25 Molecules Expressed in the AMPK Pathway After Exercise in Type 2 Diabetes: Evidence Map

Franca, Raquel da; Santana, Andrea Penha; Evangelista, Apolo Anunciação dos Santos; Lima, Tamara dos Santos; Oliveira, Dyandra Fernanda Lima de; Brito-Gomes, Jorge Luiz de; Carvalho, Ferdinando Oliveira

doi:10.1590/1678-4324-2025240925

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Review - Biological, Medical and Health Technologies • Braz. arch. biol. technol. 68 • 2025 • https://doi.org/10.1590/1678-4324-2025240925 linkcopy

25 Molecules Expressed in the AMPK Pathway After Exercise in Type 2 Diabetes: Evidence Map

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This study investigates the expression of molecules in the AMPK pathway following physical exercise in people with type 2 diabetes, considering aerobic, resistance, and combined exercises. Although the literature indicates intracellular signaling in the AMP-activated protein kinase (AMPK) pathway occurs after exercise, it is essential to compile this information to support clinical decision-making. To summarize evidence on the expression of molecules in the AMPK pathway in people with type 2 diabetes following aerobic, resistance, and combined exercise. This integrative review included searches in MEDLINE/PubMed, SciELO, and Lilacs databases (2004-2024). After applying filters, duplicate evaluations, and screening titles and abstracts, nine studies met the eligibility criteria. An increase in the expression of 25 molecules, particularly GLUT4 and PGC1-α, was observed, with combined exercise proving more effective than aerobic and resistance exercises alone. Aerobic, resistance, and combined exercises can increase the expression of molecules in the AMPK pathway in people with type 2 diabetes, with combined exercise being the most effective. There are differences not only between exercise types but also in volume, intensity, and frequency.

Keywords:
Aerobic exercise; resistance exercise; signaling route; GLUT4; glycemic control.

Combined exercise activates AMPK signaling more effectively than isolated exercises.

AMPK pathway shows a marked rise in key molecules, especially GLUT4 and PGC1-α.

Training volume, intensity, and frequency affect AMPK molecule expression levels.

Databases	Search Strategies	Filters Applied
MEDLINE/ PubMed	((((("training exercise"[Title/Abstract] OR "resistance training"[Title/Abstract] OR "high intensity interval training"[Title/Abstract] OR "endurance training"[Title/Abstract] OR "combined training"[Title/Abstract]) AND "Genes"[Title/Abstract]) OR "Molecules"[Title/Abstract] OR "AMPK"[Title/Abstract] OR "signaling pathway"[Title/Abstract]) AND "type 2 diabetes mellitus"[Title/Abstract] AND "Adult"[Title/Abstract]) OR (("protein s"[All Fields] OR "proteinous"[All Fields] OR "proteins"[MeSH Terms] OR "proteins"[All Fields] OR "protein"[All Fields]) AND "glucose transport"[Title/Abstract])) AND (("Enzymes"[Title/Abstract] AND "PCR"[Title/Abstract]) OR "Microarray"[Title/Abstract] OR "RT-PCR"[Title/Abstract])	Publication Year: 2004-2024 Language: English, Spanish, and Portuguese Sample: Humans
SciELO	(ab:("type 2 diabetes mellitus")) AND ("exercise") AND ("molecules") OR ("enzyme") OR ("proteins")	Publication Year: 2004-2024 Language: Portuguese, English, and Spanish Sample: Humans
Lilacs	(Exercise OR resistance training OR endurance training OR combined training) AND (Genes OR Signal way OR molecules OR AMPK) AND (PCR OR microarray OR rt-PCR)	Publication Year: 2004-2024 Language: Portuguese, English, and Spanish Sample: Humans

