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Glucose Tolerance is Linked to Postprandial Fuel Use Independent of Exercise Dose

GILBERTSON, NICOLE M.1; EICHNER, NATALIE Z. M.1; FRANCOIS, MONIQUE1; GAITÁN, JULIAN M.1; HEISTON, EMILY M.1; WELTMAN, ARTHUR1,2; MALIN, STEVEN K.1,2,3

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Medicine & Science in Sports & Exercise: October 2018 - Volume 50 - Issue 10 - p 2058–2066
doi: 10.1249/MSS.0000000000001667
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Abstract

Nearly 86 million adults in the United States have prediabetes and are at risk for type 2 diabetes (T2D) (1). Prediabetes is characterized by blood glucose concentrations that are higher than normal but below T2D criteria (1). The exact cause for this hyperglycemia is multifactorial, but metabolic inflexibility is considered a primary contributor to whole-body insulin resistance (2,3). Metabolic inflexibility is defined as the reduced capacity to switch from primarily fat oxidation in the fasted state to CHO utilization after insulin stimulation. Interestingly, metabolic inflexibility is exacerbated in adults with prediabetes compared with weight-matched adults with normal glucose tolerance (2), suggesting that without lifestyle or pharmacological intervention, these etiological factors could worsen and increase the propensity for developing T2D (1).

Habitual exercise improves glucose tolerance (4–7) in adults at risk for T2D, although the exact dose required is unclear. Several studies have recently suggested that when compared with conventional long-term continuous (CONT) training, interval (INT) exercise has similar effects on improving glucose tolerance in overweight/obese adults with normal glucose tolerance, prediabetes, or T2D (5,6,8,9). However, other studies comparing these exercise doses used varying INT prescriptions that were not work matched to CONT training. Although this suggests individuals may derive improved glucose control from less time spent exercising, newer work suggests that in work-matched conditions, INT training may be a more effective exercise dose at reducing blood glucose when compared with CONT exercise. In fact, Karstoft et al. (9) demonstrated that 16 wk of INT exercise improved glycemic control as assessed by continuous glucose monitors in adults with T2D more so than CONT training. This observation raises the possibility that INT is optimal for glycemic control when exercise doses are matched on workload. However, many long-term exercise studies promote clinically meaningful reductions in weight and fat, thereby producing a gap in our understanding of work-matched CONT versus INT exercise independent of these changes in body composition on glucose tolerance in adults with prediabetes. Moreover, the mechanism(s) by which this improvement in glucose tolerance after INT versus CONT is not well understood. In adults with or at risk for developing T2D, short-term INT and CONT exercises reduce insulin resistance in the absence of weight loss and changes in fasting free fatty acids (FFA) as assessed by fasting blood samples (i.e., HOMA-IR) (10) or oral glucose tolerance tests (OGTT) (11,12). These findings therefore suggest that enhanced insulin action in liver and/or skeletal muscle may contribute to glucose homeostasis after short-term exercise, although the effect of INT versus CONT exercise on reducing circulating postprandial FFA and adipose insulin resistance is unknown. This is clinically important because lower FFA is related to alleviating metabolic inflexibility and peripheral insulin resistance (3,13). Thus, the purpose of the present study was to evaluate the effect of a short-term work-matched INT versus CONT training intervention on glucose tolerance in adults with prediabetes in the absence of clinically meaningful weight/fat loss. We hypothesized that, when compared with CONT, INT training would elicit greater improvements in glucose tolerance in association with increased metabolic flexibility and reduced adipose tissue and whole-body insulin resistance.

