Recent Publications of BIIC Members

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NCBI: db=pubmed; Term=Gray JP OR Heart E OR Zarrouki B OR Corkey BE OR Bonner-Weir S OR Urano F OR Cline GW OR Sharp GW OR Holz GG OR Weir GC OR Kulkarni RN OR Tornheim K OR Kibbey RG OR Fonseca SG OR Straub SG OR Jetton TL OR Poitout V OR Prentki M
Updated: 5 hours 42 min ago

Type 1 diabetes alters lipid handling and metabolism in human fibroblasts and peripheral blood mononuclear cells.

Fri, 12/08/2017 - 15:55
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Type 1 diabetes alters lipid handling and metabolism in human fibroblasts and peripheral blood mononuclear cells.

PLoS One. 2017;12(12):e0188474

Authors: Jones Iv AR, Coleman EL, Husni NR, Deeney JT, Raval F, Steenkamp D, Dooms H, Nikolajczyk BS, Corkey BE

Abstract
Triggers of the autoimmune response that leads to type 1 diabetes (T1D) remain poorly understood. A possibility is that parallel changes in both T cells and target cells provoke autoimmune attack. We previously documented greater Ca2+ transients in fibroblasts from T1D subjects than non-T1D after exposure to fatty acids (FA) and tumor necrosis factor α (TNFα). These data indicate that metabolic and signal transduction defects present in T1D can be elicited ex vivo in isolated cells. Changes that precede T1D, including inflammation, may activate atypical responses in people that are genetically predisposed to T1D. To identify such cellular differences in T1D, we quantified a panel of metabolic responses in fibroblasts and peripheral blood cells (PBMCs) from age-matched T1D and non-T1D subjects, as models for non-immune and immune cells, respectively. Fibroblasts from T1D subjects accumulated more lipid, had higher LC-CoA levels and converted more FA to CO2, with less mitochondrial proton leak in response to oleate alone or with TNFα, using the latter as a model of inflammation. T1D-PBMCs contained and also accumulated more lipid following FA exposure. In addition, they formed more peroxidized lipid than controls following FA exposure. We conclude that both immune and non-immune cells in T1D subjects differ from controls in terms of responses to FA and TNFα. Our results suggest a differential sensitivity to inflammatory insults and FA that may precede and contribute to T1D by priming both immune cells and their targets for autoimmune reactions.

PMID: 29206239 [PubMed - in process]

Considerations and guidelines for mouse metabolic phenotyping in diabetes research.

Mon, 11/20/2017 - 05:13
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Considerations and guidelines for mouse metabolic phenotyping in diabetes research.

Diabetologia. 2017 Nov 16;:

Authors: Alquier T, Poitout V

Abstract
Mice are the most commonly used species in preclinical research on the pathophysiology of metabolic diseases. Although they are extremely useful for identifying pathways, mechanisms and genes regulating glucose and energy homeostasis, the specificities of the various mouse models and methodologies used to investigate a metabolic phenotype can have a profound impact on experimental results and their interpretation. This review aims to: (1) describe the most commonly used experimental tests to assess glucose and energy homeostasis in mice; (2) provide some guidelines regarding the design, analysis and interpretation of these tests, as well as for studies using genetic models; and (3) identify important caveats and confounding factors that must be taken into account in the interpretation of findings.

PMID: 29143855 [PubMed - as supplied by publisher]

Mechanisms by which a Very-Low-Calorie Diet Reverses Hyperglycemia in a Rat Model of Type 2 Diabetes.

Fri, 11/17/2017 - 03:28
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Mechanisms by which a Very-Low-Calorie Diet Reverses Hyperglycemia in a Rat Model of Type 2 Diabetes.

Cell Metab. 2017 Nov 08;:

Authors: Perry RJ, Peng L, Cline GW, Wang Y, Rabin-Court A, Song JD, Zhang D, Zhang XM, Nozaki Y, Dufour S, Petersen KF, Shulman GI

Abstract
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 (VPC), 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.

PMID: 29129786 [PubMed - as supplied by publisher]

Daclatasvir and asunaprevir treatment in patients infected by genotype 1b of hepatitis C virus with no or subtle resistant associated substitutions (RAS) in NS5A-Y93.

Fri, 11/10/2017 - 23:07
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Daclatasvir and asunaprevir treatment in patients infected by genotype 1b of hepatitis C virus with no or subtle resistant associated substitutions (RAS) in NS5A-Y93.

