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Impact of gain-of-function mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) on glucose and lipid homeostasis.

Recent Publications of BIIC Members - Wed, 03/15/2017 - 01:58
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Impact of gain-of-function mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) on glucose and lipid homeostasis.

Osteoporos Int. 2017 Mar 10;:

Authors: Foer D, Zhu M, Cardone RL, Simpson C, Sullivan R, Nemiroff S, Lee G, Kibbey RG, Petersen KF, Insogna KL

Abstract
LRP5 loss-of-function mutations have been shown to cause profound osteoporosis and have been associated with impaired insulin sensitivity and dysregulated lipid metabolism. We hypothesized that gain-of-function mutations in LRP5 would also affect these parameters. We therefore studied individuals with LRP5 gain-of-function mutations exhibiting high bone mass (HBM) phenotypes and found that while there was no detected change in insulin sensitivity, there was a significant reduction in serum LDL.
INTRODUCTION: Wnt signaling through LRP5 represents a newly appreciated metabolic pathway, which potentially represents a target for drug discovery in type 2 diabetes and hyperlipidemia. Studies in animal models suggest a physiologic link between LRP5 and glucose and lipid homeostasis; however, whether it plays a similar role in humans is unclear. As current literature links loss-of-function LRP5 to impaired glucose and lipid metabolism, we hypothesized that individuals with an HBM-causing mutation in LRP5 would exhibit improved glucose and lipid homeostasis. Since studies in animal models have suggested that Wnt signaling augments insulin secretion, we also examined the effect of Wnt signaling on glucose-stimulated insulin secretion on human pancreatic islets.
METHODS: This was a matched case-control study. We used several methods to assess glucose and lipid metabolism in 11 individuals with HBM-causing mutations in LRP5. Affected study participants were recruited from previously identified kindreds with HBM-causing LRP5 mutations and included 9 males and 2 females. Two subjects that were being treated with insulin for type 2 diabetes were excluded from our analysis, as this would have obscured our ability to determine the impact of gain-of-function LRP5 mutations on glucose metabolism. The mean age of the evaluated study subjects was 55 ± 7 with a mean BMI of 27.2 ± 2.0. Control subjects were matched and recruited from the general community at an equivalent ratio, with 18 males and 4 females (mean age 56 ± 4; mean BMI 27.2 ± 1.0). Study testing was conducted at an academic medical center.
RESULTS: There were no statistically significant differences between affected and matched control populations for HbA1c (p = 0.06), eAG (p = 0.06), insulin (p = 0.82), HOMA-B (p = 0.34), or HOMA-IR (p = 0.66). The mean Insulin Sensitivity Index (ISI) was also similar between control and affected individuals. Total cholesterol (p = 0.43), triglycerides (TG) (p = 0.56), and HDL (p = 0.32) were not different between the same two groups. In a small subset of studied subjects, intramyocellular and hepatic lipid content were similar in the affected individuals and controls when quantified by proton magnetic resonance spectroscopy (MRS). However, the mean value for serum LDL was significantly lower (p = 0.04) in affected individuals. In primary human islets, there were no differences between control and Wnt treatment groups for insulin secretion measured as area under the curve (AUC) for first phase (p = 0.17) or second phase (p = 0.33) insulin secretion.
CONCLUSIONS: Although our sample size was small, our data do not support the hypothesis that HBM-causing LRP5 mutations, associated with increased Wnt signaling, improve glucose metabolism in humans. However, it does appear that LRP5 variants may affect LDL metabolism, a major risk factor for coronary artery disease. The molecular mechanisms underpinning this effect warrant further study.

PMID: 28283687 [PubMed - as supplied by publisher]

Metabolic fate of glucose and candidate signaling and excess-fuel detoxification pathways in pancreatic β-cells.

Recent Publications of BIIC Members - Sat, 03/11/2017 - 22:44
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Metabolic fate of glucose and candidate signaling and excess-fuel detoxification pathways in pancreatic β-cells.

