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Much is known about the effect of parent-child relationships on child health; less is known about how parent-child relationships influence parent health. To assess the association between aspects of the parent-child relationship and parent metabolic outcomes, and whether these associations are moderated by parent gender. Five metabolic outcomes (systolic and diastolic blood pressure, heart rate, total cholesterol and glycated hemoglobin) were assessed among 261 parents (45.83 ± 5.50 years) of an adolescent child (14.57 ± 1.072 years). Parents completed questionnaires assessing their child's hassles and the quality of their days with their child. Parents' perceptions of their child's hassles were associated with parent heart rate (B = 2.954, SE = 1.267, p = 0.021) and cholesterol (B = 0.028, SE = 0.011, p = 0.010), such that greater perceived child hassles were associated with higher heart rate and cholesterol levels, on average. These associations were not moderated by parent gender (all ps > 0.30). Parent report of their day with their child was not associated with parent metabolic outcomes (all ps > 0.20). Parent gender moderated the association between parent report of their day with their child and parent systolic blood pressure (B = 13.861, SE = 6.200, p = 0.026), such that less positive reports were associated with higher blood pressure readings among fathers, but not mothers. This study suggests that parent metabolic health may in part be influenced by aspects of the parent-child relationship., Author(s): Emily J. Jones [sup.1] , Edith Chen [sup.2] [sup.3] , Cynthia S. Levine [sup.2] [sup.3] , Phoebe H. Lam [sup.2] , Vivian Y. Liu [sup.2] , Hannah M. C. [...]

Obesity and overnutrition increase levels of reactive sugar- and lipid-derived aldehydes called reactive carbonyl species (RCS). Increased tissue and circulating RCS levels have been tied to insulin resistance and inflammation, but previous pharmacological approaches to target RCS have had equivocal outcomes. In this issue of theJCI, Anderson et al. present evidence for the development and implementation of carnisonol, a compound that is biologically stable in vivo and shows impressive effects on improving metabolism and inflammation in rodent models of diet-induced obesity and metabolic dysfunction., IntroductionStudies examining the mechanisms that drive insulin resistance and hyperglycemia have been a particular area of focus because of the rising rates of type 2 diabetes. Accumulating evidence shows a [...]

Evolving research sheds light on a possibly unique form of depression among the elderly., Author(s): Nicole Wetsman [sup.1] Author Affiliations: (1) Nicole Wetsman is a freelance science and health reporter based in, New York, USA In 2002, soon after receiving her doctorate in psychology, [...]

The neuropeptide kisspeptin regulates reproduction by stimulating gonadotropin- releasing hormone (GnRH) neurons via the kisspeptin receptor KISS1R. In addition to GnRH neurons, KISS1R is expressed in other brain areas and peripheral tissues, which suggests that kisspeptin has additional functions beyond reproduction. Here, we studied the energetic and metabolic phenotype in mice lacking kisspeptin signaling (Kisslr KO mice). Compared with WT littermates, adult Kisslr KO females displayed dramatically higher BW, leptin levels, and adiposity, along with strikingly impaired glucose tolerance. Conversely, male Kisslr KO mice had normal BW and glucose regulation. Surprisingly, despite their obesity, Kisslr KO females ate less than WT females; however, Kisslr KO females displayed markedly reduced locomotor activity, respiratory rate, and energy expenditure, which were not due to impaired thyroid hormone secretion. The BW and metabolic phenotype in Kisslr KO females was not solely reflective of absent gonadal estrogen, as chronically ovariectomized Kisslr KO females developed obesity, hyperleptinemia, reduced metabolism, and glucose intolerance compared with ovariectomized WT females. Our findings demonstrate that in addition to reproduction, kisspeptin signaling influences BW, energy expenditure, and glucose homeostasis in a sexually dimorphic and partially sex steroid-independent manner; therefore, alterations in kisspeptin signaling might contribute, directly or indirectly, to some facets of human obesity, diabetes, or metabolic dysfunction., Introduction The neuropeptide kisspeptin (encoded by KISS1) and its receptor, KISS1R (formerly known as GPR54), are key regulators of reproduction. Humans and mice with mutations in these genes show impaired [...]

The intrauterine environment is a major contributor to increased rates of metabolic disease in adults. Intra-hepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy that affects 0.5%-2% of [...]

Insulin resistance (IR) and hyperinsulinemia are hallmarks of the metabolic syndrome, as are central adiposity, dyslipidemia, and a predisposition to type 2 diabetes, atherosclerotic cardiovascular disease, hypertension, and certain cancers. [...]

Insulin resistance is a fundamental pathogenic factor present in various metabolic disorders including obesity and type 2 diabetes (1). Although skeletal muscle accounts for 70-90% of insulin-stimulated glucose disposal (2,3), [...]

Fetal exposure to inflammatory mediators is associated with a greater risk of brain injury and may cause endothelial dysfunction; however, nearly all the evidence is derived from gram-negative bacteria. Intrapleural injections of OK-432, a killed Su-strain of Streptococcus pyogenes, has been used to treat fetal chylothorax. In this study, we evaluated the neural and cardiovascular effects of OK-432 in preterm fetal sheep (104 [+ or -] 1 days, term 147 days). OK-432 (0.1 mg, n = 6) or saline vehicle (n = 7) was infused in the fetal pleura, and fetuses were monitored for 7 days. Blood samples were taken routinely for plasma nitrite measurement. Fetal brains were taken for histological assessment at the end of the experiment. Between 3 and 7 h postinjection, OK-432 administration was associated with transient suppression of fetal body and breathing movements and electtroencephalogram activity (P < 0.05), increased carotid and femoral vascular resistance (P < 0.05), but no change in blood pressure. Brain activity and behavior then returned to normal except in one fetus that developed seizures. OK-432 fetuses showed progressive, sustained vasodilatation (P < 0.05), with lower blood pressure after 4 days (P < 0.05), but normal heart rate. There were no changes in plasma nitrite levels. Histological studies showed bilateral infarction in the dorsal limb of the hippocampus of the fetus that developed seizures, but no injury in other fetuses. We conclude that a single low-dose injection of OK-432 can be associated with risk of focal cerebral injury in the preterm fetus and chronic central and peripheral vasodilatation that does not appear to be mediated by nitric oxide. prenatal infection; endothelial dysfunction; seizures doi: 10.1152/ajpregu.00116.2010.

The hyperinsulism/hyperammonemia (HI/HA) syndrome is caused by glutamate dehydrogenase (GDH) gain-of-function mutations that reduce the inhibition by GTP, consequently increasing the activity of GDH in vivo. The source of the hyperammonemia in the HI/HA syndrome remains unclear. We examined the effect of systemic activation of GDH on ammonia metabolism in the rat. 2-Aminobicyclo[2,2,1]heptane-2-carboxylic acid (BCH) is a nonmetabolizable analog of the natural GDH allosteric activator leucine. A dose of 100 [micro]mol BCH/100 g rat resulted in a mild systemic hyperammonemia. Using arterial-venous (A-V) differences, we exclude the liver, intestine, and skeletal muscle as major contributors to this BCH-induced hyperammonemia. How ever, renal ammonia output increased, as demonstrated by an increase in A-V difference for ammonia across the kidney in BCH-treated animals. Isolated renal cortical tubules incubated with BCH increased the rate of ammoniagenesis from glutamine by 40%. The flux through GDH increased more than twofold when BCH was added to renal mitochondria respiring on glutamine. The flux through glutaminase was not affected by BCH, whereas glutamate-oxaloacetate transaminase flux decreased when normalized to glutaminase flux. These data show that increased renal ammoniagenesis due to activation of GDH can explain the BCH-induced hyperammonemia. These results are discussed in relation to the organ source of the ammonia in the HI/HA syndrome as well as the role of GDH in regulating renal ammoniagenesis. kidney; mitochondria; glutaminase; 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid doi: 10.1152/ajpendo.00028.2010.

