Role of Exercise and Dietary Supplements in the Management of Prediabetes and Type 2 Diabetes

Tinna Traustadóttir, PhD
Panayiotis D. Tsitouras, MD
Volume 18 - Number 10 - November/December, 2010

This article is the seventh in a continuing series on diabetes in the elderly. The sixth article in the series, “Macrovascular Disease in Elderly Patients with Diabetes,” was published in the October issue of the Journal.

Introduction

Prediabetes and type 2 diabetes are conditions commonly managed by geriatricians and other clinicians treating older patients. Currently, approximately 58% of individuals age 60 years or older have either type 2 diabetes or impaired fasting glucose, and the prevalence of type 2 diabetes is expected to nearly double in the next 20 years.1,2 The undisputed first line of management of prediabetes and type 2 diabetes is through diet and exercise, usually described as the “cornerstones” of treatment, management, and prevention. Clinicians should continue to stress the importance of lifestyle modifications, regardless of whether the patient also requires pharmacologic therapy. In patients who meet the criteria for prediabetes (impaired fasting glucose or impaired glucose tolerance), lifestyle interventions such as diet and exercise have been shown to substantially decrease the incidence of type 2 diabetes.3-5 Additionally, exercise reduces systemic low-grade inflammation, lowers mean arterial blood pressure (especially in individuals with hypertension), and may improve lipid profile in patients with type 2 diabetes.6-8

The use of dietary supplements to help prevent type 2 diabetes or control blood glucose levels in patients with type 2 diabetes has been promoted for many decades. However, the scientific evidence for the efficacy of many of these supplements has often been lacking. Many of the existing studies on dietary supplements to manage blood glucose levels are poorly designed. In addition, the lack of Food and Drug Administration oversight over dietary supplements makes it difficult to ascertain the validity of the manufacturers’ claims as well as the actual active substance content and quality.

The purpose of this article is to provide physicians and other healthcare practitioners with guidelines for developing an evidence-based exercise prescription for patients with type 2 diabetes or for individuals who are at risk of developing type 2 diabetes. We will also examine the clinical evidence for the efficacy of dietary supplements in the treatment of type 2 diabetes. Although diet plays an important role in the management of type 2 diabetes, discussion of diet is beyond the scope of this article.

Prescribing Exercise for Patients with Type 2 Diabetes or Prediabetes

When prescribing exercise to patients, healthcare providers need to provide a detailed description of the mode of exercise, frequency, intensity, duration, and rate of progression. The following sections will examine the recommendations for each of these areas based on available research.

Mode of Exercise
The most relevant question regarding mode of exercise is whether to recommend aerobic training, resistance training, or both. Surprisingly, there have been very few studies that have compared the effects of concurrent aerobic and resistance training to that of performing just one of these activities. There is strong evidence in support of aerobic exercise, such as walking or cycling, to reduce glycated hemoglobin (HbA1c). In addition, aerobic training has been shown to reduce fat mass (especially visceral fat) and plasma triglyceride levels.7 Resistance training is also effective in improving glycemic control, decreasing fat mass, counteracting age-related loss of muscle mass, and decreasing visceral adiposity.9 Studies directly comparing aerobic training with resistance training have found that while both modalities lowered HbA1c, the effect was greater with resistance training.10 Additionally, resistance training was reported to be more successful in improving patient-reported health status and well-being.11

It is important to note that the beneficial effects of regular exercise on glycemic control and insulin sensitivity occur even without weight loss.7 However, especially in patients who are overweight or obese, exercise training aimed at improving body composition would be expected to have greater effects because insulin-stimulated glucose uptake occurs mainly in skeletal muscle. Insulin-stimulated glucose uptake is positively correlated with muscle mass and negatively correlated with fat mass.12 In addition, obesity is a risk factor for diabetes and diabetes-related comorbidities, independent of lack of physical activity.13 This makes a strong case for including both aerobic training and resistance training, which, in combination with proper nutrition, is the best method to simultaneously increase muscle mass and decrease fat mass. In addition, studies suggest that the combination of aerobic and resistance training is superior to either modality alone in improving glycemic control.14,15 Another study reported an improved endothelial function in patients with type 2 diabetes after 3 months of combined aerobic and resistance training.16 These patients were then followed for an additional 24 months, and the exercise group had a significantly lower incidence of cardiovascular events as compared with the control group.16

