Table of Contents  

Sivaraman and Weickert: Nutrition and exercise in the treatment of type 2 diabetes mellitus

Introduction

Diet factors are now assumed to be the leading cause of chronic disease worldwide.1 One in three Americans born in 2000 or later and every second person in high-risk ethnic populations will develop type 2 diabetes mellitus (T2DM).2 T2DM is a significant cause of morbidity related to cardiovascular disease (CVD), blindness, kidney and nerve disease, arthritis, obstructive sleep apnoea syndrome (OSAS), psychological ill health, amputation and premature mortality.3

Chronic overconsumption of energy leads to weight gain and excess intra-abdominal fat, which predispose to insulin resistance,4 probably the strongest single predictor for the development of 2DM.5,6 Appropriate dietary measures and physical activity as part of a healthy lifestyle show substantial and clinically relevant effects in both the prevention and treatment of insulin resistance and T2DM. Lifestyle measures that aim to increase insulin sensitivity are of particular interest in this context. As weight loss and reduction of abdominal fat mass are almost invariably associated with improved insulin sensitivity,4 any sustainable energy-reduced and safe diet, ideally in combination with increased exercise levels, may be used both in patients with T2DM and in subjects at high risk. However, apart from weight loss, isoenergetic changes in the quality of ingested foods and in the macronutrient composition appear to exert additional important effects on insulin ensitivity,710 with adverse, neutral or protective effects of specific foods.1,1113 However, this remains a controversial topic.

Chronic reduction in energy expenditure attributed to decreased physical activity is assumed to be another major contributor to the global epidemic of overweight and T2DM.14 Exercise has been shown to increase insulin sensitivity both acutely and in the long term, in addition to reducing weight and body fat mass, lowering blood glucose levels and improving cardiovascular function.15 However, many patients with T2DM are not physically active.16

We review current concepts and controversies regarding the modulation of glucose metabolism and diabetes risk using lifestyle measures.

Methods

We searched PubMed for original papers and review articles up to April 2012 using a combination of query terms that included ‘type 2 diabetes’, ‘nutrition’, ‘exercise’, ‘metabolic syndrome’, ‘insulin resistance’, ‘dyslipidaemia’, ‘adipokines’, ‘gut hormones’, ‘pro-inflammatory factors’, ‘obesity’ and many others that were assumed to be relevant. Relevant articles were also selected among reference lists in published papers. Using these search criteria, more than 1000 relevant original papers and review articles were identified. We then hand selected studies and review articles covering the relevant areas, excluding articles that provided similar information to the selected ones. When data from larger or more robust trials were available, studies with small sample sizes were excluded, as well as studies that showed high losses to follow-up and/or differential losses between the comparison groups.

The role of nutrition in the prevention and treatment of type 2 diabetes mellitus

Recommendations in current guidelines

Nutritional recommendations in current guidelines17 for the treatment of patients with T2DM and subjects at high risk of developing diabetes generally recommend weight loss of at least 7% in overweight/obese patients; a cholesterol intake < 200 mg/day; restriction of the intake of saturated fats to < 7% of energy intake; a high-fibre intake of at least 14 g/1000 kcal; and, in newer guidelines, relaxed restrictions on protein intake, e.g. protein intake of 15–20% of energy as long as kidney function is normal.17 Furthermore, intake of trans fat should be minimized.17 The use of low glycaemic index (GI) and glycaemic-load carbohydrates may provide a modest additional benefit for glycaemic control over that observed when total carbohydrate is considered alone.17 Finally, routine supplementation with antioxidants, such as vitamins E and C and carotene, is not advised because of lack of evidence of efficacy and increasing concerns related to long-term safety.17,18

Effects of weight loss

Obesity, and particularly accumulation of intra-abdominal fat mass, is the most common cause of insulin resistance and T2DM. Simply being overweight [body mass index (BMI) > 25 kg/m2 raises the risk of developing T2DM by a factor of 3,19 whereas even relatively modest weight reduction in obese patients with poorly controlled T2DM can markedly reduce plasma glucose concentrations. As weight loss progresses and is maintained, an improvement in glycaemic control is reflected by reductions in markers of glycaemic control such as glycated haemoglobin (HbA1c).20,21 Thus, a guiding principle in the treatment of patients with T2DM has been the recommendation to lose weight.22

However, even in the general overweight population, sustained weight loss appears too difficult to achieve. Weight-loss trials in diabetic patients are relatively consistent, showing initial success which typically plateaus after 4–6 months, followed by weight regain.23 In an 18-month study that compared the use of different dietary guidelines for T2DM, no significant changes in body weight were observed.24 In a 2-year study in 811 overweight adults, energy-reduced diets resulted in clinically meaningful weight loss regardless of the macronutrient composition (fat, protein or carbohydrates), with comparable effects of all diets on feelings of satiety and hunger, satisfaction with the diet, and attendance rates at group sessions; however, attendance at instructional sessions was strongly associated with weight loss (0.2 kg per session attended), indicating that adherence to any chosen diet may be a crucial factor and could be even more important than the macronutrient composition of the diet per se.25 This phenomenon has been described previously: in a study investigating the effectiveness of four popular diets (Atkins, Ornish, Weight Watchers and Zone) on weight loss, each diet modestly reduced body weight and several cardiac risk factors at 1 year, with low overall dietary adherence rates to all diets. However, increased adherence was associated with significantly greater weight loss and cardiac risk factor reductions in each diet group.26

Even under well-controlled conditions, sustained weight loss is in patients with T2DM is generally moderate (4% or 4.6 kg) and typically results only in a small decrease in HbA1c of ∼0.5%.27 At least in the short term, low-carbohydrate, high-protein diets may result in better weight loss than traditional low-fat diets.28 However, regardless of the dietary strategy, it appears to be difficult to achieve sustained therapeutic weight loss, particularly in patients with T2DM as compared with the general (overweight/obese) population. Generally, in obese individuals energy expenditure begins to drop as soon as body weight starts to decline,23,29,30 and powerful hypothalamic hormonal responses are induced in an effort to prevent further weight loss.23 However, in patients with diabetes, additional factors have been proposed that may further prevent sustained relevant weight loss. Energy expenditure is increased in the hyperglycaemic state as a result of increased protein turnover and could drop towards normal after improvement of glycaemic control.23,31,32

Furthermore, improved glycaemic control results in reduced glucosuria and thus decreased energy excretion in the urine. This increased retention of energy may lead to weight regain if energy intake does not drop further.23 Furthermore, many obese patients with T2DM are typically sedentary and may have barriers to exercising, including neuropathy, foot ulcers, heart disease23 and anxiety about experiencing hypoglycaemia. In addition, medication with certain antidiabetic drugs, including insulin, sulfonylureas, and thiazolidinediones, causes weight gain.23 Thus, achieving and maintaining both weight loss and relevant exercise levels is often not realistic in overweight/obese patients with T2DM. Furthermore, typically recommended exercise levels that are probably sufficient to improve glycaemic control and cardiovascular risk (e.g. 150 min/week of brisk walking) are usually inefficient to achieve relevant weight loss.33 The optimal volume of exercise to achieve sustained major weight loss appears to be much larger, some 60 min/day or more when relying on exercise alone as a weight-loss strategy.3,33

Little is known about the composition of body weight during weight regain, particularly in patients with T2DM. In the European multicentre Diet, Obesity and Genes (DioGenes) trial in overweight non-diabetic subjects, a modest increase in protein content and a modest reduction in the GI led to a more successful maintenance of weight loss after an initial energy-reduced diet.34 However, after 6 months, maintenance of weight loss was only marginally better with a high protein intake than with low protein intake (−0.71 kg or −1.1. kg, depending on combination with a low- or high-GI diet) and failed to reach significance in the full model, despite the large number (548) of completers in study.34 Furthermore, when investigating the body composition in postmenopausal women after intentional weight loss, followed by weight regain, for every 1 kg fat lost during weight loss intervention, 0.26 kg lean tissue was lost; but for every 1 kg fat regained over the following year, only 0.12 kg lean tissue was regained. These results indicate that fat mass is regained to a greater degree than is lean mass in those who experience weight regain after initial weight loss.35

Although weight loss and reduction of abdominal fat mass in patients with T2DM are in principle powerful tools for reducing insulin resistance, sustained relevant weight loss in these patients appears to be difficult to achieve. Therefore, it seems reasonable to explore specific metabolic effects of different (isoenergetic) foods and macronutrients on insulin sensitivity both in patients with T2DM and in individuals who are at high risk of developing T2DM.710

Effects of dietary components on insulin resistance and diabetes risk

An increasing number of studies indicate that isoenergetic changes in the macronutrient composition and the quality of ingested foods may exert additional important effects on insulin sensitivity, independent of weight loss. The effects of different nutrients on diabetes risk and glycaemic control are summarized in Table 1.

