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Fatty acid-binding proteins (FABPs) facilitate the diffusion of fatty acids within cellular cytoplasm. Compared with C57Bl/6J mice maintained on a high-fat diet, adipose-FABP (A-FABP) null mice exhibit increased fat mass, decreased lipolysis, increased muscle glucose oxidation, and attenuated insulin resistance, whereas overexpression of epithelial-FABP (E-FABP) in adipose tissue results in decreased fat mass, increased lipolysis, and potentiated insulin resistance. To identify the mechanisms that underlie these processes, real-time PCR analyses indicate that the expression of hormone-sensitive lipase is reduced, while perilipin A is increased in A-FABP/aP2 null mice relative to E-FABP overexpressing mice. In contrast, de novo lipogenesis and expression of genes encoding lipoprotein lipase, CD36, long-chain acyl-CoA synthetase 5, and diacylglycerol acyltransferase are increased in A-FABP/aP2 null mice relative to E-FABP transgenic animals. Consistent with an increase in de novo lipogenesis, there was an increase in adipose C16:0 and C16:1 acyl-CoA pools. There were no changes in serum free fatty acids between genotypes. Serum levels of resistin were decreased in the E-FABP transgenic mice, whereas serum and tissue adiponectin were increased in A-FABP/aP2 null mice and decreased in E-FABP transgenic animals; leptin expression was unaffected. These results suggest that the balance between lipolysis and lipogenesis in adipocytes is remodeled in the FABP null and transgenic mice and is accompanied by the reprogramming of adipokine expression in fat cells and overall changes in plasma adipokines.

We hypothesized that increased capacity for brain utilization of nonglucose substrates (monocarboxylic acids [MCAs]) by upregulation of the MCA transporters may contribute metabolic substrates during hypoglycemia. To test this hypothesis, we assessed brain acetate metabolism in five well-controlled type 1 diabetic subjects and six nondiabetic control subjects using 13C magnetic resonance spectroscopy during infusions of [2-13C]acetate during hypoglycemia (∼55 mg/dl). Acetate is transported into the brain through MCA transporters that are also used for lactate and ketones. Brain acetate concentrations were over twofold higher in the subjects with diabetes than the control subjects (P = 0.01). The fraction of oxidative metabolism from acetate (P = 0.015) and the rate of MCA transport (P = 0.01) were also approximately twofold higher in the diabetic subjects. We conclude that during hypoglycemia MCA transport in the brain was increased by appoximately twofold in patients with well-controlled type 1 diabetes, as reflected by higher brain acetate concentrations and rates of acetate oxidation. This upregulation would potentially allow a similar twofold increase in the transport of other MCAs, including lactate, during insulin-induced hypoglycemia. These data are consistent with the hypothesis that upregulation of MCA transport may contribute to the maintenance of brain energetics during hypoglycemia in patients with type 1 diabetes.

Dietary modulation of carcinogenesis-related pathwaysDietary item or component studied: fish oilPathways studied: adiponectin gene expressionStudy type (in vitro, animals, humans): 129Sv miceTissue/biological material/sample size: total plasmaMode of exposure (if in vivo) (acute, chronic, root of exposure): chronic (15 days) and acute dietImpact on pathway (including dose-response): 31+-2.8, n=4 vs 25.6+-3.5, n=4μgr/ml plasma adiponectin in 14.5%fish oil-fed mice. KEYWORDS CLASSIFICATION: Adiponectin;Adipose Tissue;Animals;Antigens,CD36;blood;deficiency;dietary modulation of carcinogenesis-related pathways;drug effects;DNA Primers;Epididymis;Epoxy Compounds;Fish Oils;genetics;Gene Expression Regulation;Male;Mice;Mice,Inbred Strains;Mice,Knockout;Oils;pharmacology;physiology;PPAR gamma;Research;Reverse Transcriptase Polymerase Chain Reaction;secretion;Transcription,Genetic; Adiponectin has insulin-sensitizing, antiatherogenic, and anti-inflammatory properties, but little is known about factors that regulate its secretion. To examine the effect of fish oil on adiponectin secretion, mice were fed either a control diet or isocaloric diets containing 27% safflower oil or 27, 13.5, and 8% menhaden fish oil. Within 15 days, fish oil feeding raised plasma adiponectin concentrations two- to threefold in a dose-dependent manner, and the concentrations remained approximately twofold higher for 7 days when the fish oil diet was replaced by the safflower oil diet. Within 24 h, fish oil markedly induced transcription of the adiponectin gene in epididymal adipose tissue but not in subcutaneous fat. The increase of plasma adiponectin by fish oil was completely blocked by administration of the peroxisome proliferator-activated receptor (PPAR)gamma inhibitor bisphenol-A-diglycidyl ether. In contrast, there was no effect of fish oil feeding on adiponectin secretion in PPARalpha-null mice. These data suggest that fish oil is a naturally occurring potent regulator of adiponectin secretion in vivo and that it does so through a PPARgamma-dependent and PPARalpha-independent manner in epididymal fat.

A male infant was diagnosed with partial androgen insensitivity caused by a novel mutation in the androgen receptor. At 3.5 months of age, he received 100 mg of testosterone intramuscularly over the course of 3 months to increase phallic size. He developed pubic hair after 5 months and signs of progressive central precocious puberty when re-examined at 17.5 months, which subsequently was suppressed with depot leuprolide.

Primary hyperparathyroidism is a very rare complication following radioactive iodine therapy. There is typically a latency period of more than a decade following radiation exposure and, therefore, it is observed almost exclusively in adults. Consequently, pediatricians are not aware of the association. We present a case of primary hyperparathyroidism due to a solitary parathyroid adenoma occurring in an adolescent male two years following radioactive iodine treatment for papillary thyroid carcinoma. Periodic screening of serum calcium following ablative doses of radioactive iodine for thyroid cancer may be justified even in adolescents.

Authors assessed temporal changes in mental health-related drug utilization and costs in an older population.This was a population-based, cross-sectional time-series analysis of more than 1.4 million residents of Ontario, Canada, age 65 years or older. The study examined mental health-related drug utilization and costs, as derived from administrative databases from 1993 through 2002. They assessed use of antidepressants, antipsychotics, mood stabilizers, benzodiazepines, and acetylcholinesterase inhibitors (AChEIs), assessing trends over time.The prevalence of mental health-related drug use increased from 21.3% of the older population in the beginning of 1993 to 23.8% by the end of 2002. The proportion of benzodiazepine prescriptions was the highest of all such drugs, but declined from approximately 67% of prescriptions, in 1993, to 38%, in 2002. Significant temporal increases were observed for use of antidepressants (5.6%, in 1993, to 10.9%, in 2002), antipsychotics (1.9% in 1993; 2.9% in 2002), and AChEIs (0.1% in 1999; 1.5% in 2002). These increases were associated with a 210% increase in total standardized expenditures on mental health-related drugs, from approximately $32 per older resident ($40 million total) in 1993 to $99 per older resident ($149 million total) in 2002. AChEIs accounted for fewer than 6% of prescriptions, but 25% of the costs.Significant shifts in prescription of mental health-related drugs and their costs have occurred over the past decade among older individuals with the introduction of newer, more expensive agents. Future research should address the appropriate balancing of increased costs versus their benefits in this population.