Clinical Recommendations for Mode of Exercise in Older Persons

  • A combination of aerobic exercise and resistance training
  • For individuals with very low functional status and those who have difficulty walking, resistance training alone can enhance glycemic control and physical function

Frequency
The American College of Sports Medicine (ACSM) position stand on exercise for individuals with type 2 diabetes recommends a frequency of 3 to 5 days per week for aerobic training and 2 days per week for resistance training.17 The evidence for greater muscular gains in older individuals from performing three weekly sessions of resistance training as compared with two are equivocal.9,18 A recent study showed that two weekly sessions of combined aerobic and resistance training in patients with type 2 diabetes were sufficient to significantly increase aerobic capacity and strength, and resulted in the lowering of HbA1c, fasting glucose levels, systolic blood pressure, and low-density lipoprotein cholesterol levels after 1 year.19

Healthcare providers should keep in mind that the effect of acute exercise on improving insulin action is lost within 24 to 48 hours; thus, it may be necessary for patients to perform physical activity at a minimal frequency of every other day to maintain these beneficial effects. Furthermore, greater benefits may be achieved with higher frequency.20 Resistance training or muscle-strengthening activity should not be performed on consecutive days, allowing for at least 1 day of recovery in between exercise sessions. Aerobic exercise, however, can be performed on consecutive days.

Clinical Recommendations for Frequency of Exercise in Older Persons

  • Aerobic exercise: 3-5 days per week
  • Resistance exercise: 2-3 days per week on nonconsecutive days

 

Intensity and Duration
Because intensity and duration are usually inversely related, they need to be addressed together when prescribing an exercise regimen. Higher-intensity exercise sessions are generally only tolerated for shorter durations, while lower-intensity sessions can have longer durations. Note that “duration” refers to the duration within an exercise session, not the duration of an exercise program. The length of published study interventions varies widely, anywhere from a few weeks up to 1 to 2 years; however, the beneficial effects of exercise are not well maintained unless the exercise regimen is continued. Therefore, the practitioner must convey to the patient the importance of adopting regular exercise or physical activity as “life-long” therapy and not a short-term cure.

In this section, we will discuss aerobic exercise and resistance exercise separately, because intensity and duration are measured differently within these two recommended modes of exercise.

Aerobic exercise. The intensity level of aerobic exercise can differentially affect the blood glucose response, depending on whether the patient is lean or obese. In patients with type 2 diabetes who are lean, the glucose response to acute exercise is much more variable than in patients who are obese, so it would be necessary to evaluate the response on an individual basis. In patients with type 2 diabetes who are obese, blood glucose level generally decreases in response to mild- or moderate-intensity exercise, but often increases in response to high-intensity exercise. The response also varies depending on the duration of the exercise session and the patient’s blood glucose levels at the start of the exercise. Nevertheless, studies that have examined the effect of exercise intensity on blood glucose levels have found that interventions with high(er) intensity result in greater lowering of HbA1c, greater increase in insulin sensitivity, and greater improvement in aerobic fitness.21,22

The energy expenditure of a single aerobic exercise session is positively associated with the exercise-induced changes in glucose homeostasis. Several investigators have suggested that the minimal dose of weekly energy expenditure from exercise should be approximately 1000 kcal, with 2000 kcal likely providing more optimal results.13,23 Exercise duration and intensity are directly related to energy expenditure; thus, to achieve the target energy expenditure, a lower intensity level must be of longer duration.13