Authors, Year, and Country	Objectives	Journal, Database, and IF	Research Method	Sample	Intervention protocols	Sample collection for biochemical analysis
Holten et al. (2004) [¹⁶] Denmark	Analyze whether strength training increases insulin-mediated glucose uptake, GLUT4 content, and insulin signaling in skeletal muscle in patients with type 2 diabetes.	Diabetes MEDLINE/PubMed IF = 7.7	Clinical Trial	n = 17 adults GC = 7 with normal glucose tolerance GI = 10 with type 2 diabetes	Supervised RT 3x/week, sessions of up to 30 min, over 6 weeks. Weeks 1-2: 3x10 repetitions (50% 1-RM). Weeks 3-6: 4x8-12 repetitions (70-80% 1-RM). Last 2 weeks: exhaustive sets (8-12 repetitions). Rest: >90 s between sets, >2 min between stations	The biopsies were performed 16 hours after the participants completed their last RT session.
Chris-Roberts et al. (2004) [¹⁷] USA	Valuate the relative contributions of improvements in insulin receptor signaling, GLUT4 protein expression, and GS activity to training-induced increases in insulin sensitivity.	Metabolism MEDLINE/PubMed IF = 9.8	Parallel Clinical Trial	n = 22 people GC = 16 nondiabetic GI = 6 with type 2 diabetes	Supervised AE 3x/week, starting at 60% VO2peak for 20 min per session, over 8 weeks of intervention. Progressive increase over 8 weeks to 70% VO2peak, 45 min, 4x/week. Heart rate used as an intensity indicator.	Muscle biopsies were performed before and after 8 weeks of AE.
Wojtaszewski et al. (2005) [¹⁸] Denmark	Investigate the effect of strength training and type 2 diabetes on the expression of isoforms and the heterotrimeric composition of AMPK in human skeletal muscle.	The Journal of Physiology MEDLINE/PubMed IF = 5.5	Parallel Clinical Trial	n = 17 adults GC = 7 with normal glucose tolerance (sex unspecified) GI = 10 with type 2 diabetes	Supervised RT, 3x/week, sessions up to 30 min, for 6 weeks. Weeks 1-2: 3x10 repetitions (50% 1 RM). Weeks 3-6: 4x8-12 repetitions (70-80% 1 RM). Last 2 weeks: exhaustive sets. Rest: ~90 s between sets, ~2 min between exercises. 3 RM test at the beginning and end of the training.	The biopsy time points were: 16 to 18 hours after the last training session, with 30 minutes of supine rest before performing biopsies of the vastus lateralis muscle of the trained (T) and untrained (UT) legs.
O’Gorman et al. (2006) [¹⁹] Ireland	Assess the impact of acute short-term exercise training on whole-body insulin-mediated glucose disposal and signaling transduction along the canonical insulin signaling cascade.	Diabetologia MEDLINE/PubMed IF = 8.2	Parallel Clinical Trial	n = 15 GC = 7 obese nondiabetic GI = 8 obese with type 2 diabetes (sex unspecified)	Supervised AE for 1 week at ∼75% VO2peak for 1 hour on a stationary cycle ergometer. The intensity was determined based on heart rate (±5 beats per minute) corresponding to 75% VO2peak, measured by indirect calorimetry. Blood pressure and heart rate were monitored before, during, and after exercise.	The vastus lateralis muscle biopsies were performed at baseline and 16 hours after an acute exercise session and short-term physical training (7 days).
Wang, Simar e Whang (2009) [²⁰] Australia	Review the morphological and metabolic adaptations of skeletal muscle to exercise training in adults with type 2 diabetes or impaired glucose tolerance.	Diabetes/MetabolismResearch and Reviews MEDLINE/PubMed IF= 8.0	Systematic Review	n = 18 RCTs and non-randomized	RT a 50-80% 1RM, 2-3 sets of 8-10 repetitions. AE of Low intensity (1 study), moderate (6), high (6); 30-60 min/session (mean 48 ± 9 min). Combined exercise: AE (80-90% VO₂max) + RT (50%). Variation in the total duration of interventions: 4-52 weeks. Majority with supervision.	The sample timing was: interval between the last exercise session and biopsy: 16-96 h (median: 60 h; interquartile range: 80 h).
Sriwijitkamol et al. (2007) [²¹] UK	Determine whether individuals with type 2 diabetes and moderate to severe obesity (BMI > 30 kg/m2) exhibit impaired AMPK signaling.	Diabetes PubMed IF = 7.7	Clinical Trial	n = 28 people GC = 8 obese nondiabetic and 8 lean nondiabetic GI = 12 obese with type 2 diabetes	Two acute protocols (50% and 70% VO₂max), 40 minutes of AE (cycling. A 4-6 week interval between sessions.	The vastus lateralis muscle biopsies were performed at four time points: before exercise (fasted and at basal rest), after 10 minutes, after 40 minutes of exercise, and 150 minutes post-exercise (during recovery).
Vind et al. (2011) [²²] Denmark	Investigate whether type 2 diabetes is associated with abnormalities in insulin-induced site-specific phosphorylation of TBC1D4 in skeletal muscle; examine the effect of resistance exercise training on TBC1D4 and other key insulin signaling events in well-controlled obese individuals with and without type 2 diabetes.	Diabetologia MEDLINE/PubMed IF = 8.2	Clinical Trial	n = 26 obese men with type 2 diabetes GC = 13 obese men with normal glucose tolerance GI = 13 obese men with type 2 diabetes	AE on a stationary bike at ~65% VO₂max, with 4-5 sessions/week (20-35 min), for 10 weeks.	Skeletal muscle biopsies were obtained from the vastus lateralis muscle before and after insulin, 1-2 weeks prior to the training protocol, and 48 hours after the last exercise session.
Hussey et al. (2012) [²³] Australia	Determine the effect of a single bout of exercise on GLUT4 gene expression in muscles of patients with type 2 diabetes and control subjects, accounting for age and body mass index.	Diabetes, Obesity and Metabolism MEDLINE/PubMed IF = 5.8	Clinical Trial	n = 18 adults GI = 9 people with type 2 diabetes GC = 9 people with normal glucose tolerance	A 60-minute session of AE (cycle ergometer) at ∼55% peak power output (WMax).	Skeletal muscle biopsies were obtained at the beginning of the study, immediately after exercise, and 3 hours post-exercise.
García-Hermoso et al. (2023) [²⁴] Spain	Investigate the effects of exercise training on exerkines in patients with type 2 diabetes to determine the ideal exercise prescription.	Journal of Sport and Health Science MEDLINE/PubMed IF = 11.7	Systematic Review of RCTs	n = 40 RCTs with 2,160 people in total 1,281 people with diabetes in GI 879 people with diabetes in GC	RT, CE, and AE protocols: Weekly frequency ranged from 2 to 5 sessions; session volume varied between 15 and 75 minutes across trials. Total intervention duration ranged from 8 to 96 weeks. Intensity for AE varied between 40-95% of HRmax, 40-85% of VO₂peak, and 50-80% of maximal oxygen consumption. RT intensity ranged from 40-80% of 1RM and 3.6 to 6 METs.	The timing of the sample collection was not specified.

