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ARTICLE Exercise-nutrient interactions for improved postprandial glycemic control and insulin sensitivity1 Jenna B. Gillen, Stephanie Estafanos, and Alexa Govette Abstract: Type 2 diabetes (T2D) is a rapidly growing yet largely preventable chronic disease. Exaggerated increases in blood glucose concentration following meals is a primary contributor to many long-term complications of the disease that decrease quality of life and reduce lifespan. Adverse health consequences also manifest years prior to the development of T2D due to underlying insulin resistance and exaggerated postprandial concentrations of the glucose-lowering hormone in- sulin. Postprandial hyperglycemic and hyperinsulinemic excursions can be improved by exercise, which contributes to the well-established benefits of physical activity for the prevention and treatment of T2D. The aim of this review is to describe the postprandial dysmetabolism that occurs in individuals at risk for and with T2D, and highlight how acute and chronic exercise can lower postprandial glucose and insulin excursions. In addition to describing the effects of traditional moder- ate-intensity continuous exercise on glycemic control, we highlight other forms of activity including low-intensity walking, high-intensity interval exercise, and resistance training. In an effort to improve knowledge translation and implementation of exercise for maximal glycemic benefits, we also describe how timing of exercise around meals and post-exercise nutri- tion can modify acute and chronic effects of exercise on glycemic control and insulin sensitivity. Novelty: � Exaggerated postprandial blood glucose and insulin excursions are associated with disease risk. � Both a single session and repeated sessions of exercise improve postprandial glycemic control in individuals with and with- out T2D. � The glycemic benefits of exercise can be enhanced by considering the timing and macronutrient composition of meals around exercise. Key words: exercise, glucose, insulin, type 2 diabetes, insulin resistance, nutrition, postprandial. Résumé : Le diabète de type 2 (« T2D ») est une maladie chronique en croissance rapide mais grandement évitable. Les augmenta- tions excessives de la glycémie après les repas sont l’un des principaux contributeurs à de nombreuses complications à long terme de la maladie qui diminuent la qualité de vie et en réduisent la durée. Des conséquences néfastes sur la santé se manifestent égale- ment des années avant le développement du T2D en raison de la résistance à l’insuline sous-jacente et des concentrations post- prandiales excessives de l’insuline, une hormone hypoglycémiante. Les excursions hyperglycémiques et hyperinsulinémiques postprandiales peuvent être améliorées par l’exercice afin d’engendrer les bénéfices bien établis de l’activité physique pour la prévention et le traitement du T2D. L’objectif de cette revue est de décrire le dysmétabolisme postprandial qui survient chez les personnes à risque et atteintes de T2D et de souligner comment l’exercice aigu et chronique peut réduire les excursions post- prandiales de glucose et d’insuline. En plus de décrire les effets de l’exercice continu traditionnel d’intensité modérée sur le con- trôle glycémique, nous mettons en évidence d’autres formes d’activité, notamment la marche à faible intensité, les exercices par intervalles à haute intensité et l’entraînement contre résistance. Dans un souci d’améliorer l’application des connaissances et la mise en œuvre de l’exercice pour des bénéfices glycémiques maximaux, nous décrivons également comment le moment de l’exercice dans le contexte des repas et l’alimentation postexercice peuvent modifier les effets aigus et chroni- ques de l’exercice sur le contrôle glycémique et la sensibilité à l’insuline. [Traduit par la Rédaction] Les nouveautés : � Des excursions postprandiales excessives de glycémie et d’insuline sont associées à un risque de maladie. � Une seule séance et des séances répétées d’exercice améliorent le contrôle glycémique postprandial chez les personnes avec et sans T2D. � Les avantages glycémiques de l’exercice peuvent être améliorés en tenant compte dumoment et de la composition enmacro- nutriments des repas dans le contexte de l’exercice. Mots-clés : exercice, glucose, insuline, diabète de type 2, résistance à l’insuline, nutrition, postprandial. Received 26 February 2021. Accepted 1 June 2021. J.B. Gillen, S. Estafanos, and A. Govette. Faculty of Kinesiology and Physical Education, University of Toronto, Toronto, ONM5S 2C9, Canada. Corresponding author: Jenna B. Gillen (email: jenna.gillen@utoronto.ca). 1This paper received the 2020 Applied Physiology, Nutrition, and Metabolism (APNM) Award for Nutrition Translation, which was granted by the Canadian Nutrition Society in conjunctionwith Canadian Science Publishing and the Editorial Staff of APNM. Copyright remains with the author(s) or their institution(s). Permission for reuse (free in most cases) can be obtained from copyright.com. Appl. Physiol. Nutr. Metab. 46: 856–865 (2021) dx.doi.org/10.1139/apnm-2021-0168 Published at www.cdnsciencepub.com/apnm on 3 June 2021. 856 A pp l. Ph ys io l. N ut r. M et ab . D ow nl oa de d fr om c dn sc ie nc ep ub .c om b y 18 7. 3. 24 8. 