores were similar among the groups (Table 4).

MSNA

MSNA significantly increased with hypoglycemia in AM EUG and AM CON (P < 0.05) but failed to increase during hypoglycemia in both AM EX and AM HYPO (Fig. 6).


Figure 6
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  		Fig. 6. Muscle sympathetic nerve activity (MSNA) during the basal and final 30 min of the hyperinsulinemic (9 pmol·kg–1·min–1) hypoglycemic clamp in T1DM subjects who underwent a hyperinsulinemic euglycemia (AM EUG), hypoglycemia (AM HYPO), control (AM CON), or moderate-intensity exercise (AM EX) in the morning. Values are means ± SE. *P < 0.05, basal vs. final 30 min.

 

   DISCUSSION
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
We have previously reported in nondiabetic individuals that posthypoglycemic insulin resistance could provide a protective mechanism against repeated hypoglycemia by compensating for the blunted neuroendocrine/autonomic nervous system responses (13). The current study extends those findings by demonstrating in T1DM that both morning exercise and hypoglycemia can blunt the key counterregulatory mechanism of epinephrine but not symptom responses during afternoon hypoglycemia. The differential metabolic effects (lack of a restraining effect on glucose Rd and blunted EGP after exercise compared with the hypoglycemia induced decreased Rd) suggests that, acutely, exercise may have even greater potential to reduce some metabolic counterregulatory responses during subsequent hypoglycemia in T1DM compared with a bout of prior hypoglycemia.

Epinephrine and the increase in MSNA (but not norepinephrine, symptom scores, or pancreatic polypeptide) were blunted in response to subsequent hypoglycemia by both prior exercise and hypoglycemia. Previously (33), we demonstrated that both basal and MSNA responses together with pancreatic polypeptide responses to hypoglycemia were reduced following two antecedent 90-min bouts of previous-day exercise at both 30 and 50% VO2 max. These data suggest that the lower volume of exercise in this present study (i.e., only one exercise bout) had less of an impact on blunting subsequent responses to hypoglycemia. This current finding is consistent with previous work demonstrating that a lower "dose" of hypoglycemia (i.e., shorter duration) resulted in blunting of some (i.e., neuroendocrine responses) but not all (i.e., preservation of symptoms) counterregulatory responses to subsequent hypoglycemia (9). Regulation of symptomatic responses to hypoglycemia is complex, and it is not uncommon to see a dissociation between sympathetic drive and autonomic symptoms (9, 11, 17, 32). In addition, it is also possible that we did not have enough statistical power to detect a difference in symptom scores after the morning stress. Nevertheless, preservation of symptoms has clinical relevance, as symptom awareness of hypoglycemia is an important defense against falling glycemia. Of concern is that the reduced sympathetic nervous drive (epinephrine and MSNA) occurring after morning exercise or hypoglycemia combined with absent glucagon responses (20) and the inability of T1DM to regulate insulin levels during hypoglycemia remove three primary, critical defenses against the stress in these patients.

Plasma norepinephrine responses were numerically smaller following morning exercise, but this did not reach statistical significance, although it should be noted that norepinephrine levels are influenced by large changes in clearance at several differing tissues (i.e., liver, gut, and synaptic cleft). This makes changes in plasma norepinephrine a relatively small experimental signal to measure during hypoglycemia. Thus it is possible that a larger sample size may have demonstrated significantly reduced norepinephrine responses following morning exercise.

The blunted epinephrine responses following morning exercise appeared to have a significant effect on altering glucose kinetics during afternoon hypoglycemia. In longer-duration T1DM individuals (and thus greater insulin deficiency), epinephrine is the primary mechanism to acutely increase EGP during hypoglycemia. Additionally, epinephrine also plays a major role by limiting peripheral glucose uptake by directly inhibiting hexokinase activity and glucose phosphorylation and indirectly increasing free fatty acid levels (2, 26). Thus the blunted epinephrine responses during afternoon hypoglycemia following morning exercise would be expected to be a major factor for the reduced EGP. Interestingly, despite similarly blunted epinephrine responses in AM HYPO, EGP was not reduced compared with AM EUG. This may be explained by a relative induction of hepatic insulin resistance following the morning episode of hypoglycemia.

