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Although it is well-established that reductions in the ratio of insulin to glucagon in the portal vein have a major role in the dysregulation of hepatic glucose metabolism in type-2 diabetes.sup.1-3, the mechanisms by which glucagon affects hepatic glucose production and mitochondrial oxidation are poorly understood. Here we show that glucagon stimulates hepatic gluconeogenesis by increasing the activity of hepatic adipose triglyceride lipase, intrahepatic lipolysis, hepatic acetyl-CoA content and pyruvate carboxylase flux, while also increasing mitochondrial fat oxidation--all of which are mediated by stimulation of the inositol triphosphate receptor 1 (INSP3R1). In rats and mice, chronic physiological increases in plasma glucagon concentrations increased mitochondrial oxidation of fat in the liver and reversed diet-induced hepatic steatosis and insulin resistance. However, these effects of chronic glucagon treatment--reversing hepatic steatosis and glucose intolerance--were abrogated in Insp3r1 (also known as Itpr1)-knockout mice. These results provide insights into glucagon biology and suggest that INSP3R1 may represent a target for therapies that aim to reverse nonalcoholic fatty liver disease and type-2 diabetes. A role and mechanism of action are identified for INSP3R1 in the stimulation of hepatic gluconeogenesis and mitochondrial oxidation by glucagon, suggesting that INSP3R1 may be a target for ameliorating dysregulation of hepatic glucose metabolism., Author(s): Rachel J. Perry [sup.1] [sup.2] , Dongyan Zhang [sup.1] , Mateus T. Guerra [sup.1] , Allison L. Brill [sup.2] , Leigh Goedeke [sup.1] , Ali R. Nasiri [sup.1] , [...]

Impaired 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. Insulins 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.

In the version of this article originally published, the V.sub.PC and V.sub.CS flux data shown in Fig. 6e,f were inadvertently duplicated from Fig. 5j,k. The correct data are now shown in Fig. 6e,f. In these corrected data, V.sub.PC flux in response to chronic oral metformin treatment was still significantly decreased (Fig. 6e), and there was still no impact of metformin on V.sub.CS flux (Fig. 6f). Therefore, the text describing these data remains the same and this correction does not change the conclusion of this study., Author(s): Anila K. Madiraju [sup.1] [sup.2] [sup.3] , Yang Qiu [sup.1] [sup.4] , Rachel J. Perry [sup.1] , Yasmeen Rahimi [sup.1] , Xian-Man Zhang [sup.1] , Dongyan Zhang [sup.1] , [...]

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D), but whether NAFLD plays a causal role in the pathogenesis of T2D is uncertain. One proposed mechanism linking NAFLD to hepatic insulin resistance involves diacylglycerol-mediated (DAG-mediated) activation of protein kinase C-ζ (PKCζ) and the consequent inhibition of insulin receptor (INSR) kinase activity. However, the molecular mechanism underlying PKCζinhibition of INSR kinase activity is unknown. Here, we used mass spectrometry to identify the phosphorylation site [Thr.sup.1160] as a PKCζ substrate in the functionally critical INSR kinase activation loop. We hypothesized that [Thr.sup.1160] phosphorylation impairs INSR kinase activity by destabilizing the active configuration of the INSR kinase, and our results confirmed this prediction by demonstrating severely impaired INSR kinase activity in phosphomimetic T1160E mutants. Conversely, the INSR T1160A mutant was not inhibited by PKCζ in vitro. Furthermore, mice with a threonine-to-alanine mutation at the homologous residue [Thr.sup.1150] ([Insr.sup.T1150A] mice) were protected from high fat diet-induced hepatic insulin resistance. InsrTm0A mice also displayed increased insulin signaling, suppression of hepatic glucose production, and increased hepatic glycogen synthesis compared with WT controls during hyperinsulinemic clamp studies. These data reveal a critical pathophysiological role for INSR [Thr.sup.1160] phosphorylation and provide further mechanistic links between PKCζ and INSR in mediating NAFLD-induced hepatic insulin resistance., Introduction Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized nations (1). NAFLD is observed in nearly 100% of obese people with type 2 diabetes (T2D) [...]

