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Significance Sarcopenia, or aging-associated muscle atrophy, increases the risk of falls and fractures and is associated with metabolic disease. Because skeletal muscle is a major contributor to glucose handling after a meal, sarcopenia has significant effects on whole-body glucose metabolism. Despite the high prevalence and potentially devastating consequences of sarcopenia, no effective therapies are available. Here, we show that treatment of mice with an anti-myostatin antibody for just 4 wk increased muscle mass and strength in both young and old mice. In old mice, this increase in muscle mass was accompanied by an improvement in muscle insulin sensitivity. These data provide support for myostatin inhibition as a potential therapeutic strategy for aging-associated sarcopenia and insulin resistance.

Endothelial nitric oxide synthase (eNOS) dysfunction induces insulin resistance and glucose intolerance. Tetrahydrobiopterin (BH4) is an essential cofactor of eNOS that regulates eNOS activity. In the diabetic state, BH4 is oxidized to 7,8-dihydrobiopterin, which leads to eNOS dysfunction owing to eNOS uncoupling. The current study investigates the effects of BH4 on glucose metabolism and insulin sensitivity in diabetic mice. Single administration of BH4 lowered fasting blood glucose levels in wild-type mice with streptozotocin (STZ)-induced diabetes and alleviated eNOS dysfunction by increasing eNOS dimerization in the liver of these mice. Liver has a critical role in glucose-lowering effects of BH4 through suppression of hepatic gluconeogenesis. BH4 activated AMP kinase (AMPK), and the suppressing effect of BH4 on gluconeogenesis was AMPK-dependent. In addition, the glucose-lowering effect and activation of AMPK by BH4 did not appear in mice with STZ-induced diabetes lacking eNOS. Consecutive administration of BH4 in ob/ob mice ameliorated glucose intolerance and insulin resistance. Taken together, BH4 suppresses hepatic gluconeogenesis in an eNOS-dependent manner, and BH4 has a glucose-lowering effect as well as an insulin-sensitizing effect in diabetic mice. BH4 has potential in the treatment of type 2 diabetes.

Metformin, the major target of which is liver, is commonly used to treat type 2 diabetes. Although metformin activates AMP-activated protein kinase (AMPK) in hepatocytes, the mechanism of activation is still not well known. To investigate AMPK activation by metformin in liver, we examined the role of reactive nitrogen species (RNS) in suppression of hepatic gluconeogenesis.To determine RNS, we performed fluorescence examination and immunocytochemical staining in mouse hepatocytes. Since metformin is a mild mitochondrial complex I inhibitor, we compared its effects on suppression of gluconeogenesis, AMPK activation and generation of the RNS peroxynitrite (ONOO(-)) with those of rotenone, a representative complex I inhibitor. To determine whether endogenous nitric oxide production is required for ONOO(-) generation and metformin action, we used mice lacking endothelial nitric oxide synthase (eNOS).Metformin and rotenone significantly decreased gluconeogenesis and increased phosphorylation of AMPK in wild-type mouse hepatocytes. However, unlike rotenone, metformin did not increase the AMP/ATP ratio. It did, however, increase ONOO(-) generation, whereas rotenone did not. Exposure of eNOS-deficient hepatocytes to metformin did not suppress gluconeogenesis, activate AMPK or increase ONOO(-) generation. Furthermore, metformin lowered fasting blood glucose levels in wild-type diabetic mice, but not in eNOS-deficient diabetic mice.Activation of AMPK by metformin is dependent on ONOO(-). For metformin action in liver, intra-hepatocellular eNOS is required.

Although mutations in the Wnt/β-catenin signaling pathway are linked with the metabolic syndrome and type 2 diabetes in humans, the mechanism is unclear. High-fat-fed male C57BL/6 mice were treated for 4 wk with a 2′-O-methoxyethyl chimeric antisense oligonucleotide (ASO) to decrease hepatic and adipose expression of β-catenin. β-Catenin mRNA decreased by ≈80% in the liver and by 70% in white adipose tissue relative to control ASO-treated mice. β-Catenin ASO improved hepatic insulin sensitivity and increased insulin-stimulated whole body glucose metabolism, as assessed during hyperinsulinemic-euglycemic clamp in awake mice. β-Catenin ASO altered hepatic lipid composition in high-fat-fed mice. There were reductions in hepatic triglyceride (44%, P < 0.05) and diacylglycerol content (60%, P < 0.01) but a 30% increase in ceramide content (P < 0.001). The altered lipid content was attributed to decreased expression of sn-1,2 diacylglycerol acyltransferase and mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase and an increase in serine palmitoyl transferase. The decrease in cellular diacyglycerol was associated with a 33% decrease in PKCε activation (P < 0.05) and 64% increase in Akt2 phosphorylation (P < 0.05). In summary, Reducing β-catenin expression decreases expression of enzymes involved in hepatic fatty acid esterification, ameliorates hepatic steatosis and lipid-induced insulin resistance.—Popov, V. B., Jornayvaz, F. R., Akgul, E. O., Kanda, S., Jurczak, M. J., Zhang, D., Abudukadier, A., Majumdar, S. K., Guigni, B., Petersen, K. F., Manchem, V. P., Bhanot, S., Shulman, G. I., Samuel, V. T. Second-generation antisense oligonucleotides against β-catenin protect mice against diet-induced hepatic steatosis and hepatic and peripheral insulin resistance.

SummaryImpaired insulin-mediated suppression of hepatic glucose production (HGP) plays a major role in the pathogenesis of type 2 diabetes (T2D), yet the molecular mechanism by which this occurs remains unknown. Using a novel in vivo metabolomics approach, we show that the major mechanism by which insulin suppresses HGP is through reductions in hepatic acetyl CoA by suppression of lipolysis in white adipose tissue (WAT) leading to reductions in pyruvate carboxylase flux. This mechanism was confirmed in mice and rats with genetic ablation of insulin signaling and mice lacking adipose triglyceride lipase. Insulin’s ability to suppress hepatic acetyl CoA, PC activity, and lipolysis was lost in high-fat-fed rats, a phenomenon reversible by IL-6 neutralization and inducible by IL-6 infusion. Taken together, these data identify WAT-derived hepatic acetyl CoA as the main regulator of HGP by insulin and link it to inflammation-induced hepatic insulin resistance associated with obesity and T2D.