J Med Virol. 2017 Nov 07;:

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

Abstract
(Backgrounds and Aims) In this study, we investigated the real-world data of the first approved interferon free regimen in Japan; daclatasvir and asunaprevir (DCV+ASV) in chronic hepatitis C patients infected HCV genotype 1b with no or subtle amount of baseline resistant associated substitutions (RAS). (Patients and Methods) Among 924 patients registered in our multicenter study, 750 patients that were proven not to be infected with NS5A-Y93H resistant associated substitutions (RAS) by direct sequencing and to have no or subtle amount (less than 20%) of NS5A-Y93H RAS by probe assays (Cycleave or PCR invader assay) were included in this study. We investigated the anti-viral effect and factors associated with SVR12. In statistical analysis, P<0.05 was considered as significant. (Results) The SVR12 rate in this population was 92.1% (562/618). Factors associated with SVR12 were; male (Odds ratio: 2.128; 95%CI: 1.134-4.000, P=0.019); lower serum γGTP (Odds ratio: 1.007; 95%CI: 1.002-1.012, P=0.006); lower HCV-RNA (Odds ratio: 1.848; 95%CI: 1.087-3.145, P=0.023) and RVR (Odds ratio: 6.250; 95%CI: 2.445-15.873, P<0.001). No patients with γ GTP≧80IU/l without RVR showed SVR12 (0/4, 0%) and (1) patients with γ GTP≧20-<80IU/l and HCV-RNA≧6.5 logIU/ml without RVR (5/10, 50%) and (2) female patients with RVR but γ GTP≧80IU/l and HCV-RNA≧6.5 logIU/ml (7/13, 53.8%) showed a low SVR12 rate (Conclusions) In the present study, we showed a good viral response with DCV-ASV treatment and identified four predictive factors associated with SVR12. These four markers could be good predictive markers for the viral effect of this treatment regimen in patients with no or subtle amount of RAS in NS5A-Y93. This article is protected by copyright. All rights reserved.

PMID: 29111616 [PubMed - as supplied by publisher]

Identification of islet-enriched long non-coding RNAs contributing to β-cell failure in type 2 diabetes.

Tue, 11/07/2017 - 22:53
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Identification of islet-enriched long non-coding RNAs contributing to β-cell failure in type 2 diabetes.

Mol Metab. 2017 Nov;6(11):1407-1418

Authors: Motterle A, Gattesco S, Peyot ML, Esguerra JLS, Gomez-Ruiz A, Laybutt DR, Gilon P, Burdet F, Ibberson M, Eliasson L, Prentki M, Regazzi R

Abstract
OBJECTIVE: Non-coding RNAs constitute a major fraction of the β-cell transcriptome. While the involvement of microRNAs is well established, the contribution of long non-coding RNAs (lncRNAs) in the regulation of β-cell functions and in diabetes development remains poorly understood. The aim of this study was to identify novel islet lncRNAs differently expressed in type 2 diabetes models and to investigate their role in β-cell failure and in the development of the disease.
METHODS: Novel transcripts dysregulated in the islets of diet-induced obese mice were identified by high throughput RNA-sequencing coupled with de novo annotation. Changes in the level of the lncRNAs were assessed by real-time PCR. The functional role of the selected lncRNAs was determined by modifying their expression in MIN6 cells and primary islet cells.
RESULTS: We identified about 1500 novel lncRNAs, a number of which were differentially expressed in obese mice. The expression of two lncRNAs highly enriched in β-cells, βlinc2, and βlinc3, correlated to body weight gain and glycemia levels in obese mice and was also modified in diabetic db/db mice. The expression of both lncRNAs was also modulated in vitro in isolated islet cells by glucolipotoxic conditions. Moreover, the expression of the human orthologue of βlinc3 was altered in the islets of type 2 diabetic patients and was associated to the BMI of the donors. Modulation of the level of βlinc2 and βlinc3 by overexpression or downregulation in MIN6 and mouse islet cells did not affect insulin secretion but increased β-cell apoptosis.
CONCLUSIONS: Taken together, the data show that lncRNAs are modulated in a model of obesity-associated type 2 diabetes and that variations in the expression of some of them may contribute to β-cell failure during the development of the disease.

PMID: 29107288 [PubMed - in process]

Pathogenesis of hypothyroidism-induced NAFLD is driven by intra- and extrahepatic mechanisms.

Sun, 10/29/2017 - 16:54
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Pathogenesis of hypothyroidism-induced NAFLD is driven by intra- and extrahepatic mechanisms.

Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):E9172-E9180

Authors: Ferrandino G, Kaspari RR, Spadaro O, Reyna-Neyra A, Perry RJ, Cardone R, Kibbey RG, Shulman GI, Dixit VD, Carrasco N

Abstract
Hypothyroidism, a metabolic disease characterized by low thyroid hormone (TH) and high thyroid-stimulating hormone (TSH) levels in the serum, is strongly associated with nonalcoholic fatty liver disease (NAFLD). Hypothyroidism-induced NAFLD has generally been attributed to reduced TH signaling in the liver with a consequent decrease in lipid utilization. Here, we found that mildly hypothyroid mice develop NAFLD without down-regulation of hepatic TH signaling or decreased hepatic lipid utilization. NAFLD was induced by impaired suppression of adipose tissue lipolysis due to decreased insulin secretion and to a reduced response of adipose tissue itself to insulin. This condition leads to increased shuttling of fatty acids (FAs) to the liver, where they are esterified and accumulated as triglycerides. Lipid accumulation in the liver induces hepatic insulin resistance, which leads to impaired suppression of endogenous glucose production after feeding. Hepatic insulin resistance, synergistically with lowered insulin secretion, increases serum glucose levels, which stimulates de novo lipogenesis (DNL) in the liver. Up-regulation of DNL also contributes to NAFLD. In contrast, severely hypothyroid mice show down-regulation of TH signaling in their livers and profound suppression of adipose tissue lipolysis, which decreases delivery of FAs to the liver. The resulting lack of substrates for triglyceride esterification protects severely hypothyroid mice against NAFLD. Our findings demonstrate that NAFLD occurs when TH levels are mildly reduced, but, paradoxically, not when they are severely reduced. Our results show that the pathogenesis of hypothyroidism-induced NAFLD is both intra- and extrahepatic; they also reveal key metabolic differences between mild and severe hypothyroidism.

PMID: 29073114 [PubMed - in process]

Standardized Mixed-Meal Tolerance and Arginine Stimulation Tests Provide Reproducible and Complementary Measures of β-Cell Function: Results From the Foundation for the National Institutes of Health Biomarkers Consortium Investigative Series.

Thu, 10/26/2017 - 16:06
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Standardized Mixed-Meal Tolerance and Arginine Stimulation Tests Provide Reproducible and Complementary Measures of β-Cell Function: Results From the Foundation for the National Institutes of Health Biomarkers Consortium Investigative Series.

Diabetes Care. 2016 Sep;39(9):1602-13

Authors: Shankar SS, Vella A, Raymond RH, Staten MA, Calle RA, Bergman RN, Cao C, Chen D, Cobelli C, Dalla Man C, Deeg M, Dong JQ, Lee DS, Polidori D, Robertson RP, Ruetten H, Stefanovski D, Vassileva MT, Weir GC, Fryburg DA, Foundation for the National Institutes of Health β-Cell Project Team

Abstract
OBJECTIVE: Standardized, reproducible, and feasible quantification of β-cell function (BCF) is necessary for the evaluation of interventions to improve insulin secretion and important for comparison across studies. We therefore characterized the responses to, and reproducibility of, standardized methods of in vivo BCF across different glucose tolerance states.
RESEARCH DESIGN AND METHODS: Participants classified as having normal glucose tolerance (NGT; n = 23), prediabetes (PDM; n = 17), and type 2 diabetes mellitus (T2DM; n = 22) underwent two standardized mixed-meal tolerance tests (MMTT) and two standardized arginine stimulation tests (AST) in a test-retest paradigm and one frequently sampled intravenous glucose tolerance test (FSIGT).
RESULTS: From the MMTT, insulin secretion in T2DM was >86% lower compared with NGT or PDM (P < 0.001). Insulin sensitivity (Si) decreased from NGT to PDM (∼50%) to T2DM (93% lower [P < 0.001]). In the AST, insulin secretory response to arginine at basal glucose and during hyperglycemia was lower in T2DM compared with NGT and PDM (>58%; all P < 0.001). FSIGT showed decreases in both insulin secretion and Si across populations (P < 0.001), although Si did not differ significantly between PDM and T2DM populations. Reproducibility was generally good for the MMTT, with intraclass correlation coefficients (ICCs) ranging from ∼0.3 to ∼0.8 depending on population and variable. Reproducibility for the AST was very good, with ICC values >0.8 across all variables and populations.
CONCLUSIONS: Standardized MMTT and AST provide reproducible and complementary measures of BCF with characteristics favorable for longitudinal interventional trials use.

PMID: 27407117 [PubMed - indexed for MEDLINE]

α-Lipoic Acid as Adjunctive Treatment for Schizophrenia: An Open-Label Trial.

Mon, 10/23/2017 - 12:53
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α-Lipoic Acid as Adjunctive Treatment for Schizophrenia: An Open-Label Trial.