Low-carbohydrate, high-fat ketogenic diets (KD) have been suggested to be more effective in promoting weight loss than conventional caloric restriction, whereas their effect on hepatic glucose and lipid metabolism and the mechanisms by which they may promote weight loss remain controversial. The aim of this study was to explore the role of KD on liver and muscle insulin sensitivity, hepatic lipid metabolism, energy expenditure, and food intake. Using hyperinsulinemic-euglycemic clamps, we studied insulin action in mice fed a KD or regular chow (RC). Body composition was assessed by [sup.1]H magnetic resonance spectroscopy. Despite being 15% lighter (P < 0.001) than RC-fed mice because of a 17% increase in energy expenditure (P < 0.001), KD-fed mice manifested severe hepatic insulin resistance, as reflected by decreased suppression (0% vs. 100% in RC-fed mice, P < 0.01) of endogenous glucose production during the clamp. Hepatic insulin resistance could be attributed to a 350% increase in hepatic diacylglycerol content (P < 0.001), resulting in increased activation of PKC[epsilon] (P < 0.05) and decreased insulin receptor substrate-2 tyrosine phosphorylation (P < 0.01). Food intake was 56% (P < 0.001) lower in KD-fed mice, despite similar caloric intake, and could partly be attributed to a more than threefold increase (P < 0.05) in plasma N-acylphosphatidylethanolamine concentrations. In conclusion, despite preventing weight gain in mice, KD induces hepatic insulin resistance secondary to increased hepatic diacylglycerol content. Given the key role of nonalcoholic fatty liver disease in the development of type 2 diabetes and the widespread use of KD for the treatment of obesity, these results may have potentially important clinical implications. nonalcoholic fatty liver disease; weight loss; diacylglycerol; ceramide; protein kinase C[epsilon]; FGF21 doi: 10.1152/ajpendo.00361.2010.

Nonalcoholic fatty liver disease is strongly associated with hepatic insulin resistance and type 2 diabetes mellitus, but the molecular signals linking hepatic fat accumulation to hepatic insulin resistance are unknown. [...]

Research has been conducted on conjugate anions. The equilibrium acidities and oxidation potentials of these anions in dimethyl sulfoxide have been investigated and the details are reported.

Research was conducted to examine the role of adjacent onium cations and remote substituents on the H-A+ bond equilibrium acidities in dimethyl sulfoxide solution. The study is an extension of previous investigation on ylide thermodynamic stability scale and its implication for the importance of resonance effect on ylide stabilities. Results suggest that part of the stabilization in the phosphonium and sulfonium ylide cases arises from the backbonding stabilization involving the o* and/or 3d orbital participation.

Research was conducted to determine the influence of enolization enthalpies at 0 and 298 K for nine aliphatic carbonyl and nine aliphatic thiocarbonyl compounds using ab initio complete basis set fourth-order model calculations. Results reveal lower enolization enthalpies for the thiocarbonyl compounds because of higher thioenol tautomer concentrations compared to the corresponding carbonyl compounds. On the other hand, the enolization enthalpies for the cycloketones and thiocycloketones relied upon the size of the cyclic ring.

Free energy data for C-H heterolysis to carbenium ion and hydride in solution was obtained for a series of compounds using a new thermodynamic cycle based on gas-phase C-H bond dissociation enthalpy (BDE). The BDE of the H-R bond in the gas phase was used to calculate the Gibbs free energy for the homolytic cleavage of the bond in solution. Dimethyl sulfoxide and MeCN data for hydride transfer was also compared.

Research was conducted to evaluate the radical substituent effects of fluorine and trifluoromethyl groups from the computed C-H homolytic bond dissociation enthalpies of 30 fluorinated compounds. Results showed a strengthening of the sp(super 3) C-H bond with the introduction of three alpha-fluorine substituents. However, the entry of one or two substituents resulted in the weakening of C-H bond strength due to resonance delocalization.

An investigation of the bond dissociation enthalpies (BDEs) of the C-H bonds adjacent to various radical centers derived from 11 saturated hydrocarbons revealed that these were 33.5 +/- 3 kcal/mol at 298 K. While the BDEs of the C-H bonds beside nine allylic and benzylic radical centers were found to be 48 +/- 3 kcal/mol at 298 K, those adjacent to the benzylic PhCH2CH2* radical was only 29.7 and 30.5 kcal/mol at 0 and 298 K, respectively. Those of vinylic C-H bonds near four vinylic and three allylic radical centers were found to be 35.5 +/- 3.5 kcal/mol and 56.5 +/- 3 kcal/mol both at 298 K, respectively.