DIABETES TECHNOLOGY & THERAPEUTICS Volume 15, Supplement 1, 2013 ª Mary Ann Liebert, Inc. DOI: 10.1089/dia.2013.1511

ORIGINAL ARTICLE

Advances in Exercise, Physical Activity, and Diabetes Mellitus Michael C. Riddell1, Lisa Miadovnik1, Montgomery Simms2, Benjamin Li2, and Howard Zisser2,3

Introduction

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erhaps better than any other single medication or lifestyle choice, regular exercise prevents type 2 diabetes. For people with type 1 diabetes, increased physical activity can provide a whole host of health benefits and enhance one’s quality of life—except that it can be rather frustrating from a glycemic management perspective. This year, we highlight 11 leading peer-reviewed, original manuscripts on exercise, physical activity, and diabetes that were published in the period from July 1, 2011 to June 30, 2012. This year’s articles continue to support the notion that exercise may be the best medicine for people with impaired glucose tolerance and for people with established diabetes. Supervised exercise training counterbalances the adverse effects of insulin therapy in overweight/ obese subjects with type 2 diabetes

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Departments of Clinical and Molecular Medicine, ‘‘La Sapienza’’ University, Rome, Italy; 2Diabetes Unit, Sant’Andrea Hospital, Rome, Italy; 3Metabolic Fitness Association, Monterotondo, Rome, Italy; 4School of Science, University of Greenwich, London, United Kingdom; 5Laboratory of Clinical Chemistry, Sant’Andrea Hospital, Rome, Italy; and 6Department of Clinical Pharmacology and Epidemiology, Consorzio Mario Negri Sud, S. Maria Imbaro, Chieti, Italy Diabetes Care 2012; 35: 39–41

Background Individuals with type 2 diabetes are often treated with insulin therapy to improve glycemic control (1, 2), but this treatment typically causes weight gain and may worsen chronic inflammation (2–4). While insulin therapy decreases

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Methods Seventy-three insulin-treated patients from a subset of the Italian Diabetes Exercise Study were randomized to either training (resistance and aerobic) or standard counseling for 12 months. Clinical and laboratory parameters were assessed at baseline and at the end of the study. Results

Balducci S 1,2,3, Zanuso S 4, Cardelli P 1,5, Salerno G 1,5, Fallucca S1,5, Nicolucci A 6, Pugliese G1,2; Italian Diabetes Exercise Study (IDES) Investigators

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cardiovascular disease (CVD) risk by correcting elevated plasma glucose levels, chronic inflammation has also been linked to CVD and thus may counteract the benefit of the insulin-mediated decrease in plasma glucose levels. Exercise may ameliorate the presence of inflammation and excess body mass gain from insulin therapy, but this hypothesis has not yet been studied.

No major adverse events were observed during the study, including severe hypoglycemia. Total physical activity volume was significantly higher in the exercise group versus the counseling-only group (controls). Daily insulin dose increased in the controls (*20%, p < 0.02) but decreased in the exercise group (*15%, p < 0.05). HbA1c, BMI, waist circumference, blood pressure, LDL, high-sensitivity C-reactive protein (hs-CRP; a marker of inflammation), and CHD risk score were all significantly reduced in the exercisers only. Conclusion Regular exercise is associated with reductions in insulin requirements for patients with type 2 diabetes. Moreover, improvements in HbA1c with a combination of aerobic and resistance exercise are associated with reductions in markers of adiposity and inflammation (WC, BMI, hs-CRP) that are negatively affected by insulin treatment. This supports the concept that exercise may counterbalance the adverse effects of insulin therapy on adiposity and inflammation, either directly or via reduction of daily insulin dose.

School of Kinesiology and Health Science, York University, Toronto, Canada Sansum Diabetes Research Institute, Santa Barbara, CA University of California at Santa Barbara, Santa Barbara, CA

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ADVANCES IN EXERCISE, PHYSICAL ACTIVITY, AND DIABETES MELLITUS Comment Many patients with type 2 diabetes experience weight gain as a consequence of starting insulin therapy, which may invite a whole host of future health problems. Moreover, these patients are already at high risk for CVD, in part due to chronic inflammation, which may be worsened with insulin therapy (5). This is the first study we know of that shows exercise can reverse some of the anabolic and pro-inflammatory effects of insulin therapy. It is interesting to note that despite receiving exercise counseling, the control group did not see nearly the same benefits despite increasing their physical activity levels from 0.6 – 1.3 to 6.9 – 4.4 METs/hour/week. Perhaps the reason behind this is that the improvements seen in the supervised exercisers are volume- and intensity-specific. Future work should be done to confirm this.

(p < 0.05 for both). Interestingly, in the EM intervention, there was no significant change in FFM. Both exercising groups, whether taking metformin or the placebo, increased aerobic capacity by *10% (p < 0.05). Fasting insulin concentrations improved 13%–25% after M, EP, and EM (p < 0.05), with no difference between groups. Both EM and EP saw similarly lowered fasting C-peptide levels. In terms of NEFAs, EP saw a decrease in circulating levels, which was reversed in the EM groups. Finally, increased NOGD, VO2 peak, and weight loss were correlated with greater insulin sensitivity. Conclusion Exercise training improves insulin sensitivity in participants with prediabetes, and the addition of metformin appears to blunt the full effects of training. When metformin is combined with exercise training, there appears to be a slightly blunted rise in insulin sensitivity.

Independent and combined effects of exercise training and metformin on insulin sensitivity in individuals with prediabetes

Comment With the growing recognition of prediabetes as an intermediary step in developing type 2 diabetes, interventions to halt or delay this progression are of urgent need. There appears to be no additive effect of metformin combined with exercise on whole-body insulin sensitivity— and in fact, the rise in insulin sensitivity associated with exercise appears to be somewhat blunted when metformin is introduced (although this difference did not achieve statistical significance). Nonetheless, the benefits of metformin are clearly seen in its ability to induce weight loss and improve glycemia without the requirement of exercise. In essence, for those who can commit to regular exercise, an exercise prescription is likely still the best ‘‘medicine.’’