The enhanced lipolysis (as indicated by NEFA and glycerol levels) and fat oxidation rates (as indicated by the indirect calorimetry and beta-hydroxybutyrate data) occurring following morning exercise and hypoglycemia also appeared to influence glucose kinetics during afternoon hypoglycemia. Elevations of NEFA have been shown to reduce glucose utilization during hypoglycemia in nondiabetic volunteers (15). In fact, glucose Rd was reduced following AM HYPO compared with all other groups but was similar to control groups during afternoon hypoglycemia following AM EX. Of note, there were significantly greater reductions in both NEFA and glycerol during afternoon hypoglycemia following AM HYPO or AM EX, indicating a greater utilization over production of these substrates. Thus the enhanced fat metabolism appeared to cause a degree of insulin resistance after AM HYPO, whereas, after AM EX, glucose Rd was similar to control studies due to the actions of exercise to enhance glucose Rd (27), thereby offsetting the effects of fat to reduce insulin sensitivity.

Ninety minutes of prolonged moderate exercise were used in the present study. This model of exercise is representative of a variety of physical activities typically undertaken by individuals with T1DM (e.g., soccer, tennis, cycling). Whether differing durations or greater intensities of antecedent exercise may influence subsequent counterregulatory responses to hypoglycemia in T1DM needs to be determined. Changes in these parameters (i.e., differences in duration and work intensities) appear to influence responses to subsequent hypoglycemia in nondiabetic individuals, as other studies examining same day-effects of prior exercise on subsequent counterregulatory responses to hypoglycemia have shown divergent results. For example, prolonged exercise in dogs reduced counterregulatory responses to immediate subsequent glucoprivation (28) but not in response to subsequent hyperinsulinemic hypoglycemia (27). In nondiabetic humans, one bout of prolonged exercise (60 min at 60% VO2 max) had no effect on counterregulatory responses to subsequent (90 min postexercise) hypoglycemia (31). In addition, the results of both the present study and our previous 2-day study where exercise occurred almost 24 h earlier (33) showed that antecedent exercise blunted epinephrine, MSNA, and EGP responses to subsequent hypoglycemia. In contrast, in the current study, fat metabolism and nonoxidative glucose disposal were all increased after prior exercise, whereas in the 2-day study fat metabolism was reduced and glucose Rd and oxidative glucose disposal were significantly greater during day 2 hypoglycemia compared with the control group. Thus our current and previous data, together with the contrasting data summarized here (27, 31) suggest that duration, volume, intensity, and time elapsed after prior exercise may all influence metabolic counterregulatory responses to subsequent hypoglycemia.

In summary, the combined effects of exercise on the sympathetic nervous system and metabolic responses to subsequent hypoglycemia suggest that, acutely, exercise is a potent risk factor for hypoglycemia in T1DM. It would seem that, after prolonged moderate exercise in T1DM patients, a time course of autonomic nervous system and metabolic changes are activated that contribute to exercise-induced hypoglycemia. These physiological counterregulatory deficits are apparent within hours after morning exercise or hypoglycemia and persist for at least 24 h. These data underscore the importance of strict glucose monitoring and adjustments of insulin replacement doses after exercise in T1DM patients in order for them to enjoy the benefits of exercise without an increased risk of subsequent hypoglycemia.


   GRANTS
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by a research grant from the Juvenile Diabetes Foundation International, a Diabetes Research and Training Grant (5P60 AM-20593), a Clinical Research Center Grant (MO1 RR-00095), and a National Heart, Lung, and Blood Institute Grant (5PO1 HL-056693-07).


   ACKNOWLEDGMENTS
 
We thank Donna Tate, Damon Maes, Ginger Barnett, Eric Allen, Angelina Penaloza, Pam Venson, and Wanda Snead for expert technical assistance. We are also grateful for the superb care and help provided by the nursing staff of the Vanderbilt General Clinical Research Center.


   FOOTNOTES
 

Address for reprint requests and other correspondence: D. Sandoval, Univ. of Cincinnati, 2170 E. Galbraith Rd., Bldg. E, Rm. 317, Cincinnati, OH 45237 (e-mail: darleen.sandoval{at}uc.edu)

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.