Neonatal hyperoxia impairs vascular and alveolar growth in mice and decreases endothelial progenitor cells. To determine the role of bone marrow-derived cells in restoration of neonatal lung structure after injury, we studied a novel bone marrow myeloid progenitor cell population from Tie2-green fluorescent protein (GFP) transgenic mice (bone marrow-derived angiogenic cells; BMDAC). We hypothesized that treatment with BMDAC would restore normal lung structure in infant mice during recovery from neonatal hyperoxia. Neonatal mice (1-day-old) were exposed to 80% oxygen for 10 days. BMDACs (1 x [10.sup.5]), embryonic endothelial progenitor cells, mouse embryonic fibroblasts (control), or saline were then injected into the pulmonary circulation. At 21 days of age, saline-treated mice had enlarged alveoli, reduced septation, and a reduction in vascular density. In contrast, mice treated with BMDAC had complete restoration of lung structure that was indistinguishable from room air controls. BMDAC comprised 12% of distal lung cells localized to pulmonary vessels or alveolar type II (AT2) cells and persist (8.8%) for 8 wk postinjection. Coculture of AT2 cells or lung endothelial cells (luEC) with BMDAC augmented AT2 and IuEC cell growth in vitro. We conclude that treatment with BMDAC after neonatal hyperoxia restores lung structure in this model of bronchopulmonary dysplasia. bronchopulmonary dysplasia; stem cell; oxygen; alveolar type 2 cell; endothelial cell doi:10.1152/ajplung.00089.2009

Atypical protein kinase C (aPKC) isoforms mediate insulin effects on glucose transport in muscle and adipose tissues and lipid synthesis in liver and support other metabolic processes, expression of enzymes needed for islet insulin secretion and hepatic glucose production/release, CNS appetite suppression, and inflammatory responses. In muscle, selective aPKC deficiency impairs glucose uptake and produces insulin resistance and hyperinsulinemia, which, by activating hepatic aPKC, provokes inordinate increases in lipid synthesis and produces typical 'metabolic syndrome' features. In contrast, hepatic aPKC deficiency diminishes lipid synthesis and protects against metabolic syndrome features. Unfortunately, aPKC is deficient in muscle but paradoxically conserved in liver in obesity and type 2 diabetes mellitus; this combination is particularly problematic because it promotes lipid and carbohydrate abnormalities. Accordingly, metabolic effects of aPKCs can be 'good' or 'bad,' depending upon nutritional status; thus, muscle glucose uptake, islet insulin secretion, hepatic glucose and lipid production/release, and adipose fat synthesis/ storage would be important for survival during periods of limited food availability and therefore be 'good.' However, during times of food surfeit, excessive activation of hepatic aPKC, whether caused by overnutrition or impairments in extrahepatic effects of insulin, would lead to inordinate increases in hepatic lipid synthesis and metabolic syndrome features and therefore be 'bad.' In keeping with these ideas, the inhibition of hepatic aPKC markedly ameliorates lipid and carbohydrate abnormalities in experimental models of obesity and type 2 diabetes. We postulate that a similar approach may be useful for treating humans. doi:10.1152/ajpendo.00608.2009.

Gu L, Zhang GF, Kombu RS, Allen F, Kutz G, Brewer WU, Roe CR, Brunengraber H. Parenteral and enteral metabolism of anaplerotic triheptanoin in normal rats. II. Effects on lipolysis, glucose production, and liver acyl-CoA profile. Am J Physiol Endocrinol Metab 298: E362-E371, 2010. First published November 10, 2009; doi:10.1152/ajpendo.00384.2009.--The anaplerotic odd-mediumchain triglyceride triheptanoin is used in clinical trials for the chronic dietary treatment of patients with long-chain fatty acid oxidation disorders. We previously showed (Kinman RP, Kasumov T, Jobbins KA, Thomas KR, Adams JE, Brunengraber LN, Kutz G, Brewer WU, Roe CR, Brunengraber H. Am J Physiol Endocrinol Metab 291: E860-E866, 2006) that the intravenous infusion of triheptanoin increases lipolysis traced by the turnover of glycerol. In this study, we tested whether lipolysis induced by triheptanoin infusion is accompanied by the potentially harmful release of long-chain fatty acids. Rats were infused with heptanoate [+ or -] glycerol or triheptanoin. Intravenous infusion of triheptanoin at 40% of caloric requirement markedly increased glycerol endogenous [R.sub.a] but not oleate endogenous [R.sub.a]. Thus, the activation of lipolysis was balanced by fatty acid reesterification in the same cells. The liver acyl-CoA profile showed the accumulation of intermediates of heptanoate [beta]-oxidation and [C.sub.5]-ketogenesis and a decrease in free CoA but no evidence of metabolic perturbation of liver metabolism such as propionyl overload. Our data suggest that triheptanoin, administered either intravenously or intraduodenally, could be used for intensive care and nutritional support of metabolically decompensated long-chain fatty acid oxidation disorders. doi: 10.1152/ajpendo.00384.2009

After a constant insulin infusion is initiated, determination of steady-state conditions for glucose infusion rates (GIR) typically requires [greater than or equal to] 3 h. The glucose infusion follows a simple time-dependent rise, reaching a plateau at steady state. We hypothesized that nonlinear fitting of abbreviated data sets consisting of only the early portion of the clamp study can provide accurate estimates of steady-state GIR. Data sets from two independent laboratories were used to develop and validate this approach. Accuracy of the predicted steady-state GDR was assessed using regression analysis and Altman-Bland plots, and precision was compared by applying a calibration model. In the development data set (n = 88 glucose clamp studies), fitting the full data set with a simple monoexponential model predicted reference GDR values with good accuracy (difference between the 2 methods -0.37 mg * [kg.sup.-1] * [min.sup.-l]) and precision [root mean square error (RMSE) = 1.11], validating the modeling procedure. Fitting data from the first 180 or 120 min predicted final GDRs with comparable accuracy but with progressively reduced precision [fitGDR-180 RMSE = 1.27 (P = NS vs. fitGDR-full); fitGDR-120 RMSE = 1.56 (P < 0.001)]. Similar results were obtained with the validation data set (n = 183 glucose clamp studies), confirming the generalizability of this approach. The modeling approach also derives kinetic parameters that are not available from standard approaches to clamp data analysis. We conclude that fitting a monoexponential curve to abbreviated clamp data produces steady-state GDR values that accurately predict the GDR values obtained from the full data sets, albeit with reduced precision. This approach may help reduce the resources required for undertaking clamp studies. fitting; insulin doi: 10.1152/ajpendo.00603.2009