A good starting recommendation for sedentary individuals with prediabetes or type 2 diabetes is to have them gradually increase their physical activity levels until they can exercise for 30 minutes continuously in a single session. However, initially, the daily exercise can be divided into shorter sessions, such as three 10-minute sessions.17 Intensity can be prescribed by using a subjective 10-point scale relative to the individual’s perception of effort. On a scale of 0 to 10, “0” indicates resting or sitting and “10” indicates an all-out effort. Moderate-intensity aerobic exercise is performed at an effort of 5 to 6 and should bring about a noticeable increase in heart rate and breathing. Vigorous-intensity aerobic exercise is performed at an effort of 7 to 8 and should result in significant increases in heart rate and breathing.20 The ACSM and the American Heart Association recommend that individuals over the age of 65 years and individuals age 50 to 64 years with clinically significant conditions or functional limitations need 150 minutes per week of moderate-intensity aerobic exercise or 60 minutes per week of vigorous-intensity exercise in order to promote and maintain health.20 This volume of exercise is in addition to routine activities of daily living and can be performed as a combination of moderate- and vigorous-intensity activity.20

A simple way to monitor exercise duration and motivate individuals to increase physical activity is through the use of pedometers. Researchers in Britain investigated the effects of a structured education program for persons with impaired glucose tolerance (mean age, 65 years) aimed at promoting walking activity.24 Participants in this study were followed for 12 months and were randomly assigned to one of three groups: a control group; a group that received the education program; and a group that received the education program and pedometers. The results of this study showed that persons in the pedometer group substantially increased their walking activity as compared with the control group, and this was the only group to significantly improve fasting and 2-hour post-challenge glucose, despite no changes in body weight or waist circumference.24 The structured education program used in this study recommends personalized steps-per-day goals based on the individual starting point. In another study that set steps-per-day goals, sedentary individuals were encouraged to increase their activity level by approximately 3000 steps per day, which is equivalent to 30 minutes of walking. Moderately active individuals (ie, those achieving > 6000 steps/day) were encouraged to increase the daily activity to approximately 9000 steps per day.25

Resistance exercise. The exact dose response of varying intensity in resistance training has not been adequately studied and may vary between populations depending on previous training experience.26 A general recommendation for achieving an increase in muscle mass and beneficial health effects is to do 1 to 2 sets of 8 to 15 repetitions per set, using a resistance of more than 60% of an individual’s one repetition maximum (1RM), and including all major muscle groups.17,27 The resistance exercise can be done using body weight, resistance bands, and/or weights (machines or free weights), depending on the individual’s present condition and prior experience. As muscular adaptation occurs and training experience increases, it may be necessary to increase training volume via modulation of intensity and number of sets for proper training stimulus. We have previously described the recommended progression of resistance training programs in older individuals, which could also be applied to patients with prediabetes or type 2 diabetes.28

Clinical Recommendations for Intensity and Duration of Exercise in Older Persons

  • For aerobic exercise: vary the intensity between moderate and vigorous on different days for a minimal duration of 30 minutes and 20 minutes, respectively, per session
  • For resistance exercise: perform exercise for all major muscle groups (8-10), 2 sets of 8-12 repetitions per exercise at an intensity of moderate to high (60%-80% 1RM)

Rate of Progression
An individual’s rate of progression will depend on many factors, including age, functional status at the start of the exercise program, adherence to the prescribed exercise program, disease complications, and goals. As mentioned earlier in this article, it is important that the exercise program is regarded as a long-term, or life-long, therapy. A gradual phase-in of increased physical activity and exercise has a much better chance of becoming a sustained routine.29 Initial progressions in the exercise program should focus on increasing frequency and duration until the recommended levels are reached, followed by progressions in intensity levels.17

For those individuals who have low exercise tolerance and/or high discomfort with aerobic exercise, it may be beneficial to focus on progressing in resistance training. Improvements in muscular function may help overcome the difficulty with aerobic endurance, which can then be gradually added to the regimen.9,10