   REFERENCES
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Abumrad NN, Rabin D, Diamond MC, and Lacy WW. Use of a heated superficial hand vein as an alternative site for measurement of amino acid concentration and for the study of glucose and alanine kinetics in man. Metabolism 30: 936–940, 1981.[CrossRef][Web of Science][Medline]
  2. Aslesen R and Jensen J. Effects of epinephrine on glucose metabolism in contracting rat skeletal muscles. Am J Physiol Endocrinol Metab 275: E448–E456, 1998.[Abstract/Free Full Text]
  3. Borg MA, Tamborlane WV, Shulman GI, and Sherwin RS. Local lactate perfusion of the ventromedial hypothalamus suppresses hypoglycemic counterregulation. Diabetes 52: 663–666, 2003.[Abstract/Free Full Text]
  4. Causon R, Caruthers M, and Rodnight R. Assay of plasma catecholamines by liquid chromatography with electrical detection. Anal Biochem 116: 223–226, 1981.[CrossRef][Web of Science][Medline]
  5. Choi IY, Seaquist ER, and Gruetter R. Effect of hypoglycemia on brain glycogen metabolism in vivo. J Neurosci Res 72: 25–32, 2003.[CrossRef][Web of Science][Medline]
  6. Cox D, Cryer PE, Gonder-Frederick L, Clarke WL, and Antain B. Perceived symptoms in the recognition of hypoglycemia. Diabetes Care 16: 519–527, 1993.[Abstract]
  7. Dalsgaard MK, Ogoh S, Dawson EA, Yoshiga CC, Quistorff B, and Secher NH. Cerebral carbohydrate cost of physical exertion in humans. Am J Physiol Regul Integr Comp Physiol 287: R534–R540, 2004.[Abstract/Free Full Text]
  8. Davis SN, Galassetti P, Wasserman DH, and Tate D. Effects of antecedent hypoglycemia on subsequent counterregulatory responses to exercise. Diabetes 49: 73–81, 2000.[Abstract]
  9. Davis SN, Mann S, Galassetti P, Neill RA, Tate D, Ertl AC, and Costa F. Effects of differing durations of antecedent hypoglycemia on counterregulatory responses to subsequent hypoglycemia in normal humans. Diabetes 49: 1897–1903, 2000.[Abstract]
  10. Davis SN, Shavers C, and Costa F. Differential gender responses to hypoglycemia are due to alterations in CNS drive and not glycemic thresholds. Am J Physiol Endocrinol Metab 279: E1054–E1063, 2000.[Abstract/Free Full Text]
  11. Davis SN, Shavers C, Costa F, and Mosqueda-Garcia R. Role of cortisol in the pathogenesis of deficient counterregulation after antecedent hypoglycemia in normal man. J Clin Invest 98: 680–691, 1996.[Web of Science][Medline]
  12. Davis SN, Shavers C, Mosqueda-Garcia R, and Costa F. Effects of differing antecedent hypoglycemia on subsequent counterregulation in normal humans. Diabetes 46: 1328–1335, 1997.[Abstract]
  13. Davis SN and Tate D. Effects of morning hypoglycemia on neuroendocrine and metabolic responses to subsequent afternoon hypoglycemia in normal man. J Clin Endocrinol Metab 86: 2043–2050, 2001.[Abstract/Free Full Text]
  14. DeFronzo RA, Tobin K, and Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol Endocrinol Metab Gastrointest Physiol 237: E216–E223, 1979.
  15. Fanelli C, Calderone S, Epifano L, DeVincenzo A, Modarelli F, Pampanelli S, Perriello G, DeFeo P, Brunetti P, and Gerich JE. Demonstration of a critical role for free fatty acids in mediating counterregulatory stimulation of gluconeogenesis and suppresion of glucose utilization in humans. J Clin Invest 92: 1617–1622, 1993.[Web of Science][Medline]
  16. Frayn KN. Calculation of substrate oxidation rates in vivo from gaseous exchange. J Appl Physiol 55: 628–634, 1983.[Abstract/Free Full Text]
  17. Galassetti P, Mann S, Tate D, Neill RA, Costa F, Wasserman DH, and Davis SN. Effect of antecedent prolonged exercise on subsequent counterregulatory responses to hypoglycemia. Am J Physiol Endocrinol Metab 280: E908–E917, 2001.[Abstract/Free Full Text]
  18. Galassetti P, Neill RA, Tate D, Ertl AC, Wasserman DH, and Davis SN. Sexual dimorphism in counterregulatory responses to hypoglycemia after antecedent exercise. J Clin Endocrinol Metab 86: 3516–3524, 2001.[Abstract/Free Full Text]