Jorgensen W, Gam C, Andersen JL, Schjerling P, Scheibye-Knudsen M, Mortensen OH, Grunnet N, Nielsen MO, Quistorff B. Changed mitochondrial function by pre- and/or postpartum diet alterations in sheep. Am J Physiol Endocrinol Metab 297: E1349-E1357, 2009. First published October 13, 2009; doi: 10.1152/ajpendo.00505.2009.--In a sheep model, we investigated diet effects on skeletal muscle mitochondria to look for fetal programming. During pregnancy, ewes were fed normally (N) or were 50% food restricted (L) during the last trimester, and lambs born to these ewes received a normal (N) or a high-fat diet (H) for the first 6 mo of life. We examined mitochondrial function in permeabilized muscle fibers from the lambs at 6 mo of age (adolescence) and after 24 mo of age (adulthood). The postpartum H diet for the lambs induced an ~30% increase (P < 0.05) of mitochondrial [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] and an ~50% increase (P < 0.05) of the respiratory coupling ratio (RCR) combined with lower levels of UCP3 and PGC-1[alpha] mRNA levels (P < 0.05). These effects proved to be reversible by a normal diet from 6 to 24 mo of age. However, at 24 too, a long-term effect of the maternal gestational diet restriction (fetal programming) became evident as a lower [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] (~40%, P < 0.05), a lower state 4 respiration (~40%, P < 0.05), and lower RCR (~15%, P < 0.05). Both PGC-l[alpha] and UCP3 mRNA levels were increased (P < 0.05). Two analyzed muscles were affected differently, and muscle rich in type I fibers was more susceptible to fetal programming. We conclude that fetal programming, seen as a reduced [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] in adulthood, results from gestational undernutrition. Postnatal high-fat diet results in a pronounced RCR and [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII], increase in adolescence. However, these effects are reversible by diet correction and are not maintained in adulthood. metabolic syndrome; high-fat diet; nutrient restriction; maternal diet; respiratory coupling ratio doi: 10.1152/ajpendo.00505.2009

Type 2 diabetes and obesity are associated with an enhanced release of a number of adipocytokines. Hyperinsulinemia, frequently present in type 2 diabetes and obesity, might be one of the drivers of the enhanced production of adipocytokines. The aim of this study was to investigate the interstitial levels of cytokines in subcutaneous adipose tissue (SCAT) in response to hyperinsulinemia and the effect of weight-reducing hypocaloric diet on this regulation in obese subjects. Thirteen obese premenopausal women participated in the study. Concentrations of seven cytokines were measured in plasma and in AT interstitial fluid collected by microdialysis during a euglycemichyperinsulinemic clamp and during control infusion of physiological saline. A subgroup of six women underwent a 4-wk very-low-calorie diet (VLCD). Microdialysis during the clamp was performed before and at the end of VLCD. Hyperinsulinemia induced an increase of monocyte chemoatractant protein (MCP-1) and IL-6 SCAT interstitial and plasma levels and elevated IL-8 levels in SCAT. The relative changes of IL-6 levels in the dialysate correlated with changes of IL-8 and MCP-1. The interstitial and plasma levels of IL-1[beta], IL-10, TNF[alpha], and plasminogen activator inhibitor (PAI-1) remained unchanged in response to hyperinsulinemia. VLCD resulted in enhancement of the hyperinsulinemia-induced augmentation of MCP-1, IL-6, and IL-8 interstitial levels. In conclusion, hyperinsulinemia upregulates the interstitial levels of MCP-1, IL-6, and IL-8 in SCAT in obese women, whereas it does not affect IL-1[beta], IL-10, TNF[alpha], and PAI-1 levels. Hypocaloric diet associated with weight reduction enhances the hyperinsulinemia-induced upregulation of MCP-1, IL-6, and IL-8 in SCAT. microdialysis; adipose tissue; adipokines doi: 10.1152/ajpendo.00086.2009.

The purpose of this study was to determine the long-term impact of obesity and related metabolic abnormalities in the absence and presence of hypertension on renal injury and salt-sensitivity of blood pressure. Markers of renal injury and blood pressure salt sensitivity were assessed in 52- to 55-wk-old normotensive melanocortin-4 receptor-deficient (MC4R-/-) mice and lean C57BL/6J wild-type (WT) mice and in 22-wk-old MC4R-/- and WT mice made hypertensive by [N.sup.G]-nitro-L-arginine methyl ester (L-NAME) in the drinking water for 8 wk. Old MC4R-/- mice were 60% heavier, hyperinsulinemic, and hyperleptinemic but had similar mean arterial pressure (MAP) as WT mice (115 [+ or -] 2 and 117 [+ or -] 2 mmHg) on normal salt diet (0.4% NaCl). A high-salt diet (4.0% NaCl) for 12 days did not raise MAP in obese or lean mice [[DELTA]MAP: MC4R (-/-) 4 [+ or -] 2 mmHg; WT, 2 [+ or -] 1 mmHg]. Obese MC4R-/- mice had 23% greater glomerular tuft area and moderately increased GFR compared with WT mice. Bowman's space, total glomerular area, mesangial matrix, urinary albumin excretion (UAE), renal TGF-[beta] and collagen expression were not significantly different between old MC4R-/- and WT mice. Renal lipid content was greater but renal macrophage count was markedly lower in MC4R-/- than WT mice. Mild increases in MAP during L-NAME treatment (~16 mmHg) caused small, but greater, elevations in UAE, renal TGF-[beta] content, and macrophage infiltration in MC4R-/compared with WT mice without significant changes in glomerular structure. Thus despite long-term obesity and multiple metabolic abnormalities, MC4R-/- mice have no evidence of renal injury or salt-sensitivity of blood pressure. These observations suggest that elevations in blood pressure may be necessary for obesity and related metabolic abnormalities to cause major renal injury or that MC4R-/mice are protected from renal injury by mechanisms that are still unclear. metabolic syndrome; renal injury; salt sensitivity

Endocrine effects of adipose-derived adiponectin on skeletal muscle have been shown to account, at least in part, for the anti-diabetic effects of this adipokine. Recently, the concept of myokines has gained credence, and the potential for skeletal muscle to produce adiponectin has been suggested. Here we demonstrated an increased level of adiponectin mRNA and protein expression as well as protein secretion in response to rosiglitazone treatment in L6 muscle cells. This correlated with the ability of rosiglitazone to enhance insulin sensitivity for stimulation of protein kinase B (Akt) phosphorylation and glucose transport; rosiglitazone also corrected high-glucose-induced insulin resistance in L6 cells. Overexpression of adiponectin confirmed the functional significance of local production of adiponectin in muscle cells via elevated glucose uptake and increased insulin sensitivity. In obese diabetic db/db mice, there was a change in the adiponectin expression profile in soleus and extensor digitorum longus (EDL) muscle with less high molecular weight (HMW) and more medium (MMW)/low (LMW) molecular weight species detected. Induction of obesity and insulin resistance in rats by feeding a high-fat high-sucrose diet also led to decreased muscle HMW adiponectin content that could be corrected by rosiglitazone treatment. In summary, we show the ability of skeletal muscle cells to produce adiponectin, which can mediate autocrine metabolic effects, thus establishing adiponectin as a bona fide myokine. We also demonstrate that skeletal muscle adiponectin production is altered in animal models of obesity and diabetes and that these changes can be corrected by rosiglitazone. adiponectin; myokine; glucose uptake; obesity; insulin sensitivity