Endocrine defensive mechanisms provide for energy supply during hypoglycemia. Intramyocellular lipids (IMCL) were recently shown to contribute to energy supply during exercise.The objective of this study was to assess the contribution of IMCL compared with lipolysis and endogenous glucose production (EGP) to insulin-mediated hypoglycemia counterregulation in patients with type 1 diabetes mellitus (T1DM).This was a prospective explorative study performed in a university research facility.Six well-controlled T1DM (age, 29 +/- 4 yr; body mass index, 23.4 +/- 1.0 kg/m2; hemoglobin A1c, 6.3 +/- 0.1%) and six nondiabetic humans (controls; age, 28 +/- 2 yr; body mass index, 23.4 +/- 1.0 kg/m2; hemoglobin A1c, 5.1 +/- 0.1%) were studied.We performed 240-min hypoglycemic (approximately 3 mM)-hyperinsulinemic (0.8 mU/kg x min) clamps on separate days to measure: 1) systemic lipolysis ([2H5]glycerol turnover), EGP ([6,6-(2)H2]glucose), and local lipolysis in abdominal s.c. adipose tissue and gastrocnemius muscle (microdialysis); and 2) IMCL (by 1H nuclear magnetic resonance spectroscopy) in soleus and tibialis anterior muscle.The main outcome measures were changes in IMCL during prolonged hypoglycemia.At baseline, EGP, glycerol turnover, and IMCL were not different between the groups. During hypoglycemia, hormonal counterregulation was blunted in T1DM (peak: glucagon, 68 +/- 4 vs. 170 +/- 37 pg/ml; cortisol, 16 +/- 2 vs. 24 +/- 2 microg/dl; epinephrine, 274 +/- 84 vs. 597 +/- 212 pg/ml; all P0.05 vs. control). T1DM had approximately 50% lower EGP (4.6 +/- 0.6 vs. 10.9 +/- 0.5 micromol/kg x min; P0.005), but approximately 40% higher glycerol turnover (374 +/- 21 vs. 272 +/- 19 micromol/kg x min; P0.01). Glycerol concentrations in muscle (T1DM, 302 +/- 22 control, 346 +/- 17 micromol/liter) and adipose tissue (264 +/- 25 vs. 318 +/- 25 micromol/liter) did not differ between groups. IMCL in soleus and tibialis anterior muscle did not change from baseline during hypoglycemia.In well-controlled T1DM, impaired hypoglycemia counterregulation is associated with decreased glucose production and augmented whole body lipolysis, which cannot be explained by either hydrolysis of muscle triglycerides or increased abdominal s.c. adipose tissue lipolysis.

The principal abnormalities of the metabolic syndrome are abdominal obesity, atherogenic dyslipidemia, hypertension, insulin resistance, inflammation, and prothrombotic states. This review focuses ...

Insulin resistance in skeletal muscle and heart plays a major role in the development of type 2 diabetes and diabetic heart failure and may be causally associated with altered lipid metabolism. Hormone-sensitive lipase (HSL) is a rate-determining enzyme in the hydrolysis of triglyceride in adipocytes, and HSL-deficient mice have reduced circulating fatty acids and are resistant to diet-induced obesity. To determine the metabolic role of HSL, we examined the changes in tissue-specific insulin action and glucose metabolism in vivo during hyperinsulinemic euglycemic clamps after 3 wk of high-fat or normal chow diet in awake, HSL-deficient (HSL-KO) mice. On normal diet, HSL-KO mice showed a twofold increase in hepatic insulin action but a 40% decrease in insulin-stimulated cardiac glucose uptake compared with wild-type littermates. High-fat feeding caused a similar increase in whole body fat mass in both groups of mice. Insulin-stimulated glucose uptake was reduced by 50–80% in skeletal muscle and heart of wild-type mice after high-fat feeding. In contrast, HSL-KO mice were protected from diet-induced insulin resistance in skeletal muscle and heart, and these effects were associated with reduced intramuscular triglyceride and fatty acyl-CoA levels in the fat-fed HSL-KO mice. Overall, these findings demonstrate the important role of HSL on skeletal muscle, heart, and liver glucose metabolism.

SummaryIn order to investigate the role of mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase 1 (mtGPAT1) in the pathogenesis of hepatic steatosis and hepatic insulin resistance, we examined whole-body insulin action in awake mtGPAT1 knockout (mtGPAT1−/−) and wild-type (wt) mice after regular control diet or three weeks of high-fat feeding. In contrast to high-fat-fed wt mice, mtGPAT1−/− mice displayed markedly lower hepatic triacylglycerol and diacylglycerol concentrations and were protected from hepatic insulin resistance possibly due to a lower diacylglycerol-mediated PKCϵ activation. Hepatic acyl-CoA has previously been implicated in the pathogenesis of insulin resistance. Surprisingly, compared to wt mice, mtGPAT1−/− mice exhibited increased hepatic insulin sensitivity despite an almost 2-fold elevation in hepatic acyl-CoA content. These data suggest that mtGPAT1 might serve as a novel target for treatment of hepatic steatosis and hepatic insulin resistance and that long chain acyl-CoA’s do not mediate fat-induced hepatic insulin resistance in this model.

Insulin resistance plays a major role in the development of type 2 diabetes and may be causally associated with increased intracellular fat content. Transgenic mice with adipocyte-specific overexpression of FOXC2 (forkhead transcription factor) have been generated and shown to be protected against diet-induced obesity and glucose intolerance. To understand the underlying mechanism, we examined the effects of chronic high-fat feeding on tissue-specific insulin action and glucose metabolism in the FOXC2 transgenic (Tg) mice. Whole-body fat mass were significantly reduced in the FOXC2 Tg mice fed normal diet or high-fat diet compared with the wild-type mice. Diet-induced insulin resistance in skeletal muscle of the wild-type mice was associated with defects in insulin signaling and significant increases in intramuscular fatty acyl CoA levels. In contrast, FOXC2 Tg mice were completely protected from diet-induced insulin resistance and intramuscular accumulation of fatty acyl CoA. High-fat feeding also blunted insulin-mediated suppression of hepatic glucose production in the wild-type mice, whereas FOXC2 Tg mice were protected from diet-induced hepatic insulin resistance. These findings demonstrate an important role of adipocyte-expressed FOXC2 on whole-body glucose metabolism and further suggest FOXC2 as a novel therapeutic target for the treatment of insulin resistance and type 2 diabetes.