Malin SK, Gerber R, Chipkin SR, Braun B Energy Metabolism Laboratory, Department of Kinesiology, University of Massachusetts, Amherst, Massachusetts Diabetes Care 2012; 35: 131–6

Background Metformin (6) and exercise (7,8) are two treatment modalities known to increase peripheral insulin sensitivity and aid in weight loss, thus reducing the risk of diabetes (9). There is a pressing need to understand the independent and additive effects of the two treatments on insulin sensitivity and glucose management so that ideal prevention strategies can be implemented for people with prediabetes. Methods Thirty-two otherwise healthy individuals with impaired glucose tolerance (IGT) were equally distributed to placebo (P), metformin (M), exercise training with placebo (EP), or exercise training with metformin (EM) for 12 weeks. The exercise groups were supervised for three sessions a week, each session lasting 60 to 75 minutes and consisting of either cycle ergometer work at 70% peak HR (1 · /week) or cycle ergometer plus resistance training at 70% of 1RM (2 · /week). Insulin sensitivity was measured after a 24-hour fast by a euglycemic, hyperinsulinemic clamp enriched with labeled glucose. Blood samples were analyzed for C-peptide, stable isotope enrichment, nonesterified fatty acids (NEFAs), and nonoxidized glucose disposal (NOGD). Results Both M and EM interventions induced significant weight loss compared to P, while the exercise-alone intervention (EP) had no effect on weight. Both EM and EP reduced body fat (*4%), but there was no effect on central fat. Body fat percentage and central fat percentage saw no change in any intervention. Fat-free mass (FFM) increased in EP compared to M, while M saw a decrease in FFM compared to placebo

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Exercise therapy in type 2 diabetes: is daily exercise required to optimize glycemic control? van Dijk JW 1, Tummers K1, Stehouwer CD 2, Hartgens F 3, van Loon LJ1 1

Human Movement Sciences, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre + , Maastricht, The Netherlands; 2Internal Medicine, CARIM Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre + , Maastricht, The Netherlands; 3Epidemiology and Surgery, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Centre + , Maastricht, The Netherlands Diabetes Care 2012; 35: 948–54

Background Exercise is known to have very helpful but transient effects on insulin sensitivity; thus it has been proposed that daily exercise is the preferred method of optimizing glycemic control (10, 11). Given that a single bout of exercise typically limits hyperglycemia (12–14) and increases insulin sensitivity (10, 15, 16) throughout the subsequent day, this study aimed to determine whether daily exercise brought an equal or additional improvement to glycemic control compared to exercising every other day.

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RIDDELL ET AL.

Methods Thirty male patients with type 2 diabetes were included in a randomized control crossover study consisting of three intervention periods. Each intervention period tested the impact of moderate intensity exercise (50% of maximal workload) on 48-hour blood glucose levels using continuous glucose monitors under standardized dietary, but otherwise free living, conditions. The frequency and duration of the exercise sessions varied, with one intervention consisting of a single 60minute bout of exercise on day one, another consisting of 30 minutes of exercise on days one and two, and a third intervention period consisting of no exercise. Each period was separated by at least four days. Blood samples were collected for analysis of blood glucose, insulin, and HbA1c content. Results All subjects completed each of the interventions and were compliant with medication and dietary standardization. Average blood glucose concentrations over the 48-hour period were reduced from 9.1 – 0.4 mmol/L in the control group to 8.3 – 0.3 mmol/L in both the nondaily and daily exercise groups (p < 0.001). There were no differences between the ability of each exercise treatment to lower the average blood glucose concentrations in the first 24-h and second 24-h of the 48-h assessment period. Hyperglycemia was reduced from 7:40 – 1 hours:minutes per day, to 5:46 – 0:58 in daily and 5:51 – 0:47 in nondaily exercise groups (p < 0.001). The prevalence of hypoglycemia did not change when exercise was performed every day vs. every other day, but tended to be higher overall in the insulin-treated vs non-insulin-treated subjects. Conclusion Postprandial hyperglycemia is highly prevalent in both insulin-treated and non–insulin-treated patients with type 2 diabetes. A single bout of just 30 minutes of exercise significantly reduces prevalence of hyperglycemia during the next 48 hours as does 60 minutes of exercise performed every other day. Thus, when total work is matched, daily exercise of short duration is equally as effective at optimizing glycemic control as more prolonged, less frequent exercise.

and thus a 30-minute session every day would be advised. This study validates that either regimen is acceptable so long as total work is matched and thus encourages fitness practitioners and healthcare providers to consider the individual needs of their clients when prescribing exercise programs.

Effects of performing resistance exercise before versus after aerobic exercise on glycemia in type 1 diabetes Yardley JE1,2, Kenny GP1,2, Perkins BA 3, Riddell MC 4, Malcolm J 5,6, Boulay P 7, Khandwala F 8, Sigal RJ 6,8,9 1

Human and Environmental Physiology Research Unit, University of Ottawa, Ottawa, Ontario, Canada; 2Institute of Population Health, University of Ottawa, Ottawa, Ontario, Canada; 3 University Health Network, Toronto General Hospital, Toronto, Ontario, Canada; 4School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada; 5Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; 6Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; 7Champlain Diabetes Regional Coordination Centre, Ottawa, Ontario, Canada; 8 Alberta Health Services, Calgary, Alberta, Canada; 9Departments of Medicine, Cardiac Sciences and Community Health Sciences, and Faculties of Medicine and Kinesiology, University of Calgary, Calgary, Alberta, Canada Diabetes Care 2012; 35: 669–75

Background Past studies have supported the inclusion of both resistance and aerobic exercise in the composition of an effective strategy for improving morbidity and mortality in people with diabetes. To maximize time-efficiency, individuals may choose to perform both types of exercise within the same session, although it is unclear from a blood sugar management perspective which exercise modality should be performed first. The purpose of this study was to compare resistance, then aerobic vs. aerobic then resistance exercise on short-term glycemia in persons with type 1 diabetes. Methods