The proper glycosylation of proteins trafficking through the Golgi apparatus depends upon the conserved oligomeric Golgi (COG) complex. Defects in COG can cause fatal congenital disorders of glycosylation (CDGs) in humans. The recent discovery of a form of CDG, caused in part by a COG4 missense mutation changing Arg 729 to Trp, prompted us to determine the 1.9 [Angstrom] crystal structure of a Cog4 C-terminal fragment. Arg 729 is found to occupy a key position at the center of a salt bridge network, thereby stabilizing Cog4's small C-terminal domain. Studies in HeLa cells reveal that this C-terminal domain, while not needed for the incorporation of Cog4 into COG complexes, is essential for the proper glycosylation of cell surface proteins. We also find that Cog4 bears a strong structural resemblance to exocyst and Dsl1p complex subunits. These complexes and others have been proposed to function by mediating the initial tethering between transport vesicles and their membrane targets; the emerging structural similarities provide strong evidence of a common evolutionary origin and may reflect shared mechanisms of action. congenital disorder of glycosylation | Golgi apparatus multi-subunit tethering complex | vesicle trafficking | X-ray crystallography

Objectives: To evaluate the associations between serum complement factor 3 (C3) and several anthropometrical, biochemical and lifestyle features in healthy young adults, emphasizing on the putative effect of selenium intake on C3 concentrations. Methods: This study enrolled 100 healthy young adults aged 18-34 years. Anthropometric and blood pressure measurements and lifestyle features were analyzed. Fasting blood samples were collected for the measurement of glucose, total cholesterol, HDL-cholesterol, LDL-cholesterol, triacylglycerols and C3 concentrations. Nail samples were collected for the analysis of selenium concentrations. Results: Values of BMI (P=0.034), sum of skinfold thicknesses (STs) (P=0.021), body fat mass (BFM) (P=0.023), percentage of overweight subjects (P=0.007), serum triacylglycerols (P=0.012) and nail selenium (P=0.001) were significantly different between subjects above and below the median of serum C3 concentrations. The following correlations with serum C3 were identified tricipital ST (P=0.033), sum of STs (P=0.012), BMI (P=0.008), BFM (P=0.018), waist-to-height ratio (P=0.016), serum glucose (P=0.045), serum triacylglycerols (P=0.001) and nail selenium (P=0.006). Circulating C3 showed a positive association with several adiposity markers such as BMI (P=0.001), waist circumference (P=0.006), waist-to-height ratio (P=0.002), BFM (P=0.025), as well as serum glucose (P=0.027) and triacylglycerols (P Conclusions: C3 seems to be related with selenium status and several anthropometrical and biochemical measurements linked to metabolic syndrome in apparently healthy young adults. These findings suggest a possible role for selenium intake in the modulation of C3, whose assessment may be an early marker of metabolic syndrome manifestations. doi:10.1038/ejcn.2008.48; published online 5 November 2008 Keywords: inflammation; complement factor 3; oxidative stress; antioxidant; selenium; metabolic syndrome, Introduction The inflammatory response triggered in the white adipose tissue has been associated with a cycle that leads to insulin resistance, atherosclerosis and typical alterations of the metabolic syndrome (Dandona [...]

Cloned 20 years ago, GLUT2 is a facilitative glucose transporter in the liver, pancreas, intestine, kidney, and brain. It ensures large bidirectional fluxes of glucose in and out the cell due to its low affinity and high capacity. It also transports other dietary sugars, such as fructose and galactose, within the range of physiological concentrations. Sugars and hormones regulate its gene expression. The contribution of GLUT2 to human metabolic diseases previously appeared modest. However, in the past decade, three major features of the GLUT2 protein have been revealed. First, GLUT2 mutations cause the severe but rare Fanconi-Bickel syndrome, mainly characterized by glycogenosis. Recently, a GLUT2 polymorphism has been associated with preferences for sugary food. Second, the GLUT2 location at the cell surface is regulated; this governs cellular activities dependent on glucose in the intestine and possibly those in the liver and pancreas. For instance, GLUT2 translocation from an intracellular pool to the apical membrane after a sugar meal transiently increases sugar uptake by enterocytes (reviewed in 32). Third, GLUT2 functions as a membrane receptor of sugar. Independently of glucose metabolism, GLUT2 detects the presence of extracellular sugar and transduces a signal to modulate cell functions, including [beta]-cell insulin secretion, renal reabsorption, and intestinal absorption according to the sugar environment. These recent developments are examined here in heath and metabolic disease, highlighting various unanswered questions. glucose transporter 2; Fanconi-Bickel syndrome; pancreas; apical membrane; sugar sensing

Adipocyte differentiation is controlled by many transcription factors, but few known downstream targets of these factors are necessary for adipogenesis. Here we report that retinol saturase (RetSat), which is an enzyme implicated in the generation of dihydroretinoid metabolites, is induced during adipogenesis and is directly regulated by the transcription factor peroxisome proliferator activated receptor [gamma] (PPAR[gamma]). Ablation of RetSat dramatically inhibited adipogenesis but, surprisingly, this block was not overcome by the putative product of RetSat enzymatic activity. On the other hand, ectopic RetSat with an intact, but not a mutated, FAD/NAD dinucleotide-binding motif increased endogenous PPAR[gamma] transcriptional activity and promoted adipogenesis. Indeed, RetSat was not required for adipogenesis when cells were provided with exogenous PPAR[gamma] ligands. In adipose tissue, RetSat is expressed in adipocytes but is unexpectedly downregulated in obesity, most likely owing to infiltration of macrophages that we demonstrate to repress RetSat expression. Thiazolidinedione treatment reversed low RetSat expression in adipose tissue of obese mice. Thus, RetSat plays an important role in the biology of adipocytes, where it favors normal differentiation, yet is reduced in the obese state. RetSat is thus a novel target for therapeutic intervention in metabolic disease. adipocyte | PPAR

Endogenous endothelin action is augmented in human obesity and type 2 diabetes and contributes to endothelial dysfunction and impairs insulin-mediated vasodilation in humans. We hypothesized that insulin resistance-associated hyperinsulinemia could preferentially drive endothelin-mediated vasoconstriction. We applied hyperinsulinemic-euglycemic clamps with higher insulin dosing in obese subjects than lean subjects (30 vs. 10 mU x [m.sup.-2] x [min.sup.-1], respectively), with the goal of matching insulin's nitric oxide (NO)-mediated vascular effects. We predicted that, under these circumstances, insulin-stimulated endothelin-I (ET-1) action (assessed with the type A endothelin receptor antagonist BQ-123) would be augmented in proportion to hyperinsulinemia. NO bioactivity was assessed using the nitric oxide synthase inhibitor [N.sup.G]-monomethyl-L-arginine. Insulin-mediated vasodilation and insulin-stimulated NO bioavailability were well matched across groups by this approach. As expected, steady-state insulin levels were approximately threefold higher in obese than lean subjects (109.2 [+ or -] 10.2 pmol/l vs. 518.4 [+ or -] 84.0, P = 0.03). Despite this, the augmentation of insulin-mediated vasodilation by BQ-123 was not different between groups. ET-1 flux across the leg was not augmented by insulin alone but was increased with the addition of BQ-123 to insulin (P = 0.01 BQ-123 effect, P = not significant comparing groups). Endothelin antagonism augmented insulin-stimulated NO bioavailability and NOx flux, but not differently between groups and not proportional to hyperinsulinemia. These findings do not support the hypothesis that insulin resistance-associated hyperinsulinemia preferentially drives endothelin-mediated vasoconstriction. endothelin-1; insulin; obesity

