The document proposes a minimal exercise regimen for type 2 diabetics that utilizes brief, moderate intensity muscle contractions after meals to lower blood glucose levels. Preliminary data from one subject who followed this regimen for nearly 3 years showed improved HbA1c levels and blood glucose control without medication. The hypothesis is that such a minimally demanding regimen can reliably lower post-meal blood sugar spikes and benefit glycemic management more than typical ADA recommendations.

1. For Diabetics: Minimal Exercise, Maximal Benefits Kathleen Broomall, Ph.D., Avi Milgrom, Helaine Alessio, Ph.D. University of Cincinnati & Miami University

2. Intoduction The ultimate goal of our research is to develop an exercise regimen that is effective in attenuating glycemic excursions and in lowering HbA1c values, significantly more than practices recommended by the ADA. Moreover, it is critical that it be widely used by type 2 diabetics.

3. In order to accomplish this, there are two, core design constraints: It must be so minimally demanding of time and effort that logistical objections are essentially eliminated, and it must reward each round of exercise psychologically and physically, with increased vigor, in order to induce adherence.

4. Underlying this regimen is an innovative approach to exercise that seeks to utilize muscles contractions as a way to pull blood glucose out of the blood stream. Preliminary research has indicated that this can be accomplished if the muscle contractions are timed in a specific manner with a particular intensity. However this research is based on a sample size of one, although the studies on that one person have been extensive (see below).

5. That muscle contractions can absorb blood glucose is not new and in the literature (see background). What is new is that blood glucose spikes can be reliably moderated with exercise that is both carefully timed and of moderate intensity and executed in brief bouts.

6. Hypothesis: Thus our hypothesis is that exercise of moderate intensity exercise will reproducibly lower blood sugar spikes to safe levels with brief bouts executed after ingestion of calories.

7. Specific Aim No.1 : To assess the effectiveness of a minimal exercise regimen in the physiological management of type 2 diabetes. The hypotheses to be tested: 1) That the total volume of exercise needed to limit a glycemic excursion for a compliant patient can be met with repeated, brief intervals of 2 - 3 minutes and 2) That the intensity of exertion can be between 65-75% VO2max., a recognized moderate exertion level.

8. Specific Aim No. 2: To assess the effectiveness of timing minimal exercise bouts only after ingestion of calories. The hypothesis to be tested: That timing the exercise after ingestion of calories is effective in moderating blood glucose spikes.

9. BACKGROUND IN SUPPORT OF REGIMEN The proposed research examines the fusion of three findings in the literature: Research demonstrating the significantly greater effectiveness of postprandial exercise over preprandial in the attenuation of glycemic excursions. Research demonstrating the effectiveness of interval-based – high and moderate intensity - in the management of glycemic excursions. PI’s preliminary data demonstrating successful management of blood glucose levels for nearly three years utilizing brief, repeated bouts of moderate intensity postprandial exercise. (See below).

10. The core finding is that contracting skeletal muscle pulls sugar out of the blood stream (Gorman et al , 2006; Hawley, 2004; Holloszy, 2005; Jessen &Goodyear,1985; Wisse et al , 2010). The mechanism involves increased insulin sensitivity involving GLUT4 but is far from being elucidated. In the management of blood sugars, muscle contractions through exercise offers a glucose sink that is largely under conscious control.

11. Secondly, in this regimen, the time to exercise is after calorie intake, i.e. postprandial, in order to most effectively attenuate glycemic excursions and to lower HbA1cs. The literature supports this timing with studies that span many years (Colberg et al 2009; Larsen et al, 1997; Poirier et al , 2000 and 2001; Larsen et al 1999; Hostmark et al 2006; Derave et al , 2007). Concludes Colberg and colleagues, “ Postprandial hyperglycemia is an established cardiovascular risk factor (O’Keefe & Bell, 2007) and oxidative damage resulting from such glycemic excursions is a factor in the development of diabetic complications that may be moderated by exercise (Tucker et al, 2008).

12. Thirdly, in 2010, Richards and colleagues (Richards et al, 2010) reported that interval training of sedentary or recreationally active young adults involving six sessions of four to seven 30 sec. bouts of very high intensity cycle ergometer exercise increased insulin sensitivity. Measurements were made using the hyperinsulinaemic euglycaemic clamp technique, considered the “gold standard.” Prior to this study in 2009, Babraj and colleagues (Babraj et al , 2009) reported indirect evidence of increased insulin sensitivity in subjects who followed high-intensity interval training using oral glucose tolerance tests (OGTT).