TABLE 1

Effect of different nutrients on diabetes risk and glucose control

Nutrient Effect on glucose metabolism Level of evidence American Diabetic Association recommendation
Total carbohydrate Unclear Moderate Minimum recommended daily allowance of 130 g/day to provide adequate glucose to central nervous system44
Simple sugars Adverse Moderate Avoid excessive intake17
Low glycaemic index carbohydrate Beneficial Moderate Encouraged. May produce modest additional benefts45
Monounsaturated fatty acids Beneficial Moderate Encouraged17
Polyunsaturated fatty acids Beneficial Moderate Two or more servings of fish per week46
Saturated fatty acids Adverse Strong Should be < % of total energy intake17
Trans-unsaturated fatty acids Adverse Moderate Should be minimized44
Protein Can increase insulin response Moderate 0.8 g high-quality protein/kg body weight. Less than 20% of energy44
Fibre Beneficial Strong At least 14 g/1000 kcal44
Alcohol, moderate Possibly beneficial Moderate Men – two drinks/day or fewer. Women – one drink/day or fewer17
Alcohol, excessive Adverse Moderate Not advised17
Vitamins C, E, carotene Unclear Moderate Not advised47
Fructose (sweetener) Unclear Moderate May adversely affect lipid profle48
Sorbitol, xylitol, tagalose, lactitol Unclear Moderate No adverse efects48

Low-fat diets

Excessive intake of total fat drives insulin resistance, irrespective of the composition of fatty acids (FAs) in the diet,36 and possibly related to increases in intramyocellular lipid content and interference of binding of insulin to its receptors.9 However, many overweight/obese patients have difficulties adhering to these diets, particularly in the longer term, resulting in only limited success. Apart from the total amount of dietary fat consumed, the type of FA appears to exert relevant additional effects on the modulation of insulin resistance, especially under conditions of a more moderate fat intake (< 30%).36

Effects of specific dietary fatty acids on insulin resistance and diabetes risk

Dietary fat is a heterogeneous blend of different FAs, with monounsaturated fatty acids (MUFAs), polyunsaturated fatty acids (PUFAs), saturated fatty acids (SFAs) and trans-unsaturated fatty acids (TFAs) as the main components.9 A high intake of TFA may lead to insulin resistance and shows adverse effects on CVD.8,37,38 Many bakery products and high-energy pre-packed foods contain sufficient amounts of TFAs and SFAs to increase insulin resistance and risk of diabetes.39 Epidemiological studies indicate a direct relation of dietary SFA with the incidence of insulin resistance or T2DM,40,41 whereas replacing SFAs by MUFAs reduces insulin resistance36 and has a beneficial effect on blood pressure, low-density lipoprotein (LDL)-cholesterol and triacylglycerols.42 However, recent research indicates that specific SFAs differ widely in function, structure and metabolic effects, with some SFAs having important and specific biological roles.43

The underlying mechanisms involved in MUFA-induced improvement of insulin sensitivity are not completely understood but may involve effects on cell membrane FA composition,8 with functional effects on membrane fluidity, ion permeability, insulin receptor binding/affinity8 and up-regulation of glucose transporters.9 Further involved mechanisms might be related to alterations in incretin responses and beta-cell function.9 Despite these findings, an increased intake of MUFA was not associated with reduced risk of T2DM in prospective cohort studies.49

There also appear to be relevant interspecies differences when comparing metabolic effects of specific FAs. In humans, n-6 PUFAs may improve insulin resistance and diabetes risk,8 whereas the reported beneficial effects of n-3 PUFAs consumption from marine origin, as shown in rodent models, do not appear to apply in humans.4,8 Importantly, no long-term randomized trials have been published to date that have investigated the effect of dietary fat composition on diabetes risk.

Effects of dietary fibre and carbohydrates

The modest success of low-fat diets has prompted research on alternative strategies, including low-carbohydrate diets, which are often high in dietary protein, and carbohydrate-rich diets, which are aimed at modulating the post prandial glucose and insulin responses and thus the GI of foods. Carbohydrates with a high GI lead to rapid onset and pronounced increases in post prandial glucose and insulin concentrations that may compromise fat oxidation, fuel partitioning and metabolic flexibility.11,50 High-GI diets have been linked to insulin resistance in epidemiological observations, whereas low-GI diets improved insulin sensitivity in patients with T2DM.11 However, separating the effects of single nutrients in complex foods on metabolic outcomes is not straightforward: many low-GI diets are also rich in cereal fibres which are insoluble in water and have only negligible effects on the GI, but are strongly and independently associated with reduced risk of T2DM in prospective cohort studies.10,12,13,51 It cannot be excluded that at least some of the effects attributed to a low GI of carbohydrate-rich foods may be related to the cereal fibre content of the diet.10,52 Indeed, meta-analyses of large prospective cohort studies consistently show a 20–30% reduction in the risk of developing T2DM in subjects consuming diets high in cereal fibre [relative risk for extreme quintiles (RR) 0.67; 95% confidence interval (CI) 0.62 to 0.72],13 whereas results regarding the protective effects of low-GI [and glycaemic load (GL)] foods are less consistent.10 Notably, main sources of cereal fibre in the large prospective cohort studies in the USA are cellulose and hemicelluloses from wheat bran10 that are insoluble in water, non-viscous and only moderately fermentable,10,53 whereas the main sources of soluble, viscous and fermentable fibre are typically fruit and vegetables. As many assume that the strong associations between fibre intake and reduced diabetes risk12,13 are mainly related to the viscous and/or gel-forming properties of soluble fibre from fruit and vegetables, as such beneficially influencing GI and blood lipids, and to metabolic effects of short-chain fatty acids (SCFAs) derived from colonic fermentation of non-digested fibre by the gut microbiota,10,5457 it is surprising that the intake of neither fruit (RR 0.96; 95% CI 0.88 to 1.04) nor vegetables (RR 1.04; 95% CI 0.94 to 1.15) shows any significant associations with reduced risk of developing T2DM.13 This is an unexpected but consistent finding, strongly indicating that other mechanisms are likely to be involved.

Indeed, insoluble cereal fibre intake, under isoenergetic conditions, increases whole-body insulin sensitivity in both short-term and more prolonged studies, as measured using euglycaemic–hyperinsulinaemic clamps.10,58,59 These effects appear to be dose dependent10 but independent of colonic fermentation, changes in dominant groups of the gut microbiota or circulating glucagon-like peptide-1 (GLP-1).10,53,59 We have recently proposed a novel concept that could help explain the improved insulin sensitivity resulting from cereal fibre intake, showing that cereal fibre may simply hinder the digestion and/or absorption of dietary protein in the upper gut, thereby preventing amino acid-induced activation of the mammalian target of rapamycin (mTOR)/translation initiation factor serine-kinase-6-1 (S6K1) signalling pathway that is known to drive insulin resistance.5961 However, further, as yet unknown, mechanisms may also be involved and need to be investigated in future studies. Examples include cereal fibre-induced modulation of gut hormones, adipokines, bile acid binding and metabolite profiles.

Effects of dietary protein

Many energy-reduced diets are difficult to follow because they require elimination of certain foods, leading to poor adherence and limited success. The only moderate effects of low-fat diets on weight reduction62 have led to a renaissance of various alternative concepts with the aim of promoting weight loss. The most common concepts include carbohydrate restriction and increasing the intake of dietary protein. Low-carbohydrate diets are attractive because they promise rapid weight loss without having to count calories, despite allowing the consumption of many palatable foods.62 High-protein diets have beneficial effects on blood lipids, body composition and weight loss, at least in the short term.28 Better weight loss with high-protein diets may be explained by the satiating effects of dietary protein, reduced choice of foods and aversion to high-dietary-fat contents in the absence of carbohydrates. Reducing the protein content of the diet from 15% to 10% results in a higher total energy intake, predominantly from savoury-flavoured foods available between meals,63 reinforcing the finding that a higher dietary protein intake may help to reduce energy intake.

However, sustained weight loss with any diet is difficult to achieve, and the long-term safety of high-protein diets remains to be investigated34,64 In the DiOGenes trial, weight regain at 1 year was only marginally lower with a high-protein intake, but both the high-protein and the high-GI diets were shown to increase low-grade inflammation,65 which could result in worsening of insulin resistance. Indeed, recent data indicate that low-carbohydrate plant-based high-protein diets, even with an amino acid profile that is assumed to have beneficial metabolic effects, may induce insulin resistance, at least under isoenergetic conditions.59 Furthermore, healthy humans who are exposed to amino acid infusions rapidly develop insulin resistance,60 with inhibition of glucose uptake being driven through phosphorylation of downstream factors of the insulin signalling cascade by S6K1.60,61 In agreement with this, long-term high protein intake has been shown to result in whole-body insulin resistance,59,66 associated with up-regulation of factors involved in the mTOR/S6K1 signalling pathway,59 increased stimulation of glucagon and insulin within the endocrine pancreas, high glycogen turnover66 and stimulation of gluconeogenesis.59,66 In the short-term, these negative effects on insulin sensitivity may be compensated by high-protein diet-induced weight loss, and, at least in physically active people, relevant increases in lean mass that are also mediated via the mTOR/S6K1 pathway.61 However, most subjects on weight loss diets are overweight/obese and typically sedentary; therefore, relevant increases in lean mass under these conditions are unlikely. In further agreement that high-protein diets cause deterioration of glucose metabolism, it was recently shown in a large prospective cohort with 10 years' follow-up that consuming 5% of energy from both animal and total protein at the expense of carbohydrates or fat increases diabetes risk by 30%.64 This reinforces the theory that high-protein diets can have adverse effects on glucose metabolism.