There is a wide interindividual variation in peripheral insulin sensitivity at any given body mass index or percent body fat among obese adolescents with normal glucose tolerance. The goals of this study were to determine whether variability in insulin sensitivity is associated with differences in patterns of lipid partitioning or substrate use under fasting and hyperinsulinemic conditions. We compared 14 obese insulin-resistant adolescents with 14 obese insulin-sensitive controls, pair matched for age, gender, pubertal stage and body composition. Insulin sensitivity was assessed by the hyperinsulinemic-euglycemic clamp, intramyocellular lipid content by (1)H-nuclear magnetic resonance and visceral fat by magnetic resonance imaging. Obese insulin-sensitive subjects had lower intramyocellular (1.64 +/- 0.68 vs.2.26 +/- 0.62% of water peak, P = 0.017) and visceral lipid deposition (45 +/- 23 vs. 77 +/- 52 cm(2), P = 0.04) and a higher level of adiponectin, compared with their obese-resistant counterparts (8.8 +/- 3.6 vs. 6.5 +/- 1.8 mug/dl, P = 0.015). Glycerol fluxes were similar between the two obese groups yet occurred in the face of different concentrations of insulin. Intramyocellular lipid and visceral fat were negatively related to insulin sensitivity. Obese insulin-sensitive adolescents are characterized by lower lipid deposition in the intramyocellular and visceral compartments and greater levels of adiponectin, despite similar degree of adiposity.

Background: The use of lithium carbonate for the treatment of mood disorders in old age has decreased at a dramatic rate in favor of valproate. Because of lithium's narrow therapeutic range, neurotoxicity can be an important complication in lithium therapy and potentially influence prescription patterns. Therefore, we compared the incidence of delirium in older adults with mood disorders who were newly dispensed either lithium or valproate. Method: Using 4 population-based administrative databases from the province of Ontario, Canada (the Ontario Drug Benefit program, the Canadian Institute for Health Information, the Ontario Health Insurance Plan, and the Registered Persons Data Base), we were able to identify a cohort of mood disorder patients 66 years and older who were newly dispensed lithium or valproate over an 8-year period (1993-2001). Measures were taken to ensure that the sample was composed of mood disorder patients. As a comparator, we included a known deliriogenic drug, benztropine. The main outcome measure was a new diagnosis of delirium on a hospitalization record during 1 year of follow-up. Results: Our study cohort consisted of 2422 new users of lithium and 2918 new users of valproate over an 8-year period. There was no statistically significant difference in the incidence of delirium between lithium (2.8 per 100 person-years) and valproate (4.1 per 100 person-years). Compared with patients who received lithium, patients who received benztropine had a significantly higher risk of delirium (p

Objective The authors sought to determine the incidence of lithium-induced hypothyroidism in a population-based cohort of older adults beginning lithium therapy and thereby to inform clinical guidelines on the frequency of monitoring necessary in this group. Methods The authors conducted a population-based observational cohort study using four administrative databases that contained information on over 1.3 million older adults in Ontario who receive universal healthcare coverage in terms of physician services, drugs, and hospitalizations. Over an 18-month period, they studied adults age ≥65 who were newly prescribed lithium or valproate, monitoring subjects for initiation of T 4 therapy (as a proxy for hypothyroidism) while they continued their lithium use. Results The authors identified 1,705 new users of lithium and 2,406 new users of valproate with similar baseline characteristics. Lithium users were significantly more likely to be treated with T 4 than were valproate users. The rate of T 4 treatment per 100 person-years was 5.65 in the lithium group and 2.70 in the valproate group. Conclusion T 4 treatment was initiated in almost 6% of lithium-treated patients, suggesting the possibility that hypothyroidism developed twice as frequently among these patients as would be expected among a mixed-age population. Increased vigilance and continued monitoring of thyroid functioning for at least 2 years is necessary in older adults beginning lithium therapy.

Objective The purpose of this study was to assess trends in utilization and costs of antipsychotic drugs among a population of older adults over time, with respect to the prevalence of users, shifts in prescribing patterns, and related financial implications. Design Cross-sectional time series of quarterly and annual antipsychotic utilization and cost were obtained from administrative databases for calendar years 1993 through 2002. Setting and Participants A population-based study of more than 1.4 million residents of the province of Ontario aged 65 years or older. Measurements Data sources used included the Ontario Drug Benefits (ODB) database and Statistics Canada census data. Results The prevalence of antipsychotic users increased by 34.8% over the study period from 2.2% at the beginning of 1993 to 3.0% of the elderly at the end of 2002 (p

In 2009, the Association of American Medical Colleges and the Howard Hughes Medical Institute released a report entitled Scientific Foundations for Future Physicians (SFFP). This report, produced in response to “concerns about the science content in the current premedical and medical education curricula”, emphasizes competencies for premedical school students rather than mandating specific courses for admission to medical school. This commentary addresses the opportunities and challenges for the chemical education community presented by SFFP, some models that have been created or suggested for teaching chemistry in the premedical curriculum, and some issues that colleges and universities should keep in mind when considering their response to SFFP.

PGC-1alpha is a coactivator of nuclear receptors and other transcription factors that regulates several metabolic processes, including mitochondrial biogenesis and respiration, hepatic gluconeogenesis, and muscle fiber-type switching. We show here that, while hepatocytes lacking PGC-1alpha are defective in the program of hormone-stimulated gluconeogenesis, the mice have constitutively activated gluconeogenic gene expression that is completely insensitive to normal feeding controls. C/EBPbeta is elevated in the livers of these mice and activates the gluconeogenic genes in a PGC-1alpha-independent manner. Despite having reduced mitochondrial function, PGC-1alpha null mice are paradoxically lean and resistant to diet-induced obesity. This is largely due to a profound hyperactivity displayed by the null animals and is associated with lesions in the striatal region of the brain that controls movement. These data illustrate a central role for PGC-1alpha in the control of energy metabolism but also reveal novel systemic compensatory mechanisms and pathogenic effects of impaired energy homeostasis.

Anaplerotic flux into the Kreb's cycle is crucial for glucose-stimulated insulin secretion from pancreatic beta-cells. However, the regulation of flux through various anaplerotic pathways in response to combinations of physiologically relevant substrates and its impact on glucose-stimulated insulin secretion is unclear. Because different pathways of anaplerosis generate distinct products, they may differentially modulate the insulin secretory response. To examine this question, we applied 13C-isotopomer analysis to quantify flux through three anaplerotic pathways: 1) pyruvate carboxylase of pyruvate derived from glycolytic sources; 2) pyruvate carboxylase of pyruvate derived from nonglycolytic sources; and 3) glutamate dehydrogenase (GDH). At substimulatory glucose, anaplerotic flux rate in the clonal INS-1 832/13 cells was approximately 40% of Kreb's cycle flux, with similar contributions from each pathway. Increasing glucose to 15 mm stimulated insulin secretion approximately 4-fold, and was associated with a approximately 4-fold increase in anaplerotic flux that could mostly be attributed to an increase in PC flux. In contrast, the addition of glutamine to the perfusion media stimulated GDH flux approximately 6-fold at both glucose concentrations without affecting insulin secretion rates. In conclusion, these data support the hypothesis that a signal generated by anaplerosis from increased pyruvate carboxylase flux is essential for glucose-stimulated insulin secretion in beta-cells and that anaplerosis through GDH does not play a major role in this process.