J Biol Chem. 2017 Mar 09;:

Authors: Mugabo Y, Zhao S, Lamontagne J, Al-Mass A, Peyot ML, Corkey BE, Joly E, Madiraju SR, Prentki M

Abstract
Glucose metabolism promotes insulin secretion in β-cells via metabolic coupling factors that are incompletely defined. Moreover, chronically elevated glucose causes β-cell dysfunction, but little is known about how cells handle excess fuels to avoid toxicity. Here we sought to determine which among the candidate pathways and coupling factors best correlates with glucose-stimulated insulin secretion (GSIS), define the fate of glucose in the β-cell, and identify pathways possibly involved in excess-fuel detoxification. We exposed isolated rat islets for 1 h to increasing glucose concentrations and measured various pathways and metabolites. Glucose oxidation, oxygen consumption, and ATP production correlated well with GSIS and saturated at 16 mM glucose. However, glucose utilization, glycerol release, triglyceride and glycogen contents, free fatty acid (FFA) content and release, and cholesterol and cholesterol esters increased linearly up to 25 mM glucose. Besides being oxidized, glucose was mainly metabolized via glycerol production and release and lipid synthesis (particularly FFA, triglycerides, and cholesterol), whereas glycogen production was comparatively low. Using targeted metabolomics in INS-1(832/13) cells, we found that several metabolites correlated well with GSIS, in particular, some Krebs cycle intermediates, malonyl-CoA, and lower ADP levels. Glucose dose dependently increased the dihydroxyacetone phosphate/glycerol 3-phosphate ratio in INS1(832/13) cells, indicating a more oxidized state of NAD in the cytosol upon glucose stimulation. Overall, the data support a role for accelerated oxidative mitochondrial metabolism, anaplerosis, and malonyl-CoA/lipid signaling in β-cell metabolic signaling and suggest that a decrease in ADP levels is important in GSIS. The results also suggest that excess-fuel detoxification pathways in β-cells possibly comprise glycerol and FFA formation and release extracellularly and the diversion of glucose carbons to triglycerides and cholesterol esters.

PMID: 28280244 [PubMed - as supplied by publisher]

Listeria monocytogenes induces an interferon-enhanced activation of the integrated stress response that is detrimental for resolution of infection in mice.

Recent Publications of BIIC Members - Wed, 03/08/2017 - 20:59
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Listeria monocytogenes induces an interferon-enhanced activation of the integrated stress response that is detrimental for resolution of infection in mice.

Eur J Immunol. 2017 Mar 07;:

Authors: Valderrama C, Clark A, Urano F, Unanue ER, Carrero JA

Abstract
Type I interferons (IFNs) induce a detrimental response during Listeria monocytogenes (L. monocytogenes) infection. We were interested in identifying mechanisms linking IFN signaling to negative host responses against L. monocytogenes infection. Herein we found that infection of myeloid cells with L. monocytogenes led to a coordinated induction of type I IFNs and activation of the integrated stress response (ISR). Infected cells did not induce Xbp1 splicing or BiP upregulation, indicating that the unfolded protein response was not triggered. CHOP (Ddit3) gene expression was upregulated during the ISR activation induced by L. monocytogenes. Myeloid cells deficient in either type I IFN signaling or PKR activation had less upregulation of CHOP following infection. CHOP deficient mice showed lower expression of innate immune cytokines and were more resistant than wild-type counterparts following L. monocytogenes infection. These findings indicate that L. monocytogenes infection induces type I IFNs, which activate the ISR through PKR, which contributes to a detrimental outcome in the infected host. This article is protected by copyright. All rights reserved.

PMID: 28267207 [PubMed - as supplied by publisher]

Daclatasvir and asunaprevir treatment in patients with severe liver fibrosis by HCV genotype 1b infection: Real world data.

Recent Publications of BIIC Members - Sun, 03/05/2017 - 19:11
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Daclatasvir and asunaprevir treatment in patients with severe liver fibrosis by HCV genotype 1b infection: Real world data.

J Gastroenterol Hepatol. 2017 Mar 04;:

Authors: Ishigami M, Hayashi K, Honda T, Kuzuya T, Ishizu Y, Ishikawa T, Nakano I, Urano F, Kumada T, Yoshioka K, Goto H, Hirooka Y

Abstract
BACKGROUNDS AND AIMS: In this study, we investigated the real-world data of the first approved interferon free regimen in Japan; daclatasvir as asunaprevir in chronic hepatitis C patients with severe fibrosis.
PATIENTS AND METHODS: Among 924 patients registered in our multicenter study, 535 patients were defined as having severe fibrosis with Fib-4 index≧3.25, and were included in this study. We investigated anti-viral effect and factors associated with SVR12, and the additional effects on serum AFP and albumin levels by eradicating virus in patients who attained SVR were investigated. In statistical analysis, P<0.05 was considered as significant levels.
RESULTS: Anti-viral effect was lower in patients with severe fibrosis at 8 and 12 weeks after start of the treatment (96.3%, 97.1% with severe fibrosis vs 99.5%, 99.2% without severe fibrosis, P=0.002 and P=0.036, respectively), and more early relapse (SVR4; 90.4% with severe fibrosis vs 95.4% without fibrosis, P=0.008) were seen in patients with severe fibrosis, however, there were no differences in SVR12 and SVR24. In the safety profiles, discontinuation rate due to liver injury (2.8% with severe fibrosis vs 3.3% without severe fibrosis) or other causes of discontinuation was not different between two groups. Serum AFP significantly decreased and serum albumin levels significantly increased as early as 4 weeks after the start of treatment.
CONCLUSIONS: Though the anti-viral effect was slightly lower in patients with severe fibrosis compared with those without, treatment with daclatasvir and asunaprevir is basically an effective, and well-tolerable treatment in these populations.