Brand-Miller and colleagues67 have proposed the carnivore connection hypothesis, suggesting that during human evolution a scarcity of dietary carbohydrates together with high intake from animal proteins led to insulin resistance. This may have provided a survival and reproductive advantage by redirecting glucose from maternal use to fetal metabolism, thus increasing birth weight and survival of the offspring,67 but could be deleterious in a high-carbohydrate environment. In this context it is interesting that populations which have only recently switched from traditional high-protein hunter–gatherer-type diets to modern high-carbohydrate diets show an excessively high prevalence of insulin resistance and T2DM compared with European populations that switched to a higher carbohydrate intake some 12 000 years ago.67,68

The role of exercise in the prevention and treatment of type 2 diabetes mellitus

Regular exercise is another cornerstone of diabetes management, along with dietary and pharmacological interventions.3,17 Both aerobic exercise and resistance training improve insulin action, at least acutely, and may have a beneficial effect on quality of life, glucose control, blood lipids, systolic blood pressure, cardiovascular risk and mortality.3 Current guidelines recommend that patients with T2DM should perform at least 150 min per week of moderate-intensity aerobic exercise and should perform resistance exercise three times per week.3,17 The US Department of Health recommends that adults > 65 years or those with disabilities follow the above recommendations if possible, or be as physically active as they are able.69

The National Institutes of Health (NIH)-AARP Diet and Health Study, in 1995 to 1996, enrolled 114 996 men and 92 483 women, aged 50–71 years without evidence of heart disease, cancer or diabetes. Incident self-reported, physician-diagnosed diabetes was identified with a follow-up survey in 2004–2006. Men and women whose diet score, physical activity level, smoking status and alcohol use were all in the low-risk group had odds ratios for diabetes of 0.61 (CI 0.56 to 0.66) and 0.43 (CI 0.34 to 0.55), respectively. When absence of overweight or obesity was added, the corresponding odds ratios were 0.28 (CI 0.23 to 0.34) and 0.16 (CI 0.10 to 0.24) for men and women, respectively. This indicates that lifestyle factors, when considered in combination, are associated with a substantial reduction in the risk of diabetes.70 Independent of exercise levels, sedentary behaviour, especially excessive television watching, is associated with a significantly elevated risk of obesity and T2DM, whereas even light to moderate activity may lower this risk.71,72

In a Danish study, 4031 patients with impaired fasting glucose or impaired glucose tolerance underwent oral glucose tolerance tests at baseline and after five years to reassess their status.73 Leisure-time physical activity at baseline was assessed by questionnaire. Physical activity was associated with a lower risk of progression to diabetes in the total study population and in individuals with impaired glucose tolerance, a condition primarily characterized by muscle insulin resistance. However, it did not predict progression to diabetes in individuals with impaired fasting glucose.73 There is some evidence that recreational physical activity performed during the year before and during the first 20 weeks of index pregnancy was also associated with significant reductions in risk of gestational diabetes.74 However, although physical activity is a key element in the prevention and management of T2DM,7582 many people with T2DM are not active.16 Furthermore, reported differences in the effects of aerobic versus resistance training, and of unstructured physical activity versus structured exercise programmes, on the risk of developing T2DM and metabolic control in patients with T2DM are incompletely understood and controversial.

Exercise intensity, aerobic exercise and resistance training

Physical activity can result in acute improvement in insulin sensitivity lasting 2–72 hours.3 Physical activity must be regular to have continued beneficial effects, and probably needs to include varying types of exercise.3 A combination of aerobic and resistance training may be more effective for the management of glucose control than either type of exercise alone.83,84 Any increase in muscle mass that may result from resistance training could contribute to glucose uptake, whereas aerobic exercise improves insulin action independent of changes in muscle mass or aerobic capacity.83 The most successful programmes for long-term weight control have involved combinations of diet, exercise and behaviour modification.3 Physical exercise, and especially combined aerobic/resistance exercise, in T2DM patients with the metabolic syndrome may also result in improvement of markers of insulin resistance and inflammation, independent of weight loss, although results are controversial.8587

Although the beneficial effects of regular exercise on physical and mental well-being are beyond doubt, less is known about their effects on weight loss, insulin resistance and diabetes risk. Aerobic exercise has been shown to improve whole-body insulin sensitivity as measured by euglycaemic–hyperinsulinaemic clamp, but there may be no significant improvement in hepatic insulin sensitivity.88 Several studies have investigated the effect of aerobic exercise on surrogate markers of cardiovascular risk in patients with T2DM. A recent meta-analysis showed significant improvements in systolic blood pressure (−6.08 mmHg; 95% CI −10.79 mmHg to −1.36 mmHg) and triglycerides (−0.3 mmol/l; 95% CI −0.48 mmol/l to −0.11 mmol/l). Combined aerobic/resistance exercise also improved these parameters, but to a lesser extent.89 Aerobic training also results in a modest increase in high-density lipoprotein-cholesterol (HDL-C) concentrations.90 However, this could have a significant effect on coronary heart disease, since a 1% increase in HDL-C levels is associated with a 3.5% decrease in mortality.91,92 Aerobic exercise of at least 3 months' duration has also been shown to decrease arterial stiffness in large arteries in a group of older adults with T2DM, hypertension and hypercholesterolaemia.93 In a study involving middle-aged obese women, high-intensity (more than lactate threshold) aerobic exercise effectively reduced total abdominal fat, subcutaneous abdominal fat and abdominal visceral fat.94 However, this benefit of aerobic exercise was not replicated in other studies.95,96 In non-dieting, overweight subjects, a higher amount of activity appears to be necessary for weight maintenance.

Resistance training, even when not associated with weight loss, improves insulin sensitivity and fasting glucose and has favourable impact on body composition.97,98 There might be subtle differences in the effect of resistance exercise in different ethnic groups. In a study involving Asian Indians, insulin resistance improved significantly following 12 weeks of training without any change in BMI, levels of total body fat, abdominal fat or lean body mass or cross-sectional skeletal muscle area of the extremities.99 A recent randomized trial examined the effect of aerobic and resistance exercise in a group of Caucasian and Afro-Caribbean patients with T2DM. Afro-Caribbean subjects responded more favourably to resistance training than did Caucasians, showing reductions in BMI (−2.57% ± 0.90% vs 2.57% ± 1.09%; P < 0.01) and improved markers of insulin resistance (−19.15% ± 9.00% vs 13.12% ± 11.86%; P < 0.05).100

Other studies have shown improvements in blood pressure, total cholesterol and abdominal fat mass with resistance exercise.101,102

Table 2 summarizes results of studies that reported effects of aerobic and/or resistance training on HbA1c.

TABLE 2

Randomised controlled trials of physical activity in diabetes (at least 100 subjects)

Source Type of intervention Dietary intervention Intervention (number) Control (number) Frequency and duration Dropout (%) HbA1c change (%)
Church et al. (2010)105 Aerobic training No 72 41 3/week, 39 weeks Intervention 4; control 10 −0.23 (−0.30 to −0.16)
Sigal et al. (2007)84 Aerobic training No 60 63 3/week, 26 weeks Intervention 20; control 5 −0.50 (−1.22 to +0.22)
Sridhar et al. (2010)108 Aerobic training No 55 50 5/week, 52 weeks Not reported −2.76 (−3.13 to −2.39)
Church et al. (2010)105 Resistance training No 73 41 3/week, 39 weeks Intervention 5; control 10 −0.15 (−0.22 to −0.08)
Sigal et al. (2007)84 Resistance training No 64 63 3/week, 26 weeks Intervention 11; control 5 −0.37 (−1.08 to +0.34)
Balducci et al. (2004)109 Aerobic and resistance training No 51 53 3/week, 52 weeks Intervention 18; control 9 −1.24 (−1.88 to +0.60)
Church et al. (2010)105 Aerobic and resistance training No 76 41 3/week, 39 weeks Intervention 5; control 10 −0.34 (−0.41 to −0.27)
Sigal et al. (2007)84 Aerobic and resistance training No 64 63 3/week, 26 weeks Intervention 13; control 5 −0.97 (−1.69 to −0.25)
Christian et al. (2008)110 Advice Yes 141 132 52 weeks Intervention 9; control 13 −0.60 (−1.00 to −0.20)
Di Loreto et al. (2003)111 Advice Yes 182 158 104 weeks Intervention 2; control 2 −0.50 (−0.62 to −0.38)
Hordern et al. (2009)112 Advice Yes 88 88 52 weeks Intervention 21; control 21 −0.70 (−1.08 to −0.32)
Jakicic et al. (2009)113 Advice Yes 2486 2575 52 weeks Intervention 4; control 4 −0.50 (−0.56 to −0.44)
Mayer-Davis et al. (2004)114 Advice Yes 49 56 52 weeks Total 19 −0.44 (−0.87 to −0.01)
van Rooijen et al. (2004)115 Advice Yes 75 74 12 weeks Intervention 6; control 4 +0.62 (−0.14 to +1.38)

