Mol. Nutr. Food Res. 2014, 00, 1–17

1

DOI 10.1002/mnfr.201400414

REVIEW

Dietary stimulators of GLUT4 expression and translocation in skeletal muscle: A mini-review Nicholas P. Gannon1 , Carole A. Conn2 and Roger A. Vaughan1,2,3,4 1

Department of Biochemistry and Molecular Biology, University of New Mexico, Health Sciences Center, School of Medicine, Albuquerque, NM, USA 2 Department of Individual, Family, and Community Education: Nutrition, University of New Mexico, Albuquerque, NM, USA 3 Department of Health, Exercise and Sports Science, University of New Mexico, Albuquerque, NM, USA 4 Department of Nutritional Sciences, Texas Tech University, Lubbock, TX, USA Chronic insulin resistance can lead to type II diabetes mellitus, which is also directly influenced by an individual’s genetics as well as their lifestyle. Under normal circumstances, insulin facilitates glucose uptake in skeletal muscle and adipose tissue by stimulating glucose transporter 4 (GLUT4) translocation and activity. GLUT4 activity is directly correlated with the ability to clear elevated blood glucose and insulin sensitivity. In diabetes, energy excess and prolonged hyperinsulinemia suppress muscle and adipose response to insulin, in part through reduced GLUT4 membrane levels. This work uniquely describes much of the experimental data demonstrating the effects of various dietary components on GLUT4 expression and translocation in skeletal muscle. These observations implicate several individual dietary chemicals as potential adjuvant therapies in the maintenance of diabetes and insulin resistance.

Received: June 19, 2014 Revised: September 7, 2014 Accepted: September 8, 2014

Keywords: Glucose uptake / Insulin resistance / Insulin sensitivity / noninsulin-dependent diabetes mellitus (NIDDM) / Type II diabetes mellitus

1 Correspondence: Dr. Roger A. Vaughan, Department of Nutritional Sciences, Texas Tech University, P.O. Box 41240, Lubbock, TX 79409, USA E-mail: [email protected] or [email protected] Abbreviations: ACC, acetyl-CoA carboxylase; Akt/PKB, protein kinase B; AMPK, 5 adenosine monophosphate activated protein kinase; APS, adaptor protein with plekstrin homology and Src homology 2 domains; AS160, Akt substrate of 160 kDa; CaMKII, calcium/calmodulin-dependent protein kinase II; CPT-1, carnitine palmitoyltransferase-1; EGCG, epigallocatechin3-O-gallate; EPA, eicosapentaenoic acid; ERR␣, estrogen-related receptor ␣; G6Pase, glucose-6-phosphatase; GEF, glucose transporter 4 enhancer factor; GLUT4, glucose transporter 4; HDAC5, histone deacetylase 5; IGF-1, insulin-like growth factor 1; IGF1R, insulin-like growth factor 1 receptor; IR, insulin receptor; ¨ IRS-1, insulin receptor substrate 1; KLF15, Kruppel-like factor 15; MEF, myocyte enhancer factor; MyoD, myogenic differentiation 1; NRF1/2, nuclear respiratory factor 1 and 2; p38 MAPK, p38 mitogen-activated protein kinase; PCr, phosphocreatine; PDK1/2, phosphoinositide-dependent kinase 1 and 2; PEPCK, phosphoenolpyruvate carboxykinase; PGC-1␣, peroxisome proliferator activated receptor ␥ coactivator 1␣; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphate; PPAG, Z-2-(␤-D C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Introduction

It is estimated that over 29 million Americans currently have diabetes, with an additional 86 million estimated to be prediabetic [1]. In 2012, both the direct and indirect financial expenditure for diabetes totaled $245 billion dollars [1]. Prediabetics are at an increased risk for future development of diabetes and approximately 35% of prediabetics become diabetic within 8 years [2]. Type II diabetes mellitus (T2DM) is characterized by insulin resistance in skeletal muscle and adipose tissue, impaired regulation of hepatic gluconeogenesis, and uncontrolled insulin secretion to compensate for insulin insensitivity [3]. Insulin resistance in type II diabetics results from the inability of target tissues (skeletal muscle and adipose) to respond to insulin signaling or impaired insulin secretion related to individual genetics, diet, and exercise habits [4–6]. During a normal insulin response,

glucopyranosyloxy)-3-phenylpropenoic acid; PPAR␣/␦/␥, peroxisome proliferator activated receptor ␣/␦/␥; PTP1B, proteintyrosine phosphatase 1B; PQQ, pyrroloquinoline quinone; Rac1, Ras-related C3 botulinum toxin substrate 1; SIRT1, sirtuin 1; T2DM, type II diabetes mellitus; TFAM, mitochondrial transcriptional factor A; TR␣1, thyroid hormone receptor ␣ 1 www.mnf-journal.com

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insulin acts to stimulate glucose uptake through intracellular enzymatic cascades that result in facilitated diffusion by glucose transporters [7–9]. In skeletal muscle, the predominant glucose transporter is glucose transporter 4 (GLUT4) [10]. Insulin acts in part to promote translocation of intracellular vesicles containing GLUT4, allowing integration with the plasma membrane. It has been shown that GLUT4 levels are significantly decreased in the skeletal muscle of type II diabetic patients as well as in severe insulin resistant patients [11, 12]. It has been postulated that potent stimulators of GLUT4 expression/translocation can lead to improved insulin sensitivity and possibly alternative treatments for insulin resistance, demonstrated experimentally through the use of GLUT4 overexpression in murine skeletal muscle [13, 14]. This work uniquely describes the effects of various dietary components on GLUT4 expression, glucose uptake, and insulin sensitivity in skeletal muscle, independent of macromolecule manipulation. Original investigations summarized in this report were included if the investigation reported data regarding (i) increases in the expressional or translocation levels of skeletal muscle GLUT4, (ii) activation of one or more important cellular signaling proteins (such as Akt) in insulin sensitivity, (iii) improved glucose clearance/uptake, reduced blood glucose, or increased insulin sensitivity following the administration of a naturally occurring dietary chemicals.