Acronym		Category	Function	Coding gene
GLUT4	Glucose transporter 4	Protein	Transports glucose from the extracellular environment to the intracellular environment in adipose and muscle tissues	SLC2A4
IL-6	Interleukin 6	Interleukin	Regulates cell growth and differentiation and plays an important role in the immune response	IL6
IL-10	Interleukin 10	Cytokine	Deactivates macrophages	IL10
IL-15	Interleukin 15	Cytokine	Induces the proliferation of natural killer cells; cells of the immune and innate systems whose main function is to kill virus-infected cells	IL15
IL-18	Interleukin 18	Cytokine	This cytokine has been implicated in injury to various organs and in potentially fatal conditions characterized by a cytokine storm	IL18
PGC1-α	Peroxisome proliferator-activated receptor γ coactivator 1α	Transcription coactivator	Participates in energy metabolism, stimulates mitochondrial biogenesis, and promotes muscle tissue remodeling	PPARGC1A
Akt2 or PKB β	Protein kinase B (PKB) 2	Protein kinase	Plays a critical role in the regulation of glucose homeostasis	AKT2
Akt1 or PKB α	Protein kinase B (PKB) 1	Protein kinase	Plays a fundamental role in cell survival regulation, insulin signaling, angiogenesis, and tumor formation	AKT1
CaMK	Calcium/calmodulin-dependent kinase	Protein	Binds to calcium ions present in the cytoplasm and regulates various target proteins in cells	CAMKK1
TBC1D4 or AS160	Rac1 protein, TBC1 member of domain family 4, AKT substrate of 160 kDa	Protein	Regulates the translocation of GLUT4 in response to stimulation	TBC1D4
HKII	Hexokinase II	Enzyme	Enzyme of the glycolytic pathway that converts glucose to glucose-6-phosphate and regulates carbohydrate metabolism	HK2
p38 MAPK	38' mitogen-activated protein kinase	Protein	Involved in cell differentiation, apoptosis, and autophagy	MAPK14
GS	Glycogen synthase	Enzyme	Converts excess free glucose into a glycogen chain	GYS2
PI3K	Phosphoinositide 3-kinase	Enzyme	Phosphorylates AKT and is involved in various cellular functions such as growth, proliferation, differentiation, mobility, survival, and intracellular trafficking	PI3K
NR4A	Subfamily of the orphan nuclear receptor superfamily	Transcription factor	Involved in important biological processes, including carcinogenesis/apoptosis control, inflammation, vascular disease, development, and metabolism of dopaminergic neurons	NR4A
ADIPOQ	Adiponectin	Protein hormone	Exerts protective effects against inflammation and may positively modulate the endocrine system	ADIPOQ
TNF-α	Tumor necrosis factor-alpha	Cytokine	A group of cytokines that induce tumor cell death and have pro-inflammatory actions	TNFA
HDAC5	Histone deacetylase 5	Enzyme	Plays a critical role in transcriptional regulation, cell cycle progression, and developmental events	HDAC5
FETUA	Fetuin A	Glycoprotein	Modulates vascular calcification, the response to systemic inflammation, bone metabolism, and insulin activity	AHSG
LEP	Leptin	Hormone	Plays an important role in the regulation of energy homeostasis	LEP
ADSF	Resistin	Protein	Acts as an insulin antagonist and blocks the central action of leptin	RET
GHRL	Ghrelin	Hormone	Stimulates appetite and plays an important role in energy homeostasis	GHRL
APLN	Apelin	Protein	Regulates various biological functions, including fluid homeostasis, cardiovascular function, and insulin secretion	APLN
IRS1	Insulin receptor substrate 1	Protein	Involved in type 2 diabetes mechanisms, insulin resistance susceptibilities, and cancer progression	IRS1
IRS2	Insulin receptor substrate 2	Protein	Involved in the regulation of glucose homeostasis and lipid metabolism	IRS2