Insulin resistance plays a primary role in the development of type 2 diabetes and may be related to alterations in fat metabolism. Recent studies have suggested that local accumulation of fat metabolites inside skeletal muscle may activate a serine kinase cascade involving protein kinase C-theta (PKC-theta), leading to defects in insulin signaling and glucose transport in skeletal muscle. To test this hypothesis, we examined whether mice with inactivation of PKC-theta are protected from fat-induced insulin resistance in skeletal muscle. Skeletal muscle and hepatic insulin action as assessed during hyperinsulinemic-euglycemic clamps did not differ between WT and PKC-theta KO mice following saline infusion. A 5-hour lipid infusion decreased insulin-stimulated skeletal muscle glucose uptake in the WT mice that was associated with 40-50% decreases in insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-1-associated PI3K activity. In contrast, PKC-theta inactivation prevented fat-induced defects in insulin signaling and glucose transport in skeletal muscle. In conclusion, our findings demonstrate that PKC-theta is a crucial component mediating fat-induced insulin resistance in skeletal muscle and suggest that PKC-theta is a potential therapeutic target for the treatment of type 2 diabetes.

Insulin resistance plays a major role in the pathogenesis of type 2 diabetes, yet despite much research the underlying mechanism responsible for it is poorly understood. In this review, some recent advances in the understanding of insulin resistance in humans that have been made by using magnetic resonance spectroscopy are discussed.

The authors reviewed the evidence-base for pharmacological treatment of mania and bipolar (BP) depression in late life. Treatment benefits and side effects may be modified by age-associated factors, such as neurocognitive impairments. Lithium and divalproex have most often been studied in elderly patients, and both may be efficacious in acute treatment of mania, but there are no controlled efficacy or effectiveness trials. The role of atypical antipsychotic agents remains to be clarified. Similarly, there are no systematic studies of the treatment of BP depression in elderly patients. The authors make suggestions for management and delineate priorities for research.

Previous studies implicate protein-tyrosine phosphatase 1B (PTP1B) and leukocyte antigen-related phosphatase (LAR) as negative regulators of insulin signaling. The expression and/or activity of PTP1B and LAR are increased in muscle of insulin-resistant rodents and humans. Overexpression of LAR selectively in muscle of transgenic mice causes whole body insulin resistance. To determine whether overexpression of PTP1B also causes insulin resistance, we generated transgenic mice overexpressing human PTP1B selectively in muscle at levels similar to those observed in insulin-resistant humans. Insulin-stimulated insulin receptor (IR) tyrosyl phosphorylation and phosphatidylinositol 3'-kinase activity were impaired by 35% and 40-60% in muscle of PTP1B-overexpressing mice compared with controls. Insulin stimulation of protein kinase C (PKC)lambda/zeta activity, which is required for glucose transport, was impaired in muscle of PTP1B-overexpressing mice compared with controls, showing that PTP1B overexpression impairs activation of these PKC isoforms. Furthermore, hyperinsulinemic-euglycemic clamp studies revealed that whole body glucose disposal and muscle glucose uptake were decreased by 40-50% in PTP1B-overexpressing mice. Overexpression of PTP1B or LAR alone in muscle caused similar impairments in insulin action; however, compound overexpression achieved by crossing PTP1B- and LAR-overexpressing mice was not additive. Antibodies against specific IR phosphotyrosines indicated overlapping sites of action of PTP1B and LAR. Thus, overexpression of PTP1B in vivo impairs insulin sensitivity, suggesting that overexpression of PTP1B in muscle of obese humans and rodents may contribute to their insulin resistance. Lack of additive impairment of insulin signaling by PTP1B and LAR suggests that these PTPs have overlapping actions in causing insulin resistance in vivo.

Objectives: To study the association between hospital admission for lithium toxicity and the use of diuretics, angiotensin-converting enzyme (ACE) inhibitors, and nonsteroidal antiinflammatory drugs (NSAIDs) in the elderly. Design: Population-based nested case-control study. Setting: Ontario, Canada. Participants: Ontario residents aged 66 and older treated with lithium. Measurements: Estimated relative risk of hospital admission for lithium toxicity. Results: From January 1992 to December 2001, 10,615 elderly patients continuously receiving lithium were identified, of whom 413 (3.9%) were admitted to the hospital at least once for lithium toxicity. After adjustment for potential confounders, a dramatically increased risk of lithium toxicity was seen within a month of initiating treatment with a loop diuretic (relative risk (RR)=5.5, 95% confidence interval (CI)=1.9–16.1) or an ACE inhibitor (RR=7.6, 95% CI=2.6–22.0). Conversely, neither thiazide diuretics nor NSAIDs were independently associated with a significantly increased risk of hospitalization for lithium toxicity. Conclusion: The use of loop diuretics or ACE inhibitors significantly increases the risk of hospitalization for lithium toxicity, particularly in naive recipients.

Objectives: To describe the incidence and dose of neuroleptic drug therapy newly dispensed for behavioral disorders to older adults admitted to nursing homes and to determine whether this use is associated with patient characteristics and contact with specialists. Design: A retrospective cohort study using administrative data from a comprehensive and universal drug program. Setting: All licensed nursing homes in Ontario, Canada. Participants: All 19,780 adults aged 66 and older who had no evidence of neuroleptic drug use in the previous year and no history of major psychosis and were newly admitted to a nursing home between April 1, 1998, and March 31, 2000. Measurements: Exposure to neuroleptic drug therapy and initial dose were measured using claims submitted to the Ontario Drug Benefit Program. Results: A prescription for a neuroleptic therapy was dispensed to 17% of older adults with no previous neuroleptic exposure within 100 days and to 24% within 1 year of their nursing home admission. New exposure to a neuroleptic therapy was less likely in women (odds ratio (OR)=0.7, 95% confidence interval (CI)=0.6–0.8) and more likely in residents with dementia (OR=3.5, 95% CI=3.2–3.8). Almost 10% of nursing home residents received an initial dose that exceeded recommended thresholds. Only 14% of those newly exposed had prior contact with a geriatrician or psychiatrist. Conclusion: Incident use of neuroleptics in Ontario nursing homes is substantial. Use of high doses suggests that some physicians may need better information about using these agents, particularly given the rapid adoption of atypical neuroleptic drug therapies.

Signal transducer and activator of transcription (STAT)3 is widely expressed in the CNS during development and adulthood. STAT3 has been implicated in the control of neuron/glial differentiation and leptin-mediated energy homeostasis, but the physiological role and degree of involvement of STAT3 in these processes is not defined and controversial because of the lack of a direct genetic model. To address this, we created mice with a neural-specific disruption of STAT3 (STAT3 N-/- ). Surprisingly, homozygous mutants were born at the expected Mendelian ratio without apparent developmental abnormalities but susceptible to neonatal lethality. Mutants that survived the neonatal period were hyperphagic, obese, diabetic, and infertile. Administering a melanocortin-3/4 receptor agonist abrogated the hyperphagia and hypothalamic immunohistochemistry showed a marked reduction in proopiomelanocortin with an increase in neuropeptide Y and agouti-related protein. Mutants had reduced energy expenditure and became hypothermic after fasting or cold stress. STAT3 N-/- mice are hyperleptinemic, suggesting a leptin-resistant condition. Concomitant with neuroendocrine defects such as decreased linear growth and infertility with accompanying increased corticosterone levels, this CNS knockout recapitulates the unique phenotype of db / db and ob / ob obese models and distinguishes them from other genetic models of obesity. Thus, STAT3 in the CNS plays essential roles in the regulation of energy homeostasis and reproduction.

