Effect of Exercise Intensity on Exogenous Glucose Requirements to Maintain Stable Glycemia At High Insulin Levels in Type 1 Diabetes

Abstract

Context

Under basal insulin levels, there is an inverted U relationship between exercise intensity and exogenous glucose requirements to maintain stable blood glucose levels in type 1 diabetes (T1D), with no glucose required for intense exercise (80% V̇O₂ peak), implying that high-intensity exercise is not conducive to hypoglycemia.

Objective

This work aimed to test the hypothesis that a similar inverted U relationship exists under hyperinsulinemic conditions, with high-intensity aerobic exercise not being conducive to hypoglycemia.

Methods

Nine young adults with T1D (mean ± SD age, 22.6 ± 4.7 years; glycated hemoglobin, 61 ± 14 mmol/mol; body mass index, 24.0 ± 3.3 kg/m², V̇O₂ peak, 36.6 ± 8.0 mL·kg^–1 min^–1) underwent a hyperinsulinemic-euglycemic clamp to maintain stable glycemia (5-6 mmol·L⁻¹), and exercised for 40 minutes at 4 intensities (35%, 50%, 65%, and 80% V̇O₂peak) on separate days following a randomized counterbalanced study design.

Main Outcome Measures

Glucose infusion rates (GIR) and glucoregulatory hormones levels were measured.

Results

The GIR (± SEM) to maintain euglycemia was 4.4 ± 0.4 mg·kg^–1 min^–1 prior to exercise, and increased significantly by 1.8 ± 0.4, 3.0 ± 0.4, 4.2 ± 0.7, and 3.5 ± 0.7 mg·kg^–1 min^–1 during exercise at 35%, 50%, 65%, and 80% V̇O₂ peak, respectively, with no significant differences between the 2 highest exercise intensities (P > .05), despite differences in catecholamine levels (P < .05). During the 2-hour period after exercise at 65% and 80% V̇O₂ peak, GIRs did not differ from those during exercise (P > .05).

Conclusions

Under hyperinsulinemic conditions, the exogenous glucose requirements to maintain stable glycemia during and after exercise increase with exercise intensity then plateau with exercise performed at above moderate intensity ( > 65% V̇O₂ peak). High-intensity exercise confers no protection against hypoglycemia.

type 1 diabetes, hyperinsulinemia, glucose intake, exercise intensity

The prevention of hypoglycemia during and after exercise is an ongoing clinical challenge in the management of type 1 diabetes (T1D). Although insulin dose reduction before exercise is generally advocated as an effective means to significantly reduce the risk of hypoglycemia (1-4), this approach is suitable only for planned exercise when insulin dose adjustments can be made in advance. Hence a number of guidelines advocate additional carbohydrate (CHO) intake to prevent exercise-mediated hypoglycemia both for unplanned and planned exercise (1-4).

Because the rate of blood glucose utilization and rate of fall in blood glucose levels (BGLs) increase with exercise of low to moderate intensity (5, 6), one might predict that the CHO intake required to maintain stable BGLs also increases with exercise intensity in individuals with T1D. However, recently we have shown that the relationship between exercise intensity performed under basal insulin levels and the amount of exogenous glucose required to maintain stable glycemia is not linear in these individuals, but follows an inverted U relationship (7), with no exogenous glucose required when exercise intensity reaches 80% peak rate of oxygen consumption (V̇O₂ peak) (7). In support of these findings, others have shown that intense aerobic exercise (80% V̇O₂ peak) performed in a basal insulinemic state not only does not require any exogenous glucose to maintain stable BGL, but also results in an increase in BGL during and early after exercise (8). Altogether, the aforementioned studies imply that high-intensity aerobic exercise performed in a basal insulinemic state is not conducive to hypoglycemia during exercise in individuals with T1D.

However, the amount of administered CHO required to prevent hypoglycemia during moderate-intensity exercise increases with insulin concentrations (9, 10) because elevated plasma insulin levels inhibit hepatic glucose production and enhance peripheral glucose uptake (9, 11, 12). Hence, high plasma insulin levels would be expected to increase the exogenous glucose requirements associated with exercise even when performed at a high intensity. On the other hand, since mild hyperinsulinemia does not have a marked effect on the increase in the rate of hepatic glucose production during intense aerobic exercise (13), little extra glucose administration may be required to maintain stable BGLs if exercise is performed under hyperinsulinemic conditions. This suggests that an inverted U relationship may also hold even under these conditions, with high-intensity exercise not being conducive to hypoglycemia. To determine whether this is the case, the primary objective of our study was to test the hypothesis that when plasma insulin levels are at the high end of the therapeutic range, there is an inverted U relationship between exercise intensity and the exogenous glucose requirements to maintain stable glycemia. We also hypothesized that little or no extra glucose is required to maintain stable BGL during high-intensity exercise. This is an important issue to address given that it is not uncommon for individuals with T1D to exercise post prandially under hyperinsulinemic conditions.

