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
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Direct Stimulation of Islet Insulin Secretion by Glycolytic and Mitochondrial Metabolites in KCl-Depolarized Islets.

Fri, 11/18/2016 - 10:25
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Direct Stimulation of Islet Insulin Secretion by Glycolytic and Mitochondrial Metabolites in KCl-Depolarized Islets.

PLoS One. 2016;11(11):e0166111

Authors: Pizarro-Delgado J, Deeney JT, Corkey BE, Tamarit-Rodriguez J

Abstract
We have previously demonstrated that islet depolarization with 70 mM KCl opens Cx36 hemichannels and allows diffusion of small metabolites and cofactors through the β-cell plasma membrane. We have investigated in this islet "permeabilized" model whether glycolytic and citric acid cycle intermediates stimulate insulin secretion and how it correlates with ATP production (islet content plus extracellular nucleotide accumulation). Glycolytic intermediates (10 mM) stimulated insulin secretion and ATP production similarly. However, they showed differential sensitivities to respiratory chain or enzyme inhibitors. Pyruvate showed a lower secretory capacity and less ATP production than phosphoenolpyruvate, implicating an important role for glycolytic generation of ATP. ATP production by glucose-6-phosphate was not sensitive to a pyruvate kinase inhibitor that effectively suppressed the phosphoenolpyruvate-induced secretory response and islet ATP rise. Strong suppression of both insulin secretion and ATP production induced by glucose-6-phosphate was caused by 10 μM antimycin A, implicating an important role for the glycerophosphate shuttle in transferring reducing equivalents to the mitochondria. Five citric acid cycle intermediates were investigated for their secretory and ATP production capacity (succinate, fumarate, malate, isocitrate and α-ketoglutarate at 5 mM, together with ADP and/or NADP+ to feed the NADPH re-oxidation cycles). The magnitude of the secretory response was very similar among the different mitochondrial metabolites but α-ketoglutarate showed a more sustained second phase of secretion. Gabaculine (1 mM, a GABA-transaminase inhibitor) suppressed the second phase of secretion and the ATP-production stimulated by α-ketoglutarate, supporting a role for the GABA shuttle in the control of glucose-induced insulin secretion. None of the other citric acid intermediates essayed showed any suppression of both insulin secretion or ATP-production by the presence of gabaculine. We propose that endogenous GABA metabolism in the "GABA-shunt" facilitates ATP production in the citric acid cycle for an optimal insulin secretion.

PMID: 27851770 [PubMed - in process]

Rpl13a small nucleolar RNAs regulate systemic glucose metabolism.

Wed, 11/09/2016 - 07:23
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Rpl13a small nucleolar RNAs regulate systemic glucose metabolism.

J Clin Invest. 2016 Nov 7;:

Authors: Lee J, Harris AN, Holley CL, Mahadevan J, Pyles KD, Lavagnino Z, Scherrer DE, Fujiwara H, Sidhu R, Zhang J, Huang SC, Piston DW, Remedi MS, Urano F, Ory DS, Schaffer JE

Abstract
Small nucleolar RNAs (snoRNAs) are non-coding RNAs that form ribonucleoproteins to guide covalent modifications of ribosomal and small nuclear RNAs in the nucleus. Recent studies have also uncovered additional non-canonical roles for snoRNAs. However, the physiological contributions of these small RNAs are largely unknown. Here, we selectively deleted four snoRNAs encoded within the introns of the ribosomal protein L13a (Rpl13a) locus in a mouse model. Loss of Rpl13a snoRNAs altered mitochondrial metabolism and lowered reactive oxygen species tone, leading to increased glucose-stimulated insulin secretion from pancreatic islets and enhanced systemic glucose tolerance. Islets from mice lacking Rpl13a snoRNAs demonstrated blunted oxidative stress responses. Furthermore, these mice were protected against diabetogenic stimuli that cause oxidative stress damage to islets. Our study illuminates a previously unrecognized role for snoRNAs in metabolic regulation.

PMID: 27820699 [PubMed - as supplied by publisher]

The Role and Future of FFA1 as a Therapeutic Target.

Sun, 11/06/2016 - 05:46
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The Role and Future of FFA1 as a Therapeutic Target.

Handb Exp Pharmacol. 2016 Nov 03;

Authors: Ghislain J, Poitout V

Abstract
Of the 415 million people suffering from diabetes worldwide, 90% have type 2 diabetes. Type 2 diabetes is characterized by hyperglycemia and occurs in obese individuals as a result of insulin resistance and inadequate insulin levels. Accordingly, diabetes drugs are tailored to enhance glucose disposal or target the pancreatic islet β cell to increase insulin secretion. The majority of the present-day insulin secretagogues, however, increase the risk of iatrogenic hypoglycemia, and hence alternatives are actively sought. The long-chain fatty acid, G protein-coupled receptor FFA1/Gpr40, is expressed in β cells, and its activation potentiates insulin secretion in a glucose-dependent manner. Preclinical data indicate that FFA1 agonism is an effective treatment to restore glucose homeostasis in rodent models of diabetes. This initial success prompted clinical trials in type 2 diabetes patients, the results of which were promising; however, the field suffered a significant setback when the lead compound TAK-875/fasiglifam was withdrawn from clinical development due to liver safety concerns. Nevertheless, recent developments have brought to light a surprising complexity of FFA1 agonist action, signaling diversity, and biological outcomes, raising hopes that with a greater understanding of the mechanisms at play the second round will be more successful.

