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PPARγ is the functioning receptor for the thiazolidinedione (TZD) class of antidiabetes drugs including rosiglitazone and pioglitazone. These drugs are full classical agonists for this nuclear receptor, but recent data have shown that many PPARγ-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPARγ by Cdk5. Here we describe novel synthetic compounds that have a unique mode of binding to PPARγ, completely lack classical transcriptional agonism and block the Cdk5-mediated phosphorylation in cultured adipocytes and in insulin-resistant mice. Moreover, one such compound, SR1664, has potent antidiabetic activity while not causing the fluid retention and weight gain that are serious side effects of many of the PPARγ drugs. Unlike TZDs, SR1664 also does not interfere with bone formation in culture. These data illustrate that new classes of antidiabetes drugs can be developed by specifically targeting the Cdk5-mediated phosphorylation of PPARγ.

Purpose of review Extensive systemic illness and treatment with immunosuppressive agents often require patients with rheumatic diseases to be monitored or managed in the pediatric intensive care unit. Additionally, severe disease-specific manifestations of childhood rheumatic disorders present pediatric rheumatologists and critical care physicians with diagnostic and treatment challenges. Although mortality from rheumatic disease in children is rare, the most severe diseases, such as pediatric systemic lupus erythematosus and juvenile dermatomyositis, remain life-threatening. Recent findings Advances in therapy have reduced the incidence of severe complications of autoimmune and inflammatory diseases and have expanded treatment options. However, patients with active underlying rheumatic disease and secondary infection who are being treated with immunosuppressive agents are most at risk for poor outcomes. Summary Here we discuss the complications of childhood rheumatic conditions that necessitate critical intervention. We discuss how improved understanding of the cellular and molecular basis of disease pathogenesis holds the promise of more targeted therapy without the adverse effects of global immunosuppression.

Lysophosphatidic acid (LPA) is an agonist for peroxisome proliferator activated receptor-γ (PPARγ). Although glycerol-3-phosphate acyltransferase-1 (GPAT1) esterifies glycerol-3-phosphate to form LPA, an intermediate in the de novo synthesis of glycerolipids, it has been assumed that LPA synthesized by this route does not have a signaling role. The availability of Chinese Hamster Ovary (CHO) cells that stably overexpress GPAT1, allowed us to analyze PPARγ activation in the presence of LPA produced as an intracellular intermediate. LPA levels in CHO-GPAT1 cells were 6-fold higher than in wild-type CHO cells, and the mRNA abundance of CD36, a PPARγ target, was 2-fold higher. Transactivation assays showed that PPARγ activity was higher in the cells that overexpressed GPAT1. PPARγ activity was enhanced further in CHO-GPAT1 cells treated with the PPARγ ligand troglitazone. Extracellular LPA, phosphatidic acid (PA) or a membrane-permeable diacylglycerol had no effect, showing that PPARγ had been activated by LPA generated intracellularly. Transient transfection of a vector expressing 1-acylglycerol-3-phosphate acyltransferase-2, which converts endogenous LPA to PA, markedly reduced PPARγ activity, as did over-expressing diacylglycerol kinase, which converts DAG to PA, indicating that PA could be a potent inhibitor of PPARγ. These data suggest that LPA synthesized via the glycerol-3-phosphate pathway can activate PPARγ and that intermediates of de novo glycerolipid synthesis regulate gene expression.

Mice overexpressing acylCoA:diacylglycerol (DAG) acyltransferase 2 in the liver (Liv- DGAT2 ) have been shown to have normal hepatic insulin responsiveness despite severe hepatic steatosis and increased hepatic triglyceride, diacylglycerol, and ceramide content, demonstrating a dissociation between hepatic steatosis and hepatic insulin resistance. This led us to reevaluate the role of DAG in causing hepatic insulin resistance in this mouse model of severe hepatic steatosis. Using hyperinsulinemic-euglycemic clamps, we studied insulin action in Liv- DGAT2 mice and their wild-type (WT) littermate controls. Here, we show that Liv- DGAT2 mice manifest severe hepatic insulin resistance as reflected by decreased suppression of endogenous glucose production (0.8 ± 41.8 vs. 87.7 ± 34.3% in WT mice, P < 0.01) during the clamps. Hepatic insulin resistance could be attributed to an almost 12-fold increase in hepatic DAG content ( P < 0.01) resulting in a 3.6-fold increase in protein kinase Cε (PKCε) activation ( P < 0.01) and a subsequent 52% decrease in insulin-stimulated insulin receptor substrate 2 (IRS-2) tyrosine phosphorylation ( P < 0.05), as well as a 64% decrease in fold increase pAkt/Akt ratio from basal conditions ( P < 0.01). In contrast, hepatic insulin resistance in these mice was not associated with increased endoplasmic reticulum (ER) stress or inflammation. Importantly, hepatic insulin resistance in Liv- DGAT2 mice was independent of differences in body composition, energy expenditure, or food intake. In conclusion, these findings strengthen the link between hepatic steatosis and hepatic insulin resistance and support the hypothesis that DAG-induced PKCε activation plays a major role in nonalcoholic fatty liver disease (NAFLD)-associated hepatic insulin resistance.

