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Lee C.C.,University of Toronto | Watkins S.M.,Lipomics Technologies | Lorenzo C.,University of Texas Health Science Center at San Antonio | Il'Yasova D.,Georgia State University | And 4 more authors.
Diabetes Care | Year: 2016

OBJECTIVE Recent studies using untargeted metabolomics approaches have suggested that plasma branched-chain amino acids (BCAAs) are associated with incident diabetes. However, little is known about the role of plasma BCAAs in metabolic abnormalities underlying diabetes and whether these relationships are consistent across ethnic populations at high risk for diabetes. We investigated the associations of BCAAs with insulin sensitivity (SI), acute insulin response (AIR), and metabolic clearance of insulin (MCRI) in a multiethnic cohort. RESEARCH DESIGN AND METHODS In 685 participants without diabetes of the Insulin Resistance Atherosclerosis Study (IRAS) (290 Caucasians, 165 African Americans, and 230 Hispanics),wemeasured plasma BCAAs (sum of valine, leucine, and isoleucine) by mass spectrometry and SI, AIR, and MCRI by frequently sampled intravenous glucose tolerance tests. RESULTS Elevated plasma BCAAs were inversely associated with SI andMCRI and positively associated with fasting insulin in regression models adjusted for potential confounders (β = 20.0012 [95% CI20.0018,20.00059], P < 0.001 for SI; β =20.0013 [95% CI 20.0018, 20.00082], P < 0.001 for MCRI; and β = 0.0015 [95% CI 0.0008, 0.0023], P < 0.001 for fasting insulin). The association of BCAA with SI was significantly modified by ethnicity, with the association only being significant in Caucasians and Hispanics. Elevated plasma BCAAs were associated with incident diabetes in Caucasians and Hispanics (multivariable-adjusted odds ratio per 1-SD increase in plasma BCAAs: 1.67 [95% CI 1.21, 2.29], P = 0.002) but not in African Americans. Plasma BCAAs were not associated with SI-adjusted AIR. CONCLUSIONS Plasma BCAAs are associated with incident diabetes and underlying metabolic abnormalities, although the associations were generally stronger in Caucasians and Hispanics. © 2016 by the American Diabetes Association.


News Article | November 4, 2016
Site: www.sciencedaily.com

By removing the protein galectin-3 (Gal3), a team of investigators led by University of California School of Medicine researchers were able to reverse diabetic insulin resistance and glucose intolerance in mouse models of obesity and diabetes. By binding to insulin receptors on cells, Gal3 prevents insulin from attaching to the receptors resulting in cellular insulin resistance. The team led by Jerrold Olefsky, MD, professor of medicine in the Division of Endocrinology and Metabolism at UC San Diego School of Medicine, showed that by genetically removing Gal3 or using pharmaceutical inhibitors to target it, insulin sensitivity and glucose tolerance could be returned to normal, even among older mice. However, obesity remained unchanged. "This study puts Gal3 on the map for insulin resistance and diabetes in mouse model," said Olefsky, associate dean for scientific affairs and senior author of the study. "Our findings suggest that Gal3 inhibition in people could be an effective anti-diabetic approach." Olefsky and other researchers have been studying how chronic tissue inflammation leads to insulin resistance in type 2 diabetes. In the paper, published in the journal Cell on November 3, researchers explain that inflammation requires macrophages -- specialized cells that destroy targeted cells. In obese adipose tissue (fat), for example, 40 percent of cells are macrophages. Macrophages in turn secrete Gal3, which then acts as a signaling protein attracting more macrophages, thus resulting in the production of even more Gal3. Furthermore, investigators identified bone marrow-derived macrophages as the source of Gal3 that leads to insulin resistance. More importantly, researchers found that Gal3 is secreted by macrophages, and can then cause insulin resistance in liver, fat cells, and muscle cells independent of inflammation. Gal3 has previously been connected to other diseases. Olefsky will continue to study Gal3 depletion as a possible therapeutic target for nonalcoholic steatohepatitis as well as heart and liver fibrosis. Study co-authors include: Pingping Li, Chinese Academy of Medical Sciences, Peking Union Medical College and UC San Diego; Shuainan Liu, Zhufang Shen, Bing Cui, Lijuan Kong, Shaocong Hou, Xiao Liang, Chinese Academy of Medical Sciences, Peking Union Medical College; Min Lu, UC San Diego, and Merck Research Laboratories; Gautum Bandyyopadhyay, Dayoung Oh, Andrew M. Johnson, Dorothy Sears, Wei Ying, Olivia Osborn, Joshua Wollam, UC San Diego; Takeshi Imamura, Shiga University of Medical Science; Salvatore Iovino, Martin Brenner, Merck Research Laboratories; Steven M. Watkins, Lipomics Technologies, Inc. This research was funded, in part, by grants from the National Institutes of Health (DK033651, DK074868, DK063491, DK09062) and Merck (LKR159915).