J Clin Psychopharmacol. 2017 Oct 19;:

Authors: Sanders LLO, Menezes CES, Chaves Filho AJM, Viana GA, Fechine FV, de Queiroz MGR, Fonseca SGDC, Vasconcelos SMM, de Moraes MEA, Gama CS, Seybolt S, Campos EM, Macêdo D, de Lucena DF

Abstract
PURPOSE/BACKGROUND: Accumulating evidence suggests an involvement of oxidative stress in the pathophysiology of schizophrenia. This offers a hypothesis-derived therapeutic approach to hinder oxidative damage and its clinical sequelae. α-Lipoic acid (ALA) is a powerful natural antioxidant indicated to treat diabetic neuropathy.
METHODS/PROCEDURES: In this pilot investigation, we administered ALA (100 mg/d) for 4 months, as an adjunct to antipsychotic medication, to 10 patients with schizophrenia.
FINDINGS/RESULTS: We found robust improvement in measures of psychopathology (63.9% reduction in Brief Psychiatric Rating Scale scores), neurocognitive parameters, extrapyramidal symptoms, and decreased lipid peroxidation.
IMPLICATIONS/CONCLUSIONS: If larger, double-blind, placebo-controlled studies confirm these preliminary findings, ALA could prove useful as adjunctive therapy for schizophrenia.

PMID: 29053478 [PubMed - as supplied by publisher]

Nutrient regulation of pancreatic β-cell proliferation.

Wed, 10/11/2017 - 07:14

Nutrient regulation of pancreatic β-cell proliferation.

Biochimie. 2017 Oct 04;:

Authors: Moullé VS, Ghislain J, Poitout V

Abstract
Excess consumption of energy-dense foods combined with a sedentary lifestyle is driving an obesity epidemic. Although obesity is closely associated with insulin resistance, most individuals meet the insulin demand by increasing their functional β-cell mass. Those who eventually develop type 2 diabetes are distinguished by a failure in this compensatory process. Although a causal role of insulin resistance in compensatory β-cell responses has received considerable experimental support, precisely how the β cell senses changes in the metabolic environment is still unknown. As metabolism of glucose, lipids and amino acids is profoundly altered in obesity, it is not surprising that these nutrients are conspicuous among the factors proposed to contribute. In this review we summarise our understanding of the role of nutrients, in particular glucose, fatty acids and amino acids in β-cell compensation with a particular emphasis on their relation to insulin resistance-induced factors and their underlying mechanism of action. Finally, we describe the concept of epigenetic programming and review recent studies illustrating how the status of the β cell epigenome is a product of its nutrient environment, and how metabolic programming of the β cell contributes to diabetes risk.

PMID: 28987628 [PubMed - as supplied by publisher]

Identification of the signals for glucose-induced insulin secretion in INS1 (832/13) β-cells using metformin-induced metabolic deceleration as a model.

Thu, 10/05/2017 - 03:10
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Identification of the signals for glucose-induced insulin secretion in INS1 (832/13) β-cells using metformin-induced metabolic deceleration as a model.

J Biol Chem. 2017 Oct 02;:

Authors: Lamontagne J, Al-Mass A, Nolan CJ, Corkey BE, Madiraju SRM, Joly E, Prentki M

Abstract
Metabolic deceleration in pancreatic β-cells is associated with inhibition of glucose-induced insulin secretion (GIIS), but only in the presence of intermediate/sub-maximal glucose concentrations. Here, we used acute metformin treatment as a tool to induce metabolic deceleration in INS1 (832/13) β-cells, with the goal of identifying key pathways and metabolites involved in GIIS. Metabolites and pathways previously implicated as signals for GIIS were measured in the cells at 2-25 mM glucose, with or without 5 mM metformin. We defined three criteria to identify candidate signals: 1) glucose-responsiveness, 2) sensitivity to metformin-induced inhibition of the glucose effect at intermediate glucose concentrations, and 3) alleviation of metformin inhibition by elevated glucose concentrations. Despite the lack of recovery from metformin-induced impairment of mitochondrial energy metabolism (glucose oxidation, O2 consumption and ATP production), insulin secretion was almost completely restored at elevated glucose concentrations. Meeting the criteria for candidates involved in promoting GIIS were the following metabolic indicators and metabolites: cytosolic NAD(+)/NADH ratio (inferred from the dihydroxyacetone phosphate:glycerol-3-phosphate ratio), mitochondrial membrane potential, ADP, Ca(2+), 1-monoacylglycerol, diacylglycerol, malonyl-CoA, and HMG-CoA. On the contrary, most of the purine and nicotinamide nucleotides, acetoacetyl-CoA, H2O2, reduced glutathione and 2-monoacylglycerol were not glucose-responsive. Overall these results underscore the significance of mitochondrial energy metabolism-independent signals in GIIS regulation, in particular, the candidate lipid signaling molecules 1-monoacylglycerol, diacylglycerol and malonyl-CoA; the predominance of KATP/Ca(2+) signaling control by low ADP.Mg(2+) rather than by high ATP levels; and a role for a more oxidized state (NAD(+)/NADH) in the cytosol during GIIS that favors high glycolysis rates.