Materials and Methods

Participants

Nine recreationally active (5.4 ± 3.7 hours/week) young individuals age 16 to 30 years with well-controlled, complication-free T1D (1, multiple daily injections; 8, continuous subcutaneous insulin infusion) were enrolled for this study (Table 1). Participants were eligible if they had an undetectable C-peptide level (< 0.05 nmol/L), a stable insulin regimen for at least 6 months prior to the study, and were not taking any prescribed medication other than insulin. Two female participants were taking oral contraception. The protocol was approved by the Princess Margaret Hospital for Children Human Research Ethics Committee, and informed consent was obtained from the participants and their parents if they were younger than 18 years.

Table 1.

Baseline characteristics of study participants

Characteristic	n = 9
Age, y	22.6 ± 4.7
Sex, male/female, n	6/3
Weight, kg	76.0 ± 11.5
Height, m	1.77 ± 0.06
BMI, kg/m2	24.0 ± 3.3
V̇O2 peak, mL (kg body weight)−1 min−1	36.6 ± 8.0
Lactate threshold, (%V̇O2 peak	59.5 ± 2.8
Diabetes duration, y	12.9 ± 5.1
HbA1c, %	7.7 ± 0.9
HbA1c, mmol/mol1	61 ± 14

Data are expressed as mean ± SD.

Abbreviations: BMI, body mass index; HbA_1c, glycated hemoglobin; V̇O₂ peak, peak rate of oxygen consumption.

Experimental design and protocol

Each participant attended a familiarization session followed by 4 testing sessions. During the familiarization session, anthropometric measurements were taken, and participants completed a V̇O₂ peak test on a cycle ergometer (Lode Corival Ergometer) connected to a computer fitted with Cyclemax software (UWA) to assess their aerobic fitness and lactate threshold. Initial workload was set at 25 watts and subsequently increased by 25 watts every 3 minutes until exhaustion, with blood sampled at each step for lactate assay. Using 30-second epochs, a plateau in oxygen consumption rate (an increase of < 150 mL·kg^–1 min^–1) and/or a respiratory exchange ratio greater than 1.15 during the last minute of exercise were the criteria for achieving V̇O₂ peak. Workloads corresponding to 35%, 50%, 65%, and 80% of V̇O₂ peak were calculated. Lactate threshold was determined by calculating the power output corresponding to the greatest perpendicular distance between the regression line relating lactate to workload and the straight line formed by the first and last points of the lactate to workload regression line (14).

All participants completed 40 minutes (or until exhaustion) of exercise at 4 exercise intensities on 4 separate days, following a randomized, counterbalanced study design, with each visit separated by at least 1 week. For 24 hours prior to testing, all participants were required to abstain from caffeine, alcohol, injecting insulin to the legs, and any physical activity other than light walking because both antecedent hypoglycemia (15) and antecedent exercise (16) affect the glucoregulatory responses to subsequent exercise. Participants were fitted with a real-time continuous glucose monitoring system (Medtronic Enlite glucose sensor) for 2 days before testing to monitor their glucose levels. In addition, participants were required to keep a food diary for 24 hours prior to the first testing session, and to match their food intake the day before their subsequent 3 testing sessions. Testing was rescheduled for any participant experiencing hypoglycemia 48 hours prior to testing. Hypoglycemia for the study purpose was defined as sensor glucose levels less than 3.5 mmol·L^–1 and confirmed with glucose meter testing. Female participants not taking oral contraceptive pills were investigated only during the follicular phase of their menstrual cycles (day 8 ± 3), and those taking oral contraception were tested during the placebo pill phase, with 4 weeks between testing sessions.

Testing sessions

The morning of testing, each participant arrived at the laboratory at 8 am after an overnight fast. Participants on multiple-daily injection insulin regimens were instructed to decrease their glargine dose by 50% the night before the study and skip their morning bolus of insulin. For those on insulin pumps, the pump was disconnected on arrival. A cannula was inserted into the dorsum of one hand and this hand was placed in a Hotbox (Omega CN370) at approximately 60°C for the sampling of arterialized venous blood. Another cannula was inserted in the contralateral antecubital fossa for the infusion of glucose and insulin.

Hyperinsulinemic-euglycemic clamp

Participants then underwent a hyperinsulinemic-euglycemic clamp. The hyperinsulinemic-euglycemic clamp technique adopted here is based on that described in De Fronzo et al (17). For this clamp, exogenous insulin was infused to create a hyperinsulinemic plateau in plasma insulin concentration, while plasma glucose level was maintained constant at stable euglycemic levels by titration of the exogenous glucose.