News Article | November 3, 2016
Site: www.eurekalert.org

By removing the protein galectin-3 (Gal3), a team of investigators led by University of California School of Medicine researchers were able to reverse diabetic insulin resistance and glucose intolerance in mouse models of obesity and diabetes. By binding to insulin receptors on cells, Gal3 prevents insulin from attaching to the receptors resulting in cellular insulin resistance. The team led by Jerrold Olefsky, MD, professor of medicine in the Division of Endocrinology and Metabolism at UC San Diego School of Medicine, showed that by genetically removing Gal3 or using pharmaceutical inhibitors to target it, insulin sensitivity and glucose tolerance could be returned to normal, even among older mice. However, obesity remained unchanged. "This study puts Gal3 on the map for insulin resistance and diabetes in mouse model," said Olefsky, associate dean for scientific affairs and senior author of the study. "Our findings suggest that Gal3 inhibition in people could be an effective anti-diabetic approach." Olefsky and other researchers have been studying how chronic tissue inflammation leads to insulin resistance in type 2 diabetes. In the paper, published in the journal Cell on November 3, researchers explain that inflammation requires macrophages -- specialized cells that destroy targeted cells. In obese adipose tissue (fat), for example, 40 percent of cells are macrophages. Macrophages in turn secrete Gal3, which then acts as a signaling protein attracting more macrophages, thus resulting in the production of even more Gal3. Furthermore, investigators identified bone marrow-derived macrophages as the source of Gal3 that leads to insulin resistance. More importantly, researchers found that Gal3 is secreted by macrophages, and can then cause insulin resistance in liver, fat cells, and muscle cells independent of inflammation. Gal3 has previously been connected to other diseases. Olefsky will continue to study Gal3 depletion as a possible therapeutic target for nonalcoholic steatohepatitis as well as heart and liver fibrosis. Study co-authors include: Pingping Li, Chinese Academy of Medical Sciences, Peking Union Medical College and UC San Diego; Shuainan Liu, Zhufang Shen, Bing Cui, Lijuan Kong, Shaocong Hou, Xiao Liang, Chinese Academy of Medical Sciences, Peking Union Medical College; Min Lu, UC San Diego, and Merck Research Laboratories; Gautum Bandyyopadhyay, Dayoung Oh, Andrew M. Johnson, Dorothy Sears, Wei Ying, Olivia Osborn, Joshua Wollam, UC San Diego; Takeshi Imamura, Shiga University of Medical Science; Salvatore Iovino, Martin Brenner, Merck Research Laboratories; Steven M. Watkins, Lipomics Technologies, Inc.