PMID: 28972173 [PubMed - as supplied by publisher]

Thymoquinone ameliorates diabetic phenotype in Diet-Induced Obesity mice via activation of SIRT-1-dependent pathways.

Thu, 09/28/2017 - 23:52
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Thymoquinone ameliorates diabetic phenotype in Diet-Induced Obesity mice via activation of SIRT-1-dependent pathways.

PLoS One. 2017;12(9):e0185374

Authors: Karandrea S, Yin H, Liang X, Slitt AL, Heart EA

Abstract
Thymoquinone, a natural occurring quinone and the main bioactive component of plant Nigella sativa, undergoes intracellular redox cycling and re-oxidizes NADH to NAD+. TQ administration (20 mg/kg/bw/day) to the Diet-Induced Obesity (DIO) mice reduced their diabetic phenotype by decreasing fasting blood glucose and fasting insulin levels, and improved glucose tolerance and insulin sensitivity as evaluated by oral glucose and insulin tolerance tests (OGTT and ITT). Furthermore, TQ decreased serum cholesterol levels and liver triglycerides, increased protein expression of phosphorylated Akt, decreased serum levels of inflammatory markers resistin and MCP-1, and decreased NADH/NAD+ ratio. These changes were paralleled by an increase in phosphorylated SIRT-1 and AMPKα in liver and phosphorylated SIRT-1 in skeletal muscle. TQ also increased insulin sensitivity in insulin-resistant HepG2 cells via a SIRT-1-dependent mechanism. These findings are consistent with the TQ-dependent re-oxidation of NADH to NAD+, which stimulates glucose and fatty acid oxidation and activation of SIRT-1-dependent pathways. Taken together, these results demonstrate that TQ ameliorates the diabetic phenotype in the DIO mouse model of type 2 diabetes.

PMID: 28950020 [PubMed - in process]

BDE-47 and BDE-85 stimulate insulin secretion in INS-1 832/13 pancreatic β-cells through the thyroid receptor and Akt.

Thu, 09/07/2017 - 11:09
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BDE-47 and BDE-85 stimulate insulin secretion in INS-1 832/13 pancreatic β-cells through the thyroid receptor and Akt.

Environ Toxicol Pharmacol. 2017 Sep 01;56:29-34

Authors: Karandrea S, Yin H, Liang X, Heart EA

Abstract
PBDEs (polybrominated diphenyl ethers) are environmental pollutants that have been linked to the development of type 2 diabetes, however, the precise mechanisms are not clear. Particularly, their direct effect on insulin secretion is unknown. In this study, we show that two PBDE congeners, BDE-47 and BDE-85, potentiate glucose-stimulated insulin secretion (GSIS) in INS-1 832/13 cells. This effect of BDE-47 and BDE-85 on GSIS was dependent on thyroid receptor (TR). Both BDE-47 and BDE-85 (10μM) activated Akt during an acute exposure. The activation of Akt by BDE-47 and BDE-85 plays a role in their potentiation of GSIS, as pharmacological inhibition of PI3K, an upstream activator of Akt, significantly lowers GSIS compared to compounds alone. This study shows that BDE-47 and BDE-85 directly act on pancreatic β-cells to stimulate GSIS, and that this effect is mediated by the thyroid receptor (TR) and Akt activation.

PMID: 28869857 [PubMed - as supplied by publisher]

Isoform-selective inhibitor of histone deacetylase 3 (HDAC3) limits pancreatic islet infiltration and protects female nonobese diabetic mice from diabetes.

Mon, 09/04/2017 - 08:49
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Isoform-selective inhibitor of histone deacetylase 3 (HDAC3) limits pancreatic islet infiltration and protects female nonobese diabetic mice from diabetes.

J Biol Chem. 2017 Aug 31;:

Authors: Dirice E, Ng R, Martinez R, Hu J, Wagner FF, Holson EB, Wagner BK, Kulkarni RN