Clinical Recommendations for Rate of Progression of Exercise in Older Persons

  • A gradual phase-in of increased physical activity and exercise
  • Initial progressions should focus on increasing frequency and duration until the recommended levels are reached, followed by progressions in intensity levels

Screening Recommendations for Patients with Type 2 Diabetes or Prediabetes Before Beginning an Exercise Program

A thorough physical examination to evaluate glycemic control and to assess for the presence of macrovascular and/or microvascular complications, including cardiovascular (blood pressure, lipid profile, electrocardiogram, stress test), vision, neurologic, nephrologic, or infectious complications, is recommended.30 An exercise stress test is recommended to test for silent myocardial ischemia if 10-year cardiovascular risk exceeds 10%.31 Roughly 17% to 22% of patients with type 2 diabetes are estimated to have silent myocardial ischemia.32 An exercise stress test is useful in most patients with type 2 diabetes who have more than two cardiovascular risk factors, who are middle-aged with disease duration of greater than 5 years, and who are over the age of 70 years.13 Because type 2 diabetes is a risk factor for cardiovascular disease, an exercise stress test prior to commencing an exercise program can uncover cardiac abnormalities and, thereby, reduce the risk of an exercise-induced cardiac event.33

Helpful Resources

  • Exercise is Medicine™: www.exerciseismedicine.org
    • This website has resources for clinicians, including tools, training, and referral mechanisms, and provides patient handouts on exercising with type 2 diabetes
  • American Association of Diabetes Educators: www.diabeteseducator.org
    • This website has resources for both physicians and patients, including information on finding a diabetes educator in your area

Role of Dietary Supplements in the Treatment of Diabetes

As previously stated, the use of dietary supplements to prevent type 2 diabetes and/or to help control blood glucose levels in persons with type 2 diabetes has been promoted for many decades. A careful review of the literature, however, indicates that there is little evidence based on well-controlled human studies to support these claims for most supplements. While a few supplements appear somewhat promising, no large-scale, controlled clinical trials exist to document such benefits.

In this section, we will review the supplements that are potentially promising based on available data and we will briefly discuss some others that have no significant scientific documentation of their effectiveness.

Vitamin D and Calcium
The data on vitamin D and calcium are summarized in a meta-analysis published in 2007.34 Animal studies suggest that vitamin D and calcium may act as modifiers of diabetic risk. Pittas et al34 analyzed human studies examining the association between vitamin D and calcium and (1) the risk for type 2 diabetes and (2) the effects of supplementation on glucose metabolism. Detailed examination of many available published studies appears to indicate that there is a relationship between insufficient vitamin D and calcium levels and type 2 diabetes. The overall evidence supports the concept that adequate vitamin D and calcium intake may prevent or delay the development of metabolic syndrome and/or type 2 diabetes in high-risk individuals; it remains unclear whether intake has any effect in controlling blood glucose levels in persons who already have type 2 diabetes. As the authors indicate, “there is a paucity of randomized controlled trials with vitamin D and/or calcium supplementation specifically designed for outcomes related to type 2 diabetes mellitus.”34

Omega-3 Fatty Acids
It has been documented that supplementing the diet with high doses of omega-3 fatty acids (15 mL, approximately 4.5 g) leads to improvement of insulin sensitivity in healthy persons and in those with prediabetes.35 In addition, it appears that omega-3 supplementation can dramatically reduce anti-inflammatory markers. In several studies, however, omega-3 supplementation in more traditional doses (up to 5 mL, approximately 1.5 g) failed to demonstrate any effectiveness in lowering blood glucose levels in persons with diabetes.

Phylloquinone (Vitamin K)1
A recent study reported on the effects of phylloquinone, also known as vitamin K1, on glucose homeostasis.36 Animal studies had suggested great benefits, but the results of the study by Yoshida et al36 were similar to those reported for omega-3 fatty acids. It appears that phylloquinone intake is associated with higher insulin sensitivity in healthy humans, but has no effect on fasting insulin levels and glucose concentration.36 We found no controlled studies of phylloquinone use in persons with diabetes in the literature.