[alpha]-Aminoadipate [delta]-semialdehyde synthase (AASS) is the bifunctional enzyme containing the lysine [alpha]-ketoglutarate reductase (LKR) and saccharopine dehydrogenase activities responsible for the first 2 steps in the irreversible catabolism of lysine. A rare disease in humans, familial hyperlysinemia, can be caused by very low LKR activity and, as expected, reduces the lysine 'requirement' of the individual. This concept was applied to a murine hepatic cell line (ATCC, FL83B) utilizing RNA interference (RNAi) to achieve AASS mRNA knockdown. Cells were antibiotic selected for stable transfection of 2 plasmids that express different short hairpin RNA sequences for AASS knockdown. Compared with the wild-type cell line, AASS mRNA abundance was reduced 79.0 [+ or -] 6.4% (P < 0.05), resulting in a 29.8 [+ or -] 5.2% (P < 0.05) reduction in AASS protein abundance, 41.3 [+ or -] 10.0% (P< 0.05) less LKR activity, and a reduction in lysine oxidation by 50.7 [+ or -] 11.8%. To determine the effect of AASS knockdown on the lysine requirement, cells were grown in media containing 12.5, 25.0, 50.0, 100, or 200 [micro]mol/L lysine. Using a segmented model approach for growth rate analysis, the lysine requirement of the cell line with AASS silencing was 43.4 [+ or -] 1.7 [micro]mol/L, ~26% lower (P< 0.05), than the lysine requirement of the wild-type cell line. These results indicate AASS knockdown decreases the lysine requirement of the cell via a reduction of lysine catabolism through the saccharopine pathway, providing the initial proof in principle that RNAi can be used to reduce the nutrient requirement of a system.

Prolonged activation of p70 S6 kinase (S6K) by insulin and nutrients leads to inhibition of insulin signaling via negative feedback input to the signaling factor IRS-1. Systemic deletion of S6K protects against diet-induced obesity and enhances insulin sensitivity in mice. Herein, we present evidence suggesting that hypothalamic S6K activation is involved in the pathogenesis of diet-induced hepatic insulin resistance. Extending previous findings that insulin suppresses hepatic glucose production (HGP) partly via its effect in the hypothalamus, we report that this effect was blunted by short-term high-fat diet (HFD) feeding, with concomitant suppression of insulin signaling and activation of S6K in the mediobasal hypothalamus (MBH). Constitutive activation of S6K in the MBH mimicked the effect of the HFD in normal chow--fed animals, while suppression of S6K by overexpression of dominant-negative S6K or dominant-negative raptor in the MBH restored the ability of MBH insulin to suppress HGP after HFD feeding. These results suggest that activation of hypothalamic S6K contributes to hepatic insulin resistance in response to short-term nutrient excess., Introduction Insulin resistance plays an important role in the pathogenesis of type 2 diabetes. It is well established that excess nutrient intake and chronic hyperinsulinemia cause insulin resistance. The mammalian [...]

Congenital hyperinsulinism is a condition of dysregulated insulin secretion often caused by inactivating mutations of the ATP-sensitive [K.sup.+] ([K.sub.ATP]) channel in the pancreatic [beta] cell. Though most disease-causing mutations of the 2 genes encoding [K.sub.ATP] subunits, ABCC8 (SUR1) and KCNJ11 (Kir6.2), are recessively inherited, some cases of dominantly inherited inactivating mutations have been reported. To better understand the differences between dominantly and recessively inherited inactivating [K.sub.ATP] mutations, we have identified and characterized 16 families with 14 different dominantly inherited [K.sub.ATP] mutations, including a total of 33 affected individuals. The 16 probands presented with hypoglycemia at ages from birth to 3.3 years, and 15 of 16 were well controlled on diazoxide, a [K.sub.ATP] channel agonist. Of 29 adults with mutations, 14 were asymptomatic. In contrast to a previous report of increased diabetes risk in dominant [K.sub.ATP] hyperinsulinism, only 4 of 29 adults had diabetes. Unlike recessive mutations, dominantly inherited [K.sub.ATP] mutant subunits trafficked normally to the plasma membrane when expressed in COSm6 cells. Dominant mutations also resulted in different channel-gating defects, as dominant ABCC8 mutations diminished channel responses to magnesium adenosine diphosphate or diazoxide, while dominant KCNJ11 mutations impaired channel opening, even in the absence of nucleotides. These data highlight distinctive features of dominant [K.sub.ATP] hyperinsulinism relative to the more common and more severe recessive form, including retention of normal subunit trafficking, impaired channel activity, and a milder hypoglycemia phenotype that may escape detection in infancy and is often responsive to diazoxide medical therapy, without the need for surgical pancreatectomy., Introduction Congenital hyperinsulinism comprises a group of genetic disorders of insulin secretion that cause persistent hypoglycemia in children (1). The most common and severe of these genetic defects is associated [...]

A study report on a patient with mitochondrial isolated complex I deficiency, the most frequently encounter OXPHOs defect expressed in skin fibroblasts and muscle tissue is presented. Results showed that the expression and activity of complex 1 and the mitochondrial depolarization could be partially reduced with a baculovirus system expressing the NDUFA2 gene on chromosome 5.

Little is known about the association of endothelial nitric oxide synthase (NOS3) gene polymorphisms and the presence of insulin resistance and the early evolution of atherosclerosis in nondiabetic subjects with cardiovascular disease (CAD) and stent implantation. The present study was performed in an attempt to better understand whether metabolic, endothelial, and angiographic findings characteristic of subjects with cardiovascular disease and in-stent restenosis are related to NOS3 variants. This is a case-control study performed from 2002 to 2006. All subjects admitted to the study were recruited in the Nord-Centre of Italy, most from Milan and its surrounding towns. Measures of glucose tolerance, insulin sensitivity, markers of endothelial dysfunction, forearm vasodilation, and adipokine levels were determined and associated to the frequency of two single-nucleotide polymorphisms of NOS3, i.e., [Glu.sup.298]Asp (rs1799983, G/T) and rs753482 (intron 18 A/C). A total of 747 subjects, not known to have diabetes, were evaluated: 333 subjects had asymptomatic CAD, 106 subjects had unstable angina and were evaluated for in-stent restenosis 6 mo after stent placement, and 308 were control subjects. The presence of TT and CC minor alleles was significantly greater in case groups compared with control subjects. At phenotypic level, subjects with the polymorphisms were characterized by hyperinsulinemia and reduced reactive hyperemia, whereas increased leptin and decreased adiponectin levels were present in subjects with restenosis in the presence of reduced minimal lumen diameter and length of stenosis almost doubled. Hyperinsulinemia, endothelial dysfunction, and a more atherogenic profile seem to be peculiar features of subjects with asymptomatic CAD and restenosis carrying NOS3 gene variants. NOS3 gene variants; coronary artery disease; type 2 diabetes

