Diabetes-Related Ankyrin Repeat Protein (DARP/Ankrd23) Modifies Glucose Homeostasis by Modulating AMPK Activity in Skeletal Muscle.

Skeletal muscle is the major site for glucose disposal, the impairment of which closely associates with the glucose intolerance in diabetic patients. Diabetes-related ankyrin repeat protein (DARP/Ankrd23) is a member of muscle ankyrin repeat proteins, whose expression is enhanced in the skeletal muscle under diabetic conditions; however, its role in energy metabolism remains poorly understood. Here we report a novel role of DARP in the regulation of glucose homeostasis through modulating AMP-activated protein kinase (AMPK) activity. DARP is highly preferentially expressed in skeletal muscle, and its expression was substantially upregulated during myotube differentiation of C2C12 myoblasts. Interestingly, DARP-/- mice demonstrated better glucose tolerance despite similar body weight, while their insulin sensitivity did not differ from that in wildtype mice. We found that phosphorylation of AMPK, which mediates insulin-independent glucose uptake, in skeletal muscle was significantly enhanced in DARP-/- mice compared to that in wildtype mice. Gene silencing of DARP in C2C12 myotubes enhanced AMPK phosphorylation, whereas overexpression of DARP in C2C12 myoblasts reduced it. Moreover, DARP-silencing increased glucose uptake and oxidation in myotubes, which was abrogated by the treatment with AICAR, an AMPK activator. Of note, improved glucose tolerance in DARP-/- mice was abolished when mice were treated with AICAR. Mechanistically, gene silencing of DARP enhanced protein expression of LKB1 that is a major upstream kinase for AMPK in myotubes in vitro and the skeletal muscle in vivo. Together with the altered expression under diabetic conditions, our data strongly suggest that DARP plays an important role in the regulation of glucose homeostasis under physiological and pathological conditions, and thus DARP is a new therapeutic target for the treatment of diabetes mellitus

Topology optimization of damping material for reducing resonance response based on complex dynamic compliance

In this research, we propose a new objective function for optimizing damping materials to reduce the resonance peak response in the frequency response problem, which cannot be achieved using existing criteria. The dynamic compliance in the frequency response problem is formulated as the scalar product of the conjugate transpose of the amplitude vector and the force vector of the loading nodes. The proposed objective function methodology is implemented using the common solid isotropic material with penalization (SIMP) method for topology optimization. The optimization problem is formulated as maximizing the complex part of the proposed complex dynamic compliance under a volume constraint. 2D and 3D numerical examples of optimizing the distribution of the damping material on the host structure are provided to illustrate the validity and utility of the proposed methodology. In these numerical studies, the proposed objective function worked well for reducing the response peak in both lower and upper excitation frequencies around the resonance. By adjusting the excitation frequency, multi-resonance peak reduction may be achieved with a single frequency excitation optimization.This research was partially supported by JSPS KAKENHI Grant Numbers 25820422 and 25630436

A Case of Laparoscopic Ileocecal Resection for Intussusception Secondary to Cecal Cancer

An 83-year-old woman presented with a right lower abdominal mass, lower abdominal pain, and distension. She had no medical or surgical history. Clinical examination revealed a right lower abdominal mass, abdominal distension, and decreased bowel sounds in the lower abdomen. Abdominal computed tomography showed an intussusception involving the ileocecal junction. A Gastrografin enema showed a tumor shadow with an irregular defect caused by the intussusception in the transverse colon. The protruding tumor was also pushed back into the cecum by the enema pressure. Colonoscopy revealed a protruding mass at the leading edge of the intussusception in the ascending colon, and biopsy results of the cecal mass indicated an adenocarcinoma. The patient underwent laparoscopic ileocecal resection of the intussuscepted cecal cancer using reduced port surgery. The resected specimen contained a type 1 tumor measuring 40mm that was histopathologically diagnosed as cecal cancer. The patient remains asymptomatic 8 months after surgery

Diabetes-Related Ankyrin Repeat Protein (DARP/Ankrd23) Modifies Glucose Homeostasis by Modulating AMPK Activity in Skeletal Muscle.

Skeletal muscle is the major site for glucose disposal, the impairment of which closely associates with the glucose intolerance in diabetic patients. Diabetes-related ankyrin repeat protein (DARP/Ankrd23) is a member of muscle ankyrin repeat proteins, whose expression is enhanced in the skeletal muscle under diabetic conditions; however, its role in energy metabolism remains poorly understood. Here we report a novel role of DARP in the regulation of glucose homeostasis through modulating AMP-activated protein kinase (AMPK) activity. DARP is highly preferentially expressed in skeletal muscle, and its expression was substantially upregulated during myotube differentiation of C2C12 myoblasts. Interestingly, DARP-/- mice demonstrated better glucose tolerance despite similar body weight, while their insulin sensitivity did not differ from that in wildtype mice. We found that phosphorylation of AMPK, which mediates insulin-independent glucose uptake, in skeletal muscle was significantly enhanced in DARP-/- mice compared to that in wildtype mice. Gene silencing of DARP in C2C12 myotubes enhanced AMPK phosphorylation, whereas overexpression of DARP in C2C12 myoblasts reduced it. Moreover, DARP-silencing increased glucose uptake and oxidation in myotubes, which was abrogated by the treatment with AICAR, an AMPK activator. Of note, improved glucose tolerance in DARP-/- mice was abolished when mice were treated with AICAR. Mechanistically, gene silencing of DARP enhanced protein expression of LKB1 that is a major upstream kinase for AMPK in myotubes in vitro and the skeletal muscle in vivo. Together with the altered expression under diabetic conditions, our data strongly suggest that DARP plays an important role in the regulation of glucose homeostasis under physiological and pathological conditions, and thus DARP is a new therapeutic target for the treatment of diabetes mellitus

Expression of DARP in mouse tissues and myotubes.

<p>(A) Quantitative analysis for DARP mRNA expression in various mouse tissues (n = 3 each). DARP was predominantly expressed in skeletal muscle. (B) Quantitative analysis for ANKRD2 or DARP mRNA expression in C2C12 cells during myogenesis (n = 4 each). Expression of DARP was substantially enhanced during myogenesis, and was predominantly expressed in mature myotube. ANKRD2 showed the less degree of up-regulation during myogenesis comparing to that of DARP.</p