OBJECTIVE Obesity-associated low-grade systemic inflammation resulting from increased adipose mass is strongly related to the development of insulin resistance and type 2 diabetes as well as other metabolic complications. Recent studies have demonstrated that the obese metabolic state can be improved by ablating certain inflammatory signaling pathways. Tumor progression locus 2 (TPL2), a kinase that integrates signals from Toll receptors, cytokine receptors, and inhibitor of κ-B kinase-β is an important regulator of inflammatory pathways. We used TPL2 knockout (KO) mice to investigate the role of TPL2 in mediating obesity-associated inflammation and insulin resistance. RESEARCH DESIGN AND METHODS Male TPL2KO and wild-type (WT) littermates were fed a low-fat diet or a high-fat diet to investigate the effect of TPL2 deletion on obesity, inflammation, and insulin sensitivity. RESULTS We demonstrate that TPL2 deletion does not alter body weight gain or adipose depot weight. However, hyperinsulinemic euglycemic clamp studies revealed improved insulin sensitivity with enhanced glucose uptake in skeletal muscle and increased suppression of hepatic glucose output in obese TPL2KO mice compared with obese WT mice. Consistent with an improved metabolic phenotype, immune cell infiltration and inflammation was attenuated in the adipose tissue of obese TPL2KO mice coincident with reduced hepatic inflammatory gene expression and lipid accumulation. CONCLUSIONS Our results provide the first in vivo demonstration that TPL2 ablation attenuates obesity-associated metabolic dysfunction. These data suggest TPL2 is a novel target for improving the metabolic state associated with obesity.

Long-chain acyl coenzyme A (acyl-CoA) synthetase isoform 1 (ACSL1) catalyzes the synthesis of acyl-CoA from long-chain fatty acids and contributes the majority of cardiac long-chain acyl-CoA synthetase activity. To understand its functional role in the heart, we studied mice lacking ACSL1 globally (Acsl1(T-/-)) and mice lacking ACSL1 in heart ventricles (Acsl1(H-/-)) at different times. Compared to littermate controls, heart ventricular ACSL activity in Acsl1(T-/-) mice was reduced more than 90%, acyl-CoA content was 65% lower, and long-chain acyl-carnitine content was 80 to 90% lower. The rate of [(14)C]palmitate oxidation in both heart homogenate and mitochondria was 90% lower than in the controls, and the maximal rates of [(14)C]pyruvate and [(14)C]glucose oxidation were each 20% higher. The mitochondrial area was 54% greater than in the controls with twice as much mitochondrial DNA, and the mRNA abundance of Pgc1α and Errα increased by 100% and 41%, respectively. Compared to the controls, Acsl1(T-/-) and Acsl1(H-/-) hearts were hypertrophied, and the phosphorylation of S6 kinase, a target of mammalian target of rapamycin (mTOR) kinase, increased 5-fold. Our data suggest that ACSL1 is required to synthesize the acyl-CoAs that are oxidized by the heart, and that without ACSL1, diminished fatty acid (FA) oxidation and compensatory catabolism of glucose and amino acids lead to mTOR activation and cardiac hypertrophy without lipid accumulation or immediate cardiac dysfunction.