Partial leptin deficiency is not uncommon in the general population. We hypothesized that leptin insufficiency could favor obesity, nonalcoholic steatohepatitis (NASH), and other metabolic abnormalities, particularly under high calorie intake. Thus, mice partially deficient in leptin (ob/+) and their wild-type (+/+) littermates were fed for 4 mo with a standardcalorie (SC) or a high-calorie (HC) diet. Some ob/+ mice fed the HC diet were also treated weekly with leptin. Our results showed that, when fed the SC diet, ob/+ mice did not present significant metabolic abnormalities except for elevated levels of plasma adiponectin. Under high-fat feeding, increased body fat mass, hepatic steatosis, higher plasma total cholesterol, and glucose intolerance were observed in +/+ mice, and these abnormalities were further enhanced in ob/+ mice. Furthermore, some metabolic disturbances, such as blunted plasma levels of leptin and adiponectin, reduced UCP1 expression in brown adipose tissue, increased plasma liver enzymes, [beta]-hydroxybutyrate and triglycerides, and slight insulin resistance, were observed only in ob/+ mice fed the HC diet. Whereas de novo fatty acid synthesis in liver was decreased in +/+ mice fed the HC diet, it was disinhibited in ob/+ mice along with the restoration of the expression of several lipogenic genes. Enhanced expression of several genes involved in fatty acid oxidation was also observed only in ob/+ animals. Leptin supplementation alleviated most of the metabolic abnormalities observed in ob/+ fed the HC diet. Hence, leptin insufficiency could increase the risk of obesity, NASH, glucose intolerance, and hyperlipidemia in a context of calorie overconsumption. fatty liver: nonalcoholic steatohepatitis; mitochondria; hyperlipidemia; adiponectin

Keywords: type 2 diabetes; insulin secretion; compound library screen; siRNA 128 Identification of Glucose-Dependant Insulin Secretion Targets in Pancreatic b Cells by Combining Defined-Mechanism Compound Library Screening and siRNA Gene [...]

The metabolic syndrome (MetS) often accompanies obesity and contributes to the increased risk of atherothrombotic events with increased body fatness. Indeed, the risks for coronary artery disease and acute vascular events are greater with obesity combined with MetS compared with obesity alone. Endothelial release of tissue-type plasminogen activator (t-PA) is a key defense mechanism against thrombosis and has been shown to be impaired with obesity. The aim of the present study was to determine whether the presence of MetS exacerbates endothelial fibrinolytic dysfunction in obese adults. Net endothelial release of t-PA was determined in vivo in response to intrabrachial infusions of bradykinin and sodium nitroprusside in 47 sedentary adults: 15 normal weight (age 57 [+ or -] 2 yr; body mass index 22.9 [+ or -] 0.5 kg/[m.sup.2]), 14 obese but otherwise healthy (55 [+ or -] 1 yr; 29.4 [+ or -] 0.3 kg/[m.sup.2]), and 18 obese with MetS (55 [+ or -] 2 yr; 32.3 [+ or -] 1 kg/[m.sup.2]). MetS was established according to National Cholesterol Education Program ATP III criteria. Net release of t-PA antigen to bradykinin was ~50% lower (P < 0.01) in the obese (from 2.5 [+ or -] 1.9 to 37.1 [+ or -] 5.3 ng x 100 ml [tissue.sup.-1] x [min.sup.-1]) and obese with MetS (from 0.4 [+ or -] 0.8 to 32.5 [+ or -] 3.8 ng x 100 ml [tissue.sup.-l] x [min.sup.-1]) compared with normal-weight (from 0.9 [+ or -] 1.0 to 74.3 [+ or -]- 8.1 ng x 100 ml [tissue.sup.-1] x [min.sup.-1]) subjects. However, there were no significant differences in the capacity of the endothelium to release t-PA in the obese and obese with MetS adults. These results indicate that the presence of the MetS does not worsen the obesity-related endothelial fibrinolytic dysfunction. endothelium; fibrinolysis

Byline: Prashant. Jauhari, Naveen. Sankhyan, Sameer. Vyas, Pratibha. Singhi Pyruvate dehydrogenase complex (PDHC) deficiency is a rare metabolic disorder that affects tissues with high energy demand such as the central [...]

Maternal nutrient restriction results in intrauterine growth restriction (IUGR) newborns that develop obesity despite normal postweaning diet. The epidemic of metabolic syndrome is attributed to programmed 'thrifty phenotype' and exposure to Western diets. We hypothesized that programmed IUGR newborns would demonstrate greater susceptibility to obesity and metabolic abnormalities in response to high-fat diet. From day 10 to term gestation and lactation, control pregnant rats received ad libitum (AdLib) food, whereas study rats were 50% food restricted (FR). Cross-fostering techniques resulted in three offspring groups: control (AdLib/AdLib), FR during pregnancy (FR/AdLib), and FR during lactation (AdLib/FR). At 3 weeks, offspring were weaned to laboratory chow or high-fat calorie diet (9% vs. 17% calorie as fat). Body composition, appetite hormones, and glucose and lipid profiles were determined in 9-mo-old male and female offspring. High-fat diet had no effect on body weight of AdLib/AdLib, but significantly increased weights of FR/AdLib and AdLib/FR offspring. High-fat diet significantly increased body fat, reduced lean body mass, and accentuated plasma leptin but not ghrelin levels in both sexes in all groups. In males, high-fat diet caused a significant increase in glucose levels in all three groups with increased insulin levels in AdLib/AdLib and AdLib/FR, but not in FR/AdLib. In females, high-fat diet had no effect on glucose but significantly increased basal insulin among all three groups. High-fat diet caused hypertriglyceridemia in all three groups although only food-restricted females exhibited hypercholesterolemia. Sex and offspring phenotype-associated effects of high-fat diet indicate differing pathophysiologic mechanisms that require specific therapeutic approaches. catch-up growth; obesity; appetite hormones; impaired glucose tolerance; lipid

Acute physiological hyperinsulinemia increases skeletal muscle capillary blood volume (CBV), presumably to augment glucose and insulin delivery. We hypothesized that insulin-mediated changes in CBV are impaired in type 2 diabetes mellitus (DM) and are improved by angiotensin-converting enzyme inhibition (ACE-I). Zucker obese diabetic rats (ZDF, n = 18) and control rats (n = 9) were studied at 20 wk of age. One-half of the ZDF rats were treated with quinapril (ZDF-Q) for 15 wk prior to study. CBV and capillary flow in hindlimb skeletal muscle were measured by contrast-enhanced ultrasound (CEU) at baseline and at 30 and 120 min after initiation of a euglycemic hyperinsulinemic clamp (3 mU x [min.sup.-1] x [kg.sup.-1]). At baseline, ZDF and ZDF-Q rats were hyperglycemic and hyperinsulinemic vs. controls. Glucose utilization in ZDF rats was 60-70% lower (P < 0.05) than in controls after 30 and 120 rain of hyperinsulinemia. In ZDF-Q rats, glucose utilization was impaired at 30 min but similar to controls at 120 rain. Basal CBV was lower in ZDF and ZDF-Q rats compared with controls (13 [+ or -] 4, 7 [+ or -] 3, and 9 [+ or -] 2 U, respectively). With hyperinsulinemia, CBV increased by about twofold in control animals at 30 and 120 min, did not change in ZDF animals, and increased in ZDF-Q animals only at 120 rain to a level similar to controls. Anatomic capillary density on immunohistology was not different between groups. We conclude that insulin-mediated capillary recruitment in skeletal muscle, which participates in glucose utilization, is impaired in animals with DM and can be partially reversed by 1 chronic ACE-I therapy. contrast ultrasound; microbubbles; blood flow; blood volume