During the clamp procedure, BGLs were monitored every 5 to 10 minutes, and the samples for measuring insulin levels were collected at regular intervals. The rate of infusion of a 20% (w/v) dextrose solution was adjusted during the procedure as per the principles of the published algorithm of De Fronzo and colleagues (17), with BGLs being maintained between 5 and 6 mmol/L. Exogenous short-acting insulin (Humalog, Eli Lilly Australia Pty Ltd), at a concentration of 1 unit of insulin per mL 0.9% (w/v) saline solution, was infused using an Alaris Asena GH syringe pump (Alaris Medical Systems) at a continuous rate of 30 mU·m^–2·min^–1 after receiving a priming dose of the same insulin during the initial 10 minutes in a logarithmically decreasing manner. This was to raise plasma insulin acutely to attain target plasma insulin levels of 300 to 550 pmol/L, which reflect the levels within the physiological range observed after the ingestion of a large CHO-rich meal (270-600 pmol/L) (9, 18-20). An insulin infusion rate of 30 mU·m^–2·min^–1 was calculated to enable attainment of the target plasma insulin levels based on the work of others who showed that primed continuous rates of 20 and 40 mU·m^–2·min^–1 results in plasma insulin concentrations of 304 ± 42 pmol/L (21) and 728 ± 35 pmol/L (17), respectively. The insulin infusion rate adopted here was also chosen because it is associated with an increased hypoglycemia risk due to plasma insulin reaching levels known to completely suppress hepatic glucose production in individuals with and without T1D (22-24). Steady state was attained 2 hours after the initiation of the clamp (17).

Exercise phase

Exercise was initiated at least 2 hours after starting the clamp, and only when BGLs were maintained between 5 and 6 mmol/L for at least 30 minutes. Glucose was infused during the exercise and recovery periods as required to maintain BGLs at the same levels maintained prior to exercise.

Once stable euglycemia was achieved for at least 30 minutes, blood samples were collected for baseline measurements of glucoregulatory hormones. Expired air was collected using an indirect calorimetry system (V Max Spectra; Sensor Medics Corp) for at least 10 minutes for the determination of baseline rates of O₂ consumption (V̇O₂) and CO₂ production (V̇CO₂). At approximately 11:30 am, each participant was asked to cycle for 40 minutes on the same cycle ergometer as that used for V̇O₂ peak testing at his or her randomly assigned intensity. The cycling sessions were performed at an intensity of (a) 35%, (b) 50%, (c) 65%, and (d) 80% V̇O₂ peak (fit individuals can sustain 80% V̇O₂ peak intensity for at least 30 minutes; [25]), separated by at least 1 week. These exercise intensities correspond to light, moderate, vigorous (low), and vigorous (high) intensity, respectively (26). During and after exercise, expired air was collected for the determination of V̇O₂ and V̇CO₂ and heart rate was monitored continuously. Blood lactate was also measured with each BGL measurement. Throughout the 2-hour period post exercise, the participants rested in a seated position.

Measurement of glucoregulatory hormones

Arterialized venous blood samples were assayed for levels of the following glucoregulatory hormones: epinephrine, norepinephrine, glucagon, growth hormones (GHs), cortisol, and insulin, as described previously (27). The methods employed for analysis were high-performance liquid chromatography for epinephrine and norepinephrine, radio immunoassay for glucagon, and chemiluminescent immunoassay for insulin, GH, and cortisol levels. Determination of serum free insulin levels was performed using a one-step noncompetitive chemiluminescent immunoassay after insulin extraction with polyethylene glycol.

Calculations

The exogenous glucose requirements to maintain stable euglycemia during exercise and recovery were determined from the glucose infusion rate (GIR) during exercise and recovery, respectively. Basal GIR was the GIR required to maintain stable BGLs prior to the start of exercise. The extra GIR required to maintain euglycemia during exercise and recovery was calculated by deducting basal GIR from measured GIR. Exercise-mediated CHO and fat oxidation rates were calculated from the V̇O₂ and V̇CO₂ measurements (28) using nonprotein respiratory stoichiometric equations (28, 29).

Statistical analyses

Data were analyzed using 1-way (treatment) or 2-way repeated-measures analysis of variance (treatment and time) and Fisher least significant difference test for posteriori analysis using SPSS software (version 20.0; SPSS Inc). Statistical significance was accepted at P less than .05. Unless otherwise stated, all results are expressed as mean ± SEM. This is the first study of its kind, and for this reason there was no information available from the literature to help us calculate the sample size required for this study, apart from a similar study conducted by our group that showed, under basal insulinemic conditions and with a sample size of 9, that there is an inverted U relationship between exercise intensity and the glucose requirements to maintain euglycemia. Based on this study, a pragmatic target sample size of 9 was selected. The study outcome that shows significant differences between exercise intensities indicates that the statistical power of this study was adequate to test our primary outcome.