PMID: 28258705 [PubMed - as supplied by publisher]

Evidence of stress in β cells obtained with laser capture microdissection from pancreases of brain dead donors.

Recent Publications of BIIC Members - Sun, 03/05/2017 - 19:11
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Evidence of stress in β cells obtained with laser capture microdissection from pancreases of brain dead donors.

Islets. 2017 Mar 04;9(2):19-29

Authors: Ebrahimi A, Jung MH, Dreyfuss JM, Pan H, Sgroi D, Bonner-Weir S, Weir GC

Abstract
Isolated islets used for transplantation are known to be stressed, which can result from the circumstances of death, in particular brain death, the preservation of the pancreas with its warm and cold ischemia, from the trauma of the isolation process, and the complex events that occur during tissue culture. The current study focused upon the events that occur before the islet isolation procedure. Pancreases were obtained from brain dead donors (n = 7) with mean age 50 (11) and normal pancreatic tissue obtained at surgery done for pancreatic neoplasms (n = 7), mean age 69 (9). Frozen sections were subjected to laser capture microdissection (LCM) to obtain β-cell rich islet tissue, from which extracted RNA was analyzed with microarrays. Gene expression of the 2 groups was evaluated with differential expression analysis for genes and pathways. Marked changes were found in pathways concerned with endoplasmic reticulum stress with its unfolded protein response (UPR), apoptotic pathways and components of inflammation. In addition, there were changes in genes important for islet cell identity. These findings advance our understanding of why islets are stressed before transplantation, which may lead to strategies to reduce this stress and lead to better clinical outcomes.

PMID: 28252345 [PubMed - in process]

Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells.

Recent Publications of BIIC Members - Thu, 03/02/2017 - 17:30
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Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells.

JCI Insight. 2017 Feb 23;2(4):e87489

Authors: Wang YY, Attané C, Milhas D, Dirat B, Dauvillier S, Guerard A, Gilhodes J, Lazar I, Alet N, Laurent V, Le Gonidec S, Biard D, Hervé C, Bost F, Ren GS, Bono F, Escourrou G, Prentki M, Nieto L, Valet P, Muller C

Abstract
In breast cancer, a key feature of peritumoral adipocytes is their loss of lipid content observed both in vitro and in human tumors. The free fatty acids (FFAs), released by adipocytes after lipolysis induced by tumor secretions, are transferred and stored in tumor cells as triglycerides in lipid droplets. In tumor cell lines, we demonstrate that FFAs can be released over time from lipid droplets through an adipose triglyceride lipase-dependent (ATGL-dependent) lipolytic pathway. In vivo, ATGL is expressed in human tumors where its expression correlates with tumor aggressiveness and is upregulated by contact with adipocytes. The released FFAs are then used for fatty acid β-oxidation (FAO), an active process in cancer but not normal breast epithelial cells, and regulated by coculture with adipocytes. However, in cocultivated cells, FAO is uncoupled from ATP production, leading to AMPK/acetyl-CoA carboxylase activation, a circle that maintains this state of metabolic remodeling. The increased invasive capacities of tumor cells induced by coculture are completely abrogated by inhibition of the coupled ATGL-dependent lipolysis/FAO pathways. These results show a complex metabolic symbiosis between tumor-surrounding adipocytes and cancer cells that stimulate their invasiveness, highlighting ATGL as a potential therapeutic target to impede breast cancer progression.

PMID: 28239646 [PubMed - in process]

Glucose Driven Changes in Beta Cell Identity Are Important for Function and Possibly Autoimmune Vulnerability during the Progression of Type 1 Diabetes.

Recent Publications of BIIC Members - Sun, 02/12/2017 - 06:34
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Glucose Driven Changes in Beta Cell Identity Are Important for Function and Possibly Autoimmune Vulnerability during the Progression of Type 1 Diabetes.