Coccinia Cordifolia Extract
Coccinia cordifolia is an herb that grows abundantly in India and has been used there for decades in the traditional treatment of diabetes. Most of the evidence is anecdotal, but a recent small but fairly well-controlled study from India found a significant decrease in fasting and postprandial glucose levels and in HbA1c levels in persons with mild diabetes who were taking Coccinia cordifolia extract, as compared with those who were taking placebo.37 It is obvious that larger, longer studies in well-defined diabetic populations are needed before any conclusions on clinical usefulness are drawn.

Chromium
Persons with diabetes have used chromium supplements for decades. In the 1970s, severe chromium depletion was found to be associated with the development of reversible diabetes and insulin resistance.38 A recently published meta-analysis attempted to evaluate most available evidence on the effect of chromium supplementation on glucose metabolism and lipids.39 As the authors found, “The evidence was limited by poor study quality, heterogeneity in methodology and results, and a lack of consensus on assessment of chromium status.”39 Overall, it appears that chromium supplementation may improve glycemia in persons with diabetes, but it is too early to make any definitive recommendations.

Xylooligosaccharides
Xylooligosaccharides are nondigestible oligosaccharides that have been shown to have some effect on glucose metabolism in rats. A recent study from China reported that, in a small number of persons with diabetes, the dietary supplementation with xylooligosaccharide for 8 weeks was effective in improving blood glucose levels.40 It is, however, premature to draw any conclusions of clinical importance.

L-Carnitine
Another common supplement sold with claims of usefulness in persons with diabetes is L-carnitine. The evidence, again, is poor. In a recently published, fairly well-controlled study, L-carnitine 2 g daily for 3 months showed no significant effect on fasting blood glucose levels and a significant—but very small—reduction in HbA1c levels (6.9% vs 6.6% in L-carnitine vs placebo, respectively).41

Other Supplements
There are many other supplements that have been advocated for the glycemic treatment of persons with diabetes, including magnesium, lycopene, alpha-lipoic acid, vitamin C, vitamin E, selenium, and cinnamon extracts. These claims are based on anecdotal information and/or animal data. There are no well-designed and controlled studies to support these claims.

Conclusion

Although there are some limited indications that a few dietary supplements may contribute to the prevention and/or control of type 2 diabetes, the available scientific evidence does not allow us to make any clinical recommendations for any supplement currently available on the market. Furthermore, it is unclear (and probably unlikely) whether any beneficial effects from dietary supplements would be additive or synergistic to the effects of exercise and diet. Therefore, lifestyle changes aimed at increasing physical activity and eating a healthy diet remain the cornerstones of the prevention and management of type 2 diabetes. Rather than simply telling patients to increase physical activity, a more precise prescription such as that described in this article is posed to have a far greater effect on the outcome.

The authors report no relevant financial relationships.

Dr. Traustadóttir is Associate Director, Exercise Sciences, and Dr. Tsitouras is Clinical Director, Kronos Longevity Research Institute, Phoenix, AZ. Dr. Traustadóttir is also Faculty Associate, Exercise Science, Reykjavík University, Reykjavík, Iceland.

References

1. Centers for Disease Control and Prevention. National diabetes fact sheet: General information and national estimates on diabetes in the United States, 2007. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf. Accessed November 10, 2010.

2. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27(5):1047-1053.

3. Tuomilehto J, Lindstrom J, Eriksson JG, et al; Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344(18):1343-1350.

4. Burnet DL, Elliott LD, Quinn MT, Plaut AJ, Schwartz MA, Chin MH. Preventing diabetes in the clinical setting. J Gen Intern Med 2006;21(1):84-93.