Results

Participant’s response to exercise

All 9 participants completed the 40 minutes of exercise at 35%, 50%, and 65% V̇O₂ peak. For the exercise trial at 80% V̇O₂ peak, only 2 participants completed the 40-minute exercise bout, 2 participants ceased exercise at 25 minutes, 2 at 20 minutes, 1 at 15 minutes, and 2 at 10 minutes. Relative to lactate threshold, the exercise intensities of 35%, 50%, 65%, and 80% V̇O₂ peak corresponded to intensities (mean ± SD) of 55 ± 13, 79 ± 19, 103 ± 24, and 126 ± 30% lactate threshold, respectively. The actual mean percentage V̇O₂ peak achieved during the 35%, 50%, 65% and 80% V̇O₂ peak exercise sessions for all participants were 35.3 ± 0.8, 50.7 ± 0.8, 66.3 ± 1.1, and 78.9 ± 1.0% V̇O₂ peak, respectively. The inability of most of our participants to complete the 40-minute exercise trial at 80% V̇O₂ peak is most likely due to the exercise intensity being well above the lactate threshold and thus difficult to sustain. Owing to the differences in the duration of the exercise performed at 80% V̇O₂ peak, data recorded only during baseline, midexercise, and at the end of exercise were used for the comparison of glucoregulatory hormones, as described previously (7).

Hyperinsulinemic-euglycemic clamp and glucose infusion rates to maintain euglycemia

During all the hyperinsulinemic-euglycemic clamp assessments, plasma glucose levels were maintained between 5.0 and 6.0 mmol·L^–1, with no difference between exercise intensities (P > .05, Fig. 1). The baseline GIRs were similar for all 4 exercise intensities (P > .05) before the commencement of exercise (5.4 ± 1.4, 4.4 ± 0.8, 4.3 ± 1.2, and 3.5 ± 0.8 mg·kg^–1 min^–1 prior to 35%, 50%, 65%, and 80% V̇O₂ peak, respectively). The mean extra GIR to maintain euglycemia for the total duration of exercise at 35% V̇O₂ peak (1.8 ± 0.4 mg·kg^–1 min^–1) was lower than at the other intensities (P < .05 vs 50%, 65%, and 80% V̇O₂ peak), and the mean extra GIR to maintain euglycemia at 50% V̇O₂ peak (3.0 ± 0.4 mg·kg^–1 min^–1) was lower than at 65% (4.2 ± 0.7 mg·kg^–1 min^–1; P < 0.05 vs 65% V̇O₂ peak). The mean extra GIR at 80% V̇O₂ peak (3.5 ± 0.7 mg·kg^–1 min^–1) was similar to that at 50% (P = .257) and 65% V̇O₂ peak (P = .145). Overall, the relationship between exercise intensity and GIR during exercise indicated that GIR increased with exercise intensity then plateaued with exercise performed at above moderate intensity (> 65% V̇O₂ peak). The mean extra GIR for the first 10 minutes of exercise was similar for all 4 exercise intensities (Fig. 2A). The total amount of extra glucose infused during the 40 minutes of exercise was 6.8 ± 1.2, 10.7 ± 1.8, and 11.7 ± 2.3 g at 35%, 50%, and 65% V̇O₂ peak, respectively. The individual mean GIR to maintain euglycemia during exercise is shown in Table 2. The GIR data of the first 2 participants who completed the 40-minute trial at 80% V̇O₂ peak was higher than at 65% intensity.

Table 2.

Glucose infusion rate for individual participants during exercise performed at 4 intensities

	Glucose infusion rate (mg/kg/min) at different exercise intensities
	35% V̇O2 peaka	50% V̇O2 peakb	65%V̇ V̇O2 peak	80% V̇O2 peakc
Participant 1	4.1 ± 0.8	5.5 ± 0.3	3.1 ± 1.0	5.3 ± 0.5
Participant 2	1.2 ± 0.5	0.3 ± 0.2	2.3 ± 0.7	4.5 ± 1.0
Participant 3	2.9 ± 1.1	4.5 ± 1.0	4.4 ± 1.4	3.5 ± 0.3
Participant 4	2.0 ± 1.0	2.2 ± 0.5	3.5 ± 1.3	2.0 ± 0.7
Participant 5	1.6 ± 1.0	3.5 ± 1.2	4.1 ± 1.6	5.0 ± 1.8
Participant 6	1.2 ± 0.5	2.1 ± 0.8	5.6 ± 1.3	1.0 ± 0.2
Participant 7	0.5 ± 0.4	4.0 ± 0.6	6.3 ± 1.5	3.5 ± 0.6
Participant 8	1.7 ± 1.3	4.7 ± 1.4	7.9 ± 1.9	3.6 ± 1.8
Participant 9	1.0 ± 0.3	0.5 ± 0.1	1.0 ± 0.3	2.5 ± 0.8

All data are mean ± SEM (n = 9).

Abbreviation: V̇O₂ peak, peak rate of oxygen consumption.

^aP less than .05 vs 50%, 65%, 80% V̇O₂ peak.

^bP less than .05 vs 65% V̇O₂ peak.