Comment Despite prescribing oral blood glucose-lowering medication and/or exogenous insulin to patients with type 2 diabetes, these individuals are still not protected against postprandial hyperglycemia or the cardiovascular complications that accompany the disease. This study demonstrates that a single bout of exercise for just 30 minutes has the ability to reduce hyperglycemia over the next 48 hours. It also shows that daily and every other day exercise can be equally beneficial as long as the total amount of exercise is matched (i.e., 60 minutes over two days). With the knowledge that convenience deeply impacts one’s ability and willingness to follow an exercise program, flexibility in an exercise prescription becomes paramount. While one individual may prefer a longer exercise session every other day, another individual may find 60 minutes of exercise to be too taxing,

In this crossover study, 12 physically active adults with type 1 diabetes performed 45 minutes of aerobic exercise at 60% VO2 peak followed by 45 minutes of resistance training (AR) or performed the resistance training before aerobic exercise (RA). Each of the experimental sessions were scheduled five days apart. Participants kept their food and insulin intake the same on each of the study days and wore a blinded CGM sensor for each 3-day period to quantify blood glucose levels. Results There were no differences in total energy expenditure between AR and RA, and participants’ blood glucose levels were not significantly different between trials at the start of their exercise session. Significant declines in blood glucose levels were seen during the first exercise modality in AR (9.1 – 2.4 mmol/L at baseline, 5.5 – 2.4 at 45 minutes) but not during the first exercise modality in the RA trial. The second exercise modality brought blood sugar concentration

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back up to baseline in AR trial but caused a decrease in the RA trial after 75 and 90 minutes of exercise. Significant increases in glucose were seen throughout recovery in AR while none were seen during recovery in RA. RA treatment lowered nocturnal glucose levels from 9.5 – 3.0 mmol/L pre-exercise to 8.8 – 4.0 mmol/L post-exercise (p = 0.04). The frequency of nocturnal hypoglycemia did not differ between the two exercise sessions, but the duration and depth of hypoglycemia tended to be longer and more severe after AR than RA.

Background

Conclusion

Methods

Performing resistance training before aerobic exercise, rather than the reverse, results in attenuation in the decline in glucose levels that is typically seen with exercise. It also invokes fewer exercise-associated hypoglycemic events and requires less carbohydrate supplementation during the activity.

Fifteen men with impaired glucose tolerance (IGT group) and 30 men with type 2 diabetes (15 insulin treated, INS group; 15 on oral glucose-lowering medication, OGLM group) were included in a randomized crossover experiment consisting of three intervention periods (control day, resistance exercise, endurance exercise), with the exercise sessions lasting 45 minutes. Each intervention period assessed the impact of a single exercise session on subsequent 24-hour blood glucose homeostasis, with standardized dietary, but otherwise free living, conditions.

Comment Resistance and aerobic exercise are two very different forms of physical activity and both are recommended for people with diabetes for various health reasons. Based on this study of trained individuals with type 1 diabetes, patients should consider performing resistance training before aerobic exercise if they tend to develop exerciseinduced hypoglycemia. Participating in resistance training first attenuates the decline in glucose levels during subsequent aerobic exercise, and also results in higher blood glucose levels for the duration of their activity. Participating in resistance training first may help to mobilize more fat stores initially that can then be utilized during the later aerobic bout (17), which may be beneficial for patients who tend to gain weight with insulin therapy. At the very least, this order of exercise requires less carbohydrate supplementation compared to performing aerobic and then resistance activities. Conversely, individuals that typically see exercise-associated hyperglycemia may wish to perform exercise in the reverse order, as the aerobic bout will lower their blood sugar levels to a more appropriate level for the duration of their exercise session.

Both resistance- and endurance-type exercise reduce the prevalence of hyperglycemia in individuals with impaired glucose tolerance and in insulin-treated and non-insulin-treated type 2 diabetic patients van Dijk JW 1, Manders RJ1, Tummers K 1, Bonomi AG 2, Stehouwer CD 3, Hartgens F 4, van Loon LJ 1 1

Human Movement Sciences, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre + , Maastricht, The Netherlands; 2Human Biology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre + , Maastricht, The Netherlands; 3Internal Medicine, CARIM Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre + , Maastricht, The Netherlands; 4Epidemiology and Surgery, Research School CAPHRI, Maastricht University Medical Centre + , Maastricht, The Netherlands Diabetologia 2012; 55: 1273–82

Postprandial hyperglycemia is commonly seen in patients with type 2 diabetes and is highly problematic due to its strong and independent link to later cardiovascular complications in this population (18). Structured exercise improves long-term glycemic control (19, 20) in individuals with type 2 diabetes, but further research is needed to determine the ideal exercise prescription (i.e., aerobic versus resistance training) in order to optimize the impact of exercise.

Results All participants completed each of the three interventions and adhered to their standardized diet and medication use. Average 24-h blood glucose concentrations were reduced from 7.4 – 0.2, 9.6 – 0.5, and 9.2 – 0.7 mmol/l during the control experiment to 6.9 – 0.2, 8.6 – 0.4, and 8.1 – 0.5 mmol/l (resistance-type exercise) and 6.8 – 0.2, 8.6 – 0.5, and 8.5 – 0.5 mmol/l (endurance-type exercise) over the 24-h period following a single bout of exercise in the IGT, OGLM, and INS groups, respectively (p < 0.001 for both treatments).The effect of the exercise modality on average blood glucose was not significantly different between resistance- and endurance-type exercise (p = 1.00). Prevalence of hyperglycemia was 2:11 – 0:37, 9:01 – 1:39, and 8:16 – 1.44 (hours:minutes, over 24 hours) in the IGT, OGLM, and INS groups, respectively. These hyperglycemic occurrences were reduced by 35 – 7% and 33 – 11% from resistance- and endurance-type exercise, respectively (p < 0.001 for each). There were no exercise-by-group interactions for average blood sugar level, prevalence of hyperglycemia, or prevalence of hypoglycemia, thus indicating a similar effectiveness of both types of exercise in IGT, OGLM, and INS patients. Conclusion A single session of resistance or endurance-type exercise substantially reduces the prevalence of hyperglycemia during the subsequent 24-h period in individuals with IGT and in insulin-treated and non-insulin-treated type 2 diabetic patients. Comment While the benefits of resistance exercise on glycemic control have traditionally been attributed to an increase in muscle mass and subsequent increase of glucose disposal capacity, the present study shows that there are immediate benefits to resistance exercise that are independent of gaining muscle mass. The equal impact of