21 1 on 0 8/ 23 /2 1 Fo r pe rs on al u se o nl y. https://www.copyright.com/search.action?page=simple https://www.copyright.com/search.action?page=simple http://dx.doi.org/10.1139/apnm-2021-0168 Introduction Approximately 463 million people worldwide are living with diabetes, with numbers projected to increase by 50% over the next 25 years (Saeedi et al. 2019). Across Canada, 11 million Canadians (1 in 3 adults) are living with diabetes or prediabetes, 90% of which are type 2 diabetes (T2D) (Diabetes Canada 2018). While once thought to be a disease of later life, an increasing number of young adults are among the �480 Canadians diagnosed with T2D daily. Canadians 20 years of age now have a 50% chance of developing the disease in their lifetime, with disproportionally higher risk in select populations (e.g., 80% among indigenous adults) (Diabetes Canada 2018). These numbers are alarming given that diabetes reduces lifespan by 5–15 years and causes significant physical and mental health-related complications that decrease quality of life. Exaggerated elevations in blood glucose concentration after meals, termed postprandial hyperglycemia, is a primary contrib- utor to many long-term complications of T2D, including heart attacks, cardiovascular disease (CVD) and CVD-related mortality (Hanefeld et al. 1996; Sievers et al. 1999; Ceriello et al. 2004). Indeed, the World Health Organization identifies high blood glu- cose as the third highest risk factor for premature mortality after hypertension and tobacco use (World Health Organization 2009). Exaggerated increases in the glucose-lowering hormone insulin following meals (postprandial hyperinsulinemia) often manifest years before elevations in blood glucose concentration and is an early sign of risk for T2D (Zavaroni et al. 1999). Given that carbo- hydrates induce the largest increase in blood glucose and insulin concentrations relative to the other macronutrients (fat and pro- tein), carbohydrate-restricted diets are gaining momentum as a therapeutic strategy for individuals with obesity, prediabetes and T2D (Feinman et al. 2015). However, carbohydrates remain included in dietary recommendations for adults with T2D (Sievenpiper et al. 2018) and represent a substantial portion of the diet for many indi- viduals due to preference, accessibility and/or ethnocultural norms. Therefore, increased knowledge of strategies that reduce hyper- glycemia and hyperinsulinemia associated with carbohydrate intake is of utmost importance for nutrition professionals, health- care practitioners, and the�11million Canadians living with predia- betes or T2D. Lifestyle modification that includes regular physical activity can reduceon postprandial glucose peaks with the use of continuous glucose monitoring in type 2 diabetes. Am. J. 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Personalized nutrition by prediction of glycemic responses. Cell, 163(5): 1079–1094. doi:10.1016/j.cell.2015.11.001. PMID:26590418. Gillen et al. 865 Published by Canadian Science Publishing A pp l. Ph ys io l. N ut r. M et ab . D ow nl oa de d fr om c dn sc ie nc ep ub .c om b y 18 7. 3. 24 8. 21 1 on 0 8/ 23 /2 1 Fo r pe rs on al u se o nl y. http://dx.doi.org/10.2337/dc14-2474 http://www.ncbi.nlm.nih.gov/pubmed/25852207 http://dx.doi.org/10.7326/M14-1189 http://www.ncbi.nlm.nih.gov/pubmed/25732273 http://dx.doi.org/10.1210/clinem/dgaa345 http://www.ncbi.nlm.nih.gov/pubmed/32492705 http://dx.doi.org/10.1016/j.diabres.2019.107843 http://www.ncbi.nlm.nih.gov/pubmed/31518657 http://dx.doi.org/10.1007/s00125-018-4767-z http://dx.doi.org/10.1007/s00125-018-4767-z http://www.ncbi.nlm.nih.gov/pubmed/30426166 http://dx.doi.org/10.1249/MSS.0000000000002211 http://www.ncbi.nlm.nih.gov/pubmed/31809409 http://dx.doi.org/10.1016/j.jcjd.2017.10.009 http://www.ncbi.nlm.nih.gov/pubmed/29650114 http://dx.doi.org/10.2337/diabetes.48.4.896 http://www.ncbi.nlm.nih.gov/pubmed/10102709 http://dx.doi.org/10.7326/0003-4819-147-6-200709180-00005 http://www.ncbi.nlm.nih.gov/pubmed/17876019 http://dx.doi.org/10.1111/sms.12875 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http://www.who.int/healthinfo/global_burden_disease/GlobalHealthRisks_report_full.pdf http://www.who.int/healthinfo/global_burden_disease/GlobalHealthRisks_report_full.pdf http://dx.doi.org/10.1016/S0026-0495(99)90195-6 http://www.ncbi.nlm.nih.gov/pubmed/10459563 http://dx.doi.org/10.1016/j.cell.2015.11.001 http://www.ncbi.nlm.nih.gov/pubmed/26590418 Article Introduction Postprandial glycemic control along the spectrum of glucose tolerance Etiology of postprandial hyperglycemia and hyperinsulinemia Prevalence and perils of postprandial hyperglycemia and hyperinsulinemia Measurement of postprandial glycemia and insulinemia Exercise as a therapeutic strategy for reducing postprandial glucose and insulin excursions Phase 1: Exercise can immediately lower blood glucose concentration Influence of acute exercise-nutrient timing on postprandial glycemic excursions Influence of exercise ‘snacks’ on postprandial glycemic and insulinemic excursions Phase 2: Exercise can acutely improve insulin sensitivity for hours after exercise Influence of post-exercise macronutrient intake on acute improvements in insulin sensitivity Phase 3: Repeated sessions of exercise result in adaptations that improve glycemic control Influence of fasted vs. fed state exercise on training-induced improvements in insulin sensitivity and glycemic control Future directions and conclusion Conflict of interest statement References > /ConvertImagesToIndexed true /MaxSubsetPct 99 /Binding /Left /PreserveDICMYKValues false /GrayImageMinDownsampleDepth 2 /MonoImageMinResolution 1200 /sRGBProfile (sRGB IEC61966-2.1) /AntiAliasColorImages false /GrayImageDepth -1 /PreserveFlatness true /CompressPages true /GrayImageMinResolution 150 /CalCMYKProfile (U.S. Web Coated \050SWOP\051 v2) /PDFXBleedBoxToTrimBoxOffset [ 0.0 0.0 0.0 0.0 ] /AutoFilterGrayImages true /EncodeColorImages true /AlwaysEmbed [ ] /EndPage -1 /DownsampleColorImages true /ASCII85EncodePages false /PreserveEPSInfo false 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/EmbedJobOptions true /MonoImageDownsampleType /Average /DetectBlends true /EncodeGrayImages true /ColorImageDownsampleType /Average /EmitDSCWarnings false /AutoFilterColorImages true /DownsampleGrayImages true /GrayImageDict > /AntiAliasMonoImages false /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict] >> /ColorImageAutoFilterStrategy /JPEG /ColorImageMinResolutionPolicy /OK /ColorImageResolution 300 /PDFXRegistryName () /MonoImageFilter /CCITTFaxEncode /CalGrayProfile (Gray Gamma 2.2) /ColorImageMinDownsampleDepth 1 /JPEG2000GrayImageDict > /ColorImageDepth -1 /DetectCurves 0.1 /PDFXTrapped /False /ColorImageFilter /DCTEncode /TransferFunctionInfo /Preserve /PDFX3Check false /ParseICCProfilesInComments true /ColorACSImageDict > /DSCReportingLevel 0 /PDFXOutputConditionIdentifier () /PDFXCompliantPDFOnly false /AllowTransparency false /PreserveCopyPage true /UsePrologue false /StartPage 1 /MonoImageDownsampleThreshold 1.0 /GrayImageDownsampleThreshold 1.0 /CheckCompliance [ /None ] /CreateJDFFile