Defective melanocortin signaling causes hyperphagic obesity in humans and the melanocortin-4 receptor knockout mouse (MC4R−/−). The human disease most commonly presents, however, as haploinsufficiency of the MC4R. This study validates the MC4R+/− mouse as a model of the human disease in that, like the MC4R−/−, the MC4R+/− mouse also exhibits a sustained hyperphagic response to dietary fat. Furthermore, both saturated and monounsaturated fats elicit this response. N-acylphosphatidylethanolamine (NAPE) is a signaling lipid induced after several hours of high-fat feeding, that, if dysregulated, might explain the feeding behavior in melanocortin obesity syndrome. Remarkably, however, MC4R−/− mice produce elevated levels of NAPE and are fully responsive to the anorexigenic activity of NAPE and oleoylethanolamide. Interestingly, additional differences in N-acylethanolamine (NAE) biochemistry were seen in MC4R−/− animals, including reduced plasma NAE levels and elevated hypothalamic levels of fatty acid amide hydrolase expression. Thus, while reduced expression of NAPE or NAE does not explain the high-fat hyperphagia in the melanocortin obesity syndrome, alterations in this family of signaling lipids are evident. Analysis of the microstructure of feeding behavior in response to dietary fat in the MC4R−/− and MC4R+/− mice indicates that the high-fat hyperphagia involves defective satiation and an increased rate of food intake, suggesting defective satiety signaling and enhanced reward value of dietary fat.

OBJECTIVE Inhibition of the Na+-glucose cotransporter type 2 (SGLT2) is currently being pursued as an insulin-independent treatment for diabetes; however, the behavioral and metabolic consequences of SGLT2 deletion are unknown. Here, we used a SGLT2 knockout mouse to investigate the effect of increased renal glucose excretion on glucose homeostasis, insulin sensitivity, and pancreatic β-cell function. RESEARCH DESIGN AND METHODS SGLT2 knockout mice were fed regular chow or a high-fat diet (HFD) for 4 weeks, or backcrossed onto the db/db background. The analysis used metabolic cages, glucose tolerance tests, euglycemic and hyperglycemic clamps, as well as isolated islet and perifusion studies. RESULTS SGLT2 deletion resulted in a threefold increase in urine output and a 500-fold increase in glucosuria, as well as compensatory increases in feeding, drinking, and activity. SGLT2 knockout mice were protected from HFD-induced hyperglycemia and glucose intolerance and had reduced plasma insulin concentrations compared with controls. On the db/db background, SGLT2 deletion prevented fasting hyperglycemia, and plasma insulin levels were also dramatically improved. Strikingly, prevention of hyperglycemia by SGLT2 knockout in db/db mice preserved pancreatic β-cell function in vivo, which was associated with a 60% increase in β-cell mass and reduced incidence of β-cell death. CONCLUSIONS Prevention of renal glucose reabsorption by SGLT2 deletion reduced HFD- and obesity-associated hyperglycemia, improved glucose intolerance, and increased glucose-stimulated insulin secretion in vivo. Taken together, these data support SGLT2 inhibition as a viable insulin-independent treatment of type 2 diabetes.

Sirtuin-1 (SirT1) is a nutrient-sensing deacetylase whose levels and activity increase with caloric restriction to preserve euglycemia and promote efficient energy utilization. Focusing on data obtained in vivo, we review how SirT1 orchestrates the adaptive response to fasting by stimulating hepatic gluconeogenesis and fatty acid oxidation, increasing circulating adiponectin levels, and limiting immune activation. Finally, we consider its viability as a therapeutic target for the treatment of type 2 diabetes.

Invariant natural killer T cells (iNKTs) are innate-like T cells that are highly concentrated in the liver and recognize lipids presented on the MHC-like molecule CD1d. Although capable of a myriad of responses, few essential functions have been described for iNKTs. Among the many cell types of the immune system implicated in metabolic control and disease, iNKTs seem ideally poised for such a role, yet little has been done to elucidate such a possible function. We hypothesized that lipid presentation by CD1d could report on metabolic status and engage iNKTs to regulate cellular lipid content through their various effector mechanisms. To test this hypothesis, we examined CD1d deficient mice in a variety of metabolically stressed paradigms including high fat feeding, choline-deficient feeding, fasting, and acute inflammation. CD1d deficiency led to a mild exacerbation of steatosis during high fat or choline-deficient feeding, accompanied by impaired hepatic glucose tolerance. Surprisingly, however, this phenotype was not observed in Jα18−/− mice, which are deficient in iNKTs but express CD1d. Thus, CD1d appears to modulate some metabolic functions through an iNKT-independent mechanism.

