Time and dose selective glucose metabolism for glucose homeostasis and energy conversion in the liver.

Hepatic glucose metabolism serves dual purposes: maintaining glucose homeostasis and converting glucose into energy sources; however, the underlying mechanisms are unclear. We quantitatively measured liver metabolites, gene expression, and phosphorylated insulin signaling molecules in mice orally administered varying doses of glucose, and constructed a transomic network. Rapid phosphorylation of insulin signaling molecules in response to glucose intake was observed, in contrast to the more gradual changes in gene expression. Glycolytic and gluconeogenic metabolites and expression of genes involved in glucose metabolism including glucose-6-phosphate, G6pc, and Pck1, demonstrated high glucose dose sensitivity. Whereas, glucokinase expression and glycogen accumulation showed low glucose dose sensitivity. During the early phase after glucose intake, metabolic flux was geared towards glucose homeostasis regardless of the glucose dose but shifted towards energy conversion during the late phase at higher glucose doses. Our research provides a comprehensive view of time- and dose-dependent selective glucose metabolism.

DNA hypomethylation characterizes genes encoding tissue-dominant functional proteins in liver and skeletal muscle.

Each tissue has a dominant set of functional proteins required to mediate tissue-specific functions. Epigenetic modifications, transcription, and translational efficiency control tissue-dominant protein production. However, the coordination of these regulatory mechanisms to achieve such tissue-specific protein production remains unclear. Here, we analyzed the DNA methylome, transcriptome, and proteome in mouse liver and skeletal muscle. We found that DNA hypomethylation at promoter regions is globally associated with liver-dominant or skeletal muscle-dominant functional protein production within each tissue, as well as with genes encoding proteins involved in ubiquitous functions in both tissues. Thus, genes encoding liver-dominant proteins, such as those involved in glycolysis or gluconeogenesis, the urea cycle, complement and coagulation systems, enzymes of tryptophan metabolism, and cytochrome P450-related metabolism, were hypomethylated in the liver, whereas those encoding-skeletal muscle-dominant proteins, such as those involved in sarcomere organization, were hypomethylated in the skeletal muscle. Thus, DNA hypomethylation characterizes genes encoding tissue-dominant functional proteins.

In vivo transomic analyses of glucose-responsive metabolism in skeletal muscle reveal core differences between the healthy and obese states.

Metabolic regulation in skeletal muscle is essential for blood glucose homeostasis. Obesity causes insulin resistance in skeletal muscle, leading to hyperglycemia and type 2 diabetes. In this study, we performed multiomic analysis of the skeletal muscle of wild-type (WT) and leptin-deficient obese (ob/ob) mice, and constructed regulatory transomic networks for metabolism after oral glucose administration. Our network revealed that metabolic regulation by glucose-responsive metabolites had a major effect on WT mice, especially carbohydrate metabolic pathways. By contrast, in ob/ob mice, much of the metabolic regulation by glucose-responsive metabolites was lost and metabolic regulation by glucose-responsive genes was largely increased, especially in carbohydrate and lipid metabolic pathways. We present some characteristic metabolic regulatory pathways found in central carbon, branched amino acids, and ketone body metabolism. Our transomic analysis will provide insights into how skeletal muscle responds to changes in blood glucose and how it fails to respond in obesity.

Pseudoarthrosis of the ilium after periacetabular osteotomy that was treated by cemented total hip arthroplasty: a case report.

BACKGROUND: Preserving the hip joint to delay arthroplasty for patients with acetabular dysplasia-associated early-stage osteoarthritis has become more common, and several surgical procedures have demonstrated pain relief and improved hip joint function. Periacetabular osteotomy, one of the joint-preserving surgical procedures of the hip, provides favorable outcomes, although there are no reports of total hip arthroplasty being used to treat pseudoarthrosis of the periacetabular osteotomy segment. Therefore, we report a case of pseudoarthrosis in the osteotomy segment after periacetabular osteotomy. The patient was treated using modified total hip arthroplasty and achieved a favorable short-term outcome. CASE PRESENTATION: A 62-year-old Japanese woman was diagnosed with bilateral acetabular dysplasia at the age of 50 years, and underwent right and left periacetabular osteotomy at the ages of 52 and 55 years, respectively. When she was 61-years old, she experienced repeated episodes of left coxalgia during walking, with increasing pain at rest, and subsequently visited our department. Plain radiography and computed tomography of her left hip joint confirmed pseudoarthrosis of the periacetabular osteotomy segment. In addition, narrowing of her left hip joint space was observed, which indicated advanced osteoarthritis of the hip. Therefore, she underwent left total hip arthroplasty when she was 62-years old. During the surgery, fibrous fusion of the periacetabular osteotomy segment was confirmed via fluoroscopy, although no abnormal mobility was observed. Thus, the osteotomy segment was fixed with one absorbable screw and two bone pegs (which were prepared using allogeneic bone), and the acetabular cup was fixed using cement. Her postoperative course was generally favorable and bone fusion of the periacetabular osteotomy segment was confirmed at 3 years and 6 months after surgery. Her modified Harris hip score was 43 before the surgery and had improved to 90 at the final follow-up. CONCLUSIONS: Modified total hip arthroplasty was successfully used to treat osteoarthritis of the hip and pseudoarthrosis of the periacetabular osteotomy segment. This procedure achieved pseudoarthrosis region bone fusion and a favorable postoperative outcome.