5. Jacobs-van der Bruggen MA, Bos G, Bemelmans WJ, Hoogenveen RT, Vijgen SM, Baan CA. Lifestyle interventions are cost-effective in people with different levels of diabetes risk: Results from a modeling study. Diabetes Care 2007;30(1):128-134.

6. Halle M, Berg A, Garwers U, et al. Influence of 4 weeks’ intervention by exercise and diet on low-density lipoprotein subfractions in obese men with type 2 diabetes. Metabolism 1999;48(5):641-644.

7. Thomas DE, Elliott EJ, Naughton GA. Exercise for type 2 diabetes mellitus. Cochrane Database Syst Rev 2006;3:CD002968.

8. Stewart LK, Flynn MG, Campbell WW, et al. The influence of exercise training on inflammatory cytokines and C-reactive protein. Med Sci Sports Exerc 2007;39(10):1714-1719.

9. Strasser B, Siebert U, Schobersberger W. Resistance training in the treatment of the metabolic syndrome: A systematic review and meta-analysis of the effect of resistance training on metabolic clustering in patients with abnormal glucose metabolism. Sports Med 2010;40(5):397-415.

10. Bweir S, Al-Jarrah M, Almalty AM, et al. Resistance exercise training lowers HbA1c more than aerobic training in adults with type 2 diabetes. Diabetol Metab Syndr 2009;1(1):27.

11. 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 randomised trial. Diabetologia 2010;53(4):632-640.

12. Yki-Järvinen H, Koivisto VA. Effects of body composition on insulin sensitivity. Diabetes 1983;32(10):965-969.

13. Praet SF, van Loon LJ. Exercise therapy in type 2 diabetes. Acta Diabetol 2009;46(4):263-278.

14. Sigal RJ, Kenny GP, Boule NG, et al. Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: A randomized trial. Ann Intern Med 2007;147(6):357-369.

15. Hills AP, Shultz SP, Soares MJ, et al. Resistance training for obese, type 2 diabetic adults: A review of the evidence. Obes Rev 2010;11(10):740-749.

16. Okada S, Hiuge A, Makino H, et al. Effect of exercise intervention on endothelial function and incidence of cardiovascular disease in patients with type 2 diabetes. J Atheroscler Thromb 2010;17(8):828-833.

17. Albright A, Franz M, Hornsby G, et al. American College of Sports Medicine position stand. Exercise and type 2 diabetes. Med Sci Sports Exerc 2000;22(7):1345-1360.

18. Braith RW, Graves JE, Pollock ML, Leggett SL, Carpenter DM, Colvin AB. Comparison of 2 vs 3 days/week of variable resistance training during 10- and 18-week programs. J Int Sports Med 1989;10(6):450-454.

19. Fatone C, Guescini M, Balducci S, et al. Two weekly sessions of combined aerobic and resistance exercise are sufficient to provide beneficial effects in subjects with type 2 diabetes mellitus and metabolic syndrome. J Endocrinol Invest 2010;33(7):489-495.

20. Nelson ME, Rejeski WJ, Blair SN, et al. Physical activity and public health in older adults: Recommendation from the American College of Sports Medicine and the American Heart Association. Med Sci Sports Exerc 2007;39(8):1435-1445.

21. O’Donovan G, Kearney E, Nevill A, Woolf-May K, Bird S. The effects of 24 weeks of moderate- or high-intensity exercise on insulin resistance. Eur J Appl Physiol 2005;95(5):522-528.

22. DiPietro L, Dziura J, Yeckel CW, Neufer PD. Exercise and improved insulin sensitivity in older women: Evidence of the enduring benefits of higher intensity training. J Appl Physiol 2006;100(1):142-149.

23. Di Loreto C, Fanelli C, Lucidi P, et al. Make your diabetic patients walk: Long-term impact of different amounts of physical activity on type 2 diabetes. Diabetes Care 2005;28(6):1295-1302.