This longitudinal study of 196 caregiver/care receiver dyads was undertaken to determine the variables predictive of caregiver decision to institutionalize a dependent with dementia. Seven variables (use of services, enjoyment of caregiving, caregiver burden and health, caregiver rating and reaction to care receiver behavior and memory problems, and presence of troublesome behaviors) predicted the decision to institutionalize. Six variables (caregiver health and burden, use of services, care receiver cognitive function and troublesome behaviors, and caregiver reaction to behaviors) predicted actual institutionalization at 18 months.

To determine the temporal sequence of pregnancy-induced changes in insulin action and secretion, awake midpregnant (11-12 days) and late pregnant (19-20 days) rats underwent a two-step euglycemic hyperinsulinemic or a hyperglycemic clamp study after a 24-h fast. During euglycemia, insulin-stimulated increments in glucose uptake and clearance in midpregnant rats were reduced by 60-70% at the lower dose (insulin approximately 360 pM) and by 20-30% at the higher dose (insulin approximately 1,750 pM; P < 0.01 vs. virgin controls). Insulin action was also diminished in late pregnant rats. However, the magnitude of resistance did not increase. Insulin-mediated suppression of glucose production was only minimally impaired in midpregnancy. In contrast, glucose production was virtually unchanged in late pregnancy, even at the highest insulin dose. During hyperglycemia, insulin responses in late pregnancy were markedly increased 5-fold above controls and 2.5-fold above midpregnant rats (P < 0.05). We conclude that rat pregnancy is characterized by the early appearance of peripheral insulin resistance. As pregnancy progresses toward term, marked hepatic insulin resistance and insulin hypersecretion develop, whereas peripheral insulin resistance demonstrates negligible changes. These data imply that insulin hypersecretion during late pregnancy is most closely linked to hepatic insulin resistance, at least in 24-h-fasted animals.

Postprandial storage of carbohydrate as glycogen in muscle was quantitated in normal subjects (n = 8) by natural abundance 13C-nuclear magnetic resonance spectroscopy with proton decoupling in a 4.7-tesla magnet. After an overnight fast three basal measurements of gastrocnemius muscle glycogen were made and a mixed meal was given. Muscle glycogen concentration rose from 83.3 +/- 5.2 to a maximum of 100.2 +/- 6.7 mmol/l muscle at 4.9 h (P < 0.01) and fell thereafter to 90.6 +/- 5.9 mmol/l muscle at 7 h postprandially (P < 0.006). The meal brought about an increase in plasma glucose from 5.4 +/- 0.2 to 7.3 +/- 0.4 mmol/l at 30 min but this was followed by a rapid fall to 6.2 +/- 0.4 mmol/l at 75 min. Plasma insulin rose from 62.4 +/- 11.4 to 900 +/- 216 pmol/l at 30 min and declined steadily thereafter. It was calculated from total muscle mass measurements and estimation of carbohydrate absorption rates that at peak muscle glycogen concentrations between 26 and 35% of the absorbed carbohydrate was stored as muscle glycogen. These data quantitate the role of skeletal muscle glycogen synthesis in postprandial carbohydrate storage and demonstrate that this tissue acts as a dynamic buffer to maintain glucose homeostasis during postprandial substrate storage.

The clock -drawing test was used in a longitudinal study of 183 dementing individuals and their caregivers. Clock-drawing performance was measured by a simple standardized score which correlated significantly with other measures of cognitive function. Clock performance showed high individual consistency of performance as well as a significant deterioration from the initial level of performance to that obtained at 1-year follow-up. Dementing individuals who had experienced a significantly greater decline in clock-drawing performance at 1-year follow-up were more likely to have caregivers who had already decided to institutionalize them. This suggests that the caregiver's decision to institutionalize was based in part on the perception of a rapid decline in their dependant's cognitive function. Thus, rate of change in cognitive function may prove to be as important a variable as the level of deterioration. The clock-drwing test appears to be a useful adjunct in the assessment and monitoring of the progressive dementias in the community.