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both resistance- and endurance-type exercise sessions suggests that one can be exchanged for the other without reducing the positive impact of exercise on glycemic control. Consequently, a more personalized exercise prescription that fits the needs and preferences of the type 2 diabetic individual can be prescribed. It is also important to note that the effects of both types of exercise occurred independent from changes in medication, diet, and habitual physical activity. This article also demonstrates that patients with IGT spend about 9% of their day hyperglycemic if they are sedentary, and that this value can be completely normalized if either resistance or endurance exercise is performed.

The 10-year cost-effectiveness of lifestyle intervention or metformin for diabetes prevention: an intent-to-treat analysis of the DPP/DPPOS Herman WH, Edelstein SL, Ratner RE, Montez MG, Ackermann RT, Orchard TJ, Foulkes MA, Zhang P, Saudek CD, Brown MB Diabetes Prevention Program Research Group Diabetes Care 2012; 35: 723–30

RIDDELL ET AL. that focused on weight loss, physical activity, nutrition, stress management, and diabetes prevention. Direct medical costs were estimated from the resources used with the DPP/ DPPOS interventions over the 10 years. The estimated cost of the lifestyle intervention was recalculated based on administering it in a group format for 10 participants, instead of individually. Metformin cost was calculated based on the cost of generically priced Metformin. Direct medical costs outside of the study was calculated and included costs of hospital, emergency room, urgent care, outpatient services, and phone calls to healthcare providers. These were determined annually by patient self-report, and also included the price of prescription medications. Direct nonmedical costs were assessed and included costs of food, food preparation items, exercise classes, gym memberships, personal trainers, and exercise equipment or accessories. Outcomes were assessed using the cumulative quality-adjusted life-years (QALYs) accrued over 10 years. This index measures length of life adjusted for quality of life as assessed by the health utility score. One analysis for cost-effectiveness included only direct medical costs, while another included direct nonmedical costs excluding participant time. A third analysis included direct nonmedical costs including participant time. These analyses assessed the impact of covering the entire costs associated with the behavioral interventions.

Background The Diabetes Prevention Program (DPP) demonstrated that both lifestyle intervention and metformin treatment could reduce the incidence of type 2 diabetes in patients with impaired glucose tolerance (IGT) by 58% and 31%, respectively, over three years (9). The Diabetes Prevention Program Outcomes Study (DPPOS) was a 7-year follow-up to determine whether the delay in developing diabetes could be sustained if participants continued their interventions (21). In the DPPOS, the incidence of diabetes during the 10-year average was reduced in the lifestyle and metformin groups by 34% and 18% respectively, compared to placebo (21). While the researchers suggested that lifestyle would be cost-effective or cost-saving over the long-term, its implementation depends on whether it can be proven financially feasible for health plans or national programs to adopt. Methods The 10-year, within-trial, intention-to-treat analysis of the DPP/DPPOS included 3,234 participants with IGT and fasting hyperglycemia. At the start of the DPPOS, participants from all interventions were encouraged to take part in a 16session, group-based, lifestyle intervention that focused on weight loss, physical activity, nutrition, stress management, and diabetes prevention. In addition to this, the participants in the original lifestyle intervention received continued intensive lifestyle support and were advised not to take metformin. The original metformin group was advised to continue metformin use. The lifestyle intervention focused on reducing body weight through diet and regular physical activity. The medication interventions gave participants standard lifestyle recommendations in writing and prescribed either metformin or the placebo at a dose of 850 mg twice daily. At the initiation of the DPPOS, participants from all interventions were encouraged to take part in a 16-session, group-based lifestyle intervention

Results Over 10 years, the cumulative, per capita direct medical costs of the interventions were greater for lifestyle ($4,601) than metformin ($2,300) or placebo ($769). However, nonintervention-related direct medical costs were $1,853 and $2,905 greater for placebo compared with metformin and lifestyle, respectively. The per-participant costs of placebo exceeded those of lifestyle and metformin, largely due to greater use of outpatient and inpatient services, prescription medications, and a greater rate of progression to diabetes. For each of the 10 years, quality of life was better for lifestyle than for metformin or placebo. From the health system perspective, the modified societal perspective, and from the societal perspective, lifestyle cost more than placebo but was also more effective in improving QALYs. From a health system perspective, the cost of lifestyle compared with placebo was approximately $10,000 per QALY gained, with metformin having slightly lower costs and nearly the same QALY outcome as placebo. Conclusion Lifestyle is cost-effective while metformin is marginally cost-saving or cost-neutral compared with placebo. Despite lifestyle and metformin being more expensive to implement than usual care, they are cost-effective or cost-saving respectively, over a 10-year span. The cost of gaining a QALY for prevention and treatment strategies range from approximately $10,000 to $1 million. Most fall between $10,000 and $50,000 per QALY (22). A health system must consider the value of delaying or preventing development of type 2 diabetes in highrisk individuals. Considering the American Diabetes Association estimates that total per capita health care expenditures for people with diabetes are $11,744 per year, it is understandable why preventing diabetes comes with such a benefit to society as a whole.