^cOnly participants 1 and 2 completed the 40-minute trial at 80% V̇O₂ peak.

Figure 1.

Effect of exercise intensities of 35%, 50%, 65%, and 80% peak rate of oxygen consumption (V̇O₂ peak) on blood glucose levels during exercise and for 2 hours post exercise. All data are mean ± SEM (n = 9). Bold horizontal bar, exercise.

Figure 2.

Effect of exercise intensities at 35%, 50%, 65%, and 80% peak rate of oxygen consumption (V̇O₂ peak) on extra glucose infusion rate (GIR) during A, the total duration of exercise (black bar) and the first 10 minutes of exercise (gray bar), and B, during the 2 hours post exercise. All data are mean ± SEM (n = 9). *P < .05 vs 50%, 65%, and 80% V̇O₂ peak. ^$P < .05 vs 65% V̇O₂ peak. ‡P < .05 vs 65% and 80% V̇O₂ peak.

The mean extra GIRs to maintain euglycemia during the 2-hour recovery period increased with exercise intensity, reaching 1.2 ± 0.2, 1.7 ± 0.2, 3.1 ± 0.4, and 3.1 ± 0.5 mg·kg^–1 min^–1 at 35%, 50%, 65%, and 80% V̇O₂ peak (P < .05), respectively, but did not differ between 65% and 80% V̇O₂ peak (Fig. 2B). The mean extra GIR to maintain euglycemia during the 2-hour recovery period was lower than during exercise performed at 50% V̇O₂ peak (P < .05), but did not differ from the mean extra GIRs during exercise at 35%, 65%, and 80% V̇O₂ peak (P > .05). The individual mean GIR to maintain euglycemia during the 2-hour postexercise period for all participants is shown in Table 3.

Table 3.

Glucose infusion rate for individual participants during 2 hours’ recovery from 4 intensities

	Glucose infusion rate (mg/kg/min) at different exercise intensities
	35% V̇O2 peaka	50% V̇O2 peakb	65% V̇O2 peak	80% V̇O2 peakc
Participant 1	3. 7 ± 0.6	3.5 ± 0.5	1.7 ± 0.5	2.3 ± 0.6
Participant 2	2.1 ± 0.9	0.5 ± 0.2	1.7 ± 0.3	4.1 ± 0.7
Participant 3	2.5 ± 0.4	3.1 ± 0.8	3.9 ± 1.5	2.0 ± 0.6
Participant 4	0.4 ± 0.3	1.6 ± 0.4	1.8 ± 0.5	2.8 ± 0.8
Participant 5	0.7 ± 0.4	1.8 ± 0.5	1.9 ± 0.5	1.1 ± 0.4
Participant 6	0.0 ± 0.0	0.7 ± 0.2	2.6 ± 0.9	2.4 ± 0.6
Participant 7	1.7 ± 0.6	2.9 ± 1.2	5.8 ± 1.0	5.0 ± 0.9
Participant 8	1.4 ± 0.8	1.2 ± 0.6	4.8 ± 2.1	3.5 ± 1.1
Participant 9	0.7 ± 0.3	0.5 ± 0.2	1.4 ± 0.4	1.4 ± 0.7

All data are mean ± SEM (n = 9).

Abbreviation: V̇O₂ peak, peak rate of oxygen consumption.

^aP less than .05 vs 50%, 65%, and 80% V̇O₂ peak.

^bP < 0.05 vs 65 and 80% V̇O₂ peak.

^cFor the 80% V̇O₂ peak trial, participants 1 and 2 completed 40 minutes, participants 4 and 6 completed 30 minutes, participants 5 and 8 completed 20 minutes, participant 7 completed 15 minutes, and participants 3 and 9 completed 10 minutes.

The temporal pattern of rise in GIR during exercise was comparable for the 3 lowest exercise intensities for which all participants completed the 40-minute exercise session (Fig. 3). Exercise at 80% V̇O₂ peak was excluded from this comparison because the exercise duration was not the same for all participants at this intensity. A rise in GIR was detected at 10 minutes of exercise for the 3 exercise intensities of 35%, 50%, and 65% V̇O₂ peak, with these increases persisting throughout the remainder of exercise and recovery (see Fig. 3).

Figure 3.

Effect of exercise intensities at 35% (blue open circles), 50% (black circles), and 65% peak rate of oxygen consumption (V̇O2 peak; green squares) on extra glucose infusion rate (GIR) to maintain stable glycemia during exercise and 2 hours post exercise. All data are mean ± SEM (n = 9). Horizontal bar, exercise. ^#P < .05 vs time 0 (start of exercise). ^†P < .05 vs 35% V̇O₂ peak. ^¶P < .05 vs 50% V̇O₂ peak. ^§P < 0.05 vs 35 and 50% V̇O₂.