2

Induction of GLUT4 expression and translocation by exercise and insulin

2.1 Exercise Various stimuli promote the transcription of GLUT4 leading to increased glucose transport in skeletal muscle. This highly regulated process can be motivated by potent events such as insulin release following a carbohydrate-rich meal, or in response to exercise [15]. During exercise, the sarcoplasmic reticulum releases Ca2+ to elevate cytosolic concentrations and stimulate muscle contraction [16,17]. Heightened cytosolic Ca2+ concentrations increase levels of GLUT4 expression by activating the calcium/calmodulin-dependent protein kinase II (CaMKII) signaling cascade [16–19]. Specifically, intracellular pools of Ca2+ bind calmodulin, forming an active Ca2+ –calmodulin complex, ultimately activating the skeletal muscle isoform of CaMKII, which stimulates calcineurin [20–24]. Calcineurin is thought to promote GLUT4 expression [25] by dephosphorylating myocyte enhancer factor 2 (MEF2; discussed below) [26], although the exact mechanism is still debated. Additionally, exercise increases the intracellular AMP/ ATP ratio, which activates 5 adenosine monophosphate activated protein kinase (AMPK), widely considered the metabolic master-switch, leading to heightened metabolism and GLUT4 gene expression by activation via phosphorylation of various intracellular proteins and co-activators [27,28].  C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Mol. Nutr. Food Res. 2014, 00, 1–17

Peroxisome proliferator activated receptor ␥ coactivator 1␣ (PGC-1␣) is one such targeted protein and is directly implicated in metabolic disease by controlling cellular energetics, mitochondrial biogenesis [29], and GLUT4 expression [30]. Under normal conditions, PGC-1␣ is constrained to the cytosol in an inactive and acetylated form [31], however PGC1␣ must be deacetylated (possibly by sirtuin 1 (SIRT1)) and phosphorylated by AMPK, producing active PGC-1␣ [31–35]. Once in the nucleus, phosphorylated PGC-1␣ drives expression of nuclear respiratory factor 1 and 2 (NRF1/2), which forms a hetero-tetramer with phosphorylated PGC-1␣ and the estrogen-related receptor ␣ (ERR␣) [36] to ultimately increase transcription of mitochondrial transcriptional factor A (TFAM) [37]. TFAM regulates expression of the mitochondrial genome, leading to mitochondrial biogenesis with the assistance of mitochondrial transcription factors [38]. In addition, PGC-1␣ is also a potent activator of GLUT4 gene expression specifically through induction of MEF2C [39]. Of interest, PGC-1␣ also directly coactivates transcription of MEF2A [40] and indirectly through downstream action of NRF1 [41,42]. It is essential to clarify that there are multiple MEF2 isoforms (including A, C, and D) active in skeletal muscle, and their activities are dependent on stage of cellular differentiation [39, 43, 44]. Cooperation of GLUT4 enhancer factor (GEF) and MEF2A/C/D directly regulates the activation of the GLUT4 gene [43–46]. Cytosolic pools of GEF lack the ability to activate gene expression until phosphorylated by AMPK, allowing translocation into the nucleus, upstream binding of the promoter, and activation of transcriptional activity and gene expression [47, 48]. Activation and expression of the GLUT4 gene involves a coordinated effort between MEF2, the thyroid hormone receptor ␣ 1 (TR␣1), myogenic differentiation 1 (MyoD) [49], and Kr¨uppel-like factor 15 (KLF15) [50], which bind a muscle-specific GLUT4 gene enhancer [51]. AMPK also translocates to the nucleus [52] and positively regulates gene expression via phosphorylation of histone deacetylase 5 (HDAC5), which, in its dephosphorylated form, acts as an inhibitory factor and transcriptional repressor of MEF2 activity [40, 45, 53].

2.2 Insulin Insulin is known to stimulate GLUT4 translocation via two pathways: adaptor protein with plekstrin homology and Src homology 2 domains (APS)—insulin signaling pathway and phosphoinositide 3-kinase (PI3K)dependent pathway. The PI3K-dependent pathway begins when secreted insulin binds to the insulin receptor (IR), stimulating autophosphorylation through tyrosine kinase functionality of the insulin receptor substrate-1 (IRS-1), which is bound by PI3K [54–56]. Activated PI3K phosphorylates and transforms the membrane glycerophospholipid phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-trisphosphate (PIP3), which then www.mnf-journal.com

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Figure 1. Summary of GLUT4 expression and translocation in skeletal muscle. Dark bold line indicates enzymatic catalysis. Long dashed line indicates GLUT4 packaging into vesicle. Short dashed line indicates mechanism yet to be elucidated.