Front Genet. 2017;8:2

Authors: Weir GC, Bonner-Weir S

Abstract
This commentary explores the hypothesis that when autoimmunity leads to a fall of beta cell mass during the progression of type 1 diabetes (T1D), rising glucose levels cause major changes in beta cell identity. This then leads to profound changes in secretory function and less well-understood changes in beta cell susceptibility to autoimmune destruction, which may influence of rate of progression of beta cell killing.

PMID: 28174593 [PubMed - in process]

Novel Treatment of Chronic Graft-Versus-Host Disease in Mice Using the ER Stress Reducer 4-Phenylbutyric Acid.

Recent Publications of BIIC Members - Thu, 02/09/2017 - 01:15
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Novel Treatment of Chronic Graft-Versus-Host Disease in Mice Using the ER Stress Reducer 4-Phenylbutyric Acid.

Sci Rep. 2017 Feb 06;7:41939

Authors: Mukai S, Ogawa Y, Urano F, Kudo-Saito C, Kawakami Y, Tsubota K

Abstract
Chronic graft-versus-host disease (cGVHD) is a notorious complication of allogeneic hematopoietic stem cell transplantation and causes disabling systemic inflammation and fibrosis. In this novel study, we focused on a relationship between endoplasmic reticulum (ER) stress and cGVHD, and aimed to create effective treatment of cGVHD. A series of experiments were conducted using a mouse model of cGVHD. Our data suggested (1) that ER stress was elevated in organs affected by cGVHD and (2) that 4-phenylbutyric acid (PBA) could reduce cGVHD-induced ER stress and thereby alleviate systemic inflammation and fibrosis. Because fibroblasts are thought to be implicated in cGVHD-elicited fibrosis and because macrophages are reported to play a role in the development of cGVHD, we investigated cGVHD-triggered ER stress in fibroblasts and macrophages. Our investigation demonstrated (1) that indicators for ER stress and activation markers for fibroblasts were elevated in cGVHD-affected lacrimal gland fibroblasts and (2) that they could be reduced by PBA. Our work also indicated that splenic macrophages from PBA-dosed mice exhibited the lower levels of ER stress and M2 macrophage markers than those from cGVHD-affected mice. Collectively, this study suggests that the reduction of ER stress utilizing PBA can be a clinically translatable method to treat systemic cGVHD.

PMID: 28165054 [PubMed - in process]

Automated, Resin-Based Method to Enhance the Specific Activity of Fluorine-18 Clicked PET Radiotracers.

Recent Publications of BIIC Members - Thu, 02/09/2017 - 01:15
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Automated, Resin-Based Method to Enhance the Specific Activity of Fluorine-18 Clicked PET Radiotracers.

Bioconjug Chem. 2017 Feb 02;:

Authors: Pisaneschi F, Kelderhouse LE, Hardy A, Engel BJ, Mukhopadhyay U, Gonzalez-Lepera C, Gray JP, Ornelas A, Takahashi TT, Roberts RW, Fiacco SV, Piwnica-Worms D, Millward SW

Abstract
Radiolabeling of substrates with 2-[(18)F]fluoroethylazide exploits the rapid kinetics, chemical selectivity, and mild conditions of the copper-catalyzed azide-alkyne cycloaddition reaction. While this methodology has proven to result in near-quantitative labeling of alkyne-tagged precursors, the relatively small size of the fluoroethylazide group makes separation of the (18)F-labeled radiotracer and the unreacted precursor challenging, particularly with precursors >500 Da (e.g., peptides). We have developed an inexpensive azide-functionalized resin to rapidly remove unreacted alkyne precursor following the fluoroethylazide labeling reaction and integrated it into a fully automated radiosynthesis platform. We have carried out 2-[(18)F]fluoroethylazide labeling of four different alkynes ranging from <300 Da to >1700 Da and found that >98% of the unreacted alkyne was removed in less than 20 min at room temperature to afford the final radiotracers at >99% radiochemical purity with specific activities up to >200 GBq/μmol. We have applied this technique to label a novel cyclic peptide previously evolved to bind the Her2 receptor with high affinity, and demonstrated tumor-specific uptake and low nonspecific background by PET/CT. This resin-based methodology is automated, rapid, mild, and general allowing peptide-based fluorine-18 radiotracers to be obtained with clinically relevant specific activities without chromatographic separation and with only a minimal increase in total synthesis time.

PMID: 28150941 [PubMed - as supplied by publisher]

Mechanism for leptin's acute insulin-independent effect to reverse diabetic ketoacidosis.