Under resting conditions, the failing heart shifts fuel use toward greater glucose and lower free fatty acid (FFA) oxidation. We hypothesized that chronic metabolic abnormalities in patients with dilated cardiomyopathy (DCM) are associated with the absence of the normal increase in myocardial glucose uptake and maintenance of cardiac mechanical efficiency in response to pacing stress. In 10 DCM patients and 6 control subjects, we measured coronary flow by intravascular ultrasonometry and sampled arterial and coronary sinus blood. Myocardial metabolism was determined at baseline, during atrial pacing at 130 beats/min, and at 15 min of recovery by infusion of [[sup.3]H]oleate and [[sup.13]C]lactate and measurement of transmyocardial arteriovenous differences of oxygen and metabolites. At baseline, DCM patients showed depressed coronary flow, reduced uptake and oxidation of FFA, and preferential utilization of carbohydrates. During pacing, glucose uptake increased by 106% in control subjects but did not change from baseline in DCM patients. Lactate release increased by 122% in DCM patients but not in control subjects. Cardiac mechanical efficiency in DCM patients was not different compared with control subjects at baseline but was 34% lower during stress. Fatty acid uptake and oxidation did not change with pacing in either group. Our results show that in DCM there is preferential utilization of carbohydrates, which is associated with reduced flow and oxygen consumption at rest and an impaired ability to increase glucose uptake during stress. These metabolic abnormalities might contribute to progressive cardiac deterioration and represent a target for therapeutic strategies aimed at modulating cardiac substrate utilization. microcirculation

The spf-ash mutation in mice results in reduced hepatic and intestinal ornithine transcarbamylase. However, a reduction in enzyme activity only translates in reduced ureagenesis and hyperammonemia when an unbalanced nitrogen load is imposed. Six-week-old wild-type control and spf-ash mutant male mice from different genetic backgrounds (B6 and ICR) were infused intravenously with [[sup.13][C.sup.18]O]urea, L-[[sup.15][N.sub.2]]arginine, L-[5,5 [D.sub.2]]ornithine, L-[6-[sup.13]C, 4,4,5,5, [D.sub.4]]citrulline, and L-[ring-[D.sub.5]]phenylalanine to investigate the interaction between genetic background and spf-ash mutation on ureagenesis, arginine metabolism, and nitric oxide production. [ICR.sup.spf-ash] mice maintained ureagenesis (5.5 [+ or -] 0.3 mmol x [kg.sup.-1] x [h.sup.-1]) and developed mild hyperammonemia (145 [+ or -] 19 [micro]mol/1) when an unbalanced nitrogen load was imposed; however, [B6.sup.spf-ash] mice became hyperammonemic (671 [+ or -] 15 [micro]mol/l) due to compromised ureagenesis (3.4 [+ or -] 0.1 mmol x [kg.sup.-1] x [h.sup.-1]). Ornithine supplementation restored ureagenesis and mitigated hyperammonemia. A reduction in citrulline entry rate was observed due to the mutation in both genetic backgrounds (wild-type: 128, spf-ash: 60; SE 4.0 [micro]mol x [kg.sup.-1] x [h.sup.-1]). Arginine entry rate was only reduced in [B6.sup.spf-ash] mice ([B6.sup.spf-ash]: 332, [ICR.sup.spf-ash]: 453; SE 20.6 [micro]mol x [kg.sup.-1] x [h.sup.-1]). Genetic background and mutation had an effect on nitric oxide production (B6: 3.4, [B6.sup.spf-ash]: 2.8, ICR: 9.0, [ICR.sup.spf-ash]: 4.6, SE 0.7 [micro]mol x [kg.sup.-1] x [h.sup.-1]). Protein breakdown was the main source of arginine during the postabsorptive state and was higher in [ICR.sup.spf-ash] than in B6spf'ash mice (phenylalanine entry rate 479 and 327, respectively; SE 18 [micro]mol x [kg.sup.-1] x [h.sup.-1]). Our results highlight the importance of the interaction between mutation and genetic background on ureagenesis, arginine metabolism, and nitric oxide production. These observations help explain the wide phenotypic variation of ornithine transcarbamylase deficiency in the human population. arginine; nitric oxide; urea cycle

Plasma adiponectin level is significantly reduced in patients with metabolic syndrome, and vascular dysfunction is an important pathological event in these patients. However, whether adiponectin may protect endothelial cells and attenuate endothelial dysfunction caused by metabolic disorders remains largely unknown. Adult rats were fed with a regular or a high-fat diet for 14 wk. The aorta was isolated, and vascular segments were incubated with vehicle or the globular domain of adiponectin (gAd; 2 [micro]g/ml) for 4 h. The effect of gAd on endothelial function, nitric oxide (NO) and superoxide production, nitrotyrosine formation, gp[91.sup.phox] expression, and endothelial nitric oxide synthase (eNOS)/inducible NOS (iNOS) activity/expression was determined. Severe endothelial dysfunction (maximal vasorelaxation in response to ACh: 70.3 [+ or -] 3.3 vs. 95.2 [+ or -] 2.5% in control, P < 0.01) was observed in hyperlipidemic aortic segments, and treatment with gAd significantly improved endothelial function (P < 0.01). Paradoxically, total NO production was significantly increased in hyperlipidemic vessels, and treatment with gAd slightly reduced, rather than increased, total NO production in these vessels. Treatment with gAd reduced (-78%, P < 0.01) superoxide production and peroxynitrite formation in hyperlipidemic vascular segments. Moreover, a moderate attenuation (-30%, P < 0.05) in gp[91.sup.phox] and iNOS overexpression in hyperlipidemic vessels was observed after gAd incubation. Treatment with gAd had no effect on eNOS expression but significantly increased eNOS phosphorylation (P < 0.01). Most noticeably, treatment with gAd significantly enhanced eNOS (+ 83%) but reduced iNOS (-70%, P < 0.01) activity in hyperlipidemic vessels. Collectively, these results demonstrated that adiponectin protects the endothelium against hyperlipidemic injury by multiple mechanisms, including promoting eNOS activity, inhibiting iNOS activity, preserving bioactive NO, and attenuating oxidative/nitrative stress. metabolic syndrome; endothelial dysfunction; cytokine; nitric oxide; endothelial nitric oxide synthase; inducible nitric oxide synthase

A fatty liver is associated with fasting hyperinsulinemia, which could reflect either impaired insulin clearance or hepatic insulin action. We determined the effect of liver fat on insulin clearance and hepatic insulin sensitivity in 80 nondiabetic subjects [age 43 [+ or -] 1 yr, body mass index (BMI) 26.3 [+ or -] 0.5 kg/[m.sup.2]]. Insulin clearance and hepatic insulin resistance were measured by the euglycemic hyperinsulinemic (insulin infusion rate 0.3 mU x [kg.sup.-1] x [min.sup.-1] for 240 min) clamp technique combined with the infusion of [[3-.sup.3]H]glucose and liver fat by proton magnetic resonance spectroscopy. During hyperinsulinemia, both serum insulin concentrations and increments above basal remained ~40% higher (P < 0.0001) in the high (15.0 [+ or -] 1.5%) compared with the low (1.8 [+ or -] 0.2%) liver fat group, independent of age, sex, and BMI. Insulin clearance (ml x kg fat free [mass.sup.-1] x [min.sup.-1]) was inversely related to liver fat content (r = -0.52, P < 0.0001), independent of age, sex, and BMI (r = -0.37, P = 0.001). The variation in insulin clearance due to that in liver fat (range 0-41%) explained on the average 27% of the variation in fasting serum (fS)-insulin concentrations. The contribution of impaired insulin clearance to fS-insulin concentrations increased as a function of liver fat. This implies that indirect indexes of insulin sensitivity, such as homeostatic model assessment, overestimate insulin resistance in subjects with high liver fat content. Liver fat content correlated significantly with fS-insulin concentrations adjusted for insulin clearance (r = 0.43, P < 0.0001) and with directly measured hepatic insulin sensitivity (r = -0.40, P = 0.0002). We conclude that increased liver fat is associated with both impaired insulin clearance and hepatic insulin resistance. Hepatic insulin sensitivity associates with liver fat content, independent of insulin clearance. hepatic insulin resistance; homeostasis model assessment; fasting serum insulin