Lu M.,University of California at San Diego | Patsouris D.,University of California at San Diego | Li P.,University of California at San Diego | Flores-Riveros J.,Hollis Eden Pharmaceuticals | And 4 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2010

Lu M, Patsouris D, Li P, Flores-Riveros J, Frincke JM, Watkins S, Schenk S, Olefsky JM. A new antidiabetic compound attenuates inflammation and insulin resistance in Zucker diabetic fatty rats. Am J Physiol Endocrinol Metab 298: E1036-E1048, 2010. First published February 16, 2010; doi:10.1152/ajpendo.00668. 2009. - Tissue macrophage inflammatory pathways contribute to obesity-associated insulin resistance. Here, we have examined the efficacy and mechanisms of action of a novel anti-inflammatory compound (HE3286) in vitro and in vivo. In primary murine macrophages, HE3286 attenuates LPS- and TNFα-stimulated inflammation. In Zucker diabetic fatty rats, inflammatory cytokine/chemokine expression was downregulated in liver and adipose tissue by HE3286 treatment, as was macrophage infiltration into adipose tissue. In line with reduced inflammation, HE3286 treatment normalized fasting and fed glucose levels, improved glucose tolerance, and enhanced skeletal muscle and liver insulin sensitivity, as assessed by hyperinsulinemic euglycemic clamp studies. In phase 2 clinical trials, HE3286 treatment led to an enhancement in insulin sensitivity in humans. Gluconeogenic capacity was also reduced by HE3286 treatment, as evidenced by a reduced glycemic response during pyruvate tolerance tests and decreased basal hepatic glucose production (HGP) rates. Since serum levels of gluconeogenic substrates were decreased by HE3286, it indicates that the reduction of both intrinsic gluconeogenic capacity and substrate availability contributes to the decrease in HGP. Lipidomic analysis revealed that HE3286 treatment reduced liver cholesterol and triglyceride content, leading to a feedback elevation of LDL receptor and HMG-CoA reductase expression. Accordingly, HE3286 treatment markedly decreased total serum cholesterol. In conclusion, HE3286 is a novel anti-inflammatory compound, which displays both glucose-lowering and cholesterol-lowering effects. Copyright © 2010 the American Physiological Society.


Oh D.Y.,University of California at San Diego | Walenta E.,University of California at San Diego | Akiyama T.E.,Merck And Co. | Lagakos W.S.,University of California at San Diego | And 18 more authors.
Nature Medicine | Year: 2014

It is well known that the ω-3 fatty acids (ω-3-FAs; also known as n-3 fatty acids) can exert potent anti-inflammatory effects. Commonly consumed as fish products, dietary supplements and pharmaceuticals, ω-3-FAs have a number of health benefits ascribed to them, including reduced plasma triglyceride levels, amelioration of atherosclerosis and increased insulin sensitivity. We reported that Gpr120 is the functional receptor for these fatty acids and that ω-3-FAs produce robust anti-inflammatory, insulin-sensitizing effects, both in vivo and in vitro, in a Gpr120-dependent manner. Indeed, genetic variants that predispose to obesity and diabetes have been described in the gene encoding GPR120 in humans (FFAR4). However, the amount of fish oils that would have to be consumed to sustain chronic agonism of Gpr120 is too high to be practical, and, thus, a high-affinity small-molecule Gpr120 agonist would be of potential clinical benefit. Accordingly, Gpr120 is a widely studied drug discovery target within the pharmaceutical industry. Gpr40 is another lipid-sensing G protein-coupled receptor, and it has been difficult to identify compounds with a high degree of selectivity for Gpr120 over Gpr40 (ref. 11). Here we report that a selective high-affinity, orally available, small-molecule Gpr120 agonist (cpdA) exerts potent anti-inflammatory effects on macrophages in vitro and in obese mice in vivo. Gpr120 agonist treatment of high-fat diet-fed obese mice causes improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity and decreased hepatic steatosis. This suggests that Gpr120 agonists could become new insulin-sensitizing drugs for the treatment of type 2 diabetes and other human insulin-resistant states in the future. © 2014 Nature America, Inc.