recruits and activates phosphoinositide-dependent kinase 1 and 2 (PDK1/2) to then phosphorylate and activate Akt (also known as protein kinase B) (Akt/PKB) [57,58]. Once activated, Akt phosphorylates the Akt substrate of 160 kDa (AS160) leading to translocation of GLUT4 vesicles [59]. PI3K also activates Ras-related C3 botulinum toxin substrate 1 (Rac1), which is also involved in GLUT4 translocation [60, 61]. Additionally, transcription of MyoD occurs during cell differentiation through an identical PI3K-PKB pathway, however stimulated by insulin-like growth factor 1 (IGF-1) binding to the insulin-like growth factor 1 receptor (IGF-1R) [62–64]. It has also been demonstrated that p38 mitogen-activated protein kinase (p38 MAPK) is dually phosphorylated during exercise [65], insulin administration, and implicated in glucose uptake [66]. No pathway or signal cascade has been fully elucidated regarding p38 MAPK as a regulator of GLUT4 expression and translocation, however it is believed to only have a minor association. Moreover, p38 MAPK is shown to be involved in phosphorylation of MEF2 in response to exercise [67]. Figure 1 illustrates the activation, induction, and translocation of GLUT4 related to enzymatic cascades.

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Dietary stimulators of GLUT4

It is widely accepted that consumption of select foodchemicals found in nutrient-dense foods such as fruits and vegetables is ideal for individuals to meet their energy needs, while simultaneously reducing prevalence of several diseases including diabetes [68–74]. Although not an exhaustive list of all known dietary stimulators of GLUT4 expression and translocation, the following discussion reviews experimental evidence supporting dietary stimulation of GLUT4 and associated physiological adaptations including improved insulin sensitivity. Table 1 summarizes the results from these investigations, as well as any reported adverse effects, including cytotoxicity. Resveratrol, a polyphenol found primarily within the skins of grapes, select berries, peanuts, and most notably, fermented red wine, has been demonstrated to increase cellular glucose uptake [75, 76] and promote GLUT4 translocation [77–79]. Resveratrol treatment also increases phosphorylation of AMPK [75,77,79] along with phosphorylation of Akt [76,79]. The effects of resveratrol alter metabolism by decreasing gluconeogenic enzyme expression as well as

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WR (soleus muscle) [116]

L6 myotubes [109]

L6 myotubes [115]

L6 myotubes [112]

Agmatine

Arecoline

Arginine

Angelica keiskei extract

SD rats (spitrochlearis and soleus muscle) [122] WR (epitrochlearis muscle) [121]

L6 myotubes [18]

√

√

√

√

√

√

Blood glucose

√

Insulin sensitivity

↑p-CAMKII protein

↑p-IRS-1 protein; ↓p-ERK protein ↑p-ACC, p-CAMKI protein, FA uptake and oxidation, AMPK␣2 activity ↑MEF2A binding GLUT4 gene, GLUT4 RNA; ↓nuclear HDAC5/MEF2 ↑MEF2A, MEF2D protein, cytosolic Ca2+ ↑PGC-1␣, NRF1/2,TFAM protein, cytosolic Ca2+ ↑p-ACC protein, AMPK␣1/2 activity; ↓ATP, PCr, glycogen

↑PI3K and GLUT4 RNA; ↓triglycerides ↑Glycogen synthesis, intracellular and total c-GMP, nitrate levels, lipid oxidation, AMPK␣, p-ACC, GSK-3␣/␤, nNOS protein

↑␤-Endorphin, GLUT4 RNA; ↓PEPCK RNA and protein

Additional findings

(Continued)

3.5 mM for 2 or 15 min†

3 mM for 1 h, or 1–15 mM for 15 min†

5 mM for 5 h/day for 5 days†

10 mM for 2 h, followed by culture in serum-free medium for between 0–6 h † 5 mM for 3 h/day for 5 days†

3 mM in perfused rat hindquarters: †

Xanthoangelol and 4-hydroxyderricin at 10 ␮M for 1–4 h: treatment not cytotoxic 18-h fast. Oral administration of 50 mg/kg significant at 60 min. 250 mg/kg significant at 15, 30, and 60 min † 5 ␮M for 4 h †

Overnight fast. 1.0 mg/kg tail vein injection, three times daily for 4 days. BG measured at 30 min postinjection† 25 ␮M for 4 h: cytotoxicity > [50 ␮M] 7 mM for 6 days †

Treatment: cytooxicity

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L6 myotubes [119]

WR (gastrocnemiussoleus-plantaris muscle) [120] C2C12 myotubes [123]

√

√

√

√

√

*

√

√

p-AMPK

Caffeine

√

√

p-Akt

Glucose uptake

*

*

√*

√

GLUT4

Protein expression

Astaxanthin L6 myotubes [97]

ICR mice [112]

Model

Compound

Table 1. Summary of dietary stimulators of GLUT4 expression, translocation, and physiological adaptions in various experimental models of skeletal muscle

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Model

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WR (soleus muscle) [85] Daidzein L6 myotubes [84] KKAy/Ta Jcl mice [84] db/db mice (gastrocnemius muscle) [84] 10-Hydroxy- L6 myotubes [128] 2decenoic acid C57BL/6J (skeletal muscle) [128]

Anacardium C2C12 myotubes occiden[111] tale nut extract Curcumin C2C12 myotubes [86]

C57BL/J mice [107]

db/db mice [105]

C57BL/6J mice [106]

C57BL/6J mice [105]

C2C12 myotubes [102] WR (gastrocnemius muscle) [103]