Although insulin resistance has been traditionally associated with type 2 diabetes, recent evidence in humans and animal models indicates that insulin resistance may also develop in type 1 diabetes. A point mutation of insulin 2 gene in [Ins2.sup.Akita] mice leads to pancreatic [beta]-cell apoptosis and hyperglycemia, and these mice are commonly used to investigate type 1 diabetes and complications. Since insulin resistance plays an important role in diabetic complications, we performed hyperinsulinemic-euglycemic clamps in awake Ins2Aldta and wild-type mice to measure insulin action and glucose metabolism in vivo. Nonobese [Ins2.sup.Akita] mice developed insulin resistance, as indicated by an ~80% reduction in glucose infusion rate during clamps. Insulin resistance was due to ~50% decreases in glucose uptake in skeletal muscle and brown adipose tissue as well as hepatic insulin action. Skeletal muscle insulin resistance was associated with a 40% reduction in total GLUT4 and a threefold increase in PKC[epsilon] levels in [Ins2.sup.Akita] mice. Chronic phloridzin treatment lowered systemic glucose levels and normalized muscle insulin action, GLUT4 and PKC[epsilon] levels in [Ins2.sup.Akita] mice, indicating that hyperglycemia plays a role in insulin resistance. Echocardiography showed significant cardiac remodeling with ventricular hypertrophy that was ameliorated following chronic phloridzin treatment in [Ins2.sup.Akita] mice. Overall, we report for the first time that nonobese, insulin-deficient [Ins2.sup.Akita] mice develop type 2 diabetes phenotypes including peripheral and hepatic insulin resistance and cardiac remodeling. Our findings provide important insights into the pathogenesis of metabolic abnormalities and complications affecting type 1 diabetes and lean type 2 diabetes subjects. type 1 diabetes; mouse model; hyperglycemia; ventricular hypertrophy

Obesity and cigarette smoking are both important risk factors for insulin resistance, cardiovascular disease, and cancer. Smoking reduces appetite, which makes many people reluctant to quit. Few studies have documented the metabolic impact of combined smoke exposure (se) and high-fat-diet (HFD). Neuropeptide Y (NPY) is a powerful hypothalamic feeding stimulator that promotes obesity. We investigated how chronic se affects caloric intake, adiposity, plasma hormones, inflammatory mediators, and hypothalamic NPY peptide in animals fed a palatable HFD. Balb/c mice (5 wk old, male) were exposed to smoke (2 cigarettes, twice/day, 6 days/wk, for 7 wk) with or without HFD. Sham-exposed mice were handled similarly without se. Plasma leptin, hypothalamic NPY, and adipose triglyceride lipase (ATGL) mRNA were measured. HFD induced a 2.3-fold increase in caloric intake, increased adiposity, and glucose in both sham and se cohorts. Smoke exposure decreased caloric intake by 23%, with reduced body weight in both dietary groups. Fat mass and glucose were reduced only by se in the cho-fed animals. ATGL mRNA was reduced by HFD in se animals. Total hypothalamic NPY was reduced by HFD, but only in sham-exposed animals; se increased arcuate NPY. We conclude that although se ameliorated hyperphagia and reversed the weight gain associated with HFD, it failed to reverse fat accumulation and hyperglycemia. The reduced ATGL mRNA expression induced by combined HFD and se may contribute to fat retention. Our data support a powerful health message that smoking in the presence of an unhealthy Western diet increases metabolic disorders and fat accumulation. adipose triglyceride lipase; appetite; leptin; neuropeptide Y; tumor necrosis factor-[alpha]

CONTEXT: Manganese is a trace element, essential for physiologic functioning but neurotoxic at high doses. Common exposure sources include dietary intake as well as drinking water in some regions; toxicity is most often associated with inhalation exposures in occupational settings. In this article we describe the investigation of a pediatric case of manganism using both clinical and environmental assessment methods. CASE PRESENTATION: A previously healthy 6-year-old child presented with severe Mn neurotoxicity, iron deficiency, and elevated cobalt levels. Immediate and selected extended family members had elevated plasma Mn but remained asymptomatic. An exposure assessment identified seasonal ingestion exposures to Mn at the family&apos;s summer cottage; these were common to the four immediate family members. Well water used for drinking and cooking exceeded recommended guidelines, and foods high in Mn predominated in their diet. No inhalation exposures were identified. Only pica was unique to the patient. DISCUSSION: The combined evidence of the environmental assessment and biomonitoring of blood Mn levels supported a seasonal ingestion exposure source; this alone was insufficient to explain the toxicity because the patient&apos;s 7-year-old sibling was asymptomatic with almost identical exposures (except pica). A metabolic disorder involving divalent metals (Mn, Fe, and Co) interacting with environmental exposures is the most likely explanation. RELEVANCE TO CLINICAL OR PROFESSIONAL PRACTICE: This case report adds to the emerging body of evidence linking neurologic effects to ingestion Mn exposure. KEY WORDS: environmental medicine, manganese, manganese poisoning, toxicity, water. Environ Health Perspect 115:1776-1779 (2007). doi:10.1289/ehp.10421 available via http://dx.doi.org/[Online 23August 2007], Manganese is ubiquitous in the environment. It is essential for physiologic functioning in trace quantities, usually supplied by dietary intake. Adverse health effects are typically associated with inhalation exposures within [...]

Better understanding of the fundamental mechanisms behind metabolic diseases requires methods to monitor lipid stores on single-cell level in vivo. We have used Caenorhabditis elegans as a model organism to demonstrate the limitations of fluorescence microscopy for imaging of lipids compared with coherent anti-Stokes Raman scattering (CARS) microscopy, the latter allowing chemically specific and label-free imaging in living organisms. CARS microscopy was used to quantitatively monitor the impact of genetic variations in metabolic pathways on lipid storage in 60 specimens of C. elegans. We found that the feeding-defective mutant pha-3 contained a lipid volume fraction one-third of that found in control worms. In contrast, mutants (daf-2, daf-4 dauer) with deficiencies in the insulin and transforming growth factors (IGF and TGF-[beta]) signaling pathways had lipid volume fractions that were 1.4 and 2 times larger than controls, respectively. This was observed as an accumulation of small-sized lipid droplets in the hypodermal cells, hosting as much as 40% of the total lipid volume in contrast to the 9% for the wild-type larvae. Spectral CARS microscopy measurements indicated that this is accompanied by a shift in the ordering of the lipids from gel to liquid phase. We conclude that the degree of hypodermal lipid storage and the lipid phase can be used as a marker of lipid metabolism shift. This study shows that CARS microscopy has the potential to become a sensitive and important tool for studies of lipid storage mechanisms, improving our understanding of phenomena underlying metabolic disorders. lipid metabolism | nonlinear microscopy | obesity