  19. Galassetti P, Tate DB, Neill RA, Richardson A, Leu SY, and Davis SN. Effect of differing antecedent hypoglycemia on counterregulatory responses to exercise in type 1 diabetes. Am J Physiol Endocrinol Metab 290, E1109–E1117, 2006.[Abstract/Free Full Text]
  20. Gerich JE, Langlois M, Noacco C, Karam J, and Forsham PH. Lack of a glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alpha-cell defect. Science 182: 171–173, 1973.[Abstract/Free Full Text]
  21. Gonzalez-Alonso J, Dalsgaard MK, Osada T, Volianitis S, Dawson EA, Yoshiga CC, and Secher NH. Brain and central haemodynamics and oxygenation during maximal exercise in humans. J Physiol 557: 331–342, 2004.[Abstract/Free Full Text]
  22. Gruetter R. Glycogen: the forgotten cerebral energy store. J Neurosci Res 74: 179–183, 2003.[CrossRef][Web of Science][Medline]
  23. Hagopian W, Lever E, Cen D, Emmounoud D, Polonsky K, Pugh W, Moosa A, and Jaspan JB. Predominance of renal and absence of hepatic metabolism of pancreatic polypeptide in the dog. Am J Physiol Endocrinol Metab 245: E171–E177, 1983.[Abstract/Free Full Text]
  24. Ho RJ. Radiochemical assay of long chain fatty acid using 63NI as tracer. Anal Biochem 26: 105–113, 1970.
  25. Hunter W and Greenwood F. Preparation of [131I]-labeled human growth hormone of high specific activity. Nature 194: 495–496, 1962.[CrossRef][Medline]
  26. Jensen J, Aslesen R, Ivy JL, and Brors O. Role of glycogen concentration and epinephrine on glucose uptake in rat epitrochlearis muscle. Am J Physiol Endocrinol Metab 272: E649–E655, 1997.[Abstract/Free Full Text]
  27. Koyama Y, Galassetti P, Coker RH, Pencek RR, Lacy DB, Davis SN, and Wasserman DH. Prior exercise and the response to insulin-induced hypoglycemia in the dog. Am J Physiol Endocrinol Metab 282: E1128–E1138, 2002.[Abstract/Free Full Text]
  28. Kozlowski S, Brzezinska K, and Nazar K. Diminished adrenergic response to 2-deoxy-D-glucose after prolonged exhausting physical exercise in dogs. Acta Physiol Polonica 30: 331–335, 1979.[Medline]
  29. Lloyd B, Burrin J, Smythe P, and Alberti KGMM. Enzymatic fluorometric continuous-flow assays for blood glucose lactate, pyruvate, alanine, glycerol, and 3-hydroxybutyrate. Clin Chem 24: 1724–1729, 1978.[Abstract/Free Full Text]
  30. McGregor VP, Banarer S, and Cryer PE. Elevated endogenous cortisol reduces autonomic neuroendocrine and symptom responses to subsequent hypoglycemia. Am J Physiol Endocrinol Metab 282: E770–E777, 2002.[Abstract/Free Full Text]
  31. Rattarasarn C, Dagogo-Jack S, Zachwieja J, and Cryer PE. Hypoglycemia-induced autonomic failure in IDDM is specific for stimulus of hypoglycemia and is not attributable to prior autonomic activation. Diabetes 43: 809–818, 1994.[Abstract]
  32. Sandoval D, Ertl A, Richardson M, Tate D, and Davis S. Estrogen blunts neuroendocrine and metabolic responses to hypoglycemia. Diabetes 52: 1749–1755, 2003.[Abstract/Free Full Text]
  33. Sandoval D, Guy D, Richardson A, Ertl AC, and Davis SN. Effects of low and moderate antecedant exercise on counterregulatory responses to subsequent hypoglycemia in type 1 diabetes. Diabetes 53: 1798–1806, 2004.[Abstract/Free Full Text]
  34. Veneman T, Mitrakou A, Mokan M, Cryer PE, and Gerich JE. Effects of hyperketonemia or hyperlacticacidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycemia in normal humans. Diabetes 43: 1311–1317, 1994.[Abstract]
  35. Wall JS, Steele R, DeBodo RD, and Altszuler N. Effect of insulin on utilization and production of circulating glucose. Am J Physiol 189: 43–50, 1957.[Abstract/Free Full Text]
  36. Wide L and Porath J. Radioimmunoassay of proteins with the use of sephadex-coupled antibodies. Biochim Biophys Acta 130: 257–260, 1966.




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