Chlorogenic L6 myotubes [83] acid Cinnamon C2C12 myotubes and [104] extracts OLETF rats [104]

Compound

Table 1. Continued

√

*

√

√

√

√

√

√

√

√

√

√

Glucose uptake

√

√

p-AMPK

√

p-Akt

*

*

*

*

√*

*

√

GLUT4

Protein expression

√ √

√

√

√

√

√

√

Blood glucose

Insulin sensitivity

↑p-ACC, p-CaMKIV protein

↑p-ACC, p-CaMKIV protein, AMPK activity

↑p-ACC protein

↑Serum HDL-c; ↓p-Akt, GLUT4 RNA ↑p-ACC protein, oxygen consumption

↓Serum FFA

↑IRS-1, IR protein

↑Serum non-esterified fatty acids, protein; ↓serum creatine ↓Serum FFA, LDL-c, insulin

↑PPAR␥ protein

Additional findings

16-h fast. 1.6 mmol/kg body weight for 15, 30, or 60 min† (Continued)

25 ␮M for 90 min: treatment not cytotoxic

100 ␮M for 4 h† 0.1% of diet for 4 or 5 wk† 0.1% of diet for 4 or 5 wk†

40 ␮M for 24 h: cytotoxicity > [131] 1 ␮M for 30 min or 60 mg/kg†

25, 50, 100 ␮g/mL for 18 h: treatment not cytotoxic after 18 h

Overnight fast. 400 mg/kg/day for 21 days† Overnight fast. 150 mg/kg/day for 14 days† 6-h fast. 400 mg/kg/day for 14 days† 20 mg/kg/day for 4 wk†

30 mg/kg/day for 22 days†

16-h fast. Oral administration of 100 mg/kg/day for 15 wk† 100 or 1000 ␮g/mL for 3 h†

25 ␮M for 5 h: cytotoxicity > [50 ␮M] 30 ␮g/ml for 4 h: treatment not cytotoxic

Treatment: cytooxicity

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GK rats [127]

EPA/DHA

Human biopsy primary cultured myotubes (musculus vastus lateralis) [126] L6 myotubes [109]

L6 myotubes [96]

√

*

√

√

√

√

√

√

√

√

Glucose uptake

√

√*

*

*

√

√

√

* *

p-AMPK

p-Akt

GLUT4

Protein expression

√

√

Blood glucose

√

√

√

Insulin sensitivity

↑GLUT4 RNA; ↓body fat accumulation, adipose leptin-1 ↑PI3K protein

↑PI3K and GLUT4 RNA; ↓triglycerides ↑G6Pase, IR RNA, PGC-1␣ protein; ↓serum insulin

↑PGC-1␣ protein and RNA, GLUT4 RNA, glycolytic/oxidative metabolism, mitochondrial density ↑Glycolytic metabolism, lipid synthesis and uptake; ↓glycogen synthesis

↑AMPK protein, GLUT4 RNA; ↓serum insulin and skeletal muscle TNF-␣, IL-6, PPAR␣, PPAR␦

↑p-p38 MAPK, p-ACC

Additional findings

5 ␮M for 5 h: cytotoxicity > [50 ␮M] 40 ␮g/mL for 48 h: treatment not cytotoxic (Continued)

1.06 or 2.22% of diet for 5 wk†

25 ␮M for 4 h: cytotoxicity > [50 ␮M] 0.2% diet for 2 wk: †

0.6 mM for 24 h†

50 ␮M for 24 h: treatment not cytotoxic up to 48 h

500 ␮M for 3 h†

40 ␮M for 3 h † 12-h fast. 75 mg/kg for 1 h, or 100 nM for 15 min† 12-h fast. 75 mg/kg for 1 h, or 100 nM for 15 min† 100 nM for 15 min† 20 ␮M up to 72 h: treatment not cytotoxic up to 48 h 0.5 mg/kg for 4 wk†

Treatment: cytooxicity

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Gingerol

Fucoxanthin KKAy mice (soleus and extensor digitorum longus muscle) [98] C57BL/6J mice (skeletal muscle) [99] Ferulic acid L6 myotubes [83]

Eugenol

L6 myotubes [88] SD rats (soleus muscle) [89] C57BL/6 mice (soleus muscle) [89] L6 myotubes [89] C2C12 myotubes [91]

EGCG

C2C12 myotubes [127] Human rhabdomyosarcoma cells [129]

Model

Compound

Table 1. Continued

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C2C12 myotubes [130] KKAy mice [130]

L6 myotubes [125]

ob/ob mice (gastrocnemius muscle) [93] L6 myotubes [93] Kunming mice (gastrocnemius muscle) [94] C2C12 myotubes [94]

Propolis

Quercetin

SD rats (epitrochlearis muscle) [117] B6.BKS(D)-Leprdb /J mice [118] L6 GLUT4myc myotubes [118] CHO-HIRc-mycGLUT4eGFP cells [118] C2C12 myotubes [110] WR [110]

PQQ

PPAG

Naringenin Nitric oxide and nitric oxide precursors

L6 myotubes [97] L6 GLUT4myc myotubes [100]

Lipoic acid

L6 myotubes [101] L6 myotubes [95] L6 myotubes [114]

Model

Compound

Table 1. Continued

√

√

√

*

*

*

*

*

√

*

GLUT4

√

√

√ √

p-Akt

√

√

√

√ √

p-AMPK

Protein expression

√

√

√

√

√

√

√ √

√

Glucose uptake

√

√

√

√

√

Blood glucose

√

Insulin sensitivity

18-h fast. 20 mg/mL/day for 14 days† 1 ␮g/mL for 15 min: treatment not cytotoxic 30 mg/kg alternating days for 10 wk†

