Intact Regulation of the AMPK Signaling Network in Response to Exercise and Insulin in Skeletal Muscle of Male Patients With Type 2 Diabetes: Illumination of AMPK Activation in Recovery From Exercise

Kjøbsted, Rasmus; Pedersen, Anette Fischer; Hingst, Janne R.; Sabaratnam, Rugivan; Birk, Jesper B.; Kristensen, Jonas M.; Højlund, Kurt; Wojtaszewski, Jørgen F. P.

doi:10.2337/db15-1034

Cited by 63 publications

(86 citation statements)

References 58 publications

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“…These findings further highlight the important role of breaking up sedentary time to improve cardiometabolic markers in the general population (Healy et al, 2011) and in T2D patients using an isotemporal substitution modeling approach (Healy et al, 2011; Falconer et al, 2015), and therefore to encourage adults with diagnosed T2D to adopt BST as a strategy for improving metabolic health. The underlying mechanisms explaining the associations between BST and glycemic control are still relatively unknown, but acute light exercise bouts may activate alternative molecular signals that can bypass defects in insulin signaling in skeletal muscle, resulting in an insulin-independent increase in glucose uptake (Stanford and Goodyear, 2014) through several signal transduction pathways (Sylow et al, 2016), including the AMPK signaling network (Kjobsted et al, 2017), a function that remains intact in T2D patients (Kjobsted et al, 2016). It is important to highlight that the AMPK signaling is intensity-dependent (Birk and Wojtaszewski, 2006), however, it may also be stimulated by an increased energy expenditure resulting from skeletal muscle contractions.…”

Section: Discussionmentioning

confidence: 99%

Sedentary Patterns, Physical Activity, and Cardiorespiratory Fitness in Association to Glycemic Control in Type 2 Diabetes Patients

et al. 2017

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Background: Sedentary behavior has been considered an independent risk factor for type-2 diabetes (T2D), with a negative impact on several physiological outcomes, whereas breaks in sedentary time (BST) have been proposed as a viable solution to mitigate some of these effects. However, little is known about the independent associations of sedentary pursuits, physical activity, and cardiorespiratory fitness (CRF) variables with glycemic control. We investigated the independent associations of total sedentary time, BST, moderate-to-vigorous physical activity (MVPA), and CRF with glycemic outcomes in patients with T2D.Methods: Total sedentary time, BST, and MVPA were assessed in 66 participants (29 women) with T2D, using accelerometry. Glucose and insulin were measured during a mixed meal tolerance test, with the respective calculations of HOMA-IR and Matsuda index. Glycated hemoglobin (HbA1c) was also analyzed. CRF was measured in a maximal treadmill test with breath-by-breath gases analysis. Multiple regressions were used for data analysis.Results: Regardless of CRF, total sedentary time was positively associated with HbA1c (β = 0.25, p = 0.044). Adjusting for MVPA, total sedentary time was related to fasting glucose (β = 0.32, p = 0.037). No associations between total sedentary time and the remaining glycemic outcomes, after adjusting for MVPA. BST had favorable associations with HOMA-IR (β = −0.28, p = 0.047) and fasting glucose (β = −0.25, p = 0.046), when adjusted for MVPA, and with HOMA-IR (β = −0.25, p = 0.036), Matsuda index (β = 0.26, p = 0.036), and fasting glucose (β = −0.22, p = 0.038), following adjustment for CRF. When adjusting for total sedentary time, only CRF yielded favorable associations with HOMA-IR (β = −0.29, p = 0.039), fasting glucose (β = −0.32, p = 0.012), and glucose at 120-min (β = −0.26, p = 0.035), and no associations were found for MVPA with none of the metabolic outcomes.Conclusion: The results from this study suggest that sedentary time and patterns are relevant for the glycemic control in patients with T2D. Still, MVPA and CRF counteracted most of the associations for total sedentary time but not for the BST. MVPA was not associated with metabolic outcomes, and CRF lost some of the associations with glycemic indicators when adjusted for total sedentary time. Future interventions aiming to control/improve T2D must consider reducing and breaking up sedentary time as a viable strategy to improve glycemic control.

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Section: Discussionmentioning

confidence: 99%

Sedentary Patterns, Physical Activity, and Cardiorespiratory Fitness in Association to Glycemic Control in Type 2 Diabetes Patients

et al. 2017

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“…; Kjobsted et al . ). Thus, we also experimentally tested if the effects of EPS on AMPK activation differed with obesity.…”

Section: Introductionmentioning

confidence: 97%

“…; Kjobsted et al . ). However, there is considerable variation in the magnitude of this response (Teran‐Garcia et al .…”

Section: Introductionmentioning

confidence: 99%

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Electrical pulse stimulation induces differential responses in insulin action in myotubes from severely obese individuals