Insulin resistance in skeletal muscle plays a major role in the development of type 2 diabetes and may be causally associated with increases in intramuscular fatty acid metabolites. Fatty acid transport protein 1 (FATP1) is an acyl-CoA synthetase highly expressed in skeletal muscle and modulates fatty acid uptake and metabolism by converting fatty acids into fatty acyl-CoA. To investigate the role of FATP1 in glucose homeostasis and in the pathogenesis of insulin resistance, we examined the effect of acute lipid infusion or chronic high-fat feeding on insulin action in FATP1 KO mice. Whole-body adiposity, adipose tissue expression of adiponectin, intramuscular fatty acid metabolites, and insulin sensitivity were not altered in FATP1 KO mice fed a regular chow diet. In contrast, FATP1 deletion protected the KO mice from fat-induced insulin resistance and intramuscular accumulation of fatty acyl-CoA without alteration in whole-body adiposity. These findings demonstrate an important role of intramuscular fatty acid metabolites in causing insulin resistance and suggest that FATP1 may be a novel therapeutic target for the treatment of insulin resistance and type 2 diabetes.

An 11-year-old boy presented with a femur fracture, bone hypomineralization, and hypophosphatemia, suggesting tumor-induced rickets. Conventional radiologic techniques including magnetic resonance skeletal survey did not identify a tumor. Magnetic resonance gradient echo recall imaging demonstrated a 3-cm iliac tumor, the resection of which rapidly reversed metabolic abnormalities. This technique may be useful in identifying elusive tumors associated with tumor-induced rickets.

Insulin resistance appears to be the best predictor of the development of diabetes in the children of patients with type 2 diabetes, but the mechanism responsible is unknown.We performed hyperinsulinemic-euglycemic clamp studies in combination with infusions of [6,6-(2)H(2)]glucose in healthy, young, lean, insulin-resistant offspring of patients with type 2 diabetes and insulin-sensitive control subjects matched for age, height, weight, and physical activity to assess the sensitivity of liver and muscle to insulin. Proton ((1)H) magnetic resonance spectroscopy studies were performed to measure intramyocellular lipid and intrahepatic triglyceride content. Rates of whole-body and subcutaneous fat lipolysis were assessed by measuring the rates of [(2)H(5)]glycerol turnover in combination with microdialysis measurements of glycerol release from subcutaneous fat. We performed (31)P magnetic resonance spectroscopy studies to assess the rates of mitochondrial oxidative-phosphorylation activity in muscle.The insulin-stimulated rate of glucose uptake by muscle was approximately 60 percent lower in the insulin-resistant subjects than in the insulin-sensitive control subjects (P0.001) and was associated with an increase of approximately 80 percent in the intramyocellular lipid content (P=0.005). This increase in intramyocellular lipid content was most likely attributable to mitochondrial dysfunction, as reflected by a reduction of approximately 30 percent in mitochondrial phosphorylation (P=0.01 for the comparison with controls), since there were no significant differences in systemic or localized rates of lipolysis or plasma concentrations of tumor necrosis factor alpha, interleukin-6, resistin, or adiponectin.These data support the hypothesis that insulin resistance in the skeletal muscle of insulin-resistant offspring of patients with type 2 diabetes is associated with dysregulation of intramyocellular fatty acid metabolism, possibly because of an inherited defect in mitochondrial oxidative phosphorylation.

Obesity-associated diabetes is epidemic in industrialized societies. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is highly expressed in adipose tissue and the presumed molecular target for antidiabetic thiazolidinedione drugs that reverse insulin resistance but also promote weight gain. Phosphorylation reduces the activity of PPARgamma in vitro, but physiological relevance has not been demonstrated. We have studied mice homozygous for a mutation (S112A) that prevents PPARgamma phosphorylation. Surprisingly, the weights and adipose mass of PPARgamma-S112A mice are not greater than wild-type. Remarkably, however, genetic prevention of PPARgamma phosphorylation preserves insulin sensitivity in the setting of diet-induced obesity. Underlying this protection are smaller fat cells, elevated serum adiponectin, and reduced free fatty acid levels. Thus, the phosphorylation state of PPARgamma modulates insulin sensitivity. Compounds that prevent PPARgamma phosphorylation or ligands that induce the conformation of nonphosphorylated PPARgamma may selectively enhance insulin sensitivity without increasing body weight.

AMP-activated protein kinase (AMPK) is emerging as a key signaling pathway that modulates cellular metabolic processes. In skeletal muscle, AMPK is activated during exercise. Increased myocardial substrate metabolism during exercise could be explained by AMPK activation. Although AMPK is known to be activated during myocardial ischemia, it remains uncertain whether AMPK is activated in response to the physiological increases in cardiac work associated with exercise. Therefore, we evaluated cardiac AMPK activity in rats at rest and after 10 min of treadmill running at moderate (15% grade, 16 m/min) or high (15% grade, 32 m/min) intensity. Total AMPK activity in the heart increased in proportion to exercise intensity ( P < 0.05). AMPK activity associated with the α2-catalytic subunit increased 2.8 ± 0.4-fold ( P < 0.02 vs. rest) and 4.5 ± 0.6-fold ( P < 0.001 vs. rest) with moderate- and high-intensity exercise, respectively. AMPK activity associated with the α1-subunit increased to a lesser extent. Phosphorylation of the Thr172-regulatory site on AMPK α-catalytic subunits increased during exercise ( P < 0.001). There was no increase in Akt phosphorylation during exercise. The changes in AMPK activity during exercise were associated with physiological AMPK effects (GLUT4 translocation to the sarcolemma and ACC phosphorylation). Thus cardiac AMPK activity increases progressively with exercise intensity, supporting the hypothesis that AMPK has a physiological role in the heart.

To investigate the physiological effects of modulating the abundance of Munc18c or syntaxin 4 (Syn4) proteins on the regulation of glucose homeostasis in vivo, we generated tetracycline-repressible transgenic mice that overexpress either Munc18c or Syn4 proteins in skeletal muscle, pancreas and adipose tissue seven-, five-, and threefold over endogenous protein, respectively. Munc18c transgenic mice displayed whole-body insulin resistance during hyperinsulinemic-euglycemic clamp resulting from >41% reductions in skeletal muscle and white adipose tissue glucose uptake, but without alteration of hepatic insulin action. Munc18c transgenic mice exhibited ∼40% decreases in whole-body glycogen/lipid synthesis, skeletal muscle glycogen synthesis, and glycolysis. Glucose intolerance in Munc18c transgenic mice was reversed by repression of transgene expression using tetracycline or by simultaneous overexpression of Syn4 protein. In addition, Munc18c transgenic mice had depressed serum insulin levels, reflecting a threefold reduction in insulin secretion from islets isolated therefrom, thus uncovering roles for Munc18c and/or Syn4 in insulin granule exocytosis. Taken together, these results indicate that balance, more than absolute abundance, of Munc18c and Syn4 proteins directly affects whole-body glucose homeostasis through alterations in insulin secretion and insulin action.