METHODS

Subjects

Thirty-one obese, sedentary adults (Table 1) were recruited by newspaper advertisements and/or flyers in the local community. Subjects were screened for prediabetes using a standard 2-h 75 g OGTT and/or HbA1c after an overnight fast based on the American Diabetes Association criteria. Prediabetes phenotype was categorized as impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or IFG + IGT as previously done by our group (4) and were block randomized to INT or CONT exercise to match each phenotype between intervention groups. Subjects were excluded from participation if they were physically active (>60 min·wk−1), pregnant or lactating, smoking, or diagnosed with type 1 or type 2 diabetes. Subjects were also excluded if on medications known to influence insulin sensitivity (e.g., metformin, GLP-1 agonist, etc.). All subjects enrolled underwent physical examination with resting and exercise 12-lead EKG and biochemical testing to rule out disease. All subjects provided verbal and written informed consent as approved by our Institutional Review Board.

TABLE 1
TABLE 1:
Effect of INT or CONT exercise on body composition, fitness, and biochemistries.

Metabolic control

Subjects were instructed to refrain from caffeine or alcohol consumption as well as strenuous exercise 48-h before testing. Subjects were also instructed to refrain from taking any medications or dietary supplements 24-h before reporting to the Clinical Research Unit. On the day before admissions testing, subjects were instructed to record their diet and consume approximately 250 g of CHO to minimize influence of muscle glycogen on insulin resistance, and this diet was then repeated before posttesting. The last exercise training bout was performed approximately 24-h before postintervention metabolic testing.

Cardiorespiratory fitness

V˙O2peak was determined using a continuous progressive exercise test on a cycle ergometer with indirect calorimetry (Carefusion, Vmax CART, Yorba Linda, CA). HR and blood pressure were obtained at rest, and HR was continuously monitored using a 12-lead EKG. The power output was increased by 25 W every 2 min until subjects reached volitional exhaustion. RPE and RER were monitored throughout the test.

Body composition

After an approximate 4-h fast, body weight was measured to the nearest 0.01 kg on a digital scale with minimal clothing and without shoes, and height was measured with a stadiometer to assess body mass index. Fat mass and fat-free mass were measured using the InBody 770 Body Composition Analyzer (InBody Co., Cerritos, CA). Waist circumference was measured 2 cm above the umbilicus using a tape measure.

OGTT

After a 10- to 12-h overnight fast, subjects were admitted to the Clinical Research Unit. An indwelling catheter was placed in an antecubital vein, and fasting blood was collected before and during a 180-min 75 g OGTT. Circulating glucose, insulin, and FFA were determined at fasting and every 30 min up to 120 min and then at 180 min to assess glucose tolerance and insulin resistance. Whole-body insulin resistance was calculated as previously performed by our group as insulin tAUC180min multiplied by glucose tAUC180min (14). Adipose insulin resistance during the postprandial state was also calculated as the product of plasma insulin tAUC180min and FFA tAUC180min because insulin action suppresses lipolysis (15). RER was measured with indirect calorimetry (Carefusion, Vmax CART) at 0, 60, 120, and 180 min of the OGTT to assess fuel use. Metabolic flexibility was also defined by subtracting fasting RER from the average of postprandial RER.

Exercise interventions

Subjects completed 12 supervised, work-matched 60-min exercise sessions over 13 d on a cycle ergometer. Appropriate submaximal exercise workload was determined from the HRpeak obtained during the V˙O2peak test so that both interventions were work matched at 70% of HRpeak. INT exercise consisted of subjects completing alternating 3-min intervals at 90% of their HRpeak and then 50% of their HRpeak. CONT exercise consisted of a constant session at 70% of their HRpeak. RPE was also assessed throughout each training session to gauge intensity.

Biochemical analysis

Plasma glucose samples were analyzed immediately using the YSI 2300 StatPlus Glucose Analyzer system (Yellow Springs, OH). All other samples were centrifuged for 10 min at 4°C and 3000 rpm, aliquoted, and stored at −80°C until later analysis. All measurements pre- and posttraining were analyzed on the same plate to minimize interassay variability. Plasma for determinations of insulin and FFA was placed in vacutainers containing EDTA and the protease inhibitor aprotonin. Insulin was analyzed using an enzyme-link immunosorbent assay kits (Millipore, Billerica, MA), and circulating FFA were analyzed using an enzymatic colorimetric assay (Wako Diagnostics, Richmond, VA).