false /PDFXSetBleedBoxToMediaBox true /EmbedOpenType false /OPM 0 /PreserveOverprintSettings false /UCRandBGInfo /Remove /ColorImageDownsampleThreshold 1.0 /MonoImageDict > /GrayImageDownsampleType /Average /Description /FRA /KOR /NLD (Gebruik deze instellingen om Adobe PDF-documenten te maken waarmee zakelijke documenten betrouwbaar kunnen worden weergegeven en afgedrukt. De gemaakte PDF-documenten kunnen worden geopend met Acrobat en Adobe Reader 5.0 en hoger.) /NOR /DEU /SVE /DAN /ITA (Utilizzare queste impostazioni per creare documenti Adobe PDF adatti per visualizzare e stampare documenti aziendali in modo affidabile. I documenti PDF creati possono essere aperti con Acrobat e Adobe Reader 5.0 e versioni successive.) /JPN/CHS /SUO /ESP /CHT >> /CropMonoImages true /DefaultRenderingIntent /RelativeColorimeteric /PreserveHalftoneInfo false /ColorImageDict > /CropGrayImages true /PDFXOutputCondition () /SubsetFonts true /EncodeMonoImages true /CropColorImages true /PDFXNoTrimBoxError true >> setdistillerparams > setpagedevicediabetes risk by �60% (Knowler et al. 2002) and minimize complications for those living with T2D (Umpierre et al. 2011; Chen et al. 2015; Colberg et al. 2016).While the health benefits of exercise for those at risk for or with T2D are wide-ranging, this review focuses specifically on the role of exercise in reducing postprandial hyperglycemic and hyperinsulinemic excursions and associated mechanisms. First, we describe the development of postprandial dysmetabolism along the spectrum of glucose tolerance, and how it is measured in both clinical and research settings. We then pro- vide an overview of how acute and chronic exercise can reduce postprandial glycemia and insulinemia in those at risk for, or with, T2D. In an effort to maximize knowledge translation on the glyce- mic benefits of exercise, we also consider how exercise type and tim- ing, as well as the nutrient composition of meals around exercise, canmodify exercise-induced improvements in glycemic control. Postprandial glycemic control along the spectrum of glucose tolerance Transient increases in blood glucose and insulin concentra- tions are a normal physiological response to carbohydrate intake. Indeed, the digestion of carbohydrates consumed in isolation or as part of a mixed-macronutrient meal results in elevated blood glu- cose concentration and stimulation of the glucose-lowering hor- mone, insulin, from the pancreas (Reaven 1979). The postprandial rise in insulin concentration facilitates glucose uptake into insulin- sensitive tissues, including skeletal muscle, adipose tissue and the liver (Defronzo 2009), which lowers blood glucose concentration to basal (or pre-meal) concentrations within 2–3 h following meal ingestion (Ceriello et al. 2008) (Fig. 1A). Factors such as the amount, source, and glycemic index of the carbohydrate, as well as the nutri- ent composition of themeal, can influence themagnitude and dura- tion of glycemic and insulinemic excursions (Wolever and Miller 1995). Assuming these factors to be equal, the magnitude and dura- tion of postprandial increases in blood glucose and insulin concen- trations are largely dependent on peripheral tissue sensitivity to the hormone insulin (i.e., insulin sensitivity) and pancreatic b-cell insu- lin secretion. Etiology of postprandial hyperglycemia and hyperinsulinemia Postprandial hyperglycemia and hyperinsulinemia are initially the result of decreased insulin-stimulated glucose uptake in pe- ripheral tissues, termed insulin resistance, which can develop as a result of genetic susceptibility, but more often is explained by poor nutrition and lack of physical activity driven by environ- mental factors and socioeconomic status (Diabetes Canada 2018). In the early stages of insulin resistance, increased insulin secre- tion is typically sufficient to ‘rescue’ insulin-stimulated glucose uptake and prevent postprandial hyperglycemia (Pories et al. 1992; Mari et al. 2001) (Fig. 1B). However, in the absence of lifestylemodifi- cation or pharmacological treatment, excessive rates of insulin secretion fail to compensate for an increasing state of insulin resist- ance over time, resulting in postprandial hyperglycemic excur- sions. If detected, diagnosis of impaired glucose tolerance (IGT) or prediabetes ensues, which is associated with elevations in both postprandial insulinemic and glycemic excursions (Punthakee et al. 2018). If diagnosed with T2D, a disease characterized by fasting hyperglycemia attributable to a failure to suppress hepatic glucose production (Sonksen and Sonksen 2000), postprandial hyperglyce- mia becomes more pronounced as a result of worsening peripheral insulin resistance and/or inadequate insulin secretion. As T2D pro- gresses, a significant decline in insulin secretion can also manifest as a result of pancreatic b-cell failure, resulting in reduced postpran- dial insulin concentrations and severe glucose intolerance requiring exogenous insulin to assist in regulating postprandial blood glucose concentrations (Defronzo 2009). Themechanisms of peripheral insulin resistance are numerous and complex, and beyond the scope of the present review; we direct an interested reader to other reviews on the topic (Defronzo 2009; Petersen and Shulman 2018). Among the insulin-sensitive tissues, skeletal muscle is the primary site of glucose disposal (Ferrannini et al. 1988), and therefore plays a key role in insulin resistance and postprandial dysmetabolism. Mechanisms of skele- tal muscle insulin resistance include impaired glucose transport and phosphorylation, decreased glucose oxidation, reduced glyco- gen synthesis and impairments in the insulin signaling pathway, which collectively reduce insulin-stimulated muscle glucose uptake via glucose transporter 4 (GLUT4) (Defronzo 2009). Elevations in inflammatory cytokines and intramyocellular lipid accumulation as a result of obesity and inactivity have been shown to directly impair aspects of the insulin signaling cascade and cause hypergly- cemia (Defronzo 2009; Petersen and Shulman 2018). Prevalence and perils of postprandial hyperglycemia and hyperinsulinemia The perils of postprandial hyperglycemia for those diagnosed with prediabetes and T2D are well established. Frequent hyper- glycemic excursions induce oxidative stress, inflammation and endothelial dysfunction within blood vessels, contributing to many complications of T2D such as CVD, stroke, kidney failure, blindness, and prematuremortality (Ceriello et al. 2004; Diabetes Canada 2018). However, it is estimated that as much as 40% of pre- diabetes and T2D cases remain undiagnosed in Canada (Rosella et al. 2015) as a result of disparities in access to healthcare and/or the limitations of fasting plasma glucose (the most common Gillen et al. 857 Published by Canadian Science Publishing A pp l. Ph ys io l. N ut r. M et ab . D ow nl oa de d fr om c dn sc ie nc ep ub .c om b y 18 7. 