Effects of structured exercise interventions

Structured interventions that consist of aerobic exercise, resistance training, or both, combined with modest weight loss, may lower risk of T2DM by up to 58% in high-risk populations.3 Exercise training of more than 150 min per week is associated with greater HbA1c reduction than that training for 150 min or less per week. Previous meta-analyses103,104 found that structured exercise including aerobic and resistance training reduces HbA1c levels by approximately 0.6%. However, only one previous review separately analysed associations of aerobic exercise, resistance training and the combination of aerobic exercise and resistance training on change in HbA1c levels;103 differences among the effects of aerobic, resistance and combined training on HbA1c were marginal, with all forms of exercise training producing small improvements in HbA1c.104 Since the publication of this meta-analysis, two large randomized trials84,105 have reported contradictory findings regarding the types of structured exercise associated with declines in HbA1c levels. Sigal et al.84 found that aerobic or resistance exercise training alone improved glycaemic control, but the effects were more pronounced when combined. In contrast, Church et al.105 observed that only the combination, but not aerobic and resistance training alone, reduced HbA1c levels. Although high-intensity exercise has been previously shown to have an association with HbA1c reduction,106 others have failed to demonstrate that more intensive exercise is associated with greater declines in HbA1c.107

A recent systematic review and meta-analysis of 47 randomized controlled trials of structured exercise programmes with or without dietary intervention in subjects with T2DM showed overall HbA1c reduction of −0.67% (−0.84% to −0.49%) for subjects in an intervention group involving exercise and diet when compared with controls. In addition, structured aerobic exercise (−0.73%), structured resistance training (−0.57%) and both combined (−0.51%) were each associated with declines in HbA1c. Structured exercise of total duration more than 150 min per week was associated with HbA1c reductions of 0.89%, whereas structured exercise durations of 150 min or less per week were associated with HbA1c reductions of 0.36%. Physical activity alone without dietary input did not have any impact on glycaemic control.107 An earlier Cochrane review analysed 14 randomized controlled trials involving 377 participants comparing exercise with no exercise in subjects with T2DM. Trials ranged in duration from 8 weeks to 12 months. Compared with the control group, exercise intervention significantly improved glycaemic control, as indicated by a decrease in HbA1c of 0.6% (−0.9% to −0.3%; P < 0.05). There was no significant difference between groups in whole-body mass, probably because of an increase in fat-free mass (muscle) with exercise.104

Supervised brisk walking is possibly the easiest and most cost-effective way to improve physical activity. However, randomized controlled trials involving brisk walking three times a week in subjects with T2DM have found no significant improvement in HbA1c or other metabolic parameters, possibly because of the observed high dropout rates of up to 50%, which were attributed to injuries and lack of motivation. However, among participants who attended at least 50% of walking sessions, discontinuation or reduction in anti-diabetic drugs was achieved in one-third of subjects.116,117

Use of a pedometer with a recommendation to walk at least 10 000 steps a day may give a more objective assessment of active lifestyle. Randomized controlled trials have found a significant improvement in physical activity, but no change in metabolic parameters.118120 Again, the dropout rates are reported to be considerable, especially in the subgroups of subjects who have poor physical fitness, suggesting that the persons most in need of physical exercise are the least compliant in exercise programmes.118120 After discontinuation of exercise programme, the effects tend to taper off over the following 6–12 months, presumably because of lack of adherence. Additional support in the form of community centre-based exercise or physical therapist-directed counselling seems to maintain physical activity following cessation of supervised exercise.121123

Unstructured physical activity

In contrast to structured exercise training, physical activity is defined as any bodily movement produced by skeletal muscle contractions resulting in increased energy expenditure.124 Although structured exercise training may be available to a subset of patients with T2DM, physical activity advice is more feasible and should be offered to most of these patients. However, meta-analyses have not been performed to determine whether physical activity advice is associated with similar declines in HbA1c as those associated with structured exercise. In one study, a recommendation to increase physical activity was beneficial (0.43% HbA1c reduction), but only if combined with dietary instructions.107 In 1030 patients involved in the Finnish diabetic nephropathy study, leisure-time physical activity was assessed by a 12-month validated questionnaire expressed in metabolic equivalent units. There was a weak correlation between physical activity (r = 0.12; P = 0.007) and HbA1c level in women, but not in men. Age, obesity, smoking, insulin dose, social class, diabetic nephropathy or CVD did not explain the results.125 An earlier study evaluated 50 patients with type 1 diabetes mellitus (T1DM), 50 patients with T2DM and 70 control subjects using a questionnaire to determine the type, duration and intensity of exercise. There was no correlation between the degree of activity and HbA1c levels or hypoglycaemic events. A negative correlation was found between physical activity and daily insulin usage (r = −0.27; P < 0.05).126 A cross-sectional survey of physical activity in 221 patients with T1DM did not find any correlation with glycaemic control, but insulin requirements were lower (r = −0.20; P = 0.002) in more active subjects.127

In summary, a structured exercise programme appears to be superior to advice alone in improving physical activity levels. However, there are obvious cost and logistic implications in providing such a programme for all patients with diabetes.

Exercise and improvement in quality of life

Rejeski et al.128 found that, among overweight and obese adults with T2DM, an intensive lifestyle intervention led to a relative reduction of 48% in the severity of mobility related disability, as compared with diabetes support and education. This effect was mediated by both weight loss and better fitness. Even without changes in body weight and glycaemic control, exercise programmes have consistently shown to result in improvements in self-reported physical activity and health-related quality of life. Depressive symptoms and mental health status with aerobic and resistance exercise may also improve.129131 A relatively short duration (3 months) of vigorous aerobic exercise improves orthostatic tolerance and arterial baroreflex function in elderly patients at high cardiovascular risk.132,133 A balance exercise programme in older adults with diabetic neuropathy improves balance and trunk proprioception possibly preventing falls.134 Even though many overweight/obese patients with T2DM and coexistent morbidities may not be able to perform exercise at a level that is sufficient to result in relevant weight loss and major improvements in glycaemic control, additional benefits of even moderate increases in physical activity in these patients appear to be important.

Conclusions

Excessive energy intake in relation to physical activity leads to adiposity and insulin resistance and has been proposed as the strongest single predictor for T2DM,6 whereas weight loss is almost always associated with improved insulin sensitivity.4 Thus, any lifestyle measures that lead to weight loss and can be sustained in the long term have the potential to improve glycaemic control. Energy-reduced diets should be balanced to avoid potential detrimental effects on health, and long-term success appears to be mainly determined by the adherence to the diet, regardless of the chosen dietary strategy. However, particularly in patients with T2DM, long-term sustained weight loss appears to be difficult to achieve. In this situation isoenergetic changes in the macronutrient composition and the quality of ingested foods may exert additional important effects on insulin sensitivity, independent of weight loss. Dietary measures that may improve insulin sensitivity include using a Mediterranean-like dietary pattern, but avoiding excess intake of dietary fat, replacing SFAs and TFAs with MUFAs and n-6 PUFAs and increasing cereal fibre intake and exercise levels, particularly when choosing a low-carbohydrate, high-protein diet. It is also noteworthy that intentional weight loss through any diet and/or exercise causes not only loss of excess fat mass, but also some loss of lean body mass. An ideal weight management programme should therefore maximize fat loss and minimize the loss of muscle mass.

Most people with T2DM can perform exercise safely, but precautions must be taken in patients with severe obesity, CVD or diabetes-related neuropathic damage. Structured exercise programmes appear to be superior to simple advice to increase physical activity levels.

Weight loss, the macronutrient composition of the diet, aerobic exercise and resistance training all appear to improve insulin resistance, by distinct mechanisms. Therefore, a combination of these interventions tailored to the requirements of each subject should be one of the cornerstones of management of overweight/obese patients with T2DM.3,17,135

References

1. 

Neal B. White rice and risk of type 2 diabetes. BMJ 2012; 344:e2021.

2. 

Narayan KM, Boyle JP, Thompson TJ, Sorensen SW, Williamson DF. Lifetime risk for diabetes mellitus in the United States. JAMA 2003; 290:1884–90. http://dx.doi.org/10.1001/jama.290.14.1884

3. 

Colberg SR, Sigal RJ, Fernhall B, et al. Exercise and type 2 diabetes: the American College of Sports Medicine and the American Diabetes Association: joint position statement. Diabetes Care 2010; 33:e147–67. http://dx.doi.org/10.2337/dc10-9990

4. 