Lee Y.S.,University of California at San Diego | Kim J.-W.,University of California at San Diego | Osborne O.,University of California at San Diego | Oh D.Y.,University of California at San Diego | And 11 more authors.
Cell | Year: 2014

Adipose tissue hypoxia and inflammation have been causally implicated in obesity-induced insulin resistance. Here, we report that, early in the course of high-fat diet (HFD) feeding and obesity, adipocyte respiration becomes uncoupled, leading to increased oxygen consumption and a state of relative adipocyte hypoxia. These events are sufficient to trigger HIF-1α induction, setting off the chronic adipose tissue inflammatory response characteristic of obesity. At the molecular level, these events involve saturated fatty acid stimulation of the adenine nucleotide translocase 2 (ANT2), an inner mitochondrial membrane protein, which leads to the uncoupled respiratory state. Genetic or pharmacologic inhibition of either ANT2 or HIF-1α can prevent or reverse these pathophysiologic events, restoring a state of insulin sensitivity and glucose tolerance. These results reveal the sequential series of events in obesity-induced inflammation and insulin resistance. © 2014 Elsevier Inc.


Li P.,University of California at San Diego | Li P.,Lipomics Technologies | Spann N.J.,University of California at San Diego | Kaikkonen M.U.,University of California at San Diego | And 16 more authors.
Cell | Year: 2013

Summary Macrophage-mediated inflammation is a major contributor to obesity-associated insulin resistance. The corepressor NCoR interacts with inflammatory pathway genes in macrophages, suggesting that its removal would result in increased activity of inflammatory responses. Surprisingly, we find that macrophage-specific deletion of NCoR instead results in an anti-inflammatory phenotype along with robust systemic insulin sensitization in obese mice. We present evidence that derepression of LXRs contributes to this paradoxical anti-inflammatory phenotype by causing increased expression of genes that direct biosynthesis of palmitoleic acid and ω3 fatty acids. Remarkably, the increased ω3 fatty acid levels primarily inhibit NF-κB-dependent inflammatory responses by uncoupling NF-κB binding and enhancer/promoter histone acetylation from subsequent steps required for proinflammatory gene activation. This provides a mechanism for the in vivo anti-inflammatory insulin-sensitive phenotype observed in mice with macrophage-specific deletion of NCoR. Therapeutic methods to harness this mechanism could lead to a new approach to insulin-sensitizing therapies. © 2013 Elsevier Inc.


Ellis J.M.,University of North Carolina at Chapel Hill | Li L.O.,University of North Carolina at Chapel Hill | Wu P.-C.,University of North Carolina at Chapel Hill | Koves T.R.,Duke University | And 5 more authors.
Cell Metabolism | Year: 2010

Long-chain acyl-CoA synthetase-1 (ACSL1) contributes 80% of total ACSL activity in adipose tissue and was believed to be essential for the synthesis of triacylglycerol. We predicted that an adipose-specific knockout of ACSL1 (Acsl1A-/-) would be lipodystrophic, but compared to controls, Acsl1A-/- mice had 30% greater fat mass when fed a low-fat diet and gained weight normally when fed a high-fat diet. Acsl1A-/- adipocytes incorporated [14C]oleate into glycerolipids normally, but fatty acid (FA) oxidation rates were 50%-90% lower than in control adipocytes and mitochondria. Acsl1A-/- mice were markedly cold intolerant, and β3-adrenergic agonists did not increase oxygen consumption, despite normal adrenergic signaling in brown adipose tissue. The reduced adipose FA oxidation and marked cold intolerance of Acsl1A-/- mice indicate that normal activation of FA for oxidation in adipose tissue in vivo requires ACSL1. Thus, ACSL1 has a specific function in directing the metabolic partitioning of FAs toward β-oxidation in adipocytes. © 2010 Elsevier Inc.


Novel methods for assessing the level of triglycerides in the liver of a subject are described, comprising determining the amount of a lipid metabolite in a sample from a body fluid of the subject. The methods may be used, for example, in diagnosing and monitoring liver disorders such as steatosis, NAFLD and NASH.


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