3. 24 8. 21 1 on 0 8/ 23 /2 1 Fo r pe rs on al u se o nl y. screening tool) to identify individuals with disordered glycemic control (Leong et al. 2013). Indeed, postprandial dysmetabolism often manifests prior to elevations in fasting glucose concentra- tion (Woerle et al. 2004; Monnier et al. 2007). As such, a consider- able number of individuals with normal fasting glucose have elevated postprandial glycemia, which has been linked to CVD mortality (DECODE Study Group 2001; Lin et al. 2009). Indeed, among a cohort of seemingly healthy adults with normal fasting glucose, �40% (16 of 41 participants) reached postprandial glu- cose concentrations associated with prediabetes (>7.8 mmol/L) or T2D (>11.1 mmol/L) following ingestion of a mixed-macronutrient meal containing 50 g of carbohydrate (Hall et al. 2018). There is also increasing recognition that the underlying insulin resistance andhy- perinsulinemia that exists years prior to hyperglycemia is also asso- ciated with health consequences, including increased risk for T2D (Zavaroni et al. 1999). Thus, in an effort to treat, prevent and/or delay T2D and associated co-morbidities, interventions that reduce hyper- glycemia and hyperinsulinemia are needed not only in those with diagnosed prediabetes and T2D, but also in individuals with risk factors that may be at early stages of insulin resistance and post- prandial dysmetabolism (e.g., obesity, inactivity, advancing age). Measurement of postprandial glycemia and insulinemia In clinical practice, postprandial glucose tolerance is commonly assessed with the oral glucose tolerance test (OGTT), which involves ingestion of a 75 g glucose beverage and measurement of blood glucose concentration two hours later. In research settings, OGTTs involve repeat blood sampling over 2–3 h to characterize both glu- cose and insulin exposure viameasurements such as glucose and in- sulin peak, mean, and area under the curve (AUC) or incremental AUC (iAUC). OGTTs can also provide an estimate of insulin sensitiv- ity, using equations which have been validatedagainst the gold- standard measurement from the hyperinsulinemic-euglycemic clamp (Matsuda and DeFronzo 1999). A caveat of the OGTT as an index of postprandial glycemic control is that 75 g of pure glucose con- sumed in isolationmay not be common in daily life; however, there is some evidence that the glycemic response to the OGTT closely reflects that following a standardized mixed-macronutrient meal (Wolever et al. 1998). Postprandial responses may also bemeasured using a meal tolerance test in the laboratory, which is similar to the OGTT but involves consumption of a mixed-macronutrient meal. In addition, hemoglobin A1c (HbA1c) in a single blood sample provides an index of average blood glucose concentration over the Fig. 1. Postprandial glucose metabolism across the spectrum of glucose tolerance. The digestion of carbohydrate increases blood glucose concentration and stimulates secretion of the glucose-lowering hormone insulin from the pancreas. Insulin promotes glucose uptake into peripheral tissues, which returns blood glucose to pre-meal concentration (A). In individuals with high insulin sensitivity and normal glucose tolerance, lower concentrations of insulin facilitate glucose uptake into peripheral tissues (e.g., skeletal muscle; the largest site of glucose disposal). In individuals with reduced insulin sensitivity (e.g., prediabetes) hyperinsulinemia is needed to facilitate the same glucose uptake. In type 2 diabetes, hyperglycemia ensues as a result of increasing peripheral insulin resistance and pancreatic b-cell failure (B). Glucose (blue hexagon), insulin (yellow circle), muscle insulin receptor (blue receptor), GLUT4 (yellow transporter). Created with Biorender.com. [Colour online.] 858 Appl. Physiol. Nutr. Metab. Vol. 46, 2021 Published by Canadian Science Publishing A pp l. Ph ys io l. N ut r. M et ab . D ow nl oa de d fr om c dn sc ie nc ep ub .c om b y 18 7. 3. 24 8. 21 1 on 0 8/ 23 /2 1 Fo r pe rs on al u se o nl y. http://Biorender.com past 3 months, which postprandial glycemia is a large contributor to (Monnier et al. 2003). More recently, continuous glucose monitors (CGM) have emerged as a novel method for measuring postprandial blood glucose responses to real meals consumed under ‘free-living’ conditions (i.e., outside of the laboratory). CGM measures interstitial glu- cose concentrations every 5 min via a small sensor inserted beneath the skin (typically in the abdomen or upper arm), which provides a wealth of information on the direction, magnitude, and frequency of blood glucose oscillations throughout the day and in response to meals (Rawlings et al. 2011). Moreover, the utility of CGM for measuring meal responses has been bolstered by evidence demonstrating the reproducibility of CGM-derived postprandial glycemic responses within an individual (Zeevi et al. 2015), and validity of post-meal CGM-derived glucose con- centrations compared with gold-standard venous blood or capil- lary sampling (Röhling et al. 2019). Exercise as a therapeutic strategy for reducing postprandial glucose and insulin excursions Exercise is a cornerstone in the prevention and treatment of T2D, in part due to its established role in reducing postprandial glycemic excursions (MacLeod et al. 2013). While there is a gen- eral appreciation for this exercise-induced benefit among many professionals and patients, effective knowledge translation requires an understanding of the influence of a single exercise session (acute exercise) compared with repeated exercise sessions (chronic exercise training), the efficacy of different types of exercise (e.g., walking, high-intensity exercise, resistance exercise) and the impact of timing and macronutrient composition of meals around exercise on exercise-induced improvements in glyce- mia (Fig. 2). Phase 1: Exercise can immediately lower blood glucose concentration Exercise increases skeletal muscle energy demand, which can increase muscle glucose uptake 20-fold compared with rest (Wahren et al. 1971). In response to contractile signals during exercise, GLUT4 is translocated to the plasma membrane to facilitate glucose uptake via insulin-independent mechanisms (Wojtaszewski et al. 1999). Importantly, this exercise-induced glucose uptake pathway remains intact in adults with insulin resistance, which provides a stimulus to immediately lower blood glucose concentration in individuals with prediabetes or T2D (Martin et al. 1995). Increased blood flow to active muscle during exercise also supports the increase in muscle glucose uptake, and current hypotheses suggest that the intrinsic trans- porter activity of GLUT4 may be increased to facilitate large increases in glucose uptake during exercise (Richter 2021). The prevailing blood glucose concentration during exercise is also dependent on glucose production from the liver, which is stimu- lated by counter-regulatory hormones at rest and during exer- cise (Wahren and Ekberg 2007). As such, the net effect of exercise on glycemia is determined by the balance between hepatic glucose production and peripheral glucose uptake. In adults with prediabetes or T2D, a net reduction in blood glucose concentration during exercise is usually observed, espe- cially if performed in the postprandial state (Borror et al. 2018). For example, traditional moderate-intensity continuous exercise involving 45 min of cycling at �50% maximal oxygen uptake (V_O2max) immediately lowered blood glucose concentration, as Fig. 2. Exercise-nutrient interactions to maximize exercise-induced improvements in glycemic control and insulin sensitivity. Left panel: A single session of exercise increases contraction-mediated glucose uptake, which provides a stimulus to lower blood glucose concentration. Performing exercise after rather than before a meal leads to more consistent reductions in the postprandial glycemic excursions due to additive effects of contraction- and insulin-stimulated glucose uptake. Middle panel: After exercise, peripheral insulin sensitivity is increased for up to 48 h. Consuming carbohydrate, but not fat or protein, after exercise reduces the magnitude of this exercise-induced increase in insulin sensitivity and glycemic control. Right panel: Exercise training elicits muscle remodeling that contributes to enhanced ‘chronic’ insulin sensitivity (although this can be quickly reversed if exercise is discontinued). Performing exercise training in the fasted- compared with carbohydrate fed-state has been shown to augment training-induced improvements in muscle remodeling and insulin sensitivity in young males, but this exercise-nutrient interaction has yet to be supported in other populations, including adults with prediabetes or T2D. Created with Biorender.com. [Colour online.] Gillen et al. 859 Published by Canadian Science Publishing A pp l. Ph ys io l. N ut r. M et ab . D ow nl oa de d fr om c dn sc ie nc ep ub .c om b y 18 7. 3. 24 8. 21 1 on 0 8/ 23 /2 1 Fo r pe rs on al u se o nl y. http://Biorender.com compared with a non-exercise control, in adults with T2D (Larsen et al. 1997). More recently, a 20-minute low-volume high-intensity interval exercise (HIIE) protocol, involving 10�1-min cycling intervals at�90% HRmax interspersed with 1min of recovery, low- ered blood glucose concentration during exercise in adults with T2D (Gillen et al. 2012). Influence of acute exercise-nutrient timing on postprandial glycemic excursions The majority of studies documenting exercise-induced reduc- tions in blood glucose concentration relative to a non-exercise control condition have had participants perform exercise in the postprandial state, or after a meal (Larsen et al. 1997; Gillen et al. 2012). When exercise is performed postprandially, both contrac- tion- and insulin-mediated glucose uptake are stimulated, result- ing in an additive effect on skeletal muscle glucose uptake (Goodyear et al. 1996). Additionally, exercising in thepostpran- dial state is associated with a higher insulin to glucagon ratio (Poirier et al. 2001), which can lower hepatic glucose production (Kowalski et al. 2017). Limited studies have directly compared postprandial to pre- prandial exercise in adults with T2D; however available evidence suggests that exercise performed postprandially elicits superior reductions in meal-induced glucose excursions (Poirier et al. 2000; Colberg et al. 2009; Heden et al. 2015). For example, Colberg and colleagues demonstrated that a 20-min low-intensity walk (�2.2 mph) initiated immediately after – but not before – a mixed-macronutrient dinner lowered themeal-induced glycemic excursion in adults with T2D when measured 60 min following meal consumption (Colberg et al. 2009). Similar findings were observed by Heden et al., who demonstrated that a 30 min ses- sion of resistance exercise in adults with T2D performed 45 min after a mixed-macronutrient meal lowered plasma glucose iAUC to a greater extent than when the same exercise was performed �30 min before the meal (Heden et al. 2015). Consistent with these findings, a recent systematic review suggested that the optimal time for adults with T2D to initiate exercise is within 3 h of the largest meal of the day. In this regard, the authors con- cluded that many types of exercise are effective, including walk- ing, resistance exercise, cycling or stair climbing, with higher exercise volumes leading to more consistent reductions in post- prandial glycemia (Borror et al. 2018). Given that the evening (din- ner) meal is typically highest in energy and carbohydrate content among Western society (Almoosawi et al. 2012), postprandial exercise following dinner may be particularly beneficial. How- ever, the first meal of the day (breakfast) may