Authors and Year	Main Results Found
Holten et al. (2004) [¹⁶]	After unilateral resistance training (RT), patients with type 2 diabetes (T2D) showed a 40% increase in GLUT4 density (p<0.05). No difference in GLUT4 protein thickness was observed between the analyzed groups (p>0.05). Increases in insulin action were noted in the T2D group, along with elevated protein levels of GLUT4, PKB, and GS (p<0.05). Significant increases in insulin receptor protein content were found (p<0.05).
Chris-Roberts et al. (2004) [¹⁷]	Eight weeks of aerobic training (AT) increased GLUT4 expression by 38% and 22% in non-diabetic and diabetic individuals, respectively (p<0.05). AKT expression increased in both groups after 8 weeks of AT (p<0.05). Total GS activity increased by 46% and 45% in non-diabetic and diabetic individuals, respectively, in response to AT (p<0.01).
Wojtaszewski et al. (2005) [¹⁸]	Basal AMPK activity and the expression of protein/mRNA of catalytic isoforms (α1 and α2) and regulatory isoforms (β1, β2, γ1, γ2a, γ2b, and γ3) of AMPK were independent of T2D. Protein content of α1 (+16%), α2 (+14%), and β1 (+29%) was higher, while γ3 content was lower (-48%) in human muscles after RT compared to untrained muscles (p<0.01).
O’Gorman et al. (2006) [¹⁹]	Short-term physical training increased insulin-mediated glucose elimination in obese T2D patients (p<0.05), but not in obese non-diabetic individuals (p>0.05). Activation of IRS1, IRS2, PI3K associated with phosphotyrosine, and phosphorylated AKT substrate, AS160, an important functional Rab GTPase activator for GLUT4, remained unchanged after acute or chronic exercise.
Wang, Simar e Whang (2009) [²⁰]	Beneficial adaptations to AT, RT, and endurance training (ET) were primarily observed in muscle fiber area, capillary density, glycogen, glycogen synthase, and expressions of GLUT4 protein.
Sriwijitkamol et al. (2007) [²¹]	Low and moderate intensity AT acutely stimulated the expression of the PGC1 gene, peaking after a 150-minute rest period (p<0.05).
Vind et al. (2011) [²²]	Phosphorylation of TBC1D4 showed no differences among the studied groups (p>0.05), but the study revealed an increase of TBC1D4 of approximately 20% within groups (p<0.05). Proteins AKT1 and AKT2 showed significant differences between groups. AKT1 expression increased by 20% in the control group after exercise, while the group with T2D increased AKT1 expression by up to 50% (p<0.05). AKT2 increased in both groups (control and diabetic) by 30% to 40%, respectively.
Hussey et al. (2012) [²³]	After one session of AT, GLUT4 expression was similar in both groups (p<0.05), remaining elevated and showing reduction only after 3 hours post-intervention. At rest, the T2D group had lower expression of PGC1-α compared to the control group. However, after intervention, PGC1-α increased in both groups (p<0.05). PGC1-α gene manifestations were identified in T2D patients after acute exercise. Increases in AMPK and p38 MAPK phosphorylation enhanced the effects on GLUT4 expression after AT.
García-Hermoso et al. (2023) [²⁴]	Different exercise modalities induced changes in levels of adiponectin, fetuin-A, fibroblast growth factor-21, IL-6, IL-10, leptin, resistin, and TNF-α in T2D, but did not have significant effects on apelin, IL-18, and ghrelin compared to controls.

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[TFN1] ²
Legend: IF = impact factor; CG = control group; IG = intervention group; n = sample; USA = United States of America; GS = glycogen synthase; GLUT4 = glucose transporter 4; BMI = body mass index; T2D = type 2 diabetes; AMPK = AMP-activated protein kinase; TBC1D4 = TBC1 domain family member 4; NE = not specified; RCT = clinical trial; RTC = randomized clinical trial; IGT = impaired glucose tolerance; W = weeks; VO₂max = maximum oxygen consumption; RM= Maximum repetition; METs = metabolic equivalents; HRmax = maximal heart rate; VO₂peak = peak oxygen consumption; AE = aerobic exercise; RT = resistance exercise; CE = combined exercise. Source: The authors (2024).