Abstract
Preservation of insulin-secreting β-cells is an important goal for therapies aimed at restoring normoglycemia in patients with diabetes. One approach, the inhibition of histone deacetylases (HDACs), has been reported to suppress pancreatic islet inflammation and β-cell apoptosis in vitro. In this report, we demonstrate the efficacy of HDAC inhibitors (HDACi) in vivo. We show that daily administration of BRD3308, an isoform-selective HDAC3 inhibitor, for 2 weeks to female nonobese diabetic (NOD) mice, beginning at 3 weeks of age, followed by twice-weekly injections until age 25 weeks, protects the animals from diabetes. The preservation of β-cells was due to a significant decrease in islet infiltration of mononuclear cells. Moreover, the BRD3308 treatment increased basal insulin secretion from islets cultured in vitro. All metabolic tissues tested in vehicle- or BRD3308-treated groups showed virtually no sign of immune cell infiltration, except minimal infiltration in white adipose tissue in animals treated with the highest BRD3308 dose (10 mg/kg), providing additional evidence of protection from immune attack in the treated groups. Furthermore, pancreata from animals treated with 10 mg/kg BRD3308 exhibited significantly decreased numbers of apoptotic β-cells compared with those treated with vehicle or low-dose BRD3308. Finally, animals treated with 1 or 10 mg/kg BRD3308 had enhanced β-cell proliferation. These in vivo results point to the potential use of selective HDAC3 inhibitors as a therapeutic approach to suppress pancreatic islet infiltration and prevent β-cell death with the long-term goal of limiting the progression of type 1 diabetes.

PMID: 28860191 [PubMed - as supplied by publisher]

Intermittent Fasting Preserves Beta-Cell Mass in Obesity-induced Diabetes via the Autophagy-Lysosome Pathway.

Fri, 09/01/2017 - 06:52
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Intermittent Fasting Preserves Beta-Cell Mass in Obesity-induced Diabetes via the Autophagy-Lysosome Pathway.

Autophagy. 2017 Aug 30;:0

Authors: Liu H, Javaheri A, Godar RJ, Murphy J, Ma X, Rohatgi N, Mahadevan J, Hyrc K, Saftig P, Marshall C, McDaniel ML, Remedi MS, Razani B, Urano F, Diwan A

Abstract
Obesity-induced diabetes is characterized by hyperglycemia, insulin resistance, and progressive beta cell failure. In islets of mice with obesity-induced diabetes, we observe increased beta cell death and impaired autophagic flux. We hypothesized that intermittent fasting, a clinically sustainable therapeutic strategy, stimulates autophagic flux to ameliorate obesity-induced diabetes. Our data show that despite continued high-fat intake, intermittent fasting restores autophagic flux in islets and improves glucose tolerance by enhancing glucose-stimulated insulin secretion, beta cell survival, and nuclear expression of NEUROG3, a marker of pancreatic regeneration. In contrast, intermittent fasting does not rescue beta-cell death or induce NEUROG3 expression in obese mice with lysosomal dysfunction secondary to deficiency of the lysosomal membrane protein, LAMP2 or haplo-insufficiency of BECN1/Beclin-1, a protein critical for autophagosome formation. Moreover, intermittent fasting is sufficient to provoke beta cell death in non-obese lamp2 null mice, attesting to a critical role for lysosome function in beta cell homeostasis under fasting conditions. Beta cells in intermittently-fasted LAMP2- or BECN1-deficient mice exhibit markers of autophagic failure with accumulation of damaged mitochondria and upregulation of oxidative stress. Thus, intermittent fasting preserves organelle quality via the autophagy-lysosome pathway to enhance beta cell survival and stimulates markers of regeneration in obesity-induced diabetes.

PMID: 28853981 [PubMed - as supplied by publisher]

Glycerol-3-phosphate phosphatase/PGP: Role in intermediate metabolism and target for cardiometabolic diseases.

Sat, 08/26/2017 - 03:04
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Glycerol-3-phosphate phosphatase/PGP: Role in intermediate metabolism and target for cardiometabolic diseases.

Biochimie. 2017 Aug 04;:

Authors: Possik E, Madiraju SRM, Prentki M

Abstract
Metabolic diseases, including obesity, type 2 diabetes, and metabolic syndrome arise because of disturbances in glucose and fat metabolism, which impact associated physiological events such as insulin secretion and action, fat storage and oxidation. Even though, decades of research has contributed to our current understanding of the components involved in glucose and fat metabolism and their regulation, that led to the development of many therapeutics, there are still many unanswered questions. Glycerol-3-phosphate (Gro3P), which is formed during glycolysis, is at the intersection of glucose and fat metabolism, and the availability of this metabolite can regulate energy and intermediary metabolism in mammalian cells. During the course of evolution, mammalian cells are assumed to have lost the capacity to directly hydrolyze Gro3P to glycerol, until the recent discovery from our laboratory showing that a previously known mammalian enzyme, phosphoglycolate phosphatase (PGP), can function as Gro3P phosphatase (G3PP) and regulate this metabolite levels. Emerging evidence indicates that G3PP/PGP is an evolutionarily conserved "multi-tasking" enzyme that belongs to the superfamily of haloacid dehalogenase-like phosphatase enzymes, and is capable of hydrolyzing Gro3P, an abundant physiologically relevant substrate, as well as other metabolites including 2-phosphoglycolate, 4-phospherythronate and 2-phospholactate, which are present in much smaller amounts in cells, under normal conditions. G3PP, by regulating Gro3P levels, plays a critical role in intermediary metabolism, including glycolysis, glucose oxidation, cellular redox and ATP production, gluconeogenesis, esterification of fatty acids towards glycerolipid synthesis and fatty acid oxidation. Because of G3PP's ability to regulate energy and intermediary metabolism as well as physiological functions such as insulin secretion, hepatic glucose production, and fat synthesis, storage and oxidation, the pathophysiological role of this enzyme in metabolic diseases needs to be precisely defined. In this review, we summarize the present knowledge on the structure, function and regulation of G3PP/PGP, and we discuss its potential therapeutic role for cardiometabolic diseases.