Statistical analysis

Data were analyzed using SPSS version 24 (IBM Analytics, Armonk, NY). Nonnormally distributed data were log-transformed for analysis. Overall, 35 people enrolled into the study, but 3 subjects were excluded due to non-study-related medical conditions (e.g., pregnancy, orthostatic intolerance, and musculoskeletal pain) and 1 subject withdrew because of time commitment. As such, the remaining subjects’ data were analyzed using a two-way repeated-measures ANOVA. The 120-min FFA and FFA tAUC180min were covaried (ANCOVA) for baseline group statistical differences in fasting FFA. Pearson’s correlation was used to assess associations between outcomes. Data were presented as mean ± SEM, and significance was set at P ≤ 0.05.

RESULTS

Exercise training characteristics

There were 17 subjects (age = 47–74 yr, fasting plasma glucose = 86.0–122.0 mg·dL−1, 120-min glucose = 106.5–217.0 mg·dL−1) who completed CONT training (7 IFG, 4 IGT, and 6 IFG + IGT) and 14 subjects (age = 43–70 yr, fasting plasma glucose = 94.8–114.5 mg·dL−1, 120-min glucose = 77.3–211.0 mg·dL−1) who completed INT training (4 IFG, 3 IGT, and 7 IFG + IGT). Exercise session adherence was 96.5% and 99.3% for the INT and CONT group, respectively. Although the average percent HRpeak values across exercise sessions were 72.9% ± 1.2% for CONT and 79.3% ± 0.7% for INT training (P = 0.004), there was no difference in RPE (CONT: 12.8 ± 0.3 vs INT: 12.2 ± 0.5; P = 0.23). There was also no difference between groups in the dietary caloric (CONT 145.2 ± 202.0 vs INT −24.0 ± 198.0 kcal; P = 0.70), CHO (CONT −8.6 ± 25.6 vs INT 26.1 ± 21.9 g; P = 0.26), protein (CONT 16.1 ± 15.6 vs INT −16.2 ± 8.09 g; P = 0.16), or fat (CONT 7.2 ± 15.9 vs INT −12.3 ± 13.39 g; P = 0.38) intake 24 h before admission testing pre- and posttreatments.

Body composition and fitness

INT and CONT training reduced body mass index (P = 0.002) and fat-free mass (P < 0.001) comparably (Table 1). There was no effect on fat mass (P = 0.18). In addition, both interventions increased V˙O2peak (L·min−1) (P = 0.02) to a similar extent, although INT exercise tended to increase V˙O2peak (mL·kg−1·min−1; P = 0.09) more than CONT exercise (Table 1).

Plasma glucose, insulin, and FFA

INT and CONT training had no effect on fasting glucose, but reduced 120-min plasma glucose (P = 0.009; Table 1) and glucose tAUC180min (P = 0.01; Fig. 1A) similarly. CONT and INT exercises also induced 41.2% and 35.7% reversal of prediabetes, assessed by fasting and/or 120-min glucose concentrations, with no difference between treatments (P = 0.53). Fasting insulin was unaltered; however, circulating insulin at 120 min (P = 0.03; Table 1) and insulin tAUC180min (P = 0.004; Table 1, Fig. 1C) were reduced comparably between INT and CONT exercise treatments. Neither intervention effected fasting, 120 min, or FFA tAUC180min (Fig. 1B) after the interventions (Table 1).

FIGURE 1
FIGURE 1:
Effect of CONT and INT exercises on plasma glucose (A), FFA (B), and insulin (C) total area under the curve (tAUC). Data are presented as mean ± SEM. FFA was covaried for pretest fasting FFA. Raw data are presented ease of interpretation; however, insulin tAUC180min was log-transformed for normality. There were no group–treatment differences. *Significant (P ≤ 0.05) treatment effect.