Park

Turner

Zheng

et al. 2018

The Journal of Physiology

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Key points Exercise/exercise training can enhance insulin sensitivity through adaptations in skeletal muscle, the primary site of insulin‐mediated glucose disposal; however, in humans the range of improvement can vary substantially. The purpose of this study was to determine if obesity influences the magnitude of the exercise response in relation to improving insulin sensitivity in human skeletal muscle. Electrical pulse stimulation (EPS; 24 h) of primary human skeletal muscle myotubes improved insulin action in tissue from both lean and severely obese individuals, but responses to EPS were blunted with obesity. EPS improved insulin signal transduction in myotubes from lean but not severely obese subjects and increased AMP accumulation and AMPK Thr172 phosphorylation, but to a lesser degree in myotubes from the severely obese. These data reveal that myotubes of severely obese individuals enhance insulin action and stimulate exercise‐responsive molecules with contraction, but in a manner and magnitude that differs from lean subjects. Abstract Exercise/muscle contraction can enhance whole‐body insulin sensitivity; however, in humans the range of improvements can vary substantially. In order, to determine if obesity influences the magnitude of the exercise response, this study compared the effects of electrical pulse stimulation (EPS)‐induced contractile activity upon primary myotubes derived from lean and severely obese (BMI ≥ 40 kg/m2) women. Prior to muscle contraction, insulin action was compromised in myotubes from the severely obese as was evident from reduced insulin‐stimulated glycogen synthesis, glucose oxidation, glucose uptake, insulin signal transduction (IRS1, Akt, TBC1D4), and insulin‐stimulated GLUT4 translocation. EPS (24 h) increased AMP, IMP, AMPK Thr172 phosphorylation, PGC1α content, and insulin action in myotubes of both the lean and severely obese subjects. However, despite normalizing indices of insulin action to levels seen in the lean control (non‐EPS) condition, responses to EPS were blunted with obesity. EPS improved insulin signal transduction in myotubes from lean but not severely obese subjects and EPS increased AMP accumulation and AMPK Thr172 phosphorylation, but to a lesser degree in myotubes from the severely obese. These data reveal that myotubes of severely obese individuals enhance insulin action and stimulate exercise‐responsive molecules with contraction, but in a manner and magnitude that differs from lean subjects.

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“…It has been suggested that the activation of 5′ AMP-activated protein kinase (AMPK), which is a hallmark of exercise, may be part of the exercise-induced process that produces enhanced insulin sensitivity (Cartee 2015a; Kjobsted et al 2017; Kjobsted et al 2016; Kim et al 2004). Independent of exercise, acute prior treatment of isolated rodent skeletal muscle with 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), a pharmacological activator of AMPK, has also been reported to cause subsequently improved insulin-stimulated glucose uptake (Fisher et al 2002; Iglesias et al 2002; Kjobsted et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Prior treatment with the AMPK activator AICAR induces subsequently enhanced glucose uptake in isolated skeletal muscles from 24-month-old rats

Oki

Arias

Kanzaki

et al. 2018

Appl. Physiol. Nutr. Metab.

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5′ AMP-activated protein kinase (AMPK) activation may be part of the exercise-induced process that enhances insulin sensitivity. Independent of exercise, acute prior treatment of skeletal muscles isolated from young rats with a pharmacological activator of AMPK, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), causes subsequently improved insulin-stimulated glucose uptake (GU). However, efficacy of a single prior AICAR exposure on insulin-stimulated GU in muscles from old animals has not been studied. The purpose of this study was to determine whether brief, prior exposure to AICAR (3.5 hours before GU assessment) leads to subsequently increased GU in insulin-stimulated skeletal muscles from old rats. Epitrochlearis muscles from 24 month-old male rats were isolated and initially incubated ±AICAR (60 minutes), followed by incubation without AICAR (3 hours), then incubation ±insulin (50 minutes). Muscles were assessed for GU (via 3-O-methyl-[3H]-glucose accumulation) and site-specific phosphorylation of key proteins involved in enhanced GU, including AMPK, Akt, and Akt substrate of 160 kDa (AS160), via western blotting. Prior ex vivo AICAR treatment resulted in greater GU by insulin-stimulated muscles from 24 month-old rats. Prior AICAR treatment also resulted in greater phosphorylation of AMPK (T172) and AS160 (S588, T642 and S704). GLUT4 protein abundance was unaffected by prior AICAR and/or insulin treatment. These findings demonstrate that skeletal muscles from older rats are susceptible to enhanced insulin-stimulated GU after brief activation of AMPK by prior AICAR. Consistent with earlier research using muscles from young rodents, increased phosphorylation of AS160 is implicated in this effect that was not attributable to altered GLUT4 glucose transporter protein abundance.

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Intact Regulation of the AMPK Signaling Network in Response to Exercise and Insulin in Skeletal Muscle of Male Patients With Type 2 Diabetes: Illumination of AMPK Activation in Recovery From Exercise

Cited by 63 publications

References 58 publications

Sedentary Patterns, Physical Activity, and Cardiorespiratory Fitness in Association to Glycemic Control in Type 2 Diabetes Patients

Sedentary Patterns, Physical Activity, and Cardiorespiratory Fitness in Association to Glycemic Control in Type 2 Diabetes Patients

Electrical pulse stimulation induces differential responses in insulin action in myotubes from severely obese individuals

Prior treatment with the AMPK activator AICAR induces subsequently enhanced glucose uptake in isolated skeletal muscles from 24-month-old rats

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