Recent Publications of BIIC Members - Fri, 01/27/2017 - 21:01
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Mechanism for leptin's acute insulin-independent effect to reverse diabetic ketoacidosis.

J Clin Invest. 2017 Jan 23;:

Authors: Perry RJ, Peng L, Abulizi A, Kennedy L, Cline GW, Shulman GI

Abstract
The mechanism by which leptin reverses diabetic ketoacidosis (DKA) is unknown. We examined the acute insulin-independent effects of leptin replacement therapy in a streptozotocin-induced rat model of DKA. Leptin infusion reduced rates of lipolysis, hepatic glucose production (HGP), and hepatic ketogenesis by 50% within 6 hours and were independent of any changes in plasma glucagon concentrations; these effects were abrogated by coinfusion of corticosterone. Treating leptin- and corticosterone-infused rats with an adipose triglyceride lipase inhibitor blocked corticosterone-induced increases in plasma glucose concentrations and rates of HGP and ketogenesis. Similarly, adrenalectomized type 1 diabetic (T1D) rats exhibited decreased rates of lipolysis, HGP, and ketogenesis; these effects were reversed by corticosterone infusion. Leptin-induced decreases in lipolysis, HGP, and ketogenesis in DKA were also nullified by relatively small increases (15 to 70 pM) in plasma insulin concentrations. In contrast, the chronic glucose-lowering effect of leptin in a STZ-induced mouse model of poorly controlled T1D was associated with decreased food intake, reduced plasma glucagon and corticosterone concentrations, and decreased ectopic lipid (triacylglycerol/diacylglycerol) content in liver and muscle. Collectively, these studies demonstrate marked differences in the acute insulin-independent effects by which leptin reverses fasting hyperglycemia and ketoacidosis in a rodent model of DKA versus the chronic pleotropic effects by which leptin reverses hyperglycemia in a non-DKA rodent model of T1D.

PMID: 28112679 [PubMed - as supplied by publisher]

A Non-invasive Method to Assess Hepatic Acetyl-CoA In Vivo.

Recent Publications of BIIC Members - Fri, 01/27/2017 - 21:01
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A Non-invasive Method to Assess Hepatic Acetyl-CoA In Vivo.

Cell Metab. 2017 Jan 18;:

Authors: Perry RJ, Peng L, Cline GW, Petersen KF, Shulman GI

Abstract
Acetyl-coenzyme A (acetyl-CoA) is a critical metabolic signaling molecule that regulates gluconeogenesis, pyruvate oxidation, protein acetylation, and steroid and fatty acid biosynthesis; however, measurements of this metabolite using standard biochemical approaches are technically demanding, and there is currently no method to non-invasively assess hepatic acetyl-CoA content in vivo. To this end, we developed and validated a method to non-invasively detect differences in hepatic acetyl-CoA content in vivo across a 5-fold range of physiological acetyl-CoA concentrations by assessing the turnover of [(13)C4]β-hydroxybutyrate (β-OHB). Here, we show a strong correlation (R(2) = 0.86, p < 0.0001) between hepatic acetyl-CoA content and β-OHB turnover in rats with varying degrees of fasting hyperglycemia and insulin resistance. These studies demonstrate that β-OHB turnover can be used as a surrogate to non-invasively assess hepatic acetyl-CoA content, thereby allowing researchers to further elucidate the role of this metabolite in the regulation of hepatic gluconeogenesis and other metabolic processes in vivo.

PMID: 28111213 [PubMed - as supplied by publisher]

Argininosuccinate synthetase regulates hepatic AMPK linking protein catabolism and ureagenesis to hepatic lipid metabolism.

Recent Publications of BIIC Members - Fri, 01/27/2017 - 21:01
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Argininosuccinate synthetase regulates hepatic AMPK linking protein catabolism and ureagenesis to hepatic lipid metabolism.

Proc Natl Acad Sci U S A. 2016 06 14;113(24):E3423-30

Authors: Madiraju AK, Alves T, Zhao X, Cline GW, Zhang D, Bhanot S, Samuel VT, Kibbey RG, Shulman GI

Abstract
A key sensor of cellular energy status, AMP-activated protein kinase (AMPK), interacts allosterically with AMP to maintain an active state. When active, AMPK triggers a metabolic switch, decreasing the activity of anabolic pathways and enhancing catabolic processes such as lipid oxidation to restore the energy balance. Unlike oxidative tissues, in which AMP is generated from adenylate kinase during states of high energy demand, the ornithine cycle enzyme argininosuccinate synthetase (ASS) is a principle site of AMP generation in the liver. Here we show that ASS regulates hepatic AMPK, revealing a central role for ureagenesis flux in the regulation of metabolism via AMPK. Treatment of primary rat hepatocytes with amino acids increased gluconeogenesis and ureagenesis and, despite nutrient excess, induced both AMPK and acetyl-CoA carboxylase (ACC) phosphorylation. Antisense oligonucleotide knockdown of hepatic ASS1 expression in vivo decreased liver AMPK activation, phosphorylation of ACC, and plasma β-hydroxybutyrate concentrations. Taken together these studies demonstrate that increased amino acid flux can activate AMPK through increased AMP generated by ASS, thus providing a novel link between protein catabolism, ureagenesis, and hepatic lipid metabolism.