In the absence of any other exogenously added fuel, monomethylsuccinate, the methyl ester of succinic acid, at 10–20 mM stimulates insulin release in a biphasic pattern. In quantitative terms, first-phase release evoked by 20 mM MMSucc was comparable to that observed with 20 mM glucose but second-phase release was only 20% of the glucose-induced response. Secretion to both MMSucc and glucose was virtually abolished by the calcium channel antagonist nitrendipine (0.5 μM). In islets that had phosphoinositide pools labeled with [3H]inositol for 2 h, subsequent stimulation with 20 mM MMSucc results in dramatic and sustained increases in [3H]inositol efflux rates. Inositol phosphate levels are also increased. In contrast to secretion, the increase in phosphoinositide hydrolysis caused by MMSucc was largely resistant to nitrendipine, whereas significant reductions in glucose-induced phosphoinositide hydrolysis were observed in the presence of the calcium channel antagonist. MMSucc (2.75–10 mM) substitutes for glucose in that MMSucc supported the insulinotropic effects of the sulfonylurea tolbutamide (200 μM) and the gut hormone cholecystokinin (200 nM). A prior 15-min exposure to 20 mM MMSucc also sensitized islets to the stimulatory effects of 7.5 mM glucose. Finally, a 2-h exposure to 20 mM MMSucc desensitized the islet, in terms of both phosphoinositide hydrolysis and insulin secretion, to a subsequent exposure to 10 mM glucose. Thus, appropriate concentrations of MMSucc can cause qualitatively many of the effects induced by glucose. However, striking differences exist in the quantitative effects that are most simply explained by assuming that MMSucc is able to stimulate phosphoinositide hydrolysis to the same extent as glucose but is less able to enhance Ca2+ influx than glucose. If this view is correct, it leads to the conclusion that an intracellular calcium-independent signal derived from the metabolism of MMSucc is able to activate phosphoinositide hydrolysis in islets.

Blood concentrations of gastrin, motilin, insulin, and insulin-like growth factor-I were measured sequentially during the first 3 weeks of life in 22 very-low-birth-weight infants (birth weight 1.03 +/- 0.24 g; gestational age 28.3 +/- 1.9 weeks; mean +/- SD) who were in respiratory distress requiring mechanical ventilation and were receiving either total parenteral or enteral feedings. An increase in the blood concentration of motilin beyond the basal measurement was observed in enterally fed infants but not in infants receiving total parenteral nutrition. Motilin and gastrin concentrations were significantly increased in the enterally fed group compared with infants receiving total parenteral nutrition at 2 and 3 weeks and 1 and 3 weeks, respectively. There were no differences in serum insulin or plasma insulin-like growth factor-I concentrations between groups after the start of the study. The present data suggest that enteral nutrition in very-low-birth-weight infants is associated with a relative increase in peripheral motilin and gastrin concentrations compared with parenterally fed infants.

Mania continues to be a fascinating and important clinical entity. Its distinctive features make it amenable to systematic analysis of the genetic, environmental and biological variables that contribute to this disorder. Data from studies of the elderly may be important in helping to elucidate unanswered questions about affective disorders in younger adults. Geriatric patients offer the opportunity to study a lifetime course retrospectively and to identify familial predispositions because of prolonged exposure in first degree relatives. Finally, the nature and prevalence of heterogeneous neurological disorders, especially cerebrovascular disease, may now be clarified with modem developments in neuroimaging

Experience of the scientific and production enterprise ''Technikon” in creation of new and modernization of operating control systems over technological processes in different industrial branches is described.

To determine whether plasma lactate can be a significant fuel for human brain energy metabolism, infusions of [3-13C]lactate and1H-13C polarization transfer spectroscopy were used to detect the entry and utilization of lactate. During the 2 h infusion study,13C incorporation in the amino acid pools of glutamate and glutamine were measured with a 5 min time resolution. With a plasma concentration ([Lac]P) being in the 0.8–2.8 mmol/L range, the tissue lactate concentration ([Lac]B) was assessed as well as the fractional contribution of lactate to brain energy metabolism (CMRlac). From the measured relationship between unidirectional lactate influx (Vin) and plasma and brain lactate concentrations, lactate transport constants were calculated using a reversible Michaelis–Menten model. The results show that (1) in the physiological range, plasma lactate unidirectional transport (Vin) and concentration in tissue increase close to linearly with the lactate concentration in plasma; (2) the maximum potential contribution of plasma lactate to brain metabolism is 10% under basal plasma lactate conditions of ∼1.0 mmol/L and as much as 60% at supraphysiological plasma lactate concentrations when the transporters are saturated; (3) the half-saturation constantKTis 5.1 ± 2.7 mmol/L andVMAXis 0.40 ± 0.13 μmol · g−1· min−1(68% confidence interval); and (4) the majority of plasma lactate is metabolized in neurons similar to glucose.