PMID: 27807697 [PubMed - as supplied by publisher]

α/β-Hydrolase Domain 6 in the Ventromedial Hypothalamus Controls Energy Metabolism Flexibility.

Fri, 10/28/2016 - 00:32
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α/β-Hydrolase Domain 6 in the Ventromedial Hypothalamus Controls Energy Metabolism Flexibility.

Cell Rep. 2016 Oct 25;17(5):1217-1226

Authors: Fisette A, Tobin S, Décarie-Spain L, Bouyakdan K, Peyot ML, Madiraju SR, Prentki M, Fulton S, Alquier T

Abstract
α/β-Hydrolase domain 6 (ABHD6) is a monoacylglycerol hydrolase that degrades the endocannabinoid 2-arachidonoylglycerol (2-AG). Although complete or peripheral ABHD6 loss of function is protective against diet-induced obesity and insulin resistance, the role of ABHD6 in the central control of energy balance is unknown. Using a viral-mediated knockout approach, targeted endocannabinoid measures, and pharmacology, we discovered that mice lacking ABHD6 from neurons of the ventromedial hypothalamus (VMH(KO)) have higher VMH 2-AG levels in conditions of endocannabinoid recruitment and fail to physiologically adapt to key metabolic challenges. VMH(KO) mice exhibited blunted fasting-induced feeding and reduced food intake, energy expenditure, and adaptive thermogenesis in response to cold exposure, high-fat feeding, and dieting (transition to a low-fat diet). Our findings identify ABHD6 as a regulator of the counter-regulatory responses to major metabolic shifts, including fasting, nutrient excess, cold, and dieting, thereby highlighting the importance of ABHD6 in the VMH in mediating energy metabolism flexibility.

PMID: 27783937 [PubMed - in process]

Extracellular Redox Regulation of Intracellular Reactive Oxygen Generation, Mitochondrial Function and Lipid Turnover in Cultured Human Adipocytes.

Tue, 10/18/2016 - 19:06
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Extracellular Redox Regulation of Intracellular Reactive Oxygen Generation, Mitochondrial Function and Lipid Turnover in Cultured Human Adipocytes.

PLoS One. 2016;11(10):e0164011

Authors: Jones Iv AR, Meshulam T, Oliveira MF, Burritt N, Corkey BE

Abstract
BACKGROUND: Many tissues play an important role in metabolic homeostasis and the development of diabetes and obesity. We hypothesized that the circulating redox metabolome is a master metabolic regulatory system that impacts all organs and modulates reactive oxygen species (ROS) production, lipid peroxidation, energy production and changes in lipid turnover in many cells including adipocytes.
METHODS: Differentiated human preadipocytes were exposed to the redox couples, lactate (L) and pyruvate (P), β-hydroxybutyrate (βOHB) and acetoacetate (Acoc), and the thiol-disulfides cysteine/ cystine (Cys/CySS) and GSH/GSSG for 1.5-4 hours. ROS measurements were done with CM-H2DCFDA. Lipid peroxidation (LPO) was assessed by a modification of the thiobarbituric acid method. Lipolysis was measured as glycerol release. Lipid synthesis was measured as 14C-glucose incorporated into lipid. Respiration was assessed using the SeaHorse XF24 analyzer and the proton leak was determined from the difference in respiration with oligomycin and antimycin A.
RESULTS: Metabolites with increasing oxidation potentials (GSSG, CySS, Acoc) increased adipocyte ROS. In contrast, P caused a decrease in ROS compared with L. Acoc also induced a significant increase in both LPO and lipid synthesis. L and Acoc increased lipolysis. βOHB increased respiration, mainly due to an increased proton leak. GSSG, when present throughout 14 days of differentiation significantly increased fat accumulation, but not when added later.
CONCLUSIONS: We demonstrated that in human adipocytes changes in the external redox state impacted ROS production, LPO, energy efficiency, lipid handling, and differentiation. A more oxidized state generally led to increased ROS, LPO and lipid turnover and more reduction led to increased respiration and a proton leak. However, not all of the redox couples were the same suggesting compartmentalization. These data are consistent with the concept of the circulating redox metabolome as a master metabolic regulatory system.

PMID: 27741233 [PubMed - in process]

Impact of acute undernutrition on growth, ileal morphology and nutrient transport in a murine model.

Sat, 10/15/2016 - 17:02
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Impact of acute undernutrition on growth, ileal morphology and nutrient transport in a murine model.

Braz J Med Biol Res. 2016 Oct 10;49(10):e5340

Authors: Sampaio IC, Medeiros PH, Rodrigues FA, Cavalcante PA, Ribeiro SA, Oliveira