24. Yates T, Davies M, Gorely T, Bull F, Khunti K. Effectiveness of a pragmatic education program designed to promote walking activity in individuals with impaired glucose tolerance: A randomized controlled trial. Diabetes Care 2009;32(8):1404-1410.

25. Yates T, Davies M, Gorely T, Bull F, Khunti K. Rationale, design, and baseline data from the Pre-diabetes Risk Education and Physical Activity Recommendation and Encouragement (PREPARE) programme study: A randomized control trial. Patient Educ Couns 2008;73:264-271.

26. Peterson MD, Rhea MR, Alvar BA. Applications of the dose-response for muscular strength development: A review of meta-analytic efficacy and reliability for designing training prescription. J Strength Cond Res 2010;19(4):950-958.

27. Feigenbaum MS, Pollock MJ. Prescription of resistance training for health and disease. Med Sci Sports Exerc 1999;31(1):38-45.

28 Traustadóttir T, Tsitouras PD. Prescribing exercise for older men. Clinical Geriatrics 2009;17(7):42-47.

29. Wing RR, Epstein LH, Nowalk MP, Koeske R, Hagg S. Behavior change, weight loss, and physiological improvements in type II diabetic patients. J Consult Clin Psychol 1985;53(1):111-122.

30. Vijan S. Type 2 diabetes. Ann Intern Med 2010;152(5):ITC31-15.

31. Sigal RJ, Kenny GP, Wasserman DH, Castaneda-Sceppa C, White RD. Physical activity/exercise and type 2 diabetes. Diabetes Care 2006;29(6):1433-1438.

32. Wackers FJT, Young LH, Inzucchi SE, et al; Detection of Ischemia in Asymptomatic Diabetics Investigators. Detection of silent myocardial ischemia in asymptomatic diabetic subjects. The DIAD study [published correction appears in Diabetes Care 2005;28(2):504]. Diabetes Care 2004;27(8):1954-1961.

33. Angadi SS, Gaesser GA. Pre-exercise cardiology screening guidelines for asymptomatic patients with diabetes. Clin Sports Med 2009;28(3):379-392.

34. Pittas AG, Lau J, Hu FB, Dawson-Hughes B. The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab 2007;92(6):2017-2029.

35. Tsitouras PD, Gucciardo F, Salbe AD, Heward C, Harman SM. High omega-3 fat intake improves insulin sensitivity and reduces CRP and IL6, but does not affect other endocrine axes in healthy older adults. Horm Metab Res 2008;40:199-205.

36. Yoshida M, Booth SL, Meigs JB, Saltzman E, Jacques PF. Phylloquinone intake, insulin sensitivity, and glycemic status in men and women. Am J Clin Nutr 2008;88(1):210-215.

37. Kuriyan R, Rajendran R, Bantwal G, Kurpad AV. Effect of supplementation of Coccinia cordifolia extract on newly detected diabetic patients. Diabetes Care 2008;31(2):216-220.

38. Jeejeebhoy KN, Chu RC, Marliss EB, Greenberg GR, Bruce-Robertson A. Chromium deficiency, glucose intolerance, and neuropathy reversed by chromium supplementation, in a patient receiving long-term total parenteral nutrition. Am J Clin Nutr 1977;30(4):531-538.

39. Balk EM, Tatsioni A, Lichtenstein AH, Lau J, Pittas AG. Effect of chromium supplementation on glucose metabolism and lipids: A systematic review of randomized controlled trials. Diabetes Care 2007;30(8):2154-2163.

40. Sheu WH, Lee IT, Chen W, Chan YC. Effects of xylooligosaccharides in type 2 diabetes mellitus. J Nutr Sci Vitaminol (Tokyo) 2008;54(5):396-401.

41. Malaguarnera M, Vacante M, Avitabile T, Malaguarnera M, Cammalleri L, Motta M. L-Carnitine supplementation reduces oxidized LDL cholesterol in patients with diabetes. Am J Clin Nutr 2009;89(1):71-76.