0.3 mg/kg for 2 wk, 3.0 mg/kg for 1 wk† 1000 nM for 5 h†

100 ␮M for 3 h†

100 ␮M for 30 min†

50 mg/L in drinking water for 4 wk† 100 ␮M for 30 min†

100 ␮M for 10 min†

1000 ␮M for18 h† 150 ␮M for2 h† 10 ␮M or 6 days†

10 or 100 mM for 4 h† 2.5 mM for 15 min†

Treatment: cytooxicity

↑PPAR␣, ACC, MCAD, CPT-1, GLUT4, PGC-1␣ RNA, p-ACC protein

(Continued)

10 ␮M for 24 h: treatment not cytotoxic

200 ␮M for 48 h† ↑p-ACC; ↓blood triacylglycerol, 12-h fast. 5, 10, 20 mg/kg/day total cholesterol, for 13 wk†

↑GLUT4 RNA; ↓TNF-␣, iNOS RNA, NF␬B activation

↑p-PI3K protein

↑p-IRS, p-IR, protein

↑cGMP

↑p-ACC, p-AMPK␣ nuclear translocation

↑p-IRS-1 protein ↑p-p38MAPK protein, p38 MAPK activity, PI3K ativity, Akt activity

Additional findings

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C2C12 myotubes [92] L6 myotubes [77] db/db mice [77]

Resveratrol

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L6 myoblasts [124]

Safranal

Synephrine

√ √

√

√

√

√

√ √

√

√ √

√

√

√

√

Blood glucose

Insulin sensitivity

Treatment: cytooxicity

100 ␮M for 18 h† 100 ␮M for 4 h† ↑Glucose tolerance 5 mg/mL/100g body weight for 3 wk† Overnight fast. 10 mg/kg/day for 16 wk† 10 ␮M for 24 h† 100 ␮M for 2 h: cell morphology unaltered up to 125 ␮M 1 mg/kg/day for 15 days or ↑p-ER␣, p-IR protein; ↓serum 15 wk† cholesterol, triglycerides, uric acid ↑p-ER␣, p-p38 MAPK, p-ERK, 0.1 ␮M for 14 h: treatment not p-IR protein cytotoxic ↑PEPCK protein Overnight fast. 0.05–10 mg/kg/day for 7 days† 30 ␮M for 30 min† ↑PGC-1␣ RNA 50 ␮M for 24 h: cytotoxicity > [50 ␮M] ↓Mitochondrial content and 100 mg/kg day for 9 wk† respiration ↑p-IRS, p-IR, protein 20 ␮M for 24 h: treatment not cytotoxic 18-h fast. 20 mg/kg/day for 2 wk† ↑Glucose consumption, lactate 100 ␮M for 24 h: cytotoxicity > production [100 ␮M] ↓Triglycerides 20 ␮M for 4 h: cytotoxicity > [50 ␮M] ↑p-ACC protein

Additional findings

Abbreviations: BG, blood glucose; GK, Goto-Kakizaki rats; OLETF, Otsuka Long–Evans Tokushima fatty rat; SD, Sprague-Dawley rats; WR, Wistar rats. Notes: *GLUT4 plasma membrane translocation; † side effects not evaluated or reported by original research.

*

√

√

√

√

p-AMPK

Glucose uptake

N. P. Gannon et al.

Vanillic acid L6 myotubes [109]

SIRT1 knockout mice [82] C2C12 myotubes [113] KKAy mice [113] *

√

√

WR (soleus muscle) [76] C2C12 myotubes [76] C2C12 myocytes [81]

√

*

C2C12 myotubes [79]

p-Akt

*

*

*

*

GLUT4

Protein expression

SD rats (soleus muscle) [79]

SD rats (soleus muscle) [78] C2C12 myotubes [78] L6 myotubes [75]