PMID: 28826615 [PubMed - as supplied by publisher]

Low serum osteocalcin concentration is associated with incident type 2 diabetes mellitus in Japanese women.

Thu, 08/03/2017 - 10:39
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Low serum osteocalcin concentration is associated with incident type 2 diabetes mellitus in Japanese women.

J Bone Miner Metab. 2017 Aug 01;:

Authors: Urano T, Shiraki M, Kuroda T, Tanaka S, Urano F, Uenishi K, Inoue S

Abstract
Increasing evidence suggests that osteocalcin is involved in the regulation of glucose homeostasis. However, the relationship between serum osteocalcin levels and risk of incident type 2 diabetes mellitus is not clear. The objective of this study is to investigate whether serum osteocalcin levels are associated with the risk of incident type 2 diabetes mellitus. This study included 1691 Japanese postmenopausal women, 61 incident diabetes cases, and 1630 non-diabetic control subjects in the observation period. Baseline concentrations of intact osteocalcin, HbA1c, bone-specific alkaline phosphatase, adiponectin, leptin, urinary N-telopeptides were assessed. Serum osteocalcin levels were significantly correlated with HbA1c levels among 1691 Japanese postmenopausal women (R = -0.12, P < 0.0001). In receiver operating characteristic curve analysis, the optimal cut-off levels for serum osteocalcin to predict the development of type 2 diabetes mellitus was 6.1 ng/mL. The group with baseline osteocalcin levels <6.1 ng/mL showed a significantly higher risk for developing diabetes than the group with baseline osteocalcin levels >6.1 ng/mL (log-rank test, P  <  0.0001) during the mean observation period (7.6 ± 6.1 years; mean ± SD). In multiple Cox proportional hazard analysis, osteocalcin levels were significantly associated with development of type 2 diabetes mellitus during the observation period. Our results indicate that a decrease in serum osteocalcin levels is associated with future development of type 2 diabetes mellitus independent of conventional risk factors in Japanese postmenopausal women.

PMID: 28766135 [PubMed - as supplied by publisher]

Targeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death.

Sat, 07/22/2017 - 03:58
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Targeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death.

Sci Rep. 2017 Jul 17;7(1):5611

Authors: Clark AL, Kanekura K, Lavagnino Z, Spears LD, Abreu D, Mahadevan J, Yagi T, Semenkovich CF, Piston DW, Urano F

Abstract
Pro-inflammatory cytokines are important mediators of islet inflammation, leading to beta cell death in type 1 diabetes. Although alterations in both endoplasmic reticulum (ER) and cytosolic free calcium levels are known to play a role in cytokine-mediated beta cell death, there are currently no treatments targeting cellular calcium homeostasis to combat type 1 diabetes. Here we show that modulation of cellular calcium homeostasis can mitigate cytokine- and ER stress-mediated beta cell death. The calcium modulating compounds, dantrolene and sitagliptin, both prevent cytokine and ER stress-induced activation of the pro-apoptotic calcium-dependent enzyme, calpain, and partly suppress beta cell death in INS1E cells and human primary islets. These agents are also able to restore cytokine-mediated suppression of functional ER calcium release. In addition, sitagliptin preserves function of the ER calcium pump, sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA), and decreases levels of the pro-apoptotic protein thioredoxin-interacting protein (TXNIP). Supporting the role of TXNIP in cytokine-mediated cell death, knock down of TXNIP in INS1-E cells prevents cytokine-mediated beta cell death. Our findings demonstrate that modulation of dynamic cellular calcium homeostasis and TXNIP suppression present viable pharmacologic targets to prevent cytokine-mediated beta cell loss in diabetes.

PMID: 28717166 [PubMed - in process]

A case of a patient with granulocyte-colony stimulating factor-producing pancreatic cancer who responded to nab-paclitaxel plus gemcitabine.

Sun, 07/09/2017 - 19:30
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A case of a patient with granulocyte-colony stimulating factor-producing pancreatic cancer who responded to nab-paclitaxel plus gemcitabine.