PMID: 27247419 [PubMed - indexed for MEDLINE]

GABA Signaling Stimulates β Cell Regeneration in Diabetic Mice.

Recent Publications of BIIC Members - Sun, 01/15/2017 - 14:56
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GABA Signaling Stimulates β Cell Regeneration in Diabetic Mice.

Cell. 2017 Jan 12;168(1-2):7-9

Authors: Weir GC, Bonner-Weir S

Abstract
GABA and the antimalarial drug artemether, which acts on GABAergic pathways, can drive pancreatic cells with an α-cell phenotype toward a β-cell-like phenotype. As reported in two papers (Ben-Othman et al. and Li et al.), these drugs can stimulate the production of sufficient numbers of new β-like cells to reverse severe diabetes in mice.

PMID: 28086099 [PubMed - in process]

Glucose and fatty acids synergistically and reversibly promote beta cell proliferation in rats.

Recent Publications of BIIC Members - Sun, 01/15/2017 - 14:56
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Glucose and fatty acids synergistically and reversibly promote beta cell proliferation in rats.

Diabetologia. 2017 Jan 11;:

Authors: Moullé VS, Vivot K, Tremblay C, Zarrouki B, Ghislain J, Poitout V

Abstract
AIMS/HYPOTHESIS: The mechanisms underlying pancreatic islet mass expansion have attracted considerable interest as potential therapeutic targets to prevent or delay the onset of type 2 diabetes. While several factors promoting beta cell proliferation have been identified, in the context of nutrient excess the roles of glucose or NEFA in relation to insulin resistance remain unclear. Here we tested the hypothesis that glucose and NEFA synergistically and reversibly promote beta cell proliferation in the context of nutrient-induced insulin resistance.
METHODS: Using 72 h infusions of glucose (GLU) or the oleate-enriched lipid emulsion ClinOleic (CLI), singly or in combination, we assessed beta cell proliferation, islet mass and insulin sensitivity in male Lewis rats. The effects of nutrients and endogenous circulating factors were examined in isolated and transplanted islets. Reversibility was studied 3 and 6 days after the end of the infusion.
RESULTS: GLU infusions modestly stimulated beta cell proliferation, CLI alone had no effect and GLU+CLI infusions markedly stimulated beta cell proliferation. Insulin sensitivity was equally decreased in GLU and GLU+CLI infusions. GLU+CLI infusions also stimulated beta cell proliferation in islets transplanted under the kidney capsule, albeit to a lesser extent compared with endogenous islets. Ex vivo, the combination of glucose and NEFA enhanced beta cell proliferation in rat and human islets independently from secreted insulin, and serum from GLU+CLI-infused rats potentiated the effect of glucose. Glucose tolerance, beta cell proliferation and islet mass were all restored to normal levels 6 days after termination of the infusion.
CONCLUSIONS/INTERPRETATION: Glucose and NEFA synergistically and reversibly promote beta cell proliferation in part via direct action on the beta cell and independently from secreted insulin.

PMID: 28078385 [PubMed - as supplied by publisher]

Adipocyte Dynamics and Reversible Metabolic Syndrome in Mice with an Inducible Adipocyte-Specific Deletion of the Insulin Receptor.

Recent Publications of BIIC Members - Thu, 01/12/2017 - 12:48
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Adipocyte Dynamics and Reversible Metabolic Syndrome in Mice with an Inducible Adipocyte-Specific Deletion of the Insulin Receptor.