Insulin resistance and metabolic flexibility

Whole-body insulin resistance (P = 0.02; Fig. 2A) and adipose insulin resistance (P = 0.02; Fig. 2B) were reduced similarly between CONT and INT training treatments. INT and CONT exercises also reduced fasting RER comparably (P = 0.006; Table 2). There was no statistically significant change in postprandial RER or metabolic flexibility after the intervention (Table 2).

TABLE 2
TABLE 2:
Effect of INT or CONT exercise on fasting and postprandial substrate oxidation.
FIGURE 2
FIGURE 2:
Effect of CONT and INT exercises on whole-body (A) and postprandial adipose (B) insulin resistance. Data are presented as mean ± SEM. There were no group–treatment differences. *Significant (P ≤ 0.05) treatment effect.

Correlations

Higher preintervention glucose tAUC180min correlated with greater reductions in 120-min plasma glucose (r = −0.51, P = 0.004), adipose insulin resistance (r = −0.36, P = 0.04), and whole-body insulin resistance (r = −0.60, P = 0.000) after the intervention. Reductions in 120-min plasma glucose (r = −0.48, P = 0.01) and glucose tAUC180min (r = −0.38, P = 0.05; Fig. 3C) were associated with increased postprandial (average of 60–180 min) RER. Decreased whole-body insulin resistance was also correlated with increased 180-min RER (r = −0.42, P = 0.03; Fig. 3D). Increased V˙O2peak (L·min−1) correlated to reduced FFA tAUC180min (r = −0.36, P = 0.04). Enhanced V˙O2peak (L·min−1) (r = −0.33, P = 0.07; Fig. 3A) and improved glucose tAUC180min (r = 0.53, P = 0.003; Fig. 3B) were also related to reduced adipose insulin resistance.

FIGURE 3
FIGURE 3:
Correlations in metabolic outcomes after the intervention. The change (Δ) in postprandial adipose insulin resistance to the Δ V˙O2peak (A) and Δ in glucose tolerance (B). The Δ in glucose tolerance and the Δ in postprandial RER (C). The Δ in whole-body insulin resistance to the Δ in 180-min RER (D). Closed circles, CONT training; open circles, INT training.

DISCUSSION

In contrast to our hypothesis, the major finding of the present study is that INT exercise did not elicit greater improvement in glucose tolerance when compared with CONT training (Fig. 1A). These findings suggest that when short-term exercise training doses are matched for work, glucose regulation is improved comparably in people with prediabetes. Indeed, we showed that glucose tolerance was improved by 8.7% with CONT exercise and 12.4% with INT training. This finding is comparable with recent work in normal weight men reporting that 2 wk of cycle ergometer high-intensity INT training elicited a 12% improvement in glucose tolerance (16). In addition, glucose tolerance was improved in sedentary obese men when performing CONT exercise training at maximal fat oxidation or INT exercise at fat max (17). However, these studies were conducted in adults with normal glucose tolerance (12,16,17) or T2D (18), and it remained to be determined whether similar findings would be seen in adults with prediabetes. Furthermore, many studies have not directly compared INT with CONT training (10,12,16) but rather have explored the role of INT exercise only as a time effective means to improve glucose control. Therefore, the present findings show that over the short term, when exercise interventions are matched for work, exercise intensity is not a predominant factor driving favorable changes in glucose tolerance in people with prediabetes. Alternatively, these data suggest exercise, independent of intensity, improves glucose tolerance in a clinically meaningful way because it led to a reversal of prediabetes in approximately 40% of the subjects. These data are comparable with Jenkins et al. (19), who showed that 6 months of a standardized endurance exercise program resulted in regression from prediabetes to normal glucose tolerance in approximately 36% of adults. Taken together, our results suggest that short-term training is effective at enhancing glucose tolerance in adults with prediabetes in only 2 wk.

