Background: Whether suppression of glucose production by metformin is through AMPK-dependent inhibition of gluconeogenic gene expression remains controversial. Results: Metformin inhibits gluconeogenic gene expression in hepatocytes. Conclusion: Low metformin concentrations found in the portal vein suppress glucose production via AMPK-dependent mechanism. Significance: The hyperglucagonemia of diabetes mellitus decreases metformin suppression of glucose production through a PKA-mediated phosphorylation of the AMPK ␣ subunit at Ser-485/497.

Background:The mechanism underlying the activation of AMPK by metformin remains unclear. Results: Metformin promotes the formation of AMPK ␣␤␥ heterotrimeric complex. Conclusion: The formation of the AMPK ␣␤␥ heterotrimeric complex augments AMPK␣ phosphorylation by LKB1 and prevents dephosphorylation by protein phosphatase. Significance: Metformin-mediated formation of the AMPK ␣␤␥ heterotrimeric complex results in AMPK activation by elevating AMPK phosphorylation at Thr-172.

Background: The mechanism driving hepatic gene expression of Foxo1 in the fasted state remains unclear.Results: Activation of cAMP-PKA pathway induces Foxo1 gene expression through CREB and co-activator P300.Conclusion: P300 mediates Foxo1 gene expression by binding to Foxo1 proximal promoter.Significance: Induction of the Foxo1 gene by cAMP-PKA via P300 fully activates the gluconeogenic program during fasting to maintain euglycemia.

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Metformin is the most commonly prescribed oral anti-diabetic agent worldwide. Surprisingly, about 35% of diabetic patients either lack or have a delayed response to metformin treatment, and many patients become less responsive to metformin over time. It remains unknown how metformin resistance or insensitivity occurs. Recently, we found that therapeutic metformin concentrations suppressed glucose production in primary hepatocytes through AMPK; activation of the cAMP-PKA pathway negatively regulates AMPK activity by phosphorylating AMPK␣ subunit at Ser-485, which in turn reduces AMPK activity. In this study, we find that metformin failed to suppress glucose production in primary hepatocytes with constitutively activated PKA and did not improve hyperglycemia in mice with hyperglucagonemia. Expression of the AMPK␣1(S485A) mutant, which is unable to be phosphorylated by PKA, increased both AMPK␣ activation and the suppression of glucose production in primary hepatocytes treated with metformin. Intriguingly, salicylate/ aspirin prevents the phosphorylation of AMPK␣ at Ser-485, blocks cAMP-PKA negative regulation of AMPK, and improves metformin resistance. We propose that aspirin/salicylate may augment metformin's hepatic action to suppress glucose production.Diabetes is the fastest-growing chronic disease worldwide, and type 2 diabetes (T2D) 2 accounts for more than 90% of diabetes cases. Metformin has been used to treat T2D since the 1950s and works primarily by controlling fasting hyperglycemia (1). Now, over 150 million people worldwide take this medication; guidelines for the treatment of T2D published by the American Diabetes Association and the European Association for the Study of Diabetes in 2012 jointly recommended metformin as the initial drug for T2D treatment (2).Surprisingly, about 35% of diabetic patients either lack or have a delayed response to metformin treatment (3-6), and many patients become less responsive to metformin over time (4). It remains unknown how metformin resistance/ insensitivity occurs. Several genes have been reported to be associated with glycemic control by metformin. In particular, variants of the organic cation transporter and the metformin transporter, have been linked to a reduction in metformin action (7-9). Because of the high occurrence of metformin resistance in diabetic patients, genetic variants in known genes alone cannot explain this phenomenon; therefore, nongenetic factors may also contribute to the response to metformin.Recently, we found that treatment with metformin prior to the addition of cAMP led to greater suppression of glucose production and AMPK activation when compared with simultaneous treatment with metformin and cAMP (10), suggesting that the cAMP-PKA pathway exerts a negative effect on AMPK activation. In both diabetic animal models and human subjects, serum glucagon levels and the ratios of glucagon to insulin are often elevated (11)(12)(13)(14) and are responsible for increased hepatic glucose output and hyperglycemia in T2D (15). Elevated glucagon l...

This paper proposes a single-phase high-powerfactor ac/dc converter with soft-switching characteristic. The circuit topology is derived by integrating a boost converter and a buck converter. The boost converter performs the function of power-factor correction (PFC) to obtain high power factor and low current harmonics at the input line. The buck converter further regulates the dc-link voltage to provide a stable dc output voltage. Without using any active-clamp circuit or snubber circuit, the active switches of the proposed converter can achieve zero-voltage switching-on (ZVS) transition together with high power factor that satisfies the IEC 61000-3-2 standards over a wide load range from 30% to 100% rated power. The steady-state analysis is developed and a design example is provided. A prototype circuit of 60 W was built and tested. Experimental results verify the feasibility of the proposed circuit with satisfactory performance.