13. PRELIMINARY DATA In 1996, subject had an oral glucose tolerance test (OGTT), the results of which were fasting blood glucose of 106 mg/dl, 225 mg/dl at 30 min. after ingesting 75g sugar, 137mg/dl at 60 min., and 82 mg/dl at 2 hrs. Subject’s HbA1c was found by physician to be 6.5% in December 2007. In December 2008, subject measured fasting blood glucose of over 160 mg/dl with a glucometer and finger prick blood sample and estimated BMI was 32. In January 2009, subject began the test exercise regimen. Within 1 to 2 weeks, subject noted fasting blood glucose less than 125 mg/dl; 60 days later, subject’s physician found an HbA1c of 5.8%. Except for one HbA1c of 6.3% in June 2010, subject’s HbA1c values have remained below 6.0% for nearly 3 years since the start of the regimen with no pharmaceutical intervention, and subject lost over 50 lbs. Earlier, in April 2010, data gathered in Miami University’s Exercise Science laboratory, shown below, demonstrates the effectiveness of the regimen in lowering blood glucose and the importance of frequent bouts of training, consistent with results reported by Richards et al (Richards et al ,2010). Immediately prior to the collection of data, subject consumed a test meal of 35 g carbohydrates and 30 g saturated fat.

17. Arrows show Muscle Contraction Impulses done on 12% Incline Treadmill at 2.7 mph. Series 2: With 2.5Ib Ankle Weights, Impulses of 2min, 1min, then 2min with 2’ rests between impulses. Series 3: Without 2.5Ib Ankle Weights but not holding front bar to increase intensity ca. 10% Impulses of 2min, 2min with 2 minute rest between impulses.

18. Metabolic tests gathered during this series of tests showed subject burned fats primarily in curve 1; in curve 2 subject was slow to switch from burning fats to carbohydrates without prior exercise. However, with regimen bouts applied 3 hours in advance of test and postprandial bouts as in curve 3, carbohydrate metabolism began rapidly after meal that correlated with decreases in blood glucose. At this time, subject’s body fat was measured by bioelectric impedance to be 33-36%.

19. Longitudinal data for subject is presented below. Note the rapid shift down in baseline and the attenuation of spikes. began postprandial impulse muscle training Dec 2008 Mar 2009

20. began postprandial impulse muscle training Dec 2008 Mar 2009

21. began postprandial impulse muscle training Dec 2008 Mar 2009

22. Conclusions Funding currently being sought to expand number of test subjects! Success of subject in controlling not only individual postprandial excursions but also the clinical parameter of HbA1C < 6.0% may be in part due to ability to return metabolic systems (and not just glucocentric pathways) to a familiar state of dysfunction, so that changes in baseline dysfunction can them be assessed correctly, on a day to day basis.

23. Acknowledgements Dr. Claire Shi, Miami University, Dr. Dan Carl, University of Cincinnati

24. References Babraj JA et al. Extremely short duration high intensity interval training substantially improves insulin action in young healthy males . BMC Endocrine Disorders. 2009;9:3. Colberg S et al. Postprandial walking is better for lowering the glycemic effect of dinner than pre-dinner exercise in type 2 diabetic individuals. Journal of American Medical Directors Association. 2009;10:6:394-7. Derave W. et al. Effects of post-absorptive and postprandial exercise on glucoregulation in metabolic syndrome . Obesity. 2007;15:3: 704-11. Gorman DJ et al. Exercise training increases insulin-stimulated glucose disposal and GLUT4 (SLC2A4) protein content in patients with type 2 diabetes. Diabetologia . 2006;49:12:2983-92. Hawley JA. Exercise as a therapeutic intervention for the prevention and treament of insulin resistance. Diabetes/metabolism and reviews . 2004;20:5:383-93. Holloszy J. Exercise-induced increase in muscle insulin intensity. Journal of Applied Physiology. 2005;99:1:338-43 . Hostmark A. et al. Postprandial light physical activity blunts the blood glucose increase . Preventive Medicine. 2006:42;5:369-71. Jessen N & Goodyear L. Contraction signaling to glucose transport in skeletal muscle. Journal of Applied Physiology. 2005;99:1:330-7. Larsen J et al. the effect of moderate exercise on postprandial glucose homeostasis in NIDDM patients. Diabetologia. 1997; 40:4: 447-53. Larsen J et al. The effect of intense exercise on postprandial glucose homeostasis in type 2 diabetic patients. Diabetologia. 1999; 42:11:1282-92. O’Keefe J & Bell D. Postprandial hyperglycemia/hyperlipidemia (postprandial dysmetabolism) is a cardiovascular risk factor. The American Journal of Cardiology. 2007;100:5:899-904. Poirier P. Impact of time interval from the last meal on glucose response to exercise in subjects with type 2 diabetes. The Journal of Clinical Endocrinology and Metabolism. 2000; 85;8;2860-4. Richards J et al. Short-term sprint interval training increases insulin sensitivity in healthy adults but does not affect the thermogenic response to beta-adrenergic stimulation. The Journal of Physiology . 2010; 588: Pt15: 2961-72. Wisse W. et al. Prescription of physical activity is not sufficient to change sedentary behavior and improve glycemic control in type 2 diabetes patients. Diabetes Res. Clin. Pract. 2010; 88:2: e10 – 3.