McAuley K, Mann J. Thematic review series: patient-oriented research. Nutritional determinants of insulin resistance. J Lipid Res 2006; 47:1668–76. http://dx.doi.org/10.1194/jlr.R600015-JLR200

5. 

Vazquez G, Duval S, Jacobs DR Jr, Silventoinen K. Comparison of body mass index, waist circumference, and waist/hip ratio in predicting incident diabetes: a meta-analysis. Epidemiol Rev 2007; 29:115–28. http://dx.doi.org/10.1093/epirev/mxm008

6. 

Sung KC, Jeong WS, Wild SH, Byrne CD. Combined influence of insulin resistance, overweight/obesity, and fatty liver as risk factors for type 2 diabetes. Diabetes Care 2012; 35:717–22. http://dx.doi.org/10.2337/dc11-1853

7. 

Kastorini CM, Milionis HJ, Esposito K, Giugliano D, Goudevenos JA, Panagiotakos DB. The effect of Mediterranean diet on metabolic syndrome and its components: a meta-analysis of 50 studies and 534,906 individuals. J Am Coll Cardiol 2011; 57:1299–313. http://dx.doi.org/10.1016/j.jacc.2010.09.073

8. 

Riserus U, Willett WC, Hu FB. Dietary fats and prevention of type 2 diabetes. Prog Lipid Res 2009; 48:44–51. http://dx.doi.org/10.1016/j.plipres.2008.10.002

9. 

Thomas T, Pfeiffer AF. Foods for the prevention of diabetes: how do they work? Diabetes Metab Res Rev 2011; 28:25–49. http://dx.doi.org/10.1002/dmrr.1229

10. 

Weickert MO, Pfeiffer AF. Metabolic effects of dietary fibre consumption and prevention of diabetes. J Nutr 2008; 138:439–42.

11. 

Brand-Miller J, McMillan-Price J, Steinbeck K, Caterson I. Dietary glycaemic index: health implications. J Am Coll Nutr 2009; 28(Suppl. 1):446S–4499S.

12. 

de Munter JS, Hu FB, Spiegelman D, Franz M, van Dam RM. Whole grain, bran, and germ intake and risk of type 2 diabetes: a prospective cohort study and systematic review. PLoS Med 2007; 4:1385–95. http://dx.doi.org/10.1371/journal.pmed.0040261

13. 

Schulze MB, Schulz M, Heidemann C, Schienkiewitz A, Hoffmann K, Boeing H. Fibre and magnesium intake and incidence of type 2 diabetes: a prospective study and meta-analysis. Arch Intern Med 2007; 167:956–65. http://dx.doi.org/10.1001/archinte.167.9.956

14. 

Rassool GH. Expert report on diet, nutrition and prevention of chronic diseases. J Adv Nurs 2003; 43:544–5. http://dx.doi.org/10.1046/j.1365-2648.2003.02792.x

15. 

Zisser H, Gong P, Kelley CM, Seidman JS, Riddell MC. Exercise and diabetes. Int J Clin Pract 2011; 170(Suppl.):71–5. http://dx.doi.org/10.1111/j.1742-1241.2010.02581.x

16. 

Morrato EH, Hill JO, Wyatt HR, Ghushchyan V, Sullivan PW. Physical activity in US adults with diabetes and at risk for developing diabetes, 2003. Diabetes Care 2007; 30:203–9. http://dx.doi.org/10.2337/dc06-1128

17. 

American Diabetes Association. Standards of medical care in diabetes – 2011. Diabetes Care 2011; 34(Suppl. 1):S11–61.

18. 

Gomez-Cabrera MC, Ristow M, Vina J. Antioxidant supplements in exercise: worse than useless? Am J Physiol Endocrinol Metab 2012; 302:E476–7; author reply E478–9.

19. 

Brancati FL, Wang NY, Mead LA, Liang KY, Klag MJ. Body weight patterns from 20 to 49 years of age and subsequent risk for diabetes mellitus: the Johns Hopkins Precursors Study. Arch Intern Med 1999; 159:957–963. http://dx.doi.org/10.1001/archinte.159.9.957

20. 

Kelley DE, Wing R, Buonocore C, Sturis J, Polonsky K, Fitzsimmons M. Relative effects of calorie restriction and weight loss in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1993; 77:1287–93. http://dx.doi.org/10.1210/jc.77.5.1287

21. 

Wing RR, Koeske R, Epstein LH, Nowalk MP, Gooding W, Becker D. Long-term effects of modest weight loss in type II diabetic patients. Arch Intern Med 1987; 147:1749–53. http://dx.doi.org/10.1001/archinte.1987.00370100063012

22. 

Maggio CA, Pi-Sunyer FX. The prevention and treatment of obesity. Application to type 2 diabetes. Diabetes Care 1997; 20:1744–66.

23. 

Pi-Sunyer FX. Weight loss in type 2 diabetic patients. Diabetes Care 2005; 28:1526–7. http://dx.doi.org/10.2337/diacare.28.6.1526

24. 

Milne RM, Mann JI, Chisholm AW, Williams SM. Long-term comparison of three dietary prescriptions in the treatment of NIDDM. Diabetes Care 1994; 7:74–80. http://dx.doi.org/10.2337/diacare.17.1.74

25. 

Sacks FM, Bray GA, Carey VJ, et al. Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates. N Engl J Med 2009; 60:859–73. http://dx.doi.org/10.1056/NEJMoa0804748

26. 

Dansinger ML, Gleason JA, Griffith JL, Selker HP, Schaefer EJ. Comparison of the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: a randomized trial. JAMA 2005; 93:43–53. http://dx.doi.org/10.1001/jama.293.1.43

27. 

Redmon JB, Reck KP, Raatz SK, et al. Two-year outcome of a combination of weight loss therapies for type 2 diabetes. Diabetes Care 2005; 8:1311–15. http://dx.doi.org/10.2337/diacare.28.6.1311

28. 

Hession M, Rolland C, Kulkarni U, Wise A, Broom J. Systematic review of randomized controlled trials of low-carbohydrate vs. low-fat/low-calorie diets in the management of obesity and its comorbidities. Obes Rev 2009; 10:36–50. http://dx.doi.org/10.1111/j.1467-789X.2008.00518.x

29. 

Bray GA. Effect of caloric restriction on energy expenditure in obese patients. Lancet 1969; 2:397–8. http://dx.doi.org/10.1016/S0140-6736(69)90109-3

30. 

Heshka S, Yang MU, Wang J, Burt P, Pi-Sunyer FX. Weight loss and change in resting metabolic rate. Am J Clin Nutr 1990; 2:981–6.

31. 

Bogardus C, Taskinen MR, Zawadzki J, Lillioja S, Mott D, Howard BV. Increased resting metabolic rates in obese subjects with non-insulin-dependent diabetes mellitus and the effect of sulfonylurea therapy. Diabetes 1986; 5:1–5. http://dx.doi.org/10.2337/diabetes.35.1.1

32. 

Nair KS, Halliday D, Garrow JS. Increased energy expenditure in poorly controlled Type 1 (insulin-dependent) diabetic patients. Diabetologia 1984; 7:13–16. http://dx.doi.org/10.1007/BF00253494

33. 

Boule NG, Haddad E, Kenny GP, Wells GA, Sigal RJ. Effects of exercise on glycaemic control and body mass in type 2 diabetes mellitus: a meta-analysis of controlled clinical trials. JAMA 2001; 86:1218–27. http://dx.doi.org/10.1001/jama.286.10.1218

34. 

Larsen TM, Dalskov SM, van Baak M, et al. Diets with high or low protein content and glycaemic index for weight-loss maintenance. N Engl J Med 2010; 63:2102–13. http://dx.doi.org/10.1056/NEJMoa1007137

35. 

Beavers KM, Lyles MF, Davis CC, Wang X, Beavers DP, Nicklas BJ. Is lost lean mass from intentional weight loss recovered during weight regain in postmenopausal women? Am J Clin Nutr 2011; 4:767–74. http://dx.doi.org/10.3945/ajcn.110.004895

36. 

Vessby B, Uusitupa M, Hermansen K, et al. Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: The KANWU Study. Diabetologia 2001; 4:312–19. http://dx.doi.org/10.1007/s001250051620

37. 

Salmeron J, Hu FB, Manson JE, Stampfer MJ, Colditz GA, Rimm EB, Willett WC. Dietary fat intake and risk of type 2 diabetes in women. Am J Clin Nutr 2001; 3:1019–26.

38. 

Mozaffarian D. Trans fatty acids – effects on systemic inflammation and endothelial function. Atherosclerosis 2006; 2(Suppl. 7):29–32. http://dx.doi.org/10.1016/j.atherosclerosissup.2006.04.007

39. 