Model

Compound

Table 1. Continued

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lowering serum triglycerides and uric acid [76, 79]. Phosphorylation of select proteins indicates that resveratrol acts to influence glucose uptake via a diverse variety of pathways including p38 MAPK, PI3K/Akt, and AMPK [75, 76, 79]. In C2C12 muscle cells, resveratrol has been demonstrated to stimulate activity of SIRT1, and treatment of cells with resveratrol in combination with leucine increases SIRT1 and 3 activity [80], which can deacetylate PGC-1␣. The action of resveratrol to act on sirtuins is debatable. In C2C12 myocytes, it has been shown that moderate doses of resveratrol increase AMPK phosphorylation through a SIRT1-dependent mechanism, while high doses of resveratrol increase phosphorylation of AMPK in a SIRT1-independent fashion, to later drive gene expression of PGC-1␣, aligned with results seen in vivo [81]. Interestingly, resveratrol-treated SIRT1 knockout mice (specific to skeletal muscle) were shown to have decreased mitochondrial content and respiration [82], suggesting SIRT1 may be necessary for resveratrol to increase mitochondrial content in skeletal muscle. Antioxidants prevent damage from oxygen radicals including oxidative stress of cell structure and function. Chlorogenic acid, popularly found in green coffee bean extract, increases glucose uptake, GLUT4 gene expression, and gene expression of peroxisome proliferator activated receptor gamma (PPAR␥) [83]. An isoflavone found in soybeans, daidzein, increases phosphorylation and activation of AMPK, increasing GLUT4 translocation and glucose uptake, while simultaneously decreasing blood glucose in db/db and KK-Ay/Ta Jcl mice [84]. Similarly, curcumin, the bioactive component of the spice turmeric, increases GLUT4 translocation and increases glucose uptake in Wistar rat skeletal muscle [85, 86], assisted through phosphorylation of AMPK [86]. Curcumin also leads to the phosphorylation and inactivation of acetylCoA carboxylase (ACC), which synthesizes a required starting material for fatty acid biosynthesis, malonyl-CoA [86], further supporting a metabolic shift toward efficient utilization rather than storage of biomolecules. An abundant antioxidant (as well as a phytopolyphenol) in white and green tea and minimally in black tea, epigallocatechin-3-O-gallate (EGCG), possesses thermogenic effects and increases lipid oxidation [87] acting by inhibiting catechol-O-methyltransferase, leading to translocation of GLUT4 [88–90]. In L6 myotubes, EGCG has been shown to increase glucose uptake dependent on increased phosphorylation of Akt and AMPK [88, 91]. EGCG has also been demonstrated to increase phosphorylation of p38 MAPK and ACC [91]. These data imply that EGCG’s mechanism of action is partially via the PI3K/Akt signaling pathway. Another polyphenol and antioxidant commonly found in fruits and vegetables (notably apples and onions), quercetin, increases glucose uptake [92] via phosphorylation of Akt and AMPK leading to increased GLUT4 expression similar to the effects of both resveratrol and curcumin [93, 94]. Interestingly, quercetin also fosters adaptations in metabolism, namely phosphorylation of ACC protein (decreases fatty acid synthesis) [92], increased RNA induction of carnitine  C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

9 palmitoyltransferase-1 (CPT-1) (facilitates transfer of fatty acid into mitochondria for oxidation), medium-chain acylcoenzyme A dehydrogenase (involved in lipid oxidation), and PPAR␣ [94]. In kunming mice, as well as ob/ob mice, quercetin has been shown to decrease blood glucose, triacylglycerol, and cholesterol levels [93, 94]. Additionally, naringenin, commonly found in citrus fruits such as oranges and grapefruits, is both an antioxidant and polyphenol documented to increase glucose uptake mechanistically through induction of AMPK, without altering phosphorylation of Akt [95], indicating naringenin may not affect insulin signaling pathways to increase GLUT4 translocation. A bioactive compound found within ginger, as implied by the name, gingerol, is demonstrated to stimulate GLUT4 translocation and associated glucose uptake [96]. Astaxanthin, a reddish carotenoid associated with pink or red seafood and microalgae, promotes phosphorylation of Akt and IRS-1 leading to GLUT4 translocation and the downstream effect of increased glucose uptake [97]. Another carotenoid with similar mechanistic function, fucoxanthin, found in seaweed and brown algae chloroplast, facilitates phosphorylation of Akt resulting in increased GLUT4 expression and translocation [98] through an insulin signaling pathway. Systemically, fucoxanthin decreases blood glucose, serum insulin, adipose leptin, and body fat accumulation in response to increases of glucose-6-phosphatase (G6Pase) and IR RNA, and PGC-1␣ protein expression in KK-Ay and C57BL/6J mice [98, 99]. Lipoic acid stimulates phosphorylation of AMPK, p38 MAPK, and IRS-1 together with increasing activity of PI3K, Akt, and p38 MAPK [97, 100]. Moreover, GLUT4 translocation and increased glucose uptake is reported in L6 cells treated with lipoic acid [100, 101], indicating lipoic acid achieves this by influencing the PI3K/Akt insulin signaling pathway and a multifaceted approach by AMPK. Cinnamon and extracts derived from cinnamon are shown to increase GLUT4 protein and translocation [102, 103] leading to increased glucose uptake [104] and decreased blood glucose in C57BL/6J, db/db, and C57BLKS/J mice [105–107]. In addition, cinnamon and its constituents are shown to alter serum content, namely by increasing nonesterified fatty acids [103] and HDL-c [107]. It is supported that cinnamon may elicit these benefits by increasing phosphorylation of AMPK [104]. Previously, it has been documented that cinnamon extracts have the ability to phosphorylate and inactivate proteintyrosine phosphatase 1B (PTP1B) [108], which functions by inactivating the IR, thus increasing sensitivity to insulin. In other spices such as clove oil, basil, cinnamon, nutmeg, and bay leaf, the active constituent, eugenol, is validated to increase GLUT4 expression and glucose uptake [109]. Similarly, ferulic acid, found within grains, sweet corn, and tomatoes, also increases glucose uptake and GLUT4 expression [83]. Eugenol and ferulic acid have both been demonstrated to increase PI3K expression, providing the evidence that these particular antioxidants function via the PI3K/Akt insulin signaling cascade [83, 109]. Vanillin and vanillic acid found in www.mnf-journal.com