Nihon Shokakibyo Gakkai Zasshi. 2017;114(7):1277-1284

Authors: Kataoka K, Achiwa K, Minami Y, Fujita M, Naitoh T, Yamada M, Yamamoto H, Matsubara H, Urano F

Abstract
A 67-year-old male patient presented with an irregular mass involving the pancreatic body and tail with multiple liver/lymph node metastases. A biopsy indicated the presence of a poorly differentiated adenocarcinoma. Fever and increased white blood cell count, C-reactive protein levels, and granulocyte-colony stimulating factor (G-CSF) levels led to the diagnose of G-CSF-producing pancreatic cancer. The patient did not respond to FOLFIRINOX therapy (leucovorin, fluorouracil, irinotecan, and oxaliplatin), but nab-paclitaxel plus gemcitabine treatment was effective, resulting in tumor shrinkage and reduced G-CSF levels. After the fifth course of this therapy, exacerbation was noted, and the patient died of primary cancer 6 months after initiating the therapy. Here we report the case of this patient with G-CSF-producing pancreatic cancer who responded to chemotherapy.

PMID: 28679984 [PubMed - in process]

Lanosterol Modulates TLR4-Mediated Innate Immune Responses in Macrophages.

Fri, 06/30/2017 - 12:16
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Lanosterol Modulates TLR4-Mediated Innate Immune Responses in Macrophages.

Cell Rep. 2017 Jun 27;19(13):2743-2755

Authors: Araldi E, Fernández-Fuertes M, Canfrán-Duque A, Tang W, Cline GW, Madrigal-Matute J, Pober JS, Lasunción MA, Wu D, Fernández-Hernando C, Suárez Y

Abstract
Macrophages perform critical functions in both innate immunity and cholesterol metabolism. Here, we report that activation of Toll-like receptor 4 (TLR4) in macrophages causes lanosterol, the first sterol intermediate in the cholesterol biosynthetic pathway, to accumulate. This effect is due to type I interferon (IFN)-dependent histone deacetylase 1 (HDAC1) transcriptional repression of lanosterol-14α-demethylase, the gene product of Cyp51A1. Lanosterol accumulation in macrophages, because of either treatment with ketoconazole or induced conditional disruption of Cyp51A1 in mouse macrophages in vitro, decreases IFNβ-mediated signal transducer and activator of transcription (STAT)1-STAT2 activation and IFNβ-stimulated gene expression. These effects translate into increased survival to endotoxemic shock by reducing cytokine secretion. In addition, lanosterol accumulation increases membrane fluidity and ROS production, thus potentiating phagocytosis and the ability to kill bacteria. This improves resistance of mice to Listeria monocytogenes infection by increasing bacterial clearance in the spleen and liver. Overall, our data indicate that lanosterol is an endogenous selective regulator of macrophage immunity.

PMID: 28658622 [PubMed - in process]

Mammalian ECD protein is a novel negative regulator of the PERK arm of unfolded protein response.

Fri, 06/30/2017 - 12:16
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Mammalian ECD protein is a novel negative regulator of the PERK arm of unfolded protein response.

Mol Cell Biol. 2017 Jun 26;:

Authors: Olou AA, Sarkar A, Bele A, Gurumurthy CB, Mir RA, Ammons SA, Mirza S, Saleem I, Urano F, Band H, Band V

Abstract
The mammalian Ecdysoneless (ECD) is a highly-conserved ortholog of the Drosophila Ecd gene product whose mutations impair the synthesis of Ecdysone and produce cell-autonomous survival defects but mechanisms by which ECD functions are largely unknown. Here, we present evidence that ECD regulates endoplasmic reticulum (ER) stress response. ER stress induction led to a reduced ECD protein but this effect was not seen in PERK KO or phospho-deficient eIF2α MEFs; moreover, ECD mRNA levels were increased, suggesting impaired ECD translation as the mechanism for reduced protein levels. ECD co-localizes and co-immunoprecipitates with PERK and GRP78. ECD depletion increased the levels of p-PERK, p-eIF2α, and these effects were enhanced upon ER stress induction. Reciprocally, overexpression of ECD led to a marked decrease in p-PERK, p-eIF2α and ATF4 levels, but a robust increase in GRP78 protein levels. However, GRP78 mRNA levels were unchanged, suggesting a post-transcriptional event. Knockdown of GRP78 reversed the attenuating effect of ECD over-expression on PERK signaling. Significantly, overexpression of ECD provided a survival advantage to cells upon ER stress induction. Taken together, we demonstrate that ECD promotes survival upon ER stress by increasing GRP78 protein levels to enhance the adaptive folding protein in the ER to attenuate PERK signaling.

PMID: 28652267 [PubMed - as supplied by publisher]

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