Cascio G, Schiera G, Di Liegro I. Dietary fatty acids in metabolic syndrome, diabetes and cardiovascular diseases. Curr Diabetes Rev 2012; 8:2–17. http://dx.doi.org/10.2174/157339912798829241

40. 

Laaksonen DE, Lakka TA, Lakka HM, et al. Serum fatty acid composition predicts development of impaired fasting glycaemia and diabetes in middle-aged men. Diabet Med 2002; 9:456–64. http://dx.doi.org/10.1046/j.1464-5491.2002.00707.x

41. 

Vessby B, Aro A, Skarfors E, Berglund L, Salminen I, Lithell H. The risk to develop NIDDM is related to the fatty acid composition of the serum cholesterol esters. Diabetes 1994; 3:1353–7. http://dx.doi.org/10.2337/diabetes.43.11.1353

42. 

Riccardi G, Giacco R, Rivellese AA. Dietary fat, insulin sensitivity and the metabolic syndrome. Clin Nutr 2004; 3:447–56. http://dx.doi.org/10.1016/j.clnu.2004.02.006

43. 

Rioux V, Legrand P. Saturated fatty acids: simple molecular structures with complex cellular functions. Curr Opin Clin Nutr Metab Care 2007; 10:752–8. http://dx.doi.org/10.1097/MCO.0b013e3282f01a75

44. 

Trumbo P, Schlicker S, Yates AA, Poos M. Dietary reference intakes for energy, carbohydrate, fibre, fat, fatty acids, cholesterol, protein and amino acids. J Am Diet Assoc 2002; 2:1621–30. http://dx.doi.org/10.1016/S0002-8223(02)90346-9

45. 

Brand-Miller J, Hayne S, Petocz P, Colagiuri S. Low-glycaemic index diets in the management of diabetes: a meta-analysis of randomized controlled trials. Diabetes Care 2003; 6:2261–7. http://dx.doi.org/10.2337/diacare.26.8.2261

46. 

Erkkila AT, Lichtenstein AH, Mozaffarian D, Herrington DM. Fish intake is associated with a reduced progression of coronary artery atherosclerosis in postmenopausal women with coronary artery disease. Am J Clin Nutr 2004; 80:626–32.

47. 

Kris-Etherton PM, Lichtenstein AH, Howard BV, Steinberg D, Witztum JL. Antioxidant vitamin supplements and cardiovascular disease. Circulation 2004; 10:637–41. http://dx.doi.org/10.1161/01.CIR.0000137822.39831.F1

48. 

Franz MJ, Bantle JP, Beebe CA, et al. Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. Diabetes Care 2002; 5:148–98. http://dx.doi.org/10.2337/diacare.25.1.148

49. 

Salas-Salvado J, Martinez-Gonzalez MA, Bullo M, Ros E. The role of diet in the prevention of type 2 diabetes. Nutr Metab Cardiovasc Dis 2011; 1(Suppl. 2):B32–48. http://dx.doi.org/10.1016/j.numecd.2011.03.009

50. 

Isken F, Klaus S, Petzke KJ, Loddenkemper C, Pfeiffer AF, Weickert MO. Impairment of fat oxidation under high- vs. low-glycaemic index diet occurs before the development of an obese phenotype. Am J Physiol Endocrinol Metab 2010; 98:E287–95. http://dx.doi.org/10.1152/ajpendo.00515.2009

51. 

Pi-Sunyer X. Do glycaemic index, glycaemic load, and fibre play a role in insulin sensitivity, disposition index, and type 2 diabetes? Diabetes Care 2005; 8:2978–9. http://dx.doi.org/10.2337/diacare.28.12.2978

52. 

Weickert MO, Pfeiffer AF. Low-glycaemic index vs high-cereal fibre diet in type 2 diabetes. JAMA 2009; 1:1538; author reply 1538–9. http://dx.doi.org/10.1001/jama.2009.483

53. 

Weickert MO, Arafat AM, Blaut M, et al. Changes in dominant groups of the gut microbiota do not explain cereal-fibre induced improvement of whole-body insulin sensitivity. Nutr Metab 2011; 8:90. http://dx.doi.org/10.1186/1743-7075-8-90

54. 

Jenkins DJ, Kendall CW, Axelsen M, Augustin LS, Vuksan V. Viscous and nonviscous fibres, nonabsorbable and low glycaemic index carbohydrates, blood lipids and coronary heart disease. Curr Opin Lipidol 2000; 1:49–56. http://dx.doi.org/10.1097/00041433-200002000-00008

55. 

Chandalia M, Garg A, Lutjohann D, von Bergmann K, Grundy SM, Brinkley LJ. Beneficial effects of high dietary fiber intake in patients with type 2 diabetes mellitus. N Engl J Med 2000; 42:1392–8. http://dx.doi.org/10.1056/NEJM200005113421903

56. 

Delzenne NM, Cani PD. Gut microbiota and the pathogenesis of insulin resistance. Curr Diab Rep 2011; 1:154–9. http://dx.doi.org/10.1007/s11892-011-0191-1

57. 

Freeland KR, Wilson C, Wolever TM. Adaptation of colonic fermentation and glucagon-like peptide-1 secretion with increased wheat fibre intake for 1 year in hyperinsulinaemic human subjects. Br J Nutr 2010; 03:82–90. http://dx.doi.org/10.1017/S0007114509991462

58. 

Pereira MA, Jacobs DR Jr., Pins JJ, et al. Effect of whole grains on insulin sensitivity in overweight hyperinsulinemic adults. Am J Clin Nutr 2002; 5:848–55.

59. 

Weickert MO, Roden M, Isken F, et al. Effects of supplemented isoenergetic diets differing in cereal fibre and protein content on insulin sensitivity in overweight humans. Am J Clin Nutr 2011; 4:459–71. http://dx.doi.org/10.3945/ajcn.110.004374

60. 

Tremblay F, Krebs M, Dombrowski L, et al. Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability. Diabetes 2005; 4:2674–84. http://dx.doi.org/10.2337/diabetes.54.9.2674

61. 

Um SH, D'Alessio D, Thomas G. Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. Cell Metab 2006; 3:393–402. http://dx.doi.org/10.1016/j.cmet.2006.05.003

62. 

Malik VS, Hu FB. Popular weight-loss diets: from evidence to practice. Nat Clin Pract Cardiovasc Med 2007; 4:34–41. http://dx.doi.org/10.1038/ncpcardio0726

63. 

Gosby AK, Conigrave AD, Lau NS, et al. Testing protein leverage in lean humans: a randomized controlled experimental study. PLoS One 201; 6:e25929. http://dx.doi.org/10.1371/journal.pone.0025929

64. 

Sluijs I, Beulens JW, van der AD, Spijkerman AM, Grobbee DE, van der Schouw YT. Dietary intake of total, animal, and vegetable protein and risk of type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)-NL study. Diabetes Care 2010; 3:43–8. http://dx.doi.org/10.2337/dc09-1321

65. 

Gogebakan O, Kohl A, Osterhoff MA, et al. Effects of weight loss and long-term weight maintenance with diets varying in protein and glycaemic index on cardiovascular risk factors: the diet, obesity, and genes (DiOGenes) study: a randomized, controlled trial. Circulation 2011; 24:2829–38. http://dx.doi.org/10.1161/CIRCULATIONAHA.111.033274

66. 

Linn T, Santosa B, Gronemeyer D, et al. Effect of long-term dietary protein intake on glucose metabolism in humans. Diabetologia 2000; 3:1257–65. http://dx.doi.org/10.1007/s001250051521

67. 

Brand-Miller JC, Griffin HJ, Colagiuri S. The carnivore connection hypothesis: revisited. J Obes 2012.

68. 

Chen L, Magliano DJ, Zimmet PZ. The worldwide epidemiology of type 2 diabetes mellitus-present and future perspectives. Nat Rev Endocrinol 2012; 8:228–36.

69. 

Services UDoHaH. Physical activity guidelines for Americans. Okla Nurse 2008; 3:25.

70. 

Reis JP, Loria CM, Sorlie PD, Park Y, Hollenbeck A, Schatzkin A. Lifestyle factors and risk for new-onset diabetes: a population-based cohort study. Ann Intern Med 2011; 55:292–9.

71. 

Hu FB, Li TY, Colditz GA, Willett WC, Manson JE. Television watching and other sedentary behaviours in relation to risk of obesity and type 2 diabetes mellitus in women. JAMA 2003; 89:1785–91. http://dx.doi.org/10.1001/jama.289.14.1785

72. 

Krishnan S, Rosenberg L, Palmer JR. Physical activity and television watching in relation to risk of type 2 diabetes: the Black Women's Health Study. Am J Epidemiol 2009; 169:428–34. http://dx.doi.org/10.1093/aje/kwn344

73. 

Engberg S, Glumer C, Witte DR, Jorgensen T, Borch-Johnsen K. Differential relationship between physical activity and progression to diabetes by glucose tolerance status: the Inter99 Study. Diabetologia 2010; 3:70–8. http://dx.doi.org/10.1007/s00125-009-1587-1

74. 