also be important to target, as it has been demonstrated to elicit the largest post- prandial glycemic excursion across the day in those with T2D (Pearce et al. 2008). Post-meal exercise is also beneficial in normoglycemic individ- uals and adults with overweight and obesity (Aqeel et al. 2020). For example, 60 min of moderate-intensity continuous cycling at 65% peak oxygen uptake (V_O2peak) performed after, but not before, a mixed-macronutrient meal reduced insulin AUC in males with obesity (Edinburgh et al. 2020). In healthy, normal-weight adults, a 30 min low-intensity walk or session of body-weight resistance exercise (3 sets of 10 squats, 10 push-ups, 10 lunges, and 10 sit-ups) reduced the 2 h postprandial glucose average and AUC when per- formed immediately after a liquid breakfast meal, compared with both a non-exercise control and pre-meal exercise condi- tion (Solomon et al. 2020). A recent investigation evaluated an impressive number of exercise/meal combinations on the glyce- mic response to a high-carbohydrate breakfast meal (cornflakes with milk) in healthy adults (Bellini et al. 2021). The glycemic excursion was not lowered by pre-meal exercise, but various types of post-meal activity (30 min of resistance exercise, cycling, ellipti- cal or brisk walking) performed 15–30 min after breakfast reduced the postprandial glycemic excursion, as reflected by a lower peak and/ormean glucose concentration relative to a non-exercise con- trol. To achieve the largest benefit, beginning exercise in close proximity to the meal appears important, as brisk walking ini- tiated 15 min following breakfast led to greater improvements in postprandial glycemia than when initiated 30 min following breakfast in healthy adults (Bellini et al. 2021). Influence of exercise ‘snacks’ on postprandial glycemic and insulinemic excursions Adults spend the majority of waking hours in the postprandial state, which often coincides with periods of prolonged sitting that is characteristic of many modern occupations, methods of transportation and leisure-time activities. In adults with and without T2D, prolonged periods of sedentary time are linked with worse glycemic control and elevated postprandial glycemic and insulinemic excursions (Peddie et al. 2013; Fritschi et al. 2016). However, interrupting prolonged periods of sitting with brief, repeated activity breaks – often termed exercise ‘snacks’ – can reduce postprandial glycemia and insulinemia throughout the day. For example, �2–3 min of light-intensity treadmill walk- ing or body-weight resistance exercise every 30 min reduces post- prandial glycemic excursions in adults with T2D (Dempsey et al. 2016) and insulinemic excursions in adults whom are obese (Larsen et al. 2017) and inactive (Gillen et al. 2021). The improved glycemic control with small activity breaks throughout the day may be a result of frequently stimulating contraction-mediated muscle glucose uptake, interrupting sedentary time per se, or a combination of the two. For those with limited access to equip- ment and/or space, repeated chair stands as a form of body- weight exercise (Gillen et al. 2021) or stair climbing (Rafiei et al. 2021) may be an efficacious activity break. In addition, strategi- cally targeting postprandial periods throughout the day with less frequent, but longer activity breaks (10–15 min walks after each meal) has been demonstrated to reduce postprandial hyperglyce- mia and improves 24 h glycemic control in adults with prediabe- tes (DiPietro et al. 2013) and T2D (Reynolds et al. 2016). Phase 2: Exercise can acutely improve insulin sensitivity for hours after exercise Increased contraction-mediated muscle glucose uptake generally subsides within 3 h following exercise cessation. Subsequently, peripheral insulin sensitivity is enhanced via insulin-dependent mechanisms for up to 48 h following exercise in adults with and without insulin resistance (Devlin and Horton 1985; Mikines et al. 1988; Perseghin et al. 1996; Koopman et al. 2005; Ortega et al. 2015). The insulin-sensitizing effects of moderate-intensity continuous exercise are well-established (e.g., running or cycling for 60–90min at 50%–75% V_O2max) (Mikines et al. 1988; Perseghin et al. 1996), but other types of exercise are also effective. For example, low-intensity walking for 60 min in the afternoon improves insulin sensitivity the following morning in adults with obesity, measured with the hyperinsulinemic-euglycemic clamp (Newsom et al. 2013). On the other end of the intensity-duration spectrum, short, high-intensity efforts, involving 4–6 “all out” 30-S sprints interspersed with 4 min of recovery, has also been shown to improve insulin sensitivity for up to 48 h in healthy males, as assessed via an intravenous glucose tolerance test (Ortega et al. 2015). While less research has evaluated the effects of resistance exercise, a 40min session that targeted the lower-body and performed at 75% of 1 repetition maximum (1-RM) improved insulin sensitivity by �13% in young males when meas- ured 24 h post-exercise using an intravenous insulin tolerance test (Koopman et al. 2005). The transient increases in peripheral insulin sensitivity in the days following acute exercise facilitates increased muscle glu- cose uptake and improves glycemic control in adults with obesity and T2D. For example, reductions in CGM-derived 24 h average glucose concentrations and postprandial glycemic excursions 860 Appl. Physiol. Nutr. Metab. Vol. 46, 2021 Published by Canadian Science Publishing A pp l. Ph ys io l. N ut r. M et ab . D ow nl oa de d fr om c dn sc ie nc ep ub .c om b y 18 7. 3. 24 8. 