ADVANCES IN EXERCISE, PHYSICAL ACTIVITY, AND DIABETES MELLITUS Comment Although it is generally well accepted that lifestyle and metformin interventions are effective in preventing diabetes, at least one simulation analysis suggested that lifestyle intervention as was done in the DPP study might be too expensive for current health plans (or a national program) to implement (23). This 10-year intention-totreat study demonstrates that lifestyle intervention is indeed cost-effective and that metformin is marginally cost-saving or cost-neutral compared with usual care. As the authors point out, when a new treatment is more effective and less costly than usual care, it should be widely adopted and used. Since lifestyle intervention typically requires more personal contact for the intervention (perhaps exercise specialists and behavior therapists in addition to the usual healthcare providers), it may also provide new employment for healthcare workers. It is now time for all health and social policies to support the necessary funding required to implement intensive lifestyle interventions and metformin for this growing and vulnerable population.

Low-volume high-intensity interval training reduces hyperglycemia and increases muscle mitochondrial capacity in patients with type 2 diabetes Little J1, Gillen JB1, Percival ME1, Safdar A1,2, Tarnopolsky MA 2, Punthakee Z 2, Jung ME 3, Gibala MJ 1 Departments of 1Kinesiology and of 2Pediatrics and Medicine, McMaster University, Hamilton, Ontario; and 3School of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, British Columbia, Canada

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week training included six cycling interval workouts of 10 · (1 minute at *90% HRmax, 1 minute rest) with a 3-minute warm-up and 2-minute cool down. Perceived enjoyment was rated for a single session and for 4 weeks of 3 sessions/week. Results All participants completed the training with no complications. Training reduced heart rate during walk test from 73 – 7% to 66 – 6% HRmax. Average blood glucose over the 24-h period was reduced from 7.6 – 1.0 to 6.6 – 0.7 mmol/l after training. Citrate synthase activity and skeletal muscle mitochondrial protein were higher post-training. Mfn2 and GLUT4 protein content increased by 71% and 269%, respectively. Participants rated perceived enjoyment for a single session 8.1 – 1.0 and 3 sessions/wk 7.9 – 1.0 on a scale of 1–9. Conclusion The results show immediate effects of low-volume HIT. While many studies evaluate several months of training that result in changes in body composition, this 2-week study saw no changes in body mass. Benefits of lower glucose concentration average, notably improved postprandial control, could be the result of adaptations in skeletal muscle. HIT was an effective stimulus to increase mitochondrial capacity and protein content, as well as higher GLUT4 levels that likely play a role in improving glucose regulation. The training involved only 30 min of vigorous exercise and a total time commitment of 75 min/wk compared to current guidelines that recommend 150 min/wk of moderate exercise. Thus, HIT may be a timeefficient exercise method to improve glycemic regulation in T2D individuals. Future studies are needed to examine how long-term effects of high-intensity interval training compare to traditional aerobic and resistance exercise.

J Appl Physiol 2011; 111: 1554–60

Background Most diabetes exercise studies measure effects of highvolume, medium- to low-intensity exercise. In contrast, this study aims to examine effects of low-volume, high-intensity workouts on glucose regulation and skeletal muscle metabolic capacity in individuals with type 2 diabetes. High-intensity interval training (HIT) has been a time-efficient way to improve health and fitness in the healthy population. However, the benefits and risks of HIT for patients with diabetes is unclear. Methods Experimental design included baseline testing, a two-week training intervention, and post-testing. Participants had to meet the following criteria: T2D diagnosis at least three months before; fasting glucose ‡ 7.0 mmol/L and/or glucose tolerance test blood glucose concentration ‡ 11.1 mmol/L; not taking insulin; and no macrovascular or microvascular contraindications to exercise. Eight volunteers participated in the study with mean age 62.5 – 7.6 years, BMI 31.7 – 5.8 kg/m2, and HbA1c 6.9 – 0.7%. Baseline and post-testing consisted of a 15-minute walk test, a 24-h continuous glucose monitoring, and a muscle biopsy. Citrate synthase enzyme activity was measured using a BCA protein assay, and western blotting was performed to analyze protein content. The two-

Comment The study presents HIT as a novel therapeutic approach for diabetic patients. The finding shows impressive health benefits after only two weeks of interval training that only requires about 10 minutes of active exercise each session. Unfortunately, the study’s main drawback was that it evaluated only eight individuals who were carefully prescreened for cardiovascular disease and other diabetes-related complications. More powerful conclusions could be drawn with more participants in future studies. On a related note, a high-intensity (noninterval) exercise study investigating exercise benefits in T2D patients found that four 50 minute sessions/wk for six weeks improves functional capacity and endothelialdependent vasodilator response (24).

Reversal of muscle insulin resistance with exercise reduces postprandial hepatic de novo lipogenesis in insulin resistant individuals Rabol R1, Petersen KF 1, Dufour S 2, Flannery C 1, Shulman GI 1,2,3 Departments of 1Internal Medicine and 3Cellular & Molecular Physiology, and 2Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT Proc Natl Acad Sci USA 2011; 108: 13705-9

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Background NAFLD, which is a route cause of the metabolic syndrome. The methods do not clearly distinguish if the study had two separate study groups or if all participants performed a resting day and an exercising day. Additionally, the term ‘‘resting day’’ is not explained and remains ambiguous. The results of this article suggest further skeletal muscle glycogen synthesis and reduced fat production with continued or long-term exercise.

