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.

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In the ob/ob leptin‐deficient mouse the role of intestinal secretion is unclear. The goal of this study was to characterize jejunal function. We measured transepithelial short circuit current (Isc), across jejunum from ob/ob and lean mice (aged 14 weeks). Basal Isc was significantly decreased in the ob/ob mice (50.5±9.5 μA/cm2, n=5) compared to lean mice (95.2±20.3 μA/cm2, n=4, P<0.05). The Isc in response to forskolin (10 μM, bilateral) was similar in both groups, indicating a comparable cAMP‐dependent Isc. The Isc in response to bumetanide (100 μM, basolateral) and to acetazolamide (100 μM, bilateral) was similar for both groups, indicating analogous Cl− and HCO3− secretory components. Crypt depth was similar for both groups, indicating that structural changes do not contribute towards the reduced Isc of the ob/ob mice. Villi length was significantly increased (~100 μm) in the ob/ob mice, suggesting a greater surface area for absorptive function. Expression of the transporter protein, Glut5 (normalized to GAPDH), was significantly increased 2‐fold in ob/ob mice. These data suggest that basal jejunal Isc in ob/ob mice is ~1/2 that of lean mice, and may reflect a reduced fluidity of the jejunal content in the ob/ob mice, which may contribute to the associated diabetic phenotype. Current studies aim to determine whether the contribution of key epithelial transporters is similarly reduced in the ob/ob mice.

These studies examined the translational efficacy and the signaling consequences of in vivo treatment with two soluble ActRIIB receptor ligand trapping agents (Acceleron Pharma) in the mdx mouse model for Duchenne muscular dystrophy. A one month treatment of 30 day old mdx mice with RAP‐031 (10 mg/kg; subcutaneously, twice weekly) produced significant (p<0.05) increases in the body mass of both male (14% increase) and female (22% increase) mice. These increases were associated with proportionately larger increases in limb musculature (gastrocnemius; 30%) than in respiratory musculature (costal diaphragm; 12%). Longer periods of treatment (3 months) with RAP‐435 induced 30% increases in body mass and again produced larger proportional increases in the mass of the gastrocnemius (about 90%) than the costal diaphragm (about 43%). The 1 month RAP‐031 treatment produced relatively moderate increases in fiber density and diameter in the severely dystrophic mdx triangularis sterni (TS) muscle. However, the 3 month treatment with RAP‐435 substantially increased TS muscle mass by producing large increases in both fiber density and fiber diameter. Collagen expression and crosslinking in the mdx costal diaphragm was not influenced by treatment with RAP‐031 for periods of 1 or 3 months. The total expression of smads 2 and 3 were unaffected by RAP‐031 treatment. RAP‐031 treatment increased the expression of Smad 4 in the gastrocnemius but not in the costal diaphragm. The expression of Akt was unaffected by RAP‐031 treatment in either muscle preparation, while the proportion of phosphorylated Akt was slightly increased by RAP‐031 treatment in the gastrocnemius. These results further demonstrate the efficacy of the ActRIIB receptor ligand trapping agents in increasing dystrophic muscle mass, and suggest that muscle‐specific differences in TGF‐beta expression or smad and Akt signaling may contribute to differential effects in the limb and respiratory musculature. Grant Funding Source: Supported by NIHR15AR055360 to CGC