21 1 on 0 8/ 23 /2 1 Fo r pe rs on al u se o nl y. have been reported following an acute bout of HIIE involving 8-10x1-min cycling intervals at �90% HRmax interspersed with 1 min recovery in adults with obesity or T2D (Gillen et al. 2012; Little et al. 2014; Parker et al. 2017). Similarly, 45–60 min of moderate-intensity continuous cycling lowered the postprandial glucose AUC of next-daymeals (Oberlin et al. 2014) and prevalence of hyperglycemia by �33% over the subsequent 24 h (Van Dijk et al. 2012) in adults with T2D. In the latter study,a 45 min session of re- sistance exercise performed at 75% 1-RM reduced 24hhyperglycemia similarly to cycling exercise (VanDijk et al. 2012). Improvements in insulin-stimulated muscle glucose uptake post-exercise are primarily attributed to muscle glycogen re- synthesis and enhanced sensitivity of select proteins in the insu- lin signaling pathway (Wojtaszewski and Richter 2006). Muscle glycogen synthase activity is increased post-exercise in an effort to promote glycogen re-synthesis (Wojtaszewski et al. 2000), with elevations in glycogen synthase and muscle glucose dis- posal proportional to glycogen use during exercise (Bogardus et al. 1983). In addition, a distal protein in the insulin signaling cascade, Akt substrate of 160 kDa (AS160; also known as TBC1D4), is activated by signals from prior exercise, such as 50 adenosine mono- phosphate-activated protein kinase (AMPK), and is associated with increased insulin-stimulated glucose uptake in the post-exercise pe- riod (Treebak et al. 2006; Steenberg et al. 2019). There is also emerg- ing evidence to suggest that acute exercise redistributes GLUT4 to a more easily “recruitable” site in muscle (Knudsen et al. 2020) and enhances muscle membrane permeability to glucose in the post- exercise period (McConell et al. 2020). Influence of post-exercisemacronutrient intake on acute improvements in insulin sensitivity The time course of improvement in insulin sensitivity after exercise can be influenced by nutrition in the post-exercise pe- riod. A growing body of evidence, albeit mostly in healthy adults, suggests that replenishing the exercise-induced energy deficit with carbohydrate following moderate-intensity continuous exer- cise blunts next-day improvements in insulin sensitivity (Newsom et al. 2010; Taylor et al. 2018) and postprandial glycemic control (Schleh et al. 2020). However, when low-carbohydrate iso-energetic meals containing fat and protein (Newsom et al. 2010) or surplus calories from fat (Fox et al. 2004) are provided post-exercise, improvements in next-day insulin sensitivity are still observed. Taken together, these results suggest that acute improvements in insulin sensitivity and glycemic control are sensitive to carbo- hydrate intake, most likely as a result of muscle and/or liver gly- cogen repletion post-exercise. From a practical perspective, this may suggest that consuming low-carbohydrate meals after mod- erate-intensity continuous exercise may prolong acute improve- ments in insulin sensitivity and glycemic control, but more research is needed specifically in individuals with prediabetes and T2D. In addition, limited research has assessed the influ- ence of post-exercise nutrition following other types of exercise. Venables et al. found that consuming a high-energy carbohydrate- protein beverage (�1000 kcal; 200 g maltodextrin, 50 g whey protein) following acute resistance exercise did not blunt the exercise-induced improvement in insulin sensitivity when meas- ured 6 h post-exercise (Venables et al. 2007). This may suggest that the influence of post-exercise carbohydrate intake on exercise- induced improvements in insulin sensitivity are exercise-mode specific, but more research is needed using diverse exercise protocols. Phase 3: Repeated sessions of exercise result in adaptations that improve glycemic control Repeated sessions of exercise, or exercise training, result in adaptations that improve insulin sensitivity and glycemic con- trol in physically inactive adults (Gillen et al. 2016) and those with prediabetes or T2D (Kirwan et al. 2009; Dubé et al. 2011). Moderate-intensity continuous training (MICT) has traditionally been recommended for T2D management, but other forms of exercise including resistance training have been shown to similarly lower HbA1c after 12 weeks of training (Snowling and Hopkins 2006). When aerobic and resistance training are com- bined, greater improvements in HbA1c are observed compared with either regimen alone (Sigal et al. 2007), suggesting that adults with T2D should engage in both types of exercise. The additive effect of combined aerobic and resistance exercise on glycemic con- trol may also be in part due to the greater volume of exercise per- formed in those studies, as meta-analyses suggest that acquiring ≥150 min of exercise per week results in greater reductions in HbA1c than exercisingin insulin sensitivity and glycemic control Van Proeyen and colleagues were the first to demonstrate that performing 4 weekly sessions of MICT (60–90 min at 70% V_O2peak) in the fasted, but not carbohydrate-fed, state improved OGTT- derived insulin sensitivity and glucose tolerance after 6 weeks in healthymales (Van Proeyen et al. 2010). More recently, Edinburgh et al. also demonstrated superior effects of fasted- compared with fed-state training for improving OGTT-derived postprandial insu- linemia and insulin sensitivity inmales with overweight and obe- sity who participated in a more modest 6-week MICT protocol (30–50 min at �50%–55% peak power output, 3 times per week) (Edinburgh et al. 2020). The superior improvements in insulin sensitivity have been associated with augmented training-induced skeletal muscle remodeling, which has been accredited to enhanced fat oxidation and metabolic stress during acute exercise sessions performed in the fasted state (Van Proeyen et al. 2010; Edinburgh et al. 2020). The benefits of fasted-state training on insulin sensitivity, how- ever, appear limited to moderate-intensity exercise performed in young healthy males. High-intensity exercise performed >70% V_O2peak is carbohydrate-dependent (particularly muscle glyco- gen) regardless of nutritional timing, and therefore does not aug- ment exercise-induced fat oxidation when performed in the fasted state (Bergman and Brooks 1999). As such, when 6 weeks of low-volume HIIT, involving 10x1-min cycling intervals at 90% V_O2peak, was performed 3 times per week in the fasted vs. fed state in women with overweight and obesity, no differences in training-induced changes in insulin sensitivity, skeletal muscle mitochondrial content or GLUT4 protein content were observed (Gillen et al. 2013). It is also possible that sex-based differences partly explain the discrepancy between this study and others, as even moderate-intensity