Insulin resistance has been hypothesized to cause atherogenic dyslipidemia and nonalcoholic fatty liver disease by altering the pattern of postprandial energy storage away from skeletal muscle glycogen synthesis toward hepatic de novo lipogenesis. This insulin resistance, localized to skeletal muscle, can result in reduced plasma high-density lipoprotein concentrations and enhanced hepatic triglyceride synthesis in young, lean insulin resistant individuals. Methods Participants were young (average age 24 years), lean (average BMI 23.8), and insulin resistant (average insulin sensitivity index 2.7 dL/min per microunits/mL). Following a carbohydrate-rich meal, participants were assessed before and after 45 minutes (3 · 15 min with 5-min rest) of exercise on an elliptical trainer. Changes in glycogen and fat synthesis in muscle and liver were determined using1H and13C magnetic resonance spectroscopy, respectively. Hepatic de novo lipogenesis was measured by monitoring the incorporation of deuterium from deuterium-labeled water into plasma verylow-density lipoprotein (VLDL) triglycerides. Results Between rest and exercise days, the fasting and postprandial plasma glucose, insulin, C-peptide, triglyceride, and fatty acid concentration levels were all similar. On the morning of rest studies, liver and muscle glycogen concentrations were 105 – 9 mmol/L and 168 – 12 mmol/L, respectively, compared to 78 – 6 mmol/L and 152 – 13 mmol/L on the morning after exercise studies. After exercise, postprandial muscle glycogen synthesis increased over 300%, hepatic triglyceride synthesis decreased by 40%, and hepatic de novo lipogenesis decreased by 27%. Hepatic triglyceride synthesis and intramyocellular lipid content did not change between rest and exercise days. Conclusion This study demonstrates that skeletal muscle insulin resistance is an early therapeutic target for the treatment and prevention of atherogenic dyslipidemia and fatty liver disease in young insulin-resistant individuals who are prone to develop metabolic syndrome and type 2 diabetes. One 45-min exercise session improved postprandial skeletal muscle glycogen synthesis and decreased postprandial hepatic triglyceride synthesis and de novo lipogenesis. Exercise did not affect postprandial hepatic glycogen synthesis. The results demonstrate that regular exercise helps prevent the metabolic syndrome by normalizing muscle insulin sensitivity, which results in less glucose disposal into the liver and less hepatic lipid accumulation. Comment This study demonstrates more of the physiological mechanisms behind the beneficial effects of an acute bout of exercise on high-risk patients. Clearly, based on this eloquent work, the repartitioning of energy substrates plays a critical role in how exercise helps to prevent

Quality of life in type 2 diabetes mellitus after a very low-calorie diet and exercise Snel M 1, Sleddering MA1, Vd Peijl ID 2, Romijn JA1, Pijl H 1, Edo Meinders A1, Jazet IM 1 1

Department of Endocrinology and Metabolism/General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands; and 2Department of Physiotherapy, Leiden University Medical Center, Leiden, The Netherlands Eur J Intern Med 2012; 23: 143–9

Background Weight loss due to diet modification is known to improve quality of life (QoL), though the effects of exercise on QoL in obese type 2 diabetes patients are less clear. This study aims to look at QoL of patients committed to exercise along with diet. Methods The study involved 27 participants with mean BMI 37.2 kg/m2, age 58 years, and duration of type 2 diabetes 8.9 years. All oral blood glucose-lowering medications were discontinued three weeks prior to the start of intervention. Then, one day before intervention, insulin therapy was withheld. During the16-week period, participants followed a very lowcalorie diet (VLCD) consisting of three Modifast meals for a total of 450 kcal per day. Half of the patients were randomized to follow an exercise program simultaneously, consisting of at least four cycle-ergometer training sessions at home at 70% VO2max and one hour-long aerobic exercise supervised inhospital per week. Participants completed four QoL surveys immediately after and18 months after the intervention period. The survey scores were normalized, averaged for a total QoL score, and compared to control group scores. The control group consisted of two healthy lean controls (matched for age, gender, and race) and two healthy obese controls (also matched for BMI) per participant. Results VLCD-only and VLCD + exercise groups had similar baseline physiological and QoL characteristics. Compared to healthy controls, the baseline QoL scores in type 2 diabetic participants were significantly worse, mostly in fatigue and physical ability categories. At the end of the 16-week intervention, both groups showed significant drops in mean BMI, though the VLCD + exercise group showed a greater change of –8.7 kg/m2 compared to the –7.9 kg/m2 in the VLCD-only group. All participant QoL scores improved significantly right after the intervention, and the VLCD + exercise group scored significantly higher on11 of the 22 subscales compared

ADVANCES IN EXERCISE, PHYSICAL ACTIVITY, AND DIABETES MELLITUS to 9 of 22 in the VLCD-only group. At eighteen months after intervention, participants had regained some weight but still showed a net BMI reduction from baseline of –4.8 kg/m2 in VLCD + exercise group and –3.2 kg/m2 in VLCD-only group. Similarly, weight, waist circumference, fat mass, HbA1c, fasting glucose, fasting insulin, and insulin resistance net reductions were greater in the VLCD + exercise group compared to the VLCD-only group both immediately and 18 months after intervention. Both groups showed substantially less diabetic medication usage 18 months after intervention. From the 18-month follow-up QoL survey results, 5 of the 22 subscales remained significantly improved in the VLCD + exercise group versus only1 of 22 in the VLCD-only group. Conclusion The study shows that the 16-week intervention resulted in immediate QoL benefits in all participants, possibly associated with weight loss, discontinued insulin treatment and oral-glucose medication, elimination of drug side-effects, and improved glycemic control. However, sustained QoL improvements were achieved only in the exercise group, which showed better physical conditioning and more minutes of exercise per week at 18 months. In fact, the mean total QoL of VLCD + exercise participants after 18 months did not differ significantly from lean healthy controls. One confounding variable may be that participation in the study included counseling and education, which have been known to improve QoL (25). The improvement of QoL in patients is an important treatment goal, and patients with type 2 diabetes should be encouraged to exercise to maintain the positive effects achieved by weight loss through regular exercise. Comment Overall, the results of the study are straightforward and show pronounced benefits of exercise on sustained QoL. Impressively, the study had 100% participation and response rate. Still, QoL scores were not identical between VLCD-only and VLCD + exercise groups, which should be taken into account when comparing survey results to healthy controls. Of note, the results showed that patients in the VLCD-only group had a baseline physical activity of 24 min/week that was dropped to 0 min/week during the 16-week intervention. While 24 min/week is a relatively small difference, the complete cessation of exercise could detrimentally affect the QoL scores of the VLCDonly group during the study, and the authors do not address this. Also, many subcategories showed high p values, which may be brought down if more participants were recruited. A similar study was conducted in 2011 by the same group (26), with obese, insulin-dependent, type 2 diabetic patients, which also showed beneficial effects on low-grade inflammation.