There are several reasons that may explain why INT exercise did not elicit greater changes in glucose tolerance than CONT training. First, higher intensities of exercise are suggested to induce greater changes in body fat when compared with low- to moderate-intensity exercise (20) through, in part, elevations in metabolic rate (21,22). As such, it would be expected that INT exercise would promote greater fat loss and this would improve glucose tolerance more than CONT exercise (23). However, we observed no significant difference between weight/fat loss or waist circumference between groups. This observation suggests that when short-term training doses are matched on workload, body composition does not differentially influence glucose tolerance. However, other mechanisms underlying the improvements in glucose tolerance after short-term exercise may relate to adiposopathy (i.e., ratio of adiponectin to leptin). Adiposopathy may drive reductions in insulin resistance with short-term exercise training (24,25), and future work is warranted to examine if training intensity differentially affects glucose regulation and cardiovascular disease risk through an inflammatory mediated mechanism.

Aerobic fitness is also suggested to lower T2D risk by decreasing hepatic, skeletal muscle, and adipose tissue insulin resistance. If INT exercise promoted greater fitness than CONT training, it could be expected that enhanced regulation of one or more of these organs would lead to better glucose tolerance. We did not observe any difference in aerobic fitness though between INT and CONT exercises in the current study, suggesting that changes in fitness is unlikely to affect our results. Nevertheless, the tissue that contributes to glucose tolerance could still be differentially affected by the type of exercise performed. Prior work suggests that short-term high-intensity exercise training is effective at improving hepatic insulin resistance after 7 d of exercise in obese adults with insulin resistance (26). However, similar to short-term aerobic training study in adults with T2D (27), we report that INT or CONT exercise has no effect on fasting glucose or insulin concentrations in adults with prediabetes. This suggests that there was minimal improvement in hepatic insulin resistance after short-term CONT or INT training in these adults with prediabetes. Alternatively, improved aerobic fitness was associated with reductions in circulating FFA and adipose insulin resistance in the present study, and this improved adipose insulin resistance was directly correlated with glucose tolerance (Fig. 3B). We interpret these associations to suggest that adipose tissue may be an important regulator of glucose concentrations after short-term training independent of intensity. The mechanism by which decreased adipose insulin resistance drives glucose tolerance is beyond the scope of the present study, but it may relate to enhanced insulin action on suppressing lipolysis and/or re-esterification of FFA to intramyocellular lipids (28). In either case, the lack of change in fasting glucose and/or insulin suggests that hepatic glucose production had minimal effect on glucose tolerance improvements herein, and highlights that our measure of whole-body insulin resistance is most likely reflective of skeletal muscle glucose disposal. Thus, the reduction in circulating FFA may be an important mechanism reducing circulating glucose via alleviation in impaired skeletal muscle glucose oxidation and/or storage (13).

Impaired metabolic flexibility is considered a primary mechanism underlying impaired insulin-stimulated muscle glucose uptake (2). Although long-term exercise training studies suggest increased metabolic flexibility is related to reduced circulating glucose concentrations (4), no work exists after short-term training at different intensities matched on workload during postprandial conditions. We show for the first time that enhanced postprandial RER is associated with improved glucose tolerance (Fig. 3C) and whole-body insulin resistance (Fig. 3D) in adults with prediabetes. These findings are similar to Whyte et al. (12), who showed that 2 wk of sprint INT training significantly increased fasting fat oxidation in overweight/obese men. However, this prior study did not evaluate the changes in substrate utilization in the postprandial state nor the relationship of metabolic flexibility to glucose tolerance or insulin resistance, thereby limiting the clinical relevance of postprandial substrate metabolism to glucose control. The mechanism by which exercise improves metabolic flexibility has yet to be fully elucidated, but it has been suggested that skeletal muscle oxidative capacity is a significant predictor of insulin resistance (29). Indeed, short-term training increases skeletal muscle oxidative capacity (e.g., COX I, COX IV, citrate synthase, and β-HAD) (18,30) and is consistent with our data showing enhanced fat oxidation in the fasted state after CONT and INT training. We speculate that this enhanced fat oxidation may have reduced the deleterious effect of intramyocellular lipid species (e.g., ceramides) on insulin signaling and improved CHO oxidation and skeletal muscle glucose uptake (13,31). Taken together, these data suggest that short-term CONT or INT exercise training increases fasting fat oxidation and maintains average postprandial CHO utilization, thereby contributing to improvements in glucose tolerance.