Cardiorespiratory and metabolic variables

Prior to exercise, there were no differences in heart rate, V̇O₂, V̇CO₂, CHO and fat oxidation rate, energy production, and lactate levels between the 4 exercise intensities (P > .05, Table 4). In response to exercise, all these variables, except the fat oxidation rate, increased significantly with exercise intensity, with maximal level attained at 80% V̇O₂ peak (P < .05). Fat oxidation rates were maximal for exercise at 65% V̇O₂ peak (see Table 4).

Table 4.

Comparison of effect of exercise intensity on cardiorespiratory and metabolic variables at rest and end of exercise

		Exercise intensity (% V̇O2 peak)
		35%	50%	65%	80%
Heart rate, beats/min	Rest	89 ± 6	84 ± 4	82 ± 4	86 ± 4
	Exercise	120 ± 5a,b	142 ± 4a,c	162 ± 54a,d	183 ± 4a
V̇O2, L/min	Rest	0.28 ± 0.03	0.34 ± 0.02	0.33 ± 0.03	0.29 ± 0.03
	Exercise	1.04 ± 0.10a,b	1.49 ± 1.15a,c	1.94 ± 0.21a,d	2.32 ± 0.22a
V̇CO2, L/min	Rest	0.25 ± 0.02	0.29 ± 0.02	0.28 ± 0.02	0.26 ± 0.03
	Exercise	0.96 ± 0.10a,b	1.34 ± 0.15a,c	1.85 ± 0.21a,d	2.40 ± 0.31a
RQ	Rest	0.87 ± 0.01	0.88 ± 0.01	0.87 ± 0.02	0.88 ± 0.02
	Exercise	0.94 ± 0.01a,c	0.93 ± 0.01a,d	0.95 ± 0.02a,d	1.05 ± 0.05a
CHO oxidation, g/min	Rest	0.22 ± 0.03	0.25 ± 0.02	0.29 ± 0.01	0.23 ± 0.03
	Exercise	1.06 ± 0.11a,b	1.43 ± 0.25a,c	2.55 ± 0.61a	3.78 ± 0.76a
Fat oxidation, g/min	Rest	0.06 ± 0.01	0. 07 ± 0.01	0.07 ± 0.01	0.06 ± 0.01
	Exercise	0.13 ± 0.16a	0.18 ± 0.03a	0.19 ± 0.05d	0.08 ± 0.03
Energy cost, kJ·min–1	Rest	1.60 ± 0.63	1.66 ± 0.13	1.59 ± 0.14	1.43 ± 0.16
	Exercise	21.42 ± 2.10a,b	30.79 ± 3.30a,c	40.20 ± 4.22a,d	49.30 ± 4.93a
Lactate, mmol/L	Rest	0.63 ± 0.06	0.59 ± 0.03	0.65 ± 0.05	0.79 ± 0.05
	Exercise	0.88 ± 0.18b	1.54 ± 0.24a,c	2.61 ± 0.43a,d	6.35 ± 0.94a

All data are mean ± SEM.

Abbreviation: V̇O₂ peak, peak rate of oxygen consumption.

^aP less than .05 vs rest.

^bP less than .05 vs 50%, 65%, and 80% V̇O₂ peak.

^cP less than .05 vs 65% and 80% V̇O₂ peak.

^dP less than .05 vs 80% V̇O₂ peak.

Hormonal responses

Free serum insulin levels prior to the start of exercise were similar, with the levels being 343 ± 26, 299 ± 27, 278 ± 31, and 269 ± 46 pmol/L prior to exercising at 35%, 50%, 65%, and 80% V̇O₂ peak, respectively (these levels reflect physiological postprandial levels). Plasma insulin levels increased transiently during exercise performed at 50%, 65%, and 80% V̇O₂ peak, and returned to preexercise levels early during recovery and remained stable afterward (Fig. 4A). The rise in insulin levels during exercise was observed despite insulin infusion rates remaining constant. The levels of all other hormones before exercise were similar between trials (see Fig. 4). Epinephrine and norepinephrine levels increased during the 2 highest exercise intensities, with the highest levels attained in response to exercise at 80% V̇O₂ peak (P < .05), and with these levels decreasing rapidly to basal levels within 15 minutes post exercise (see Fig. 4C and 4D). Glucagon levels did not change significantly in response to all exercise intensities, except at 80% V̇O₂ peak, where they increased significantly before returning to baseline values within 15 minutes post exercise (Figure 4B). GH levels increased in response to exercise, with higher levels being attained in response to higher exercise intensities, reaching peak levels at the end of exercise, and declining to baseline values by 60 minutes of recovery (see Fig. 4E). Cortisol levels did not change and remained stable during exercise and recovery (see Fig. 4F).

Figure 4.