Cell Metab. 2017 Jan 04;:

Authors: Sakaguchi M, Fujisaka S, Cai W, Winnay JN, Konishi M, O'Neill BT, Li M, García-Martín R, Takahashi H, Hu J, Kulkarni RN, Kahn CR

Abstract
Insulin and IGF1 signaling are important for adipose tissue development and function; however, their role in mature adipocytes is unclear. Mice with a tamoxifen-inducible knockout of insulin and/or IGF1 receptors (IR/IGF1R) demonstrate a rapid loss of white and brown fat due to increased lipolysis and adipocyte apoptosis. This results in insulin resistance, glucose intolerance, hepatosteatosis, islet hyperplasia with hyperinsulinemia, and cold intolerance. This phenotype, however, resolves over 10-30 days due to a proliferation of preadipocytes and rapid regeneration of both brown and white adipocytes as identified by mTmG lineage tracing. This cycle can be repeated with a second round of receptor inactivation. Leptin administration prior to tamoxifen treatment blocks development of the metabolic syndrome without affecting adipocyte loss or regeneration. Thus, IR is critical in adipocyte maintenance, and this loss of adipose tissue stimulates regeneration of brown/white fat and reversal of metabolic syndrome associated with fat loss.

PMID: 28065828 [PubMed - as supplied by publisher]

Real world data of daclatasvir and asunaprevir combination therapy for HCV genotype 1b infection in patients with renal dysfunction.

Recent Publications of BIIC Members - Wed, 12/28/2016 - 06:24
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Real world data of daclatasvir and asunaprevir combination therapy for HCV genotype 1b infection in patients with renal dysfunction.

Clin Gastroenterol Hepatol. 2016 Dec 21;:

Authors: Ishigami M, Hayashi K, Honda T, Kuzuya T, Ishizu Y, Ishikawa T, Nakano I, Urano F, Kumada T, Yoshioka K, Goto H, Hirooka Y

PMID: 28013118 [PubMed - as supplied by publisher]

Propionate Increases Hepatic Pyruvate Cycling and Anaplerosis and Alters Mitochondrial Metabolism.

Recent Publications of BIIC Members - Thu, 12/15/2016 - 23:24
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Propionate Increases Hepatic Pyruvate Cycling and Anaplerosis and Alters Mitochondrial Metabolism.

J Biol Chem. 2016 Jun 03;291(23):12161-70

Authors: Perry RJ, Borders CB, Cline GW, Zhang XM, Alves TC, Petersen KF, Rothman DL, Kibbey RG, Shulman GI

Abstract
In mammals, pyruvate kinase (PK) plays a key role in regulating the balance between glycolysis and gluconeogenesis; however, in vivo regulation of PK flux by gluconeogenic hormones and substrates is poorly understood. To this end, we developed a novel NMR-liquid chromatography/tandem-mass spectrometry (LC-MS/MS) method to directly assess pyruvate cycling relative to mitochondrial pyruvate metabolism (VPyr-Cyc/VMito) in vivo using [3-(13)C]lactate as a tracer. Using this approach, VPyr-Cyc/VMito was only 6% in overnight fasted rats. In contrast, when propionate was infused simultaneously at doses previously used as a tracer, it increased VPyr-Cyc/VMito by 20-30-fold, increased hepatic TCA metabolite concentrations 2-3-fold, and increased endogenous glucose production rates by 20-100%. The physiologic stimuli, glucagon and epinephrine, both increased hepatic glucose production, but only glucagon suppressed VPyr-Cyc/VMito These data show that under fasting conditions, when hepatic gluconeogenesis is stimulated, pyruvate recycling is relatively low in liver compared with VMito flux and that liver metabolism, in particular pyruvate cycling, is sensitive to propionate making it an unsuitable tracer to assess hepatic glycolytic, gluconeogenic, and mitochondrial metabolism in vivo.

PMID: 27002151 [PubMed - indexed for MEDLINE]

Age-Dependent Control Of Energy Homeostasis by Brown Adipose Tissue in Progeny Subjected to Maternal Diet-Induced Fetal Programming.

Recent Publications of BIIC Members - Fri, 12/09/2016 - 21:57
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Age-Dependent Control Of Energy Homeostasis by Brown Adipose Tissue in Progeny Subjected to Maternal Diet-Induced Fetal Programming.

Diabetes. 2016 Dec 07;:

Authors: Dumortier O, Roger E, Pisani DF, Casamento V, Gautier N, Lebrun P, Johnston H, Lopez P, Amri EZ, Jousse C, Fafournoux P, Prentki M, Hinault C, Van Obberghen E

