5-HT(1A) activation counteracts cardiovascular but not hypophagic effects of sibutramine in rats.

The noradrenaline (NA) and serotonin reuptake inhibitor, sibutramine, gives effective weight loss, but full efficacy cannot be attained at approved doses due to cardiovascular side effects. We assessed in rats the contributions of NA and serotonin transporters to sibutramine's hypophagic and cardiovascular effects, and whether selective 5-hydroxytryptamine (5-HT(1A)) receptor activation could counteract the latter without affecting the former. Food intake was assessed in freely feeding rats and cardiovascular parameters in conscious telemetered rats.

GPR119 agonists as potential new oral agents for the treatment of type 2 diabetes and obesity.

Background: GPR119 is a Gαs-protein-coupled receptor expressed predominantly in pancreatic islets and gastrointestinal tract in humans.

Objective/methods: To review the available literature on GPR119 agonists.

Results: GPR119 de-orphanisation indicates two classes of possible endogenous agonists, phospholipids and fatty acid amides, with oleoylethanolamide and N-oleoyldopamine being the most potent.

Diverging regulation of pyruvate dehydrogenase kinase isoform gene expression in cultured human muscle cells.

The pyruvate dehydrogenase complex occupies a central and strategic position in muscle intermediary metabolism and is primarily regulated by phosphorylation/dephosphorylation. The identification of multiple isoforms of pyruvate dehydrogenase kinase (PDK1-4) and pyruvate dehydrogenase phosphatase (PDP1-2) has raised intriguing new possibilities for chronic pyruvate dehydrogenase complex control. Experiments to date suggest that PDK4 is the major isoenzyme responsible for changes in pyruvate dehydrogenase complex activity in response to various different metabolic conditions.

Proteome analysis reveals phosphorylation of ATP synthase beta -subunit in human skeletal muscle and proteins with potential roles in type 2 diabetes.

Insulin resistance in skeletal muscle is a hallmark feature of type 2 diabetes. An increasing number of enzymes and metabolic pathways have been implicated in the development of insulin resistance. However, the primary cellular cause of insulin resistance remains uncertain.

Regulation of glycogen synthase by glucose and glycogen: a possible role for AMP-activated protein kinase.

We report here use of human myoblasts in culture to study the relationships between cellular glycogen concentrations and the activities of glycogen synthase (GS) and AMP-activated protein kinase (AMPK). Incubation of cells for 2 h in the absence of glucose led to a 25% decrease in glycogen content and a significant decrease in the fractional activity of GS. This was accompanied by stimulation of both the alpha1 and alpha2 isoforms of AMPK, without significant alterations in the ratios of adenine nucleotides.

Application of (13)C-filtered (1)H NMR to evaluate drug action on gluconeogenesis and glycogenolysis simultaneously in isolated rat hepatocytes.

The effects of two inhibitors of hepatic glucose production, AICAR (5-aminoimidazole-4-carboxamide riboside) and metformin, whose precise mechanisms of action are a matter of some controversy, have been investigated in isolated rat hepatocytes by application of a novel NMR-based method whereby effects on metabolic flow from the two glucose-producing pathways, glycogenolysis and gluconeogenesis, and also lactate production, can be studied simultaneously. Hepatocytes were pre-incubated for 24 h with 15 mM 1-(13)C-glucose to load the cells with labeled glycogen, which under subsequent glycogenolytic conditions would yield predominantly 1-(13)C glucose and 3-(13)C-lactate, followed (after washing) by incubation in media with 2-(13)C-glycerol, which under subsequent gluconeogenic conditions would yield 2,5-(13)C-glucose, or if metabolized to lactate, 2-(13)C-lactate. Glucose production was then stimulated by glucagon for 3 h in the absence or presence of the inhibitors and then incubation media were analyzed by (13)C-HSQC (heteronuclear single quantum coherence)-filtered (1)H NMR spectra.

Evidence against glycogen cycling of gluconeogenic substrates in various liver preparations.

The effect of inhibition of glycogen phosphorylase by 1,4-dideoxy-1,4-imino-d-arabinitol on rates of gluconeogenesis, gluconeogenic deposition into glycogen, and glycogen recycling was investigated in primary cultured hepatocytes, in perfused rat liver, and in fed or fasted rats in vivo clamped at high physiological levels of plasma lactate. 1,4-Dideoxy-1,4-imino-d-arabinitol did not alter the synthesis of glycerol-derived glucose in hepatocytes or lactate-derived glucose in perfused liver or fed or fasted rats in vivo. Thus, 1,4-dideoxy-1,4-imino-d-arabinitol inhibited hepatic glucose output in the perfused rat liver (0.