Lipids circulate in the blood in association with plasma lipoproteins and enter the tissues either after hydrolysis or as non-hydrolyzable lipid esters. We studied cardiac lipids, lipoprotein lipid uptake, and gene expression in heart-specific lipoprotein lipase (LpL) knock-out (hLpL0), CD36 knock-out (Cd36−/−), and double knock-out (hLpL0/Cd36−/−-DKO) mice. Loss of either LpL or CD36 led to a significant reduction in heart total fatty acyl-CoA (control, 99.5 ± 3.8; hLpL0, 36.2 ± 3.5; Cd36−/−, 57.7 ± 5.5 nmol/g, p < 0.05) and an additive effect was observed in the DKO (20.2 ± 1.4 nmol/g, p < 0.05). Myocardial VLDL-triglyceride (TG) uptake was reduced in the hLpL0 (31 ± 6%) and Cd36−/− (47 ± 4%) mice with an additive reduction in the DKO (64 ± 5%) compared with control. However, LpL but not CD36 deficiency decreased VLDL-cholesteryl ester uptake. Endogenously labeled mouse chylomicrons were produced by tamoxifen treatment of β-actin-MerCreMer/LpLflox/flox mice. Induced loss of LpL increased TG levels >10-fold and reduced HDL by >50%. After injection of these labeled chylomicrons in the different mice, chylomicron TG uptake was reduced by ∼70% and retinyl ester by ∼50% in hLpL0 hearts. Loss of CD36 did not alter either chylomicron TG or retinyl ester uptake. LpL loss did not affect uptake of remnant lipoproteins from ApoE knock-out mice. Our data are consistent with two pathways for fatty acid uptake; a CD36 process for VLDL-derived fatty acid and a non-CD36 process for chylomicron-derived fatty acid uptake. In addition, our data show that lipolysis is involved in uptake of core lipids from TG-rich lipoproteins.

Our purpose was to determine pediatric endocrinologists' knowledge, attitudes, beliefs, and practices (KABPs) regarding recombinant human growth hormone (rhGH) treatment, examine care-related attitude consensus or discordance, and identify evidence-based practice gaps. We developed a survey for National Cooperative Growth Study (NCGS) investigators () to elicit their KABPs regarding GH stimulation testing as a diagnostic tool, IGF-1 monitoring for safety and dosing guidance, and pubertal dosing. Responses were compared with NCGS data from the last 20 years. Comparison between survey responses and NCGS data revealed potential discrepancies between expressed opinions and actual practice. In conclusion, this KABP survey, combined with NCGS data, suggests changes over time in diagnostic and rhGH-related therapeutic practices. Variability and inconsistency exist between the survey responses and practice trends over time as reflected in the NCGS database. Further study is necessary to provide evidence to guide rhGH treatment decisions.

The Mouse Metabolic Phenotyping Center (MMPC) Consortium was established to address the need to characterize the growing number of mouse models of metabolic diseases, particularly diabetes and obesity. A goal of the MMPC Consortium is to propose standard methods for assessing metabolic phenotypes in mice. In this article, we discuss issues pertaining to the design and performance of various tests of glucose metabolism. We also propose guidelines for the description of methods, presentation of data and interpretation of results. The recommendations presented in this article are based on the experience of the MMPC Consortium and other investigators.

Testotoxicosis, a form of gonadotropin-independent precocious puberty, results from an activating mutation of the luteinizing hormone receptor expressed in testicular Leydig cells. Affected males experience early testosterone secretion, virilization, advancing bone age, and resultant short stature. Recently, the use of combination therapy with a potent antiandrogen agent (bicalutamide) and a third-generation aromatase inhibitor (anastrozole or letrozole) was reported to yield encouraging short-term results. We present here the results of longer-term treatment (4.5 and 5 years) with this combination therapy in 2 boys who demonstrated that it is well tolerated, slows bone-age advancement in the face of continued linear growth, and prevents progression of virilization.