Abstract
Epidemiological and animal studies show that deleterious maternal environments predispose aging offspring to metabolic disorders and type 2 diabetes. Young progeny in a rat model of maternal low protein diet (LP) is normoglycemic despite collapsed insulin secretion. However, without further worsening of the insulin secretion defect glucose homeostasis deteriorates in aging LP descendants. Here we report that normoglycemic and insulinopenic 3-month-old LP progeny shows increased body temperature and energy dissipation in association with enhanced brown adipose tissue (BAT) activity. In addition, it is protected against a cold challenge and high fat diet (HFD)-induced obesity with associated insulin resistance and hyperglycemia. Surgical BAT ablation in 3-month-old LP offspring normalizes body temperature and causes postprandial hyperglycemia. At 10 months BAT activity declines in LP progeny with appearance of reduced protection to HFD-induced obesity; at 18 months LP progeny displays a BAT activity comparable to control offspring and insulin resistance and hyperglycemia occur. Together our findings identify BAT as a decisive physiological determinant of the onset of metabolic dysregulation in offspring predisposed to altered beta cell function and hyperglycemia, and place it as a critical regulator of fetal programming of adult metabolic disease.

PMID: 27927722 [PubMed - as supplied by publisher]

Metabolomics-guided insights on bariatric surgery versus behavioral interventions for weight loss.

Recent Publications of BIIC Members - Wed, 11/30/2016 - 19:04

Metabolomics-guided insights on bariatric surgery versus behavioral interventions for weight loss.

Obesity (Silver Spring). 2016 Dec;24(12):2451-2466

Authors: Tulipani S, Griffin J, Palau-Rodriguez M, Mora-Cubillos X, Bernal-Lopez RM, Tinahones FJ, Corkey BE, Andres-Lacueva C

Abstract
OBJECTIVE: To review the metabolomic studies carried out so far to identify metabolic markers associated with surgical and dietary treatments for weight loss in subjects with obesity.
METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed.
RESULTS: Thirty-two studies successfully met the eligibility criteria. The metabolic adaptations shared by surgical and dietary interventions mirrored a state of starvation ketoacidosis (increase of circulating ketone bodies), an increase of acylcarnitines and fatty acid β-oxidation, a decrease of specific amino acids including branched-chain amino acids (BCAA) and (lyso)glycerophospholipids previously associated with obesity, and adipose tissue expansion. The metabolic footprint of bariatric procedures was specifically characterized by an increase of bile acid circulating pools and a decrease of ceramide levels, a greater perioperative decline in BCAA, and the rise of circulating serine and glycine, mirroring glycemic control and inflammation improvement. In one study, 3-hydroxybutyrate was particularly identified as an early metabolic marker of long-term prognosis after surgery and proposed to increase current prognostic modalities and contribute to personalized treatment.
CONCLUSIONS: Metabolomics helped in deciphering the metabolic response to weight loss treatments. Moving from association to causation is the next challenge to move to a further level of clinical application.

PMID: 27891833 [PubMed - in process]

Clinical efficacy of fecal occult blood test and colonoscopy for dasatinib-induced hemorrhagic colitis in CML patients.

Recent Publications of BIIC Members - Mon, 11/21/2016 - 10:53
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Clinical efficacy of fecal occult blood test and colonoscopy for dasatinib-induced hemorrhagic colitis in CML patients.

Blood. 2016 Nov 18;:

Authors: Nishiwaki S, Maeda M, Yamada M, Okuno S, Harada Y, Suzuki K, Kurahashi S, Urano F, Okamura S, Sugiura I

Abstract
A positive fecal occult blood test (FOBT) is occasionally observed in some chronic myeloid leukemia (CML) patients treated with a tyrosine kinase inhibitor (TKI), and hemorrhagic colitis in patients treated with dasatinib has been reported. To clarify the frequency of TKI-induced hemorrhagic colitis and the screening efficacy of an FOBT followed by a colonoscopy, we prospectively enrolled CML patients treated with a TKI. FOBTs were performed in all patients and colonoscopy was performed in patients with positive FOBTs. When TKI-induced hemorrhagic colitis was pathologically identified, the TKI was interrupted, and the FOBTs were reevaluated. The first FOBT was positive in 10 of 30 patients. All patients with positive FOBTs were treated with dasatinib and developed no symptoms. Dasatinib-induced hemorrhagic colitis was confirmed in 6 of 18 patients treated with dasatinib (33%). Its endoscopic feature was a red flare and/or erosion. Immunohistological analyses showed CD3+, CD8+, CD56+, and Granzyme B+ cytotoxic T lymphocyte infiltration. After dasatinib discontinuation, the FOBTs became negative in all but one patient who had concurrent colorectal polyps. Dasatinib-induced hemorrhagic colitis was observed in one third of asymptomatic patients treated with dasatinib. An FOBT followed by a colonoscopy can be a useful strategy to detect the disease.

PMID: 27864292 [PubMed - as supplied by publisher]

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