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ac¸ai oil also increase glucose uptake in L6 myotubes [109]. Z-2(␤-D-glucopyranosyloxy)-3-phenylpropenoic acid (PPAG), an ␣-hydroxy acid found within Aspalathus linearis, commonly known as rooibos and contained within herbal teas, leads to increases in glucose uptake in C2C12 myotubes and decreases blood glucose in insulin resistant mice [110]. Extracts of the nut of the cashew tree, or Anacardium occidentale, facilitate increased glucose uptake mediated through phosphorylation of AMPK [111]. Furthermore, the extracts elevated oxygen consumption indicating complete mitochondrial metabolism and discouraged fatty acid biosynthesis. 4-Hydroxyderricin and xanthoangelol, the active components of the Chinese medicinal herb, Angelica keiskei, increase GLUT4 translocation along with increased glucose uptake without phosphorylation of Akt or AMPK [112], indicating the possibility of eliciting its effects from an unrelated mechanism. In ICR mice, 4-hydroxyderricin and xanthoangelol appear to decrease blood glucose [112]. Safranal, a constituent of the internationally popular spice, saffron, is a potent stimulator of glucose uptake and concurrent GLUT4 translocation [113]. Safranal appears to function through phosphorylation of AMPK, IR, and IRS, suggesting that safranal elicits its effects through both insulin-independent and -dependent mechanisms, respectively [113]. Nitric oxide and other nitric oxide precursors, such as arginine and agmatine, alter substrate oxidation and metabolic rate by stimulating glycogen synthesis, lipid oxidation, inhibiting fatty acid biosynthesis through inactivation of ACC, and suppressing gluconeogenic glucose synthesis by decreasing phosphoenolpyruvate carboxykinase (PEPCK) expression [114–116]. Similarly, these metabolites increase glucose uptake aided by GLUT4 translocation [117], stimulated by activation and phosphorylation of AMPK [114,115,118]. In L6 myotubes, supplementation with arginine increased phosphorylation of Akt, suggesting that one possible mechanism of NO-stimulated GLUT4 translocation is via the PI3K/Akt pathway [115]. Nitric oxide has also been shown to increase glucose uptake and cGMP levels [117]. Metabolic and central nervous stimulants, such as caffeine, function by increasing intracellular pools of Ca2+ [18, 19, 119] that subsequently phosphorylate and activate CAMK(I/II) and later phosphorylate and increase activity of AMPK [120–122]. Activation of the aforementioned enzymes increases glucose uptake primarily by increasing GLUT4 expression and plasma membrane translocation by altering MEF2A/D protein expression and DNA binding [119, 123]. Additionally, caffeine phosphorylates ACC, inhibiting the enzyme and decreasing fatty acid biosynthesis, further promoting mitochondrial fatty acid uptake and oxidation [120, 122]. Caffeine also decreases muscle ATP content, phosphocreatine (PCr), and glycogen content [122], altering substrate utilization and energy expenditure. The primary active component found in the areca nut (fruit of Areca catehu), arecoline, is also a potent central nervous system stimulator and treatment of L6 myotubes with arecoline increased GLUT4 expression along with glucose uptake [109]. Of interest, arecoline in C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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creases expression of PI3K and PPAR␥ [109], evidence that this compound functions via activating the PI3K/Akt pathway for GLUT4 translocation and mediates glucose homeostasis and insulin sensitivity, respectively. The ␤-2 adrenoceptor agonist found in citrus fruit, synephrine, has similar functions as naringenin and increases GLUT4 translocation, as well as phosphorylation of AMPK [124] to possibly function through an insulinindependent mechanism of GLUT4 translocation. Interestingly, a resin sealant used by bees to seal their hives, propolis, increases glucose uptake along with GLUT4 translocation [125]. In addition to phosphorylation of AMPK, propolis increases phosphorylation of PI3K [125], demonstrating that this compound modulates glucose uptake through both an insulin signaling dependent mechanism and an insulin signaling independent mechanism. Polyunsaturated fatty acids are gaining popularity for a potential role in cardiovascular disease, obesity, and diabetes mellitus. Eicosapentaenoic acid (EPA) profoundly alters muscle cell metabolism, namely by increasing glycolytic and fatty acid biosynthetic metabolism and decreasing glycogen synthesis [126]. To assist, cells increase glucose uptake [126] and GLUT4 RNA and AMPK protein expression [127]. Goto-Kakizaki rats fed 0.5g/kg body weight EPA for 28 days demonstrated decreased serum insulin, decreased RNA for IL-6 in skeletal muscle and adipose tissue, and decreased TNF-␣ in skeletal muscle, along with decreased PPAR␣ and PPAR␦ RNA [127], suggesting treatment with EPA can reduce inflammation, while simultaneously altering metabolism. 10-Hydroxy-2-decenoic acid, a medium-chain fatty acid found in royal jelly, the primary source of food of queen honeybee larva, increases GLUT4 translocation and glucose uptake through phosphorylation and increased activity of AMPK and phosphorylation of CaMKIV [128]. Moreover, this unique compound induces phosphorylation of ACC [128], indicating metabolic reprogramming through downregulation of fatty acid biosynthesis. Interestingly, in human rhabdomyosarcoma cells, our lab has demonstrated that combination EPA/DHA can increase GLUT4 RNA and PGC-1␣ RNA and protein to stimulate glycolytic and oxidative metabolism [129]. Pyrroloquinoline quinone (PQQ), a redox cofactor and antioxidant commonly found in tea, green peppers, kiwi, fermented soybeans, and papaya, increases glucose uptake, GLUT4 plasma membrane translocation, and stimulates members of insulin signaling pathways, namely p-Akt, pIR, and p-IRS [130]. Along with these stimulatory effects, PQQ also decreases blood glucose in KK-Ay mice [130]. Figure 2 summarizes aforementioned stimulators of GLUT4 translocation and potential evidenced mechanisms of actin.