The metabolic syndrome is a clustering of cardiovascular risk factors, including insulin resistance, abdominal obesity, dyslipidemia, and hypertension, and is associated with other comorbidities such as a proinflammatory state and nonalcoholic fatty liver disease (NAFLD). Its prevalence is high, especially among developed countries, and mainly reflects overnutrition and sedentary lifestyle. Moreover, the developing countries are not spared, as obesity and its related problems such as the metabolic syndrome are increasing quickly. We review the potential primary role of skeletal muscle insulin resistance in the pathophysiology of the metabolic syndrome, showing that in lean, young, insulin-resistant individuals, impaired muscle glucose transport and glycogen synthesis redirect energy derived from carbohydrate into hepatic de novo lipogenesis, promoting the development of atherogenic dyslipidemia and NAFLD. The demonstration of a link between skeletal muscle insulin resistance and the metabolic syndrome offers opportunities in targeting early defects in muscle insulin action in order to counteract the development of the disease and its related complications.

With rapid ageing of the world's population, psychiatry of old age has become a crucial discipline. This succinct guide to the scope and practice of the psychiatry of old age provides an up-to-date summary of existing knowledge, best practice and future challenges for the specialty, from a global perspective. From definitions and demography to epidemiology, aetiology, and principles of assessment, diagnosis and management, each chapter is sharp, clear and practical, enhanced by tables and diagrams for quick assimilation and reference on the ward or in the clinic. As well as the main psychiatric conditions encountered in old age, coverage also includes legal and ethical issues, and the neglected topic of alcohol and drug abuse in the elderly. Written by leading clinicians, teachers and researchers and offering a much-needed international focus, this compact guide is essential reading for practising psychiatrists and geriatricians, as well as trainees, nurses and medical students.

Although it is well established that physical activity increases mitochondrial content in muscle, the molecular mechanisms underlying this process have only recently been elucidated. Mitochondrial dysfunction is an important component of different diseases associated with aging, such as Type 2 diabetes and Alzheimer’s disease. PGC-1α (peroxisome-proliferator-activated receptor γ co-activator-1α) is a co-transcriptional regulation factor that induces mitochondrial biogenesis by activating different transcription factors, including nuclear respiratory factor 1 and nuclear respiratory factor 2, which activate mitochondrial transcription factor A. The latter drives transcription and replication of mitochondrial DNA. PGC-1α itself is regulated by several different key factors involved in mitochondrial biogenesis, which will be reviewed in this chapter. Of those, AMPK (AMP-activated protein kinase) is of major importance. AMPK acts as an energy sensor of the cell and works as a key regulator of mitochondrial biogenesis. AMPK activity has been shown to decrease with age, which may contribute to decreased mitochondrial biogenesis and function with aging. Given the potentially important role of mitochondrial dysfunction in the pathogenesis of numerous diseases and in the process of aging, understanding the molecular mechanisms regulating mitochondrial biogenesis and function may provide potentially important novel therapeutic targets.

Insulin action is purportedly modulated by Drosophila tribbles homologue 3 (TRIB3), which in vitro prevents thymoma viral proto-oncogene (AKT) and peroxisome proliferator-activated receptor-γ (PPAR-γ) activation. However, the physiological impact of TRIB3 action in vivo remains controversial. We investigated the role of TRIB3 in rats treated with either a control or Trib3 antisense oligonucleotide (ASO). Tissue-specific insulin sensitivity was assessed in vivo using a euglycaemic–hyperinsulinaemic clamp. A separate group was treated with the PPAR-γ antagonist bisphenol-A-diglycidyl ether (BADGE) to assess the role of PPAR-γ in mediating the response to Trib3 ASO. Trib3 ASO treatment specifically reduced Trib3 expression by 70% to 80% in liver and white adipose tissue. Fasting plasma glucose, insulin concentrations and basal rate of endogenous glucose production were unchanged. However, Trib3 ASO increased insulin-stimulated whole-body glucose uptake by ~50% during the euglycaemic–hyperinsulinaemic clamp. This was attributable to improved skeletal muscle glucose uptake. Despite the reduction of Trib3 expression, AKT2 activity was not increased. Trib3 ASO increased white adipose tissue mass by 70% and expression of Ppar-γ and its key target genes, raising the possibility that Trib3 ASO improves insulin sensitivity primarily in a PPAR-γ-dependent manner. Co-treatment with BADGE blunted the expansion of white adipose tissue and abrogated the insulin-sensitising effects of Trib3 ASO. Finally, Trib3 ASO also increased plasma HDL-cholesterol, a change that persisted with BADGE co-treatment. These data suggest that TRIB3 inhibition improves insulin sensitivity in vivo primarily in a PPAR-γ-dependent manner and without any change in AKT2 activity.