Dempsey JC, Butler CL, Sorensen TK, et al. A case–control study of maternal recreational physical activity and risk of gestational diabetes mellitus. Diabetes Res Clin Pract 2004; 6:203–15. http://dx.doi.org/10.1016/j.diabres.2004.03.010

75. 

Balducci S, Iacobellis G, Parisi L, et al. Exercise training can modify the natural history of diabetic peripheral neuropathy. J Diabetes Complications 2006; 20:216–23. http://dx.doi.org/10.1016/j.jdiacomp.2005.07.005

76. 

Cohen ND, Dunstan DW, Robinson C, Vulikh E, Zimmet PZ, Shaw JE. Improved endothelial function following a 14-month resistance exercise training program in adults with type 2 diabetes. Diabetes Res Clin Pract 2008; 9:405–11. http://dx.doi.org/10.1016/j.diabres.2007.09.020

77. 

Ghosh S, Khazaei M, Moien-Afshari F, et al. Moderate exercise attenuates caspase-3 activity, oxidative stress, and inhibits progression of diabetic renal disease in db/db mice. Am J Physiol Renal Physiol 2009; 96:F700–8. http://dx.doi.org/10.1152/ajprenal.90548.2008

78. 

Howorka K, Pumprla J, Haber P, Koller-Strametz J, Mondrzyk J, Schabmann A. Effects of physical training on heart rate variability in diabetic patients with various degrees of cardiovascular autonomic neuropathy. Cardiovasc Res 1997; 4:206–14. http://dx.doi.org/10.1016/S0008-6363(97)00040-0

79. 

Loimaala A, Huikuri HV, Koobi T, Rinne M, Nenonen A, Vuori I. Exercise training improves baroreflex sensitivity in type 2 diabetes. Diabetes 2003; 2:1837–42. http://dx.doi.org/10.2337/diabetes.52.7.1837

80. 

Pagkalos M, Koutlianos N, Kouidi E, Pagkalos E, Mandroukas K, Deligiannis A. Heart rate variability modifications following exercise training in type 2 diabetic patients with definite cardiac autonomic neuropathy. Br J Sports Med 2008; 2:47–54. http://dx.doi.org/10.1136/bjsm.2007.035303

81. 

Tufescu A, Kanazawa M, Ishida A, et al. Combination of exercise and losartan enhances renoprotective and peripheral effects in spontaneously type 2 diabetes mellitus rats with nephropathy. J Hypertens 2008; 6:312–21. http://dx.doi.org/10.1097/HJH.0b013e3282f2450b

82. 

Zoppini G, Targher G, Zamboni C, et al. Effects of moderate-intensity exercise training on plasma biomarkers of inflammation and endothelial dysfunction in older patients with type 2 diabetes. Nutr Metab Cardiovasc Dis 2006; 6:543–9. http://dx.doi.org/10.1016/j.numecd.2005.09.004

83. 

Cuff DJ, Meneilly GS, Martin A, Ignaszewski A, Tildesley HD, Frohlich JJ. Effective exercise modality to reduce insulin resistance in women with type 2 diabetes. Diabetes Care 2003; 6:2977–82. http://dx.doi.org/10.2337/diacare.26.11.2977

84. 

Sigal RJ, Kenny GP, Boule NG, et al. Effects of aerobic training, resistance training, or both on glycaemic control in type 2 diabetes: a randomized trial. Ann Intern Med 2007; 47:357–69.

85. 

Balducci S, Zanuso S, Nicolucci A, et al. Anti-inflammatory effect of exercise training in subjects with type 2 diabetes and the metabolic syndrome is dependent on exercise modalities and independent of weight loss. Nutr Metab Cardiovasc Dis 2010; 0:608–17. http://dx.doi.org/10.1016/j.numecd.2009.04.015

86. 

Donges CE, Duffield R, Drinkwater EJ. Effects of resistance or aerobic exercise training on interleukin-6, C-reactive protein, and body composition. Med Sci Sports Exerc 2010; 2:304–13. http://dx.doi.org/10.1249/MSS.0b013e3181b117ca

87. 

Hopps E, Canino B, Caimi G. Effects of exercise on inflammation markers in type 2 diabetic subjects. Acta Diabetol 2011; 8:183–9. http://dx.doi.org/10.1007/s00592-011-0278-9

88. 

Winnick JJ, Sherman WM, Habash DL, et al. Short-term aerobic exercise training in obese humans with type 2 diabetes mellitus improves whole-body insulin sensitivity through gains in peripheral, not hepatic insulin sensitivity. J Clin Endocrinol Metab 2008; 3:771–8. http://dx.doi.org/10.1210/jc.2007-1524

89. 

Chudyk A, Petrella RJ. Effects of exercise on cardiovascular risk factors in type 2 diabetes: a meta-analysis. Diabetes Care 2011; 4:1228–37. http://dx.doi.org/10.2337/dc10-1881

90. 

Kodama S, Tanaka S, Saito K, et al. Effect of aerobic exercise training on serum levels of high-density lipoprotein cholesterol: a meta-analysis. Arch Intern Med 2007; 67:999–1008. http://dx.doi.org/10.1001/archinte.167.10.999

91. 

Robins SJ, Collins D, Wittes JT, et al. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA 2001 285:1585–91. http://dx.doi.org/10.1001/jama.285.12.1585

92. 

Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999; 41:410–18. http://dx.doi.org/10.1056/NEJM199908053410604

93. 

Madden KM, Lockhart C, Cuff D, Potter TF, Meneilly GS. Short-term aerobic exercise reduces arterial stiffness in older adults with type 2 diabetes, hypertension, and hypercholesterolemia. Diabetes Care 2009; 2:1531–15. http://dx.doi.org/10.2337/dc09-0149

94. 

Irving BA, Davis CK, Brock DW, et al. Effect of exercise training intensity on abdominal visceral fat and body composition. Med Sci Sports Exerc 2008; 40:1863–72. http://dx.doi.org/10.1249/MSS.0b013e3181801d40

95. 

Christiansen T, Paulsen SK, Bruun JM, et al. Comparable reduction of the visceral adipose tissue depot after a diet-induced weight loss with or without aerobic exercise in obese subjects: a 12-week randomized intervention study. Eur J Endocrinol 2009; 60:759–67. http://dx.doi.org/10.1530/EJE-08-1009

96. 

Nicklas BJ, Wang X, You T, et al. Effect of exercise intensity on abdominal fat loss during calorie restriction in overweight and obese postmenopausal women: a randomized, controlled trial. Am J Clin Nutr 2009; 9:1043–52. http://dx.doi.org/10.3945/ajcn.2008.26938

97. 

Baldi JC, Snowling N. Resistance training improves glycaemic control in obese type 2 diabetic men. Int J Sports Med 2003; 4:419–23. http://dx.doi.org/10.1055/s-2003-41173

98. 

Ibanez J, Izquierdo M, Arguelles I, et al. Twice-weekly progressive resistance training decreases abdominal fat and improves insulin sensitivity in older men with type 2 diabetes. Diabetes Care 2005; 8:662–7. http://dx.doi.org/10.2337/diacare.28.3.662

99. 

Misra A, Alappan NK, Vikram NK, et al. Effect of supervised progressive resistance-exercise training protocol on insulin sensitivity, glycaemia, lipids, and body composition in Asian Indians with type 2 diabetes. Diabetes Care 2008; 1:1282–17. http://dx.doi.org/10.2337/dc07-2316

100. 

Winnick JJ, Gaillard T, Schuster DP. Resistance training differentially affects weight loss and glucose metabolism of White and African American patients with type 2 diabetes mellitus. Ethn Dis 2008; 8:152–6.

101. 

Arora E, Shenoy S, Sandhu JS. Effects of resistance training on metabolic profile of adults with type 2 diabetes. Indian J Med Res 2009; 29:515–19.

102. 

Castaneda C, Layne JE, Munoz-Orians L, et al. A randomized controlled trial of resistance exercise training to improve glycaemic control in older adults with type 2 diabetes. Diabetes Care 2002; 5:2335–41. http://dx.doi.org/10.2337/diacare.25.12.2335

103. 

Snowling NJ, Hopkins WG. Effects of different modes of exercise training on glucose control and risk factors for complications in type 2 diabetic patients: a meta-analysis. Diabetes Care 2006; 9:2518–27. http://dx.doi.org/10.2337/dc06-1317

104. 

Thomas DE, Elliott EJ, Naughton GA. Exercise for type 2 diabetes mellitus. Cochrane Database Syst Rev 2006:CD002968.

105. 

Church TS, Blair SN, Cocreham S, Johannsen N, Johnson W, Kramer K, Mikus CR, Myers V, Nauta M, Rodarte RQ, Sparks L, Thompson A, Earnest CP. Effects of aerobic and resistance training on haemoglobin A1c levels in patients with type 2 diabetes: a randomized controlled trial. JAMA 2010; 4:2253–62. http://dx.doi.org/10.1001/jama.2010.1710

106. 