Background and Purpose— The aim of this study was to determine the effectiveness of pioglitazone compared with placebo for improving insulin sensitivity among nondiabetic patients with a recent transient ischemic attack (TIA) or nondisabling ischemic stroke and impaired insulin sensitivity. Methods— Eligible subjects were men and women >45 years of age who had no history of diabetes, fasting glucose Results— Between July 2000 and June 2001, we performed oral glucose tolerance tests on 75 patients with no history of diabetes, among whom 36 (50%) were found to have impaired insulin sensitivity and fasting glucose P =0.0006). Mean C-reactive protein concentration declined from 0.30 to 0.20 mg/L among patients assigned to pioglitazone and increased from 0.41 to 0.45 mg/L among patients assigned to placebo ( P =0.06 for comparison of mean change). Conclusions— Pioglitazone is effective for improving insulin sensitivity among patients with recent TIA or stroke and impaired insulin sensitivity.

To determine the prevalence of impaired insulin sensitivity among nondiabetic patients with a recent TIA or nondisabling ischemic stroke.Eligible subjects were nondiabetic men and women over age 45 years who were hospitalized with a TIA or ischemic stroke. To measure insulin sensitivity, subjects underwent an oral glucose tolerance test between 2 and 6 months after their event. Impaired insulin sensitivity was defined by a value ofor =2.5 on the Composite Insulin Sensitivity Index derived from insulin and glucose values during the test.Between July 2000 and June 2001, we identified 177 eligible patients, among whom 105 declined to participate and 72 enrolled. The median age of participants was 71 years and 46 (64%) were men. The baseline event was stroke for 57 subjects (79%). A history of myocardial infarction (MI) was reported by 14 subjects (19%), and 16 (22%) were obese (body mass index30). Fasting glucose was normal (110 mg/dL) for 58 (80%) participants and impaired (110 to 125 mg/dL) for 14 (20%). Among 72 participants, the median insulin sensitivity index value was 2.6 (range 0.9 to 10.2). The prevalence of impaired insulin sensitivity was 36 of 72 (50%, 95% CI 38% to 62%). Impaired insulin sensitivity was more prevalent among younger patients and patients with obesity, lacunar stroke etiology, and disability (Rankin grade1).Impaired insulin sensitivity is highly prevalent among nondiabetic patients with a recent TIA or nondisabling ischemic stroke. This finding has important therapeutic implications if treatment to improve insulin sensitivity is shown to reduce risk for subsequent stroke and heart disease.

We examined the impact of adolescent obesity on circulating adiponectin levels and the relationship between adiponectin and insulin sensitivity, intramyocellular (IMCL) lipid content, plasma triglycerides, and free fatty acids. Plasma adiponectin levels were measured in 8 nonobese (percentage fat, 18 +/- 1.8) and 14 obese adolescents (percentage fat, 41 +/- 1.6). Insulin sensitivity was assessed by the euglycemic-hyperinsulinemic clamp. Intramuscular lipid content was quantified using (1)H-nuclear magnetic resonance spectroscopy, and abdominal fat distribution by magnetic resonance imaging. Adiponectin levels were lower in obese adolescents (9.2 +/- 1 microg/ml, P < 0.001) and were positively related to insulin sensitivity in all subjects (r = 0.531, P < 0.02). Strong inverse relationships were found between adiponectin and triglyceride levels (r = -0.80, P < 0.001) and IMCL (r = -0.73, P < 0.001). Triglycerides (partial r(2) = 0.52; P < 0.0002) and IMCL (partial r(2) = 0.10; P < 0.05) were the most significant predictors of adiponectin levels, explaining 62% of the variation. In conclusion, plasma adiponectin levels are reduced in adolescent obesity and related to insulin resistance, independent of total body fat and central adiposity. There is a strong relationship between adiponectin and IMCL lipid content in this pediatric population. The putative modulatory effects of adiponectin on insulin sensitivity may, in part, be mediated via its effects on IMCL lipid content.

Background Reliability should be considered when selecting a scoring system since it influences validity. CDT reliability has rarely been assessed in population based studies and in developing countries. The aim of the present study was to determine intra and inter–rater reliabilities of the CDT scored by the Shulman (2000) method, in elderly with very low formal educational level from Brazil. Methods CDTs performed by a random sample of 202 subjects of a population-based cohort of elderly were scored on two occasions by the same rater and by two independent raters. Reliability was measured using the kappa statistic, weighted kappa and the intraclass correlation coefficient. Data were stratified according to gender, age and schooling level. Results Intra and inter–rater reliabilities were excellent when CDTs were classified as ‘normal’ (scores 4 or 5) or ‘abnormal’ (scores 0 to 3) (kappa = 0.99 and 0.94, respectively) and were in the good to excellent range when scored from 0 to 5 (kappa = 0.88 and 0.74, respectively). Difficulties in distinguishing between scores 4 and 5, and a low proportion of score 1 tests were found. Conclusions The CDT scored by the Shulman (2000) method appears to have good to excellent reliability in an elderly population with very low formal educational level. However, difficulties in distinguishing between scores 4 and 5, and a low proportion of score 1 tests suggest these scores may not be totally adequate for this population. Further studies are necessary to determine the consistency of our results in similar populations. Copyright © 2003 John Wiley & Sons, Ltd.

The increased risk of hypoglycemia during intensified treatment of type 1 diabetes mellitus (T1DM) patients, who have a deficient glucagon secretory response, is largely attributed to the development of suppressed adrenomedullary responses. A consequence of this impairment of catecholamine secretion might be reduced lipolysis in major target tissues (muscle and adipose) and, in turn, increased glucose metabolism. To test this hypothesis, we used microdialysis to monitor glycerol (index of lipolysis) in the extracellular fluid of skeletal muscle and adipose tissue and assessed whole-body glucose use by measuring [6,6-2H2]glucose enrichment in plasma in seven intensively treated T1DM patients and eight nondiabetic subjects who received a 3-h insulin infusion (0.8 mU/kg·min) on two occasions: during mild-moderate hypoglycemia or euglycemia. In the hypoglycemic study, the rise in plasma epinephrine was approximately 50% less in the T1DM patients despite a greater fall in plasma glucose (to 3.0 vs. 3.5 mm in controls; P < 0.05). Moreover, the rate of glucose flux and the plasma-extracellular fluid glucose gradient in muscle was increased during hypoglycemia in T1DM subjects compared with controls. Glycerol levels in muscle, adipose, and plasma fell similarly in both groups in the first hour. Thereafter, tissue glycerol remained suppressed in the T1DM patients but rebounded significantly (P < 0.01) in the control subjects. The glycerol response in muscle and adipose tissue was significantly correlated with plasma epinephrine concentration (r = 0.73, P = 0.002; and r = 0.52, P = 0.04, respectively), and inversely correlated with whole-body glucose disposal (r = −0.51, P = 0.05; and r = −0.50, P = 0.05). To determine whether the absence of the lipolytic response is limited to deficient catecholamine release, we perfused muscle and adipose tissue in situ with the selective β2-agonist terbutaline during hyperinsulinemic euglycemia. Local addition of agonist increased glycerol and blood flow in both muscle and adipose (P < 0.01 and P < 0.05, respectively) similarly in T1DM and control subjects. We conclude that deficient release of (rather than impaired responsiveness to) catecholamines in T1DM prevents the local fat breakdown within muscle and adipose tissue that normally occurs during mild-moderate hypoglycemia. This defect within peripheral tissues may lead to a delayed increase in glucose disposal that could contribute to the severity of hypoglycemia when it is prolonged.