Understanding the molecular mechanisms of insulin resistance remains a major medical challenge of the twenty-first century. Over the last half-century, many hypotheses have been proposed to explain insulin resistance, and, most recently, inflammation associated with alterations in adipocytokines has become the prevailing hypothesis. Here we discuss diacylglycerol-mediated insulin resistance as an alternative and unifying hypothesis to explain the most common forms of insulin resistance associated with obesity and type 2 diabetes mellitus, as well as lipodystrophy and aging.

BACKGROUND Nonalcoholic fatty liver disease is associated with hepatic insulin resistance and type 2 diabetes mellitus. Whether this association has a genetic basis is unknown. METHODS In 95 healthy Asian Indian men, a group known to have a high prevalence of nonalcoholic fatty liver disease, we genotyped two single-nucleotide polymorphisms (SNPs) in the gene encoding apolipoprotein C3 (APOC3) that are known to be associated with hypertriglyceridemia (rs2854116 [T-455C] and rs2854117 [C-482T]). Plasma apolipoprotein C3 concentrations, insulin sensitivity, and hepatic triglyceride content were measured. We also measured plasma triglyceride concentrations and retinyl fatty acid ester absorption as well as plasma triglyceride clearance after oral and intravenous fat-tolerance tests. Liver triglyceride content and APOC3 genotypes were also assessed in a group of 163 healthy non-Asian Indian men. RESULTS Carriers of the APOC3 variant alleles (C-482T, T-455C, or both) had a 30% increase in the fasting plasma apolipoprotein C3 concentration, as compared with the wild-type homozygotes. They also had a 60% increase in the fasting plasma triglyceride concentration, an increase by a factor of approximately two in the plasma triglyceride and retinyl fatty acid ester concentrations after an oral fat-tolerance test, and a 46% reduction in plasma triglyceride clearance. The prevalence of nonalcoholic fatty liver disease was 38% among variant-allele carriers and 0% among wild-type homozygotes (P

OBJECTIVE Thioredoxin interacting protein (Txnip), a regulator of cellular oxidative stress, is induced by hyperglycemia and inhibits glucose uptake into fat and muscle, suggesting a role for Txnip in type 2 diabetes pathogenesis. Here, we tested the hypothesis that Txnip-null (knockout) mice are protected from insulin resistance induced by a high-fat diet. RESEARCH DESIGN AND METHODS Txnip gene-deleted (knockout) mice and age-matched wild-type littermate control mice were maintained on a standard chow diet or subjected to 4 weeks of high-fat feeding. Mice were assessed for body composition, fat development, energy balance, and insulin responsiveness. Adipogenesis was measured from ex vivo fat preparations, and in mouse embryonic fibroblasts (MEFs) and 3T3-L1 preadipocytes after forced manipulation of Txnip expression. RESULTS Txnip knockout mice gained significantly more adipose mass than controls due to a primary increase in both calorie consumption and adipogenesis. Despite increased fat mass, Txnip knockout mice were markedly more insulin sensitive than controls, and augmented glucose transport was identified in both adipose and skeletal muscle. RNA interference gene-silenced preadipocytes and Txnip−/− MEFs were markedly adipogenic, whereas Txnip overexpression impaired adipocyte differentiation. As increased adipogenesis and insulin sensitivity suggested aspects of augmented peroxisome proliferator–activated receptor-γ (PPARγ) response, we investigated Txnip's regulation of PPARγ function; manipulation of Txnip expression directly regulated PPARγ expression and activity. CONCLUSIONS Txnip deletion promotes adiposity in the face of high-fat caloric excess; however, loss of this α-arrestin protein simultaneously enhances insulin responsiveness in fat and skeletal muscle, revealing Txnip as a novel mediator of insulin resistance and a regulator of adipogenesis.