There are limitations to the study that merit acknowledgment. This study had a modest sample size in which the majority of subjects were females. We did not have the statistical power to test the independent effect of sex; however, future work is needed to evaluate the differential responsiveness to short-term CONT or INT training based on sex as men and women have differences in glucose regulation (32). In the current study, we used the OGTT to estimate insulin resistance as opposed to using the euglycemic hyperinsulinemic clamp with stable isotopes to determine peripheral and hepatic insulin resistance. Although our results of whole-body insulin resistance may be over- or underestimated, the use of the clamp limits “real-world” insight into glucose regulation. It should also be noted that without the use of stable isotopes and skeletal muscle biopsies, we cannot determine the directionality or causality of enhanced substrate oxidation and reduced whole-body insulin resistance. Thus, it remains possible that greater skeletal muscle glucose uptake leads to more CHO utilization during the postprandial period, or enhanced CHO reliance promotes more insulin-mediated glucose disposal. In either case, the association between greater postprandial CHO use with improved glucose control suggests that metabolic flexibility may be an important mechanism contributing to glucose homeostasis independent of exercise dose. Another consideration is that we estimated adipose insulin resistance by use of FFA during an OGTT. Although our postprandial measure of adipose insulin resistance is similar to the validated fasted adipose insulin resistance calculation with the multistep pancreatic clamp with FFA tracers (33), we recognize that use of glycerol may minimize concerns with re-esterification and/or alterations in FFA uptake. Thus, further work posttraining using clamps with FFA or glycerol tracers is required to confirm the effect exercise dose has on adipose insulin resistance. Previous work has suggested that prediabetes phenotypes may respond differently to high-intensity CONT exercise (34). We showed that people with IFG + IGT have blunted glucose tolerance, metabolic flexibility, and clamp-derived insulin resistance improvement after 12 wk of lifestyle intervention compared with those with IGT or IFG alone (4). As such, we block randomized people with IFG, IGT, and IFG + IGT between CONT and INT training interventions to minimize variance in response to the interventions. Treatment groups were relatively matched across phenotypes, suggesting that any difference between groups is unlikely the result of prediabetes classification. Moreover, preintervention glucose tolerance was inversely related to the change in glucose tolerance and insulin resistance, suggesting that the most severe forms of prediabetes benefited the most during this 2-wk intervention. Nonetheless, future work should consider the effect of prediabetes phenotypes on lifestyle responses to optimize personalization of exercise prescription for T2D prevention.

In conclusion, short-term exercise training, independent of intensity, is effective in improving glucose tolerance in adults with prediabetes. This enhanced glucose tolerance may be improved through fitness-related responses in insulin resistance and postprandial substrate oxidation before meaningful weight loss. This is clinically relevant as 2 wk of exercise reversed prediabetes in approximately 40% of individuals, suggesting that glycemic control may be derived in a timely manner. Further work is required to determine whether nutrition and/or pharmacological intervention could add to the effects of exercise in an intensity-based manner to optimize medical approaches to prevent and/or reverse T2D and cardiovascular disease.

The authors thank Dr. Eugene J. Barrett, M.D., for his assistance in screening subjects and helpful feedback on the work. They also thank the members of the Applied Metabolism and Physiology Laboratory for helpful discussion on the manuscript as well as the clinical research unit nursing staff, the exercise physiology core laboratory staff, and the participants for their excellent efforts. Funding was supported by the University of Virginia’s Curry School of Education and Launchpad Award to S. K. M.

The authors have nothing to disclose. The results of the present study do not constitute endorsement by the American College of Sports Medicine. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation.

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Keywords:

INSULIN RESISTANCE; OXIDATIVE CAPACITY; PREDIABETES; TYPE 2 DIABETES; EXERCISE INTENSITY

© 2018 American College of Sports Medicine