The objectives of this study were to 1) examine skeletal muscle fatty acid oxidation in individuals with varying degrees of adiposity and 2) determine the relationship between skeletal muscle fatty acid oxidation and the accumulation of long-chain fatty acyl-CoAs. Muscle was obtained from normal-weight [ n = 8; body mass index (BMI) 23.8 ± 0.58 kg/m2], overweight/obese ( n = 8; BMI 30.2 ± 0.81 kg/m2), and extremely obese ( n = 8; BMI 53.8 ± 3.5 kg/m2) females undergoing abdominal surgery. Skeletal muscle fatty acid oxidation was assessed in intact muscle strips. Long-chain fatty acyl-CoA concentrations were measured in a separate portion of the same muscle tissue in which fatty acid oxidation was determined. Palmitate oxidation was 58 and 83% lower in skeletal muscle from extremely obese (44.9 ± 5.2 nmol · g−1 · h−1) patients compared with normal-weight (71.0 ± 5.0 nmol · g−1 · h−1) and overweight/obese (82.2 ± 8.7 nmol · g−1 · h−1) patients, respectively. Palmitate oxidation was negatively ( R = −0.44, P = 0.003) associated with BMI. Long-chain fatty acyl-CoA content was higher in both the overweight/obese and extremely obese patients compared with normal-weight patients, despite significantly lower fatty acid oxidation only in the extremely obese. No associations were observed between long-chain fatty acyl-CoA content and palmitate oxidation. These data suggest that there is a defect in skeletal muscle fatty acid oxidation with extreme obesity but not overweight/obesity and that the accumulation of intramyocellular long-chain fatty acyl-CoAs is not solely a result of reduced fatty acid oxidation.

We have previously reported that a glucosensor integrating hormonal responses to hypoglycemia is located in the ventromedial hypothalamus (VMH) and that local VMH glucose perfusion blocks counterregulatory hormone responses. To determine whether the by-product of glucose metabolism, lactate, can function within the VMH as an alternative for glucose, we delivered lactate locally to the VMH, during systemic hypoglycemia. For this purpose, we combined bilateral VMH microdialysis perfusion (metabolically active l-lactate or its nonmetabolizable d-isomer) with a euglycemic-hypoglycemic clamp in conscious chronically catheterized Sprague-Dawley rats. Local VMH perfusion with l-lactate decreased counterregulatory hormone responses to hypoglycemia by 80–85% as compared with the nonmetabolizable d-lactate control. Moreover, hormonal suppression with l-lactate was accompanied by an approximate fourfold increase in the amount of exogenous glucose infused to maintain a stable hypoglycemic plateau (P < 0.05). In conclusion, the glucose-sensing mechanism in the VMH responds to lactate and, thus, is not specific for glucose. This implies that the VMH may act as a fuel sensor rather than as a glucose sensor.

The originally published version of this Article contained an error in Equation 30, which was inadvertently introduced during the production process. This has now been corrected in the PDF and HTML versions of the Article.

Summary Caloric restriction rapidly reverses type 2 diabetes (T2D), but the mechanism(s) of this reversal are poorly understood. Here we show that 3 days of a very-low-calorie diet (VLCD, one-quarter their typical intake) lowered plasma glucose and insulin concentrations in a rat model of T2D without altering body weight. The lower plasma glucose was associated with a 30% reduction in hepatic glucose production resulting from suppression of both gluconeogenesis from pyruvate carboxylase (V PC ), explained by a reduction in hepatic acetyl-CoA content, and net hepatic glycogenolysis. In addition, VLCD resulted in reductions in hepatic triglyceride and diacylglycerol content and PKCɛ translocation, associated with improved hepatic insulin sensitivity. Taken together, these data show that there are pleotropic mechanisms by which VLCD reverses hyperglycemia in a rat model of T2D, including reduced DAG-PKCɛ-induced hepatic insulin resistance, reduced hepatic glycogenolysis, and reduced hepatic acetyl-CoA content, PC flux, and gluconeogenesis.

SUMMARY Inducers of satiety are drug targets for weight loss to mitigate obesity-associated diseases. Nucleobindin-2 (Nucb2) is thought to be post-translationally processed into bioactive nesfatin-1 peptide, which reportedly induces satiety, causes weight loss, and thus improves insulin sensitivity. Here, we show that deletion of Nucb2 did not affect food intake or adiposity and, instead, caused insulin resistance in mice fed a high-fat diet. In addition, ablation of Nucb2 in orexigenic hypothalamic Agrp neurons did not affect food intake, and nesfatin-1 was detectable in serum, despite global deletion of Nucb2 protein. Upon high-fat diet feeding, the loss of Nucb2 exacerbated metabolic inflammation in adipose tissue macrophages in an NFκB-dependent manner without inducing classical M1 or alternative M2-like macrophage polarization. Furthermore, the loss of Nucb2 in myeloid cells but not in adipocytes mediated the insulin resistance in response to a high-fat diet. Our study reveals that Nucb2 links metabolic inflammation to insulin resistance without affecting weight gain and food intake., In Brief Obesity induces Nucb2 expression in adipose macrophages as an endogenous brake to restrain metabolic inflammation. Ravussin et al. show that ablation of Nucb2 globally or knockdown in orexigenic neurons and adipocytes did not affect food intake or adiposity. The loss of Nucb2 in myeloid cells drive inflammation and insulin resistance upon high-fat feeding., Graphical Abstract

Rodents are commonly used in food restriction-refeeding studies to investigate weight regain. Mice that are rationed food every 24 hours may consume all allocated food in a short time (gorge) and therefore undergo a brief well-fed period followed by an extended fasted period until the next day’s food allotment. These exaggerated metabolic states are not typical in ad-libitum fed (nibbling) mice. The aim of the current study was to elucidate the intraday and cumulative metabolic consequences of gorging (induced by food restriction) in mice during controlled refeeding. Accordingly, following a temporary food restriction, mice were fed rations similar to intakes of ad-libitum fed controls. Temporary food restriction initiated gorging behavior that persisted during refeeding; consequently, metabolism-related measurements were obtained in the gorging mice during their daily fed and fasted metabolic states. Robust differences in adipose tissue lipogenic and inflammatory gene expression were found in the gorging mice by metabolic state (fed versus fasted). Additionally, despite a reduced cumulative food intake compared to ad-libitum fed mice, restriction-induced gorging mice had increased intra-abdominal fat accumulation, diminished hepatic and peripheral insulin sensitivity, and a gene expression profile favoring lipid deposition. Our findings highlight the intraday differences in gene expression in gorging mice before and after feeding that confound comparisons with ad-libitum fed, or nibbling, mice. The present study also provides evidence that weight regain following food restriction is associated with cumulative metabolic and behavioral abnormalities in mice.