exercise (�60% V_O2peak) performed in the fasted state failed to augment training-induced gains in mito- chondrial content in women (Stannard et al. 2010). Limited research has investigated fasted-state exercise training in adults with prediabetes or T2D; however, current evidence does not support this exercise-nutrient combination in adults with T2D. In fact, Verboven et al. recently observed that 12 weeks of a combined moderate-intensity walking and cycling protocol (45 min per session) performed three times per week after rather than before breakfast led to greater improvements in HbA1c in adult males with T2D (Verboven et al. 2020), likely reflecting the superiority of repeated acute exercise training sessions per- formed in the postprandial state. To our knowledge, only one study has assessed training-induced changes in insulin sensitiv- ity in response to fasted vs. fed exercise in adults with T2D. Fol- lowing 8 weeks of a combined aerobic and strength-training program, the improvement in fasting insulin sensitivity (HOMA- IR) measured 3–5 days following training was similar regardless of nutritional state around training sessions (Brinkmann et al. 2019). The lack of difference between fasted and fed training in adults with T2D may be due to their known metabolic inflexibil- ity (Goodpaster and Sparks 2017), which limits the ability to switch between fuel sources under fasted and fed conditions. It is also important to note that studies demonstrating superior effects of fasted-state training have also required participants to remain fasted for �2 h following exercise (Van Proeyen et al. 2010; Edinburgh et al. 2020), whichwas not implemented in studies with T2D but may be necessary to obtain the augmented training responses. While rigorously controlled trials with gold-standard methodology for assessment of insulin sensitivity are still needed, current literature does not suggest that fasted-state exercise aug- ments training adaptations in adults with T2D. Indeed, the glyce- mic benefit of repeated, acute exercise sessions performed in the postprandial state appear to providemore consistent glycemic ben- efits in adults with T2D (Borror et al. 2018). Future directions and conclusion The vast majority of research within this field has been con- ducted in male participants, or mixed cohorts of males and females, with limited research specifically conducted in cohorts of females with or without T2D. Importantly, sex of participants has been found to influence exercise-induced responses, with blunted acute (Munan et al. 2020) and chronic (Boule et al. 2005; Gillen et al. 2014) improvements in glycemic control observed in females. However, failure to properly match males and females for baseline fitness and/or level of insulin resistance, or failure to control for menstrual cycle phase and/or oral contraceptive use, may confound conclusions regarding sex-based differences. Rig- orously controlled studies are needed to determine if exercise- induced effects on postprandial glycemic control are different in females compared with their male counterparts, both with and without T2D. Emerging research suggests that exercise timing (morning vs. afternoon or early evening) may explain heterogeneity amongst studies with regards to the effects of exercise on glycemic control in adults with T2D (Munan et al. 2020). Indeed, two recent studies have suggested that exercising in the afternoon, as opposed to the morning, leads to greater acute improvements in 24 h glyce- mic control (Savikj et al. 2019) and chronic improvements in insu- lin sensitivity (Mancilla et al. 2021). While the mechanisms for this remain largely unknown, future studies that thoroughly evaluate the impact of exercise timing across the day on improve- ments in glycemic control will help further optimize exercise recommendations for improved postprandial glycemic control. Finally, many acute and chronic exercise studies evaluate changes in peripheral insulin resistance using techniques that involve intravenously administered glucose and/or insulin (e.g., hyperinsulinemic-euglycemic clamps, intravenous glucose toler- ance tests). While it is indisputable that these methods represent the gold standard for determination of peripheral insulin resist- ance, they involve supra-physiological glucose and insulin doses that do not mimic glycemic and insulinemic responses to oral food consumption that is typical of Western eating patterns (e.g., multiple mixed-macronutrient meals daily). While peripheral in- sulin resistance has been demonstrated to be positively related to postprandial hyperglycemia (Dickinson et al. 2002), future studies should also focus on direct measurement of postprandial responses to high-carbohydrate and/or mixed-macronutrient whole foods in an effort to improve translation of the findings to real-world environments. Indeed, the emergence of CGM is a highly useful research tool in this regard. To conclude, acute and chronic exercise provide a powerful stimulus to reduce postprandial hyperglycemia and hyperinsu- linemia associated with carbohydrate intake. These exercise- induced improvements in glycemic control may be further pronounced if the timing of exercise around meals and post- exercise macronutrient intake are tactfully considered to augment the underlying skeletal muscle mechanisms. Additional research evaluating both the basic science and clinical application of these exercise-nutrient interactions on glycemic control will help optimize exercise and nutritional recommendations for the prevention and treatment of T2D. Conflict of interest statement The authors report no conflicts of interest. References Almoosawi, S., Winter, J., Prynne, C.J., Hardy, R., and Stephen, A.M. 2012. Daily profiles of energy and nutrient intakes: Are eating profiles chang- ing over time. Eur. J. Clin. Nutr. 66(6): 678–686. doi:10.1038/ejcn.2011.210. PMID:22190135. Aqeel, M., Forster, A., Richards, E.A., Hennessy, E., McGowan, B., and Bhadra, A., et al. 2020. The effect of timing of exercise and eating on 862 Appl. Physiol. Nutr.Metab. Vol. 46, 2021 Published by Canadian Science Publishing A pp l. Ph ys io l. N ut r. M et ab . 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