Hormonal response to exercise at intensities of 35%, 50%, 65%, and 80% peak rate of oxygen consumption (V̇O₂ peak). A, Serum insulin levels. B, Plasma glucagon levels. C, Plasma epinephrine levels. D, Plasma norepinephrine levels. E, Serum growth hormone levels. F, Serum cortisol levels. All data are mean ± SEM (n = 9). Bold horizontal bar, exercise. ^#P < .05 vs baseline (–5). ^¶P < 0.05 vs 50% V̇O₂ peak. ^§P < .05 vs 35% and 50% V̇O₂ peak. *P < .05 vs 35%, 50%, and 65% V̇O₂ peak.

Discussion

Recently we showed that there is an inverted U relationship between exercise intensity and the exogenous glucose requirements to maintain stable BGL under basal insulin levels, with no exogenous glucose being required to maintain stable glycemia during high-intensity exercise (7). These findings thus imply that hypoglycemia risk is not increased during high-intensity exercise under basal insulinemic conditions (7). What remained to be determined was whether this relationship also holds under hyperinsulinemic conditions. Here we show that when exercise is performed under therapeutic hyperinsulinemic conditions, the exogenous glucose requirements to maintain stable BGLs increase with exercise intensity, then plateau with exercise performed at above moderate intensity (> 65% V̇O₂ peak). Overall, high-intensity exercise provides no protection against hypoglycemia. The exogenous glucose demands were similarly high early after (≤ 2 hours) and during exercise, at both the higher intensities of exercise.

The relationship found here between the exogenous glucose requirements to maintain stable BGLs and exercise intensity performed under hyperinsulinemic conditions differs from the inverted U relationship previously observed for basal insulin levels (7) in individuals with similar age, V̇O₂ peak, and catecholamine responses to exercise. Indeed, these results show that the extra glucose requirements to maintain euglycemia increase with exercise intensity to reach a maximum at 65% V̇O₂ peak, with similar requirements at 65% and 80% V̇O₂ peak. These study findings that glucose must be administered to prevent BGL from falling during high-intensity aerobic exercise (80% V̇O₂ peak) performed under hyperinsulinemic conditions are in marked contrast to what is observed under basal insulinemic conditions, where many studies have shown that no glucose administration is required to maintain euglycemia at an exercise intensity of 80% V̇O₂ peak (7) or above (8, 30, 31). High-intensity aerobic exercise performed under hyperinsulinemic conditions is thus conducive to an increased risk of hypoglycemia.

Irrespective of exercise intensity, more exogenous glucose is required to maintain stable BGLs during exercise performed under hyperinsulinemic compared to basal insulin level, with these requirements at 50% and 65% V̇O₂ peak being 2.5 to 3 times higher under our hyperinsulinemic conditions than reported for basal insulin levels (7), in a study in which the age group and fitness level of the participants were similar to this study (5 participants were involved in both studies). Our finding that high plasma insulin levels increase the amount of exogenous glucose required to maintain stable glycemia during exercise is supported by the work of others (9, 10). Chokkalingam and colleagues (9) found that almost 3 times more glucose had to be infused under similar hyperinsulinemic conditions compared to low insulin conditions to maintain stable euglycemia during 45 minutes of moderate intensity exercise (65% V̇O₂ peak) in people with T1D. Similarly, Francescato and colleagues showed that the total amount of CHO required to prevent hypoglycemia during exercise increases linearly with insulin concentration (10).

The predicted additive effect of high plasma insulin levels and muscle contraction on the rate of glucose utilization (9) together with the inhibitory effect of hyperinsulinemia on hepatic glucose production (32-34) may explain why more exogenous glucose is required to prevent blood glucose from falling when exercise is performed under hyperinsulinemic compared to basal insulinemic conditions. Moreover, the significant transient rise in insulin levels observed during exercise, also reported by others (9, 13, 20, 30, 35) and probably due to decreased insulin clearance (13), may have contributed further to the increase in the exogenous glucose requirements described here. The plateauing in these requirements when exercise is performed at 80% compared to 65% V̇O₂ peak may be explained on the grounds that the catecholamine levels at 80% V̇O₂ peak may be high enough to override, at least in part, the hyperinsulinemia-mediated inhibition of hepatic glucose production, thus allowing hepatic glucose production to support some muscle glucose demands. This interpretation is consistent with catecholamines being potent activators of hepatic glucose production during high-intensity aerobic exercise (8, 30, 36). Alternatively, the higher CHO oxidation rate at 80% V̇O₂ peak compared with 65% V̇O₂ peak despite similar GIR rates at these exercise intensities could be taken as evidence of a greater reliance on muscle glycogen oxidation during high-intensity exercise (80% V̇O₂ peak), with the resulting lesser reliance on blood glucose oxidation explaining the lack of difference in GIR between exercise performed at 65% and 80% V̇O₂ peak. Finally, it is possible that the elevated levels of plasma glucagon and GH during high-intensity exercise at 80% V̇O₂ peak (see Fig. 4) may have contributed both to the stimulation of hepatic glucose production and leveling of exogenous glucose requirements.