4 Clinical trials Few clinical trials have evaluated the aforementioned naturally occurring food chemicals as tools to increase muscle www.mnf-journal.com

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Figure 2. Summary of dietary stimulators of GLUT4 expression and translocation, and their mechanisms of action in skeletal muscle. Dark bold line indicates enzymatic action. Long dashed line indicates GLUT4 packaging into vesicle or transcription of mitochondrial DNA and mitochondrial biogenesis. Short dashed line indicates mechanism yet to be elucidated. Short dotted line indicates glucose uptake.

GLUT4 content (likely because of the difficult task of harvesting muscle biopsies); however, several well-controlled trials have been performed to investigate the potential clinical role of these chemicals in managing T2DM. For example, diabetic and habitual coffee drinkers (aged 61 ± 9 years) who consumed 375 mg caffeine and were subjected to a mixedmeal tolerance test demonstrated increased serum glucose and insulin, when compared to habitual coffee drinkers administered a placebo [132]. When cinnamon was administered to 57 diabetic subjects twice daily for 3 months as 500 mg capsules, cinnamon was ineffective at lowering fasting glucose, LDL, and triglycerides [133]. Conversely, diabetic subjects given cinnamon as 1, 3, or 6 g/day for 40 days led to decreases in serum glucose, suggesting a dosedependent relationship. Moreover, 58 T2DM patients receiving 2 g/day of cinnamon for 12 wk had decreased HbA1c, fasting serum glucose, and systolic and diastolic blood pressures [134]. Additionally, short-term cinnamon administration was shown to reduce triglyceride, LDL, and total cholesterol levels [135]. Similarly, when polyphenols in green tea were supple C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

mented to 16 subjects (aged 20–65) three times daily for 16 wk, within-group comparisons revealed reduced HbA1c and serum insulin levels, although no changes in fasting glucose levels were reported [136]. Surprisingly, ten T2DM subjects (aged 42–65) taking fish oil (EPA/DHA) at 10g/day for 3 wk had increased fasting blood glucose, while fasting serum insulin and insulin sensitivity remained unchanged [137]. Fish oil administered to 11 T2DM patients (aged 61.8 ± 2.9) at 35 mg/kg/day for 3 months decreased triglyceride levels, without altering fasting glucose, serum insulin, insulin sensitivity, or HbA1c [138]. Moreover, 12 diabetic men (aged 54 ± 3) given 6 g/day of fish oil for 2 months had reduced triglycerides, but did not affect fasting blood glucose or serum insulin, or alter GLUT4 gene expression in adipose tissue [139]. A clinical trial of resveratrol was conducted with ten Chinese males with T2DM (aged 40–69) starting at 500 mg/day, increasing by 500 mg every 3 days to a maximum of 3 g/day. Resveratrol increased SIRT1 expression and phosphorylation of AMPK, along with heightened resting metabolic rate, however LDL was also elevated in the resveratrol group [140]. www.mnf-journal.com

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Future directions

Current knowledge suggests that many dietary components stimulate GLUT4 translocation and expression using in vitro and in vivo models, although much remains unknown about the precise effects that these chemicals have on diabetic individuals. For example, adequate clinical toxicology and pharmacology reports describing human tolerance to one or several of these dietary components are scarce. It is conceivable that chronic or excessive consumption of natural products (especially in supplemental forms) can have a toxic/detrimental effect. An obstacle limiting current research is the vast number of phytochemicals that comprise foods. For example, Balaji and colleagues evaluated the toxicities of 200 compounds found in turmeric, showing that 136 appear to be mutagenic, 153 to be carcinogenic, 64 to be hepatotoxic, and only 16 to appear not to have side effects [141]. Although difficult, it would be ideal to establish toxicology and pharmacology reports for individual components and “cocktails” to identify effects such as unknown nutrient–drug interactions. It would be valuable to understand which molecules have saturable benefits, leading to points of diminishing return above defined levels of consumption. Indeed, several future areas of investigation are warranted concerning the potential use of dietary components as a therapy for diabetes and insulin resistance.

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Concluding remarks

T2DM is characterized by resistance to insulin and insensitivity to insulin-regulated glucose uptake. The insulindriven expression and subsequent translocation of GLUT4 to the plasma membrane is reduced in diabetic individuals potentiated by a variety of mechanisms. Several interventions including diet and exercise, and pharmacological agents are commonly used to control diabetes. In general, the Dietary Guidelines promote a diet rich in fruits and vegetables [142], which inherently contains a myriad of macro- and micronutrients, natural compounds, and chemicals. The present report summarizes dietary components (most of which are found in foods promoted by the Dietary Guidelines) shown to stimulate GLUT4 translocation in skeletal muscle, independent of both exercise and insulin. From this work, we gather that dietary stimulators of insulin sensitivity and GLUT4 content appear to function through one (or both) of two primary mechanisms including (i) activation of GLUT4 expression via the PGC1␣/MEF/pGEF pathway, or (ii) promotion of GLUT4 translocation via the Akt/pAS160 axis. For several of the compounds summarized in this work, it is probable (and documented) that both of these potent signaling mechanisms may be targeted by a single chemical (Figure 2). Taken together, natural components may act as antidiabetic agents in their ability to mimic the effects of insulin and exercise on their related pathways to combat insulin resistance.  C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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No funding was received for this work. We would like to apologize to authors whose works were not included herein (this review is by no means exhaustive). The authors have declared no conflict of interest.

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