Boule NG, Kenny GP, Haddad E, Wells GA, Sigal RJ. Meta-analysis of the effect of structured exercise training on cardiorespiratory fitness in type 2 diabetes mellitus. Diabetologia 2003; 6:1071–81. http://dx.doi.org/10.1007/s00125-003-1160-2

107. 

Umpierre D, Ribeiro PA, Kramer CK, et al. Physical activity advice only or structured exercise training and association with HbA1c levels in type 2 diabetes: a systematic review and meta-analysis. JAMA 2011; 5:1790–19. http://dx.doi.org/10.1001/jama.2011.576

108. 

Sridhar B, Haleagrahara N, Bhat R, Kulur AB, Avabratha S, Adhikary P. Increase in the heart rate variability with deep breathing in diabetic patients after 12-month exercise training. Tohoku J Exp Med 2010; 20:107–13. http://dx.doi.org/10.1620/tjem.220.107

109. 

Balducci S, Leonetti F, Di Mario U, Fallucca F. Is a long-term aerobic plus resistance training program feasible for and effective on metabolic profiles in type 2 diabetic patients? Diabetes Care 2004; 7:841–2. http://dx.doi.org/10.2337/diacare.27.3.841

110. 

Christian JG, Bessesen DH, Byers TE, Christian KK, Goldstein MG, Bock BC. Clinic-based support to help overweight patients with type 2 diabetes increase physical activity and lose weight. Arch Intern Med 2008; 68:141–6. http://dx.doi.org/10.1001/archinternmed.2007.13

111. 

Di Loreto C, Fanelli C, Lucidi P, et al. Validation of a counseling strategy to promote the adoption and the maintenance of physical activity by type 2 diabetic subjects. Diabetes Care 2003; 6:404–8. http://dx.doi.org/10.2337/diacare.26.2.404

112. 

Hordern MD, Coombes JS, Cooney LM, Jeffriess L, Prins JB, Marwick TH. Effects of exercise intervention on myocardial function in type 2 diabetes. Heart 2009; 5:1343–9. http://dx.doi.org/10.1136/hrt.2009.165571

113. 

Jakicic JM, Jaramillo SA, Balasubramanyam A, et al. Effect of a lifestyle intervention on change in cardiorespiratory fitness in adults with type 2 diabetes: results from the Look AHEAD Study. Int J Obes 2009; 3:305–16.

114. 

Mayer-Davis EJ, D'Antonio AM, Smith SM, et al. Pounds off with empowerment (POWER): a clinical trial of weight management strategies for black and white adults with diabetes who live in medically underserved rural communities. Am J Public Health 2004; 4:1736–42. http://dx.doi.org/10.2105/AJPH.94.10.1736

115. 

van Rooijen AJ, Rheeder P, Eales CJ, et al. Effect of exercise versus relaxation on haemoglobin A1C in Black females with type 2 diabetes mellitus. QJM 2004; 97:343–51. http://dx.doi.org/10.1093/qjmed/hch061

116. 

Negri C, Bacchi E, Morgante S, et al. Supervised walking groups to increase physical activity in type 2 diabetic patients. Diabetes Care 2010; 3:2333–5. http://dx.doi.org/10.2337/dc10-0877

117. 

Praet SF, van Rooij ES, Wijtvliet A, et al. Brisk walking compared with an individualized medical fitness programme for patients with type 2 diabetes: a randomized controlled trial. Diabetologia 2008; 1:736–46. http://dx.doi.org/10.1007/s00125-008-0950-y

118. 

Araiza P, Hewes H, Gashetewa C, Vella CA, Burge MR. Efficacy of a pedometer-based physical activity program on parameters of diabetes control in type 2 diabetes mellitus. Metabolism 2006; 5:1382–7. http://dx.doi.org/10.1016/j.metabol.2006.06.009

119. 

Bjorgaas MR, Vik JT, Stolen T, Lydersen S, Grill V. Regular use of pedometer does not enhance beneficial outcomes in a physical activity intervention study in type 2 diabetes mellitus. Metabolism 2008; 7:605–11. http://dx.doi.org/10.1016/j.metabol.2007.12.002

120. 

Engel L, Lindner H. Impact of using a pedometer on time spent walking in older adults with type 2 diabetes. Diabetes Educ 2006; 2:98–107. http://dx.doi.org/10.1177/0145721705284373

121. 

Dunstan DW, Daly RM, Owen N, Jolley D, Vulikh E, Shaw J, Zimmet P. Home-based resistance training is not sufficient to maintain improved glycaemic control following supervised training in older individuals with type 2 diabetes. Diabetes Care 2005; 8:3–9. http://dx.doi.org/10.2337/diacare.28.1.3

122. 

Dunstan DW, Vulikh E, Owen N, Jolley D, Shaw J, Zimmet P. Community centre-based resistance training for the maintenance of glycaemic control in adults with type 2 diabetes. Diabetes Care 2006; 9:2586–91. http://dx.doi.org/10.2337/dc06-1310

123. 

Taylor JD, Fletcher JP, Tiarks J. Impact of physical therapist-directed exercise counseling combined with fitness centre-based exercise training on muscular strength and exercise capacity in people with type 2 diabetes: a randomized clinical trial. Phys Ther 2009; 9:884–92. http://dx.doi.org/10.2522/ptj.20080253

124. 

Sigal RJ, Kenny GP, Wasserman DH, Castaneda-Sceppa C. Physical activity/exercise and type 2 diabetes. Diabetes Care 2004; 7:2518–39. http://dx.doi.org/10.2337/diacare.27.10.2518

125. 

Waden J, Tikkanen H, Forsblom C, et al. Leisure time physical activity is associated with poor glycaemic control in type 1 diabetic women: the FinnDiane study. Diabetes Care 2005; 8:777–82. http://dx.doi.org/10.2337/diacare.28.4.777

126. 

Selam JL, Casassus P, Bruzzo F, Leroy C, Slama G. Exercise is not associated with better diabetes control in type 1 and type 2 diabetic subjects. Acta Diabetol 1992; 9:11–13. http://dx.doi.org/10.1007/BF00572822

127. 

Ligtenberg PC, Blans M, Hoekstra JB, van der Tweel I, Erkelens DW. No effect of long-term physical activity on the glycaemic control in type 1 diabetes patients: a cross-sectional study. Neth J Med 1999; 5:59–63. http://dx.doi.org/10.1016/S0300-2977(99)00039-X

128. 

Rejeski WJ, Ip EH, Bertoni AG, et al. Lifestyle change and mobility in obese adults with type 2 diabetes. N Engl J Med 2012; 66:1209–17. http://dx.doi.org/10.1056/NEJMoa1110294

129. 

Fritz T, Caidahl K, Osler M, Ostenson CG, Zierath JR, Wandell P. Effects of Nordic walking on health-related quality of life in overweight individuals with type 2 diabetes mellitus, impaired or normal glucose tolerance. Diabet Med 2011; 8:1362–72. http://dx.doi.org/10.1111/j.1464-5491.2011.03348.x

130. 

Levinger I, Selig S, Goodman C, Jerums G, Stewart A, Hare DL. Resistance training improves depressive symptoms in individuals at high risk for type 2 diabetes. J Strength Cond Res 2011; 5:2328–33. http://dx.doi.org/10.1519/JSC.0b013e3181f8fd4a

131. 

Reid RD, Tulloch HE, Sigal RJ, et al. Effects of aerobic exercise, resistance exercise or both, on patient-reported health status and well-being in type 2 diabetes mellitus: a randomized trial. Diabetologia 2011; 3:632–40. http://dx.doi.org/10.1007/s00125-009-1631-1

132. 

Madden KM, Lockhart C, Potter TF, Cuff D. Aerobic training restores arterial baroreflex sensitivity in older adults with type 2 diabetes, hypertension, and hypercholesterolemia. Clin J Sport Med 2010; 20:312–17. http://dx.doi.org/10.1097/JSM.0b013e3181ea8454

133. 

Madden KM, Lockhart CK, Potter TF, Cuff DJ, Meneilly GS. Short-term aerobic exercise reduces nitroglycerin-induced orthostatic intolerance in older adults with type 2 diabetes. J Cardiovasc Pharmacol 2011; 7:666–71. http://dx.doi.org/10.1097/FJC.0b013e31821533cc

134. 

Song CH, Petrofsky JS, Lee SW, Lee KJ, Yim J. Effects of an exercise program on balance and trunk proprioception in older adults with diabetic neuropathies. Diabetes Technol Ther 2011; 3:803–11. http://dx.doi.org/10.1089/dia.2011.0036

135. 

Ferrier KE, Nestel P, Taylor A, Drew BG, Kingwell BA. Diet but not aerobic exercise training reduces skeletal muscle TNF-alpha in overweight humans. Diabetologia 2004; 7:630–7. http://dx.doi.org/10.1007/s00125-004-1373-z



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