Expression of gluconeogenic enzymes and 11β-hydroxysteroid dehydrogenase type 1 in liver of diabetic mice after acute exercise

Abstract

During acute exercise, normoglycemia is maintained by a precise match between hepatic glucose production and its peripheral utilization. This is met by a complex interplay of hepatic responses and glucose uptake by muscle. However, the effect of a single bout of exercise on hepatic gluconeogenesis, corticosterone (CORT) secretion, and glucose homeostasis in the db/db mouse model of type 2 diabetes is poorly understood. Diabetic db/db and lean control littermates were subjected to a 30 minute session of treadmill running and sacrificed either immediately after exercise or 8 hours later. Plasma glucose levels were markedly increased in db/db mice after exercise, whereas no change in glucose was observed in lean mice. Post-exercise measurements revealed that plasma CORT levels were also significantly increased in db/db mice compared to lean mice. Plasma hypothalamic corticotropin releasing hormone and pituitary adrenocorticotropic hormone levels were reciprocally decreased in both db/db and lean mice after exercise, indicating intact feedback mechanisms. Protein expression, determined by Western blot analysis, of the glucocorticoid receptor in liver was significantly increased in db/db mice subjected to prior exercise. In liver of db/db mice, a significant increase in the expression of phosphoenolpyruvate carboxykinase was noted compared to lean mice after exercise. However, no change in the expression of glucose-6-phosphatase (G6Pase) α or β was observed in db/db mice. Expression of 11β-hydroxysteroid dehydrogenase type 1 was increased significantly in db/db mice compared to lean mice after exercise. Our results show differences in plasma glucose and protein expression of gluconeogenic enzymes after acute exercise between lean and diabetic db/db mice. The db/db diabetic mouse is hyperglycemic after acute exercise. This hyperglycemic state may be explained, in part, by enhanced endogenous CORT secretion and regulated hepatic phosphoenolpyruvate carboxykinase and 11β-hydroxysteroid dehydrogenase type 1 protein expression.

The effects of exercise training and caloric restriction on the cardiac oxytocin natriuretic peptide system in the diabetic mouse

“…While treadmill running has positive gains on metabolic risk factors and vascular function in the db/db mouse,35,36 this form of exercise is known to induce hyperglycemia by disrupting the hypothalamic–pituitary–adrenal axis, stimulate adrenal gland hypertrophy, and increase the secretion of catecholamines 39,48. We have demonstrated that db/db mice remain hyperglycemic after forced treadmill exercise, a response caused by excessive corticosterone and catecholamine production 34.…”

“…Excessive norepinephrine secretion during acute exercise is reported in hypertensive and non-hypertensive type 2 diabetic patients, and poor metabolic control is associated with postexercise hyperglycemia and hyperinsulinemia in patients with type 2 diabetes 49,50. Forced treadmill running increases the production of endogenous glucocorticoid and the expression of glucocorticoid receptor and gluconeogenic enzymes in liver from db/db mice, leading to increased hepatic glucose production 48. In addition, 11β-hydroxysteroid dehydrogenase type 1, which converts inactive cortisone to physiologically active corticosterone, is abundantly expressed in liver from db/db mice after acute exercise, contributing to an increased glucocorticoid plasma pool and insulin resistance and further explaining the hyperglycemia noted in the db/db mouse after training 34,48,51.…”

“…Forced treadmill running increases the production of endogenous glucocorticoid and the expression of glucocorticoid receptor and gluconeogenic enzymes in liver from db/db mice, leading to increased hepatic glucose production 48. In addition, 11β-hydroxysteroid dehydrogenase type 1, which converts inactive cortisone to physiologically active corticosterone, is abundantly expressed in liver from db/db mice after acute exercise, contributing to an increased glucocorticoid plasma pool and insulin resistance and further explaining the hyperglycemia noted in the db/db mouse after training 34,48,51. Despite these changes with treadmill exercise, alternating moderate-intensity exercise with high-intensity exercise in each exercise session affords cardioprotection in the db/db mouse but fails to improve the hyperglycemia and hyperinsulinemia 52.…”

<p>Anti-inflammatory and angiogenic effects of exercise training in cardiac muscle of diabetic mice</p>

“…The reasons for this effect are not known, although it has been suggested that treadmill running may worsen the diabetic state by increasing the levels of stress hormones. By its nature, chronic treadmill running is considered a form of forced exercise known to elicit an exaggerated cortisol response in the db/db mouse,24–28,32 which is a well-established risk factor contributing to visceral obesity and weight gain in diabetes and obesity,33,34 On the other hand, low-intensity voluntary running designed to mimic exercise programs for patients with chronic disorders proves to be more efficient in preventing weight gain and decreasing food intake and urinary corticosterone excretion in the db/db mouse 27,28…”

“…Evidence suggests that these maladaptations to exercise are attributed to an increase in insulin resistance from defective glucose transport and insulin signaling in skeletal muscle 27. Moreover, the db/db mouse exhibits hypercorticosteronism and increased expression of 11β-hydroxysteroid dehydrogenase type 1, both contributing to elevated rates of hepatic glucose production 24,32. Acute exercise and chronic ET further increase endogenous glucocorticoid secretion in the db/db mouse, resulting in increased rates of hepatic gluconeogenesis and hyperglycemia 24,28.…”