Copyright @ 200 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited. 9 Two Bouts of Exercise before Meals, but Not after Meals, Lower Fasting Blood Glucose KATARINA T. BORER 1 , ELIZABETH C. WUORINEN 1 , JAMIE R. LUKOS 1 , JOHN W. DENVER 3 , STEPHEN W. PORGES 3 , and CHARLES F. BURANT 1,2 1 School of Kinesiology, University of Michigan, Ann Arbor, MI; 2 Department of Internal Medicine, University of Michigan, Ann Arbor, MI; and 3 Brain-Body Center, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL ABSTRACT BORER, K. T., E. C. WUORINEN, J. R. LUKOS, J. W. DENVER, S. W. PORGES, and C. F. BURANT. Two Bouts of Exercise before Meals, but Not after Meals, Lower Fasting Blood Glucose. Med. Sci. Sports Exerc., Vol. 41, No. 8, pp. 1606–1614, 2009. Introduction: Reduced counterregulatory responses to a next-day hypoglycemic challenge and hypoglycemia result from two spaced episodes of moderate-intensity exercise and have been characterized as exercise-associated autonomic failure. We hypothesized that this phenomenon is caused by postabsorptive state at the time of exercise rather than by autonomic failure. Methods: Participants were nine healthy postmenopausal women in a crossover study. Two hours of treadmill exercise at 43% of maximal effort were performed twice a day, separated by 5 h, either 1 h before (Before-Meals trial) or 1 h after a meal (After-Meals trial). Plasma insulin, counterregulatory hormones (glucagon, growth hormone, cortisol), and metabolites (glucose, free fatty acids, ketones) were measured to evaluate the effects of nutritional timing. Analyses of HR and vagal tone were measured to assess autonomic function. Results: Before-Meals exercise, but not After-Meals exercise, reduced postabsorptive plasma glucose by 20.2% during a 16-h period, without a change in counterregulatory response, and elicited postexercise ketosis. A 49% increase in insulin–glucagon ratio during meals, a 1 mM decline in glucagon glycemic threshold, and a reduced vagal tone during exercise were associated with Before-Meals but not with After-Meals trials. Conclusions: These results demonstrate that exercise performed in postabsorptive, but not in postprandial state, lowers glucoregulatory set point and glucagon glycemic threshold and is accompanied by reduced vagal tone, counterregulatory responses, and glucagon glycemic threshold and by increased insulin–glucagon ratio. Reduced counterregulatory response, altered neuroendocrine function, and sustained lowering of blood glucose are most likely the consequences of reduced carbohydrate availability during exercise. Key Words: RESPIRATORY SINUS ARRHYTHMIA, COUNTERREGULATION, HYPOGLYCEMIA, GLUCAGON GLYCEMIC THRESHOLD, POSTEXERCISE KETOSIS, VAGAL TONE D iet and exercise are integral to the prevention of type 2 diabetes (16) by normalizing blood glucose level and preventing damage to peripheral organs that results from chronic hyperglycemia. When diet and ex- ercise fail to reduce persistent hyperglycemia, pharmaco- logical agents such as metformin (35) are added to increase peripheral insulin sensitivity, to enhance insulin secretion, or to reduce elevated hepatic glucose production. Improve- ments in the efficacy of diet and exercise could aid the pre- diabetic without the side effects of medication and with additional health benefits of exercise. Dysregulation of insulin action entails reduction in the insulin-stimulated glucose uptake and increase in hepatic glu- cose output (5,29). Hepatic glucose output is increased by glucagon, epinephrine, growth hormone (GH), and cortisol, and this provides adequate circulatory glucose supply dur- ing fasting and during up to 3 h of continuous moderate- intensity exercise. Exercise causes faster glucose clearance from plasma owing to increased insulin-independent mus- cle glucose uptake (27) even when additional glucose is concurrently introduced through food or drink (22). After 4 h of continuous low-intensity exercise (3) or 3 h of moderate-intensity exercise (2), plasma glucose gradually declines toward the hypoglycemic level, despite robust in- creases in counterregulatory response. This likely reflects a limit in hepatic glucose production capacity rather than an altered neuroendocrine response, as supplying glucose orally (6) or intravenously (10,12) normalizes plasma glucose and appropriately suppresses counterregulatory response. Glucoregulation is altered when moderate-intensity exer- cise of 90-min duration is repeated after 3 h of rest. This treatment reduces or eliminates counterregulatory response to a hyperinsulinemic hypoglycemic challenge reducing plas- ma glucose to 2.8 mM administered 6 to 24 h later (8,9, 30–33). Hepatic glucose output declines, and plasma glucose concentration declines toward hypoglycemic levels in both healthy (8,9,32,33) and type 1 diabetic subjects (30,31). This Address for correspondence: Katarina T. Borer, Ph.D., Division of Kine- siology, University of Michigan, Ann Arbor, MI 49109-2214; E-mail: Katarina@umich.edu. Submitted for publication September 2008. Accepted for publication December 2008. 0195-9131/09/4108-1606/0 MEDICINE & SCIENCE IN SPORTS & EXERCISE Ò Copyright Ó 2009 by the American College of Sports Medicine DOI: 10.1249/MSS.0b013e31819dfe14 1606 BASIC SCIENCES