Nutritional strategies to prevent hypoglycemia at exercise in diabetic adolescents Dube MC 1,2, Lavoie C 3, Galibois I 4, Weisnagel SJ 1,2,5 1

Diabetes Research Unit, CRCHUL, Quebec, Canada; 2Endocrinology and Genomics, CRCHUL, Quebec, Canada; 3Physical

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Activity Sciences Department, Universite´ du Que´bec a` TroisRivie`res, Trois-Rivie`res, Quebec, Canada; 4Department of Food Science and Nutrition, Universite´ Laval, Quebec, Canada; and 5 Faculty of Medicine, Department of Social and Preventive Medicine, Universite´ Laval, Quebec, Canada Med Sci Sports Exerc 2012; 44: 1427–32

Background Exercise-induced hypoglycemia can be a dangerous risk for patients with type 1 diabetes, especially for adolescent patients who are unlikely to plan exercise. This study tests two pre-exercise nutritional methods of preventing hypoglycemia in adolescent type 1 diabetics during and after 60 minutes of moderate exercise. The impacts on blood glucose of a carbohydrate-rich snack versus a protein-rich meal ingested prior to exercise were compared. Methods Ten type 1 diabetic subjects between ages 12–18 without diabetic complications were studied, all of whom served as their own control by receiving each of the three possible meal treatments in a randomized sequence. Three pre-exercise treatments were evaluated: 1) standardized breakfast + preexercise placebo beverage (PL); 2) standardized breakfast + pre-exercise CHO beverage (water and 8 mg of dextrose$kg-1 body weight$min-1 of exercise); and 3) protein-supplemented breakfast (8 mg of protein$kg-1 body weight$min-1 of exercise) + pre-exercise placebo beverage (PROT). Precisely 120 minutes after breakfast and 15 minutes after the beverage was taken, subjects performed 60 minutes of exercise on an ergocycle at each subject’s 50% VO2max with 30 minutes of resting recovery. If blood glucose became < 4 mmol$L-1, exercise was discontinued and CHO was taken. To measure plasma glucose, free plasma insulin, and lactate, venous blood samples were taken at 5- to 15-minute intervals throughout the trial. Results With PL, CHO, and PROT meal-treatments, blood glucose changed by –6.0 – 1.0, –1.0 – 3.1, and –4.6 – 1.9 mmol$L-1 during exercise (p = 0.0002) and by 0.2 – 0.9, –1.0 –1.1, and –0.9 –1.1 mmol$L-1 during recovery (overall, p = 0.028; PL vs. CHO and PL vs. PROT, both p < 0.05; CHO vs. PROT, p = 0.71), respectively. Hypoglycemia occurred in 40% of PL subjects, 10% of CHO subjects, and 0% of PROT subjects during exercise (p = 0.04) and in 50% of PL subjects,10% of CHO subjects, and 10% of PROT subjects during recovery (p = 0.05). There were no significant differences between groups in occurrence of hypoglycemia 24-h post-exercise, in plasma insulin levels, or in lactate response. Conclusions For adolescents with type 1 diabetes, eating a snack containing 8 mg of CHO$kg-1 of body weight$min-1 of exercise 15 minutes prior to unplanned exercise is the most effective nutritional strategy to minimize subsequent hypoglycemia. If exercise is planned, consumption of a protein-rich meal prior to exercise might also limit hypoglycemia by amplifying the post-prandial glucose spike.

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Comment

Results

This study nicely addresses the protection against hypoglycemia during and after unplanned exercise, an issue routinely faced by young patients with type 1 diabetes. It is essential to establish a reliable method of preventing exercise-induced hypoglycemia so as to allow patients to have a flexible exercise schedule during the sometimes unpredictable adolescent years. Nutritional strategies offer a way to prevent hypoglycemia without altering insulin dosages, which is particularly helpful for unplanned exercise in those patients without insulin pumps who would need to adjust their long-acting insulin dosage hours in advance. In this study, both meals and snacks were provided in liquid form, which admittedly by the authors, might cause different outcomes than would a typical meal. It could be that protein in solid form might increase blood glucose more gradually and avoid the excessive post-prandial peak while still preventing long-term hypoglycemia. Consumption of a protein-rich snack rather than one that is carbohydraterich might be an additional consideration for further research.

Compared with the early morning spot urine specimen, the 1-h post-exercise uACR increased significantly in the combined cohorts (B 13.03 mg/mmol, 95% CI 2.79–23.33, p = 0.013). Results for males and females were reported and analyzed separately due to the significant interaction between genderand exercise-induced change in uACR. There were no significant changes to uACR in control subjects or MA subjects. Increases in uACR that rose above 3.5mg/mmol in females and 2.5 mg/mmol in males were determined to be clinically significant in subjects with NA. There was a statistically significant but not a clinically significant increase in uACR of males with NA 1 h after exercise (B 1.26 mg/mmol, 95% CI 0.19–2.33), however, in females, the increase was statistically and clinically significant (B 3.55 mg/mmol, 95% CI 2.1–11.3). Increase in uACR was also significant in OP males (B 67.5, 95% CI 22–113) and females (B 21.6, 95% CI 8.4–34.8) 1 h after exercise. There were no significant differences between any groups early morning and 2-h post-exercise uACR. Systolic blood pressure (SBP) taken immediately after exercise was positively correlated with 1-h post-exercise uACR (r = 0.621, p < 0.001). Conclusions

Effect of exercise on albuminuria in people with diabetes 1,2

3

Koh KH , Dayanath B , Doery JC Teede H 5, Kerr PG1

3,4

1

, Polkinghorne KR ,

1

Department of Nephrology, Monash Medical Centre, Melbourne, Australia; 2Department of Medicine, Kuching Hospital, Sarawak, Malaysia; 3Department of Pathology, Monash Medical Centre, Melbourne, Australia; and 4Department of Medicine, and 5Jean Hailes Research Group, Monash University, Melbourne, Australia Nephrology 2011; 16: 704–709