Special delivery for fatty liver disease Nonalcoholic fatty liver disease is one of many unwelcome consequences of the global rise in obesity rates. Fat accumulation within the liver can lead to inflammation and cirrhosis, a predisposing factor for liver cancer. Treatment options are limited. Perry et al. revisit a mitochondrial uncoupling agent (2,4-dinitrophenol) that was used as a drug for weight loss in the 1930s but was discontinued because of serious toxicities. Encouragingly, an altered formulation of the drug that ensures its controlled release at low levels ameliorated fatty liver and diabetes in rodent models, without side effects. Science , this issue p. 1253

We thank Constantin-Teodosiu et al. (1) for their comments on our manuscript (2). Constantin-Teodosiu et al. interpret our data to indicate that mice with genetic activation of pyruvate dehydrogenase (PDH) by deletion of pyruvate dehydrogenase kinase isoforms 2 and 4 (DKO mice) are protected from high-fat diet (HFD)-induced muscle insulin resistance. Although Constantin-Teodosiu et al. correctly point out that HFD feeding did not worsen insulin-stimulated muscle glucose uptake in DKO mice (compare figure 2h and figure S4f from ref. 2), comparison with chow-fed WT control mice reveals that insulin-stimulated muscle glucose uptake was decreased by 50% in DKO mice on both regular chow and HFD (compare figure 2h and figure S4f of ref. 2). Therefore, to claim that DKO mice are protected from HFD-induced muscle insulin resistance is misleading. Such a claim overlooks the critical point that both chow-fed and HFD-fed DKO mice exhibit profound muscle insulin resistance. With respect to the therapeutic potential of pharmacological PDH activators, these data are therefore somewhat inauspicious.

Hibernating mammals possess a unique ability to reduce their body temperature to ambient levels, which can be as low as −2.9 °C, by active down-regulation of metabolism. Despite such a depressed physiologic phenotype, hibernators still maintain activity in their nervous systems, as evidenced by their continued sensitivity to auditory, tactile, and thermal stimulation. The molecular mechanisms that underlie this adaptation remain unknown. We report, using differential transcriptomics alongside immunohistologic and biochemical analyses, that neurons from thirteen-lined ground squirrels (Ictidomys tridecemlineatus) express mitochondrial uncoupling protein 1 (UCP1). The expression changes seasonally, with higher expression during hibernation compared with the summer active state. Functional and pharmacologic analyses show that squirrel UCP1 acts as the typical thermogenic protein in vitro. Accordingly, we found that mitochondria isolated from torpid squirrel brain show a high level of palmitate-induced uncoupling. Furthermore, torpid squirrels during the hibernation season keep their brain temperature significantly elevated above ambient temperature and that of the rest of the body, including brown adipose tissue. Together, our findings suggest that UCP1 contributes to local thermogenesis in the squirrel brain, and thus supports nervous tissue function at low body temperature during hibernation.

A central paradox in type 2 diabetes is the apparent selective nature of hepatic insulin resistance--wherein insulin fails to suppress hepatic glucose production yet continues to stimulate lipogenesis, resulting in hyperglycemia, hyperlipidemia, and hepatic steatosis. Although efforts to explain this have focused on finding a branch point in insulin signaling where hepatic glucose and lipid metabolism diverge, we hypothesized that hepatic triglyceride synthesis could be driven by substrate, independent of changes in hepatic insulin signaling. We tested this hypothesis in rats by infusing [U-(13)C] palmitate to measure rates of fatty acid esterification into hepatic triglyceride while varying plasma fatty acid and insulin concentrations independently. These experiments were performed in normal rats, high fat-fed insulin-resistant rats, and insulin receptor 2'-O-methoxyethyl chimeric antisense oligonucleotide-treated rats. Rates of fatty acid esterification into hepatic triglyceride were found to be dependent on plasma fatty acid infusion rates, independent of changes in plasma insulin concentrations and independent of hepatocellular insulin signaling. Taken together, these results obviate a paradox of selective insulin resistance, because the major source of hepatic lipid synthesis, esterification of preformed fatty acids, is primarily dependent on substrate delivery and largely independent of hepatic insulin action.

Recent studies have demonstrated that fatty acids induce insulin resistance in skeletal muscle by blocking insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase (PI3-kinase). To examine the mechanism by which fatty acids mediate this effect, rats were infused with either a lipid emulsion (consisting mostly of 18:2 fatty acids) or glycerol. Intracellular C18:2 CoA increased in a time-dependent fashion, reaching an approximately 6-fold elevation by 5 h, whereas there was no change in the concentration of any other fatty acyl-CoAs. Diacylglycerol (DAG) also increased transiently after 3-4 h of lipid infusion. In contrast there was no increase in intracellular ceramide or triglyceride concentrations during the lipid infusion. Increases in intracellular C18:2 CoA and DAG concentration were associated with protein kinase C (PKC)-theta activation and a reduction in both insulin-stimulated IRS-1 tyrosine phosphorylation and IRS-1 associated PI3-kinase activity, which were associated with an increase in IRS-1 Ser(307) phosphorylation. These data support the hypothesis that an increase in plasma fatty acid concentration results in an increase in intracellular fatty acyl-CoA and DAG concentrations, which results in activation of PKC-theta leading to increased IRS-1 Ser(307) phosphorylation. This in turn leads to decreased IRS-1 tyrosine phosphorylation and decreased activation of IRS-1-associated PI3-kinase activity resulting in decreased insulin-stimulated glucose transport activity.

Defects in liver and muscle glycogen synthesis are major factors contributing to postprandrial hyperglycemia in patients with type 2 diabetes. Therefore, activation of glycogen synthase through inhibition of glycogen synthase kinase (GSK)-3 represents a potential new therapeutic target. To examine this possibility, we performed oral glucose tolerance tests (OGTTs) and euglycemic-insulinemic clamp studies in Zucker diabetic fatty (fa/fa) rats before and after treatment with novel GSK-3 inhibitors. GSK-3 inhibition caused a 41 ± 2% (P < 0.001) and 26 ± 4% (P < 0.05) reduction in the area under the glucose and insulin concentration curves, respectively, during the OGTT. This improvement in glucose disposal could mostly be attributed to an approximate twofold increase in liver glycogen synthesis. In contrast, there was no significant increase in muscle glycogen synthesis despite an approximate threefold activation of muscle glycogen synthase activity. GSK-3 inhibitor treatment increased liver glycogen synthesis about threefold independent of insulin concentration during the clamp studies. In contrast, muscle glucose uptake and muscle glycogen synthesis were independent of drug treatment. GSK-3 inhibitor treatment lowered fasting hyperglycemia in diabetic rats by 6.0 ± 1.3 mmol/l but had no significant effect on glucose disposal during the clamp. In conclusion, GSK-3 inhibition significantly improved oral glucose disposal, mostly by increasing liver glycogen synthesis. These studies suggest that GSK-3 inhibition may represent an important new therapeutic target for treatment of patients with type 2 diabetes.