The temporal pattern of increase in GIR during both mild- and moderate-intensity exercise reveals the absence of a lag before the exogenous glucose requirements reach above resting levels, with significantly higher than basal GIR being detected as early as 10 minutes after the onset of exercise. These findings differ from past results obtained under basal insulinemic conditions, in which we found that the exogenous glucose requirements to maintain stable glycemia during exercise at 50% V̇O₂ peak increased only 20 minutes after the start of exercise (37). On clinical grounds, the absence of any lag in the rise in the exogenous glucose requirements during low- to moderate-intensity exercise performed under hyperinsulinemic conditions suggests that CHO supplementation is required even for short-duration exercise performed when prevailing insulin levels are high.

Against expectations, we found that during early recovery (< 2 hours) from moderate- (65% V̇O₂ peak) or high-intensity aerobic exercise (80% V̇O₂ peak) performed under hyperinsulinemic conditions, the average rate of exogenous glucose administered to maintain stable glycemia was as high as during exercise. To the best of our knowledge, this is the first study to compare the glucose requirements during and early after aerobic exercise performed at high or lower intensities under hyperinsulinemic conditions. The only study that has investigated such a relationship was performed in individuals in a basal insulinemic state and showed that more exogenous glucose was required to maintain stable glycemia during recovery from high-intensity aerobic exercise (80% V̇O₂ peak) than during exercise (7, 38), but with no relationship found between those increases in exogenous glucose demands post exercise and exercise intensity (7). Here, in contrast, we describe a different relationship between exercise intensity and the exogenous glucose demands to maintain stable glycemia post exercise with similar requirements at 65% and 80% V̇O₂ peak (see Fig. 2B). The increases in glucose demands post exercise probably result from the lasting stimulatory effects of muscle contraction both on glucose uptake (39) and insulin sensitivity (40-42), enhancing further the stimulatory effect of insulin on peripheral glucose utilization rate (43). On clinical grounds, our findings thus suggest that the risk of hypoglycemia under hyperinsulinemic conditions is as high while resting early after moderate or intense aerobic exercise as during exercise.

Although the plasma insulin levels achieved in this study reflect those attained post prandially 1 to 2 hours following subcutaneous insulin administration (10, 20), a limitation of our study is that only one insulin condition was tested and the insulin levels remained high for 2 hours before initiating exercise. This is a limitation considering that plasma insulin levels can vary markedly depending not only on insulin bolus dose, but also on the time-elapsed postinsulin injection (10, 20), thus implying that the effect of insulin on the counterregulatory response to exercise may thus change with time after an insulin bolus and may not completely reflect the responses observed under our near-stable hyperinsulinemic conditions. In addition, exercising at high intensity while in a postprandial state is conducive to nausea and cramping, thus potentially limiting the ecological validity of some of our findings for exercise performed at a high intensity because this exercise condition is expected to be avoided in real-life situations.

Another limitation is the lack of isotopic work to elucidate the mechanisms underlying our findings (7). Finally, because this is a study performed under controlled physiological conditions and limited to recreationally active, lean participants age 16 to 26 years, the generalizability of our findings to people not meeting those criteria is not known. In particular, given the evidence that fitness level affects both the risk of exercise-mediated hypoglycemia in individuals with T1D (44) and the glucoregulatory hormones responses to exercise in individuals without diabetes (45-47), this raises the unresolved issue of whether fitness level may affect the relationship uncovered here between exercise intensity and the exogenous glucose requirements to maintain stable glycemia during and after exercise in people with T1D.

In conclusion, this study shows that when exercise is performed under hyperinsulinemic conditions, the extra exogenous glucose requirements to maintain stable euglycemia increase with exercise intensity then plateau with exercise performed at above moderate intensity (> 65% V̇O₂ peak). High-intensity exercise provides no protection against hypoglycemia. This study also shows for the first time that the exogenous glucose demands to maintain stable glycemia are as high early after (< 2 hours) as during high-intensity exercise. Because the relationship between oral CHO intake and GIR is unknown, future studies are required to relate our GIR findings to translatable oral CHO intake equivalent in insulin-treated individuals with T1D.

Abbreviations

Abbreviations
 
• BGL

  blood glucose level

 
• CHO

  carbohydrate

 
• GH

  growth hormone

 
• GIR

  glucose infusion rate

 
• RQ

  Respiratory quotient

 
• T1D

  type 1 diabetes

 
• VO₂

  Oxygen consumption

 
• VCO₂

  Carbondioxide production

Acknowledgments

Financial Support: This work was supported by the JDRF Australian Type 1 Diabetes Clinical Research Network (4-SRA-2015–157-M-B), a special initiative of the Australian Research Council (ARC), and a Diabetes Australia Research Program Grant.

Additional Information

Disclosure Statement: The authors have nothing to disclose.

Data Availability

Some or all data sets generated during and/or analyzed during the present study are not publicly available but are available from the corresponding author on reasonable request.