Background It is recommended that physical activity be minimized prior to taking a spot urine specimen, the accepted method of albuminuria detection, because exertion may alter the albumin/creatinine ratio (uACR). However, the impact of exercise on protein excretion in patients with diabetes who have albuminuria of different stages has not been formally evaluated. This study examines the post-exercise uACR in subjects with diabetes at three stages of diabetic nephropathy and compares them with non-diabetic control subjects. Methods Thirty-five adult subjects with diabetes (32 with type 2 and 3 with type 1) and nine control subjects without diabetes participated in this study. Of those subjects with diabetes, 19 had normoalbuminuria (NA), 9 had microalbuminuria (MA), and 7 had overt proteinuria (OP). The effect of walking 1 km at a pace increasing from 3 km/h to 7 km/h on the uACR of all subjects was measured by analyzing spot urine samples taken from subjects at early morning void, just before exercise, and 1 h and 2 h following exercise.

Low-intensity exercise induced a transient increase in the albumin/creatinine ratios of subjects with diabetes, with the greatest increase observed in females. It was shown that 1-h post-exercise uACR in normoalbuminuria females could reach a uACR level indicative of microalbuminuria. Nondiabetic control subjects, however, did not experience change in uACR in response to exercise, which suggests the possibility that exertion may reveal normally undetectable kidney damage in patients with diabetes. Long-term outcomes cannot be concluded from these results and, therefore, further studies with longer duration and larger study populations should be performed. The threshold of exertion necessary to induce change in uACR still needs to be determined as well. The level of increase in uACR after exercise might be explained by the increase in SBP following exercise and would be supported by the correlation found between SBP and 1-h post-exercise uACR.

Comment Previous studies have shown that exercise can exacerbate albuminuria in people with diabetes. This study confirms that mild exercise (walking, jogging) can induce increased protein excretion in people with diabetes and examines the degree of impact on varying stages of albuminuria. While this study predominantly had participants with type 2 diabetes, another article studied how different exercise intensities affects albuminuria in patients with type 1 diabetes. They found that as exercise intensity increased, so did protein excretion (27). The findings of both studies are important in elucidating the effects of exercise on albuminuria. The ability of exercise to help predict future nephropathy and the recommended exercise intensity for people with type 1 diabetes have yet to be determined.

ADVANCES IN EXERCISE, PHYSICAL ACTIVITY, AND DIABETES MELLITUS Seven days of aerobic exercise training improves conduit artery blood flow following glucose ingestion in patients with type 2 diabetes Mikus CR1, Fairfax ST 2, Libla JL1, Boyle LJ1, Vianna LC 2, Oberlin DJ1, Uptergrove GM 3,4, Deo SH 2, Kim A 2, Kanaley JA1, Fadel PJ 2,5, Thyfault JP 1,3,4 1

Nutrition and Exercise Physiology, 2Medical Pharmacology and Physiology, and 3Internal Medicine, University of Missouri, Columbia, Missouri; 4Harry S Truman Memorial Veteran’s Hospital, Columbia, Missouri; and 5Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri

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necessary to see improvements in insulin-mediated blood flow, making it clear that short-term training has benefits independent of those provided by long-term exercise programming. There are, however, inconsistencies among studies with regard to exercise training and insulin-mediated blood flow, which should be kept in mind. Despite unchanged glucose tolerance after training in this study, the increase in Matsuda ISI indicates possible improvement in insulin sensitivity, but confirmation of this would require further study. In light of previous work, nitric oxide bioavailability might help to explain FBF improvements but further research is necessary.

J Appl Physiol 2011; 111: 657–64

Comment Background In normal individuals, insulin regulates vasodilation in the endothelium through the actions of nitric oxide and endothelin-1. Vasodilation facilitates insulin delivery and glucose uptake into various tissues. The vasodilatory process is disrupted in people with type 2 diabetes, leading to reduced blood flow and decreased glucose disposal. This study explores the potential for aerobic exercise to ameliorate conduit artery blood flow after patients with type 2 diabetes ingest glucose. Methods Eleven participants with sedentary lifestyles, non-insulin-dependent type 2 diabetes, and no advanced complications were studied to determine the effects of seven days of aerobic exercise on immediate metabolic and cardiovascular outcomes in response to an oral glucose tolerance test (OGTT). Femoral blood flow (FBF) (measured by a duplex Doppler ultrasound system), fasting glucose (measured using glucose-oxidase method), and insulin and C-peptide (analyzed by enzyme-linked immunosorbent assays) were evaluated prior to and during a 75-g OGTT given before and after a week of exercise training. Wholebody insulin sensitivity was also characterized by the Matsuda insulin sensitivity index (ISI). Daily training sessions began with 20 min of treadmill walking, followed by 20 min of stationary cycling, and ended with 20 min of treadmill walking, performed at 60%–75% of heart rate reserve. Results After seven days of aerobic training, there were no significant changes in glucose, insulin, or C-peptide in response to the OGTT, although insulin sensitivity did increase significantly (p < 0.05). While training did not affect the fasting FBF, it did significantly increase FBF in response to the OGTT by –1.9 – 0.7, + 49.4 – 0.6, + 98.4 – 0.9, + 114.0 – 1.1 ml/min above fasting FBF at 30, 60, 90, and 120 min, respectively. The measured increase in blood velocity was determined to be the cause of FBF changes because no significant change in femoral artery diameter occurred. Conclusions In people with type 2 diabetes, seven days of aerobic exercise improves femoral blood flow during glucose consumption. Only a short duration of exercise training was

The rapid improvement in blood flow observed after exercise in this study is promising for patients with type 2 diabetes as it may help boost glucose disposal. Knowing the duration of improvement in blood flow after exercise may be helpful in refining the exercise prescription for patients with diabetes. If improvements only persist with the amount of exercise performed in this study (60 min daily), it could be a difficult adjustment for many patients who live typically sedentary lives. If observed improvements in blood flow could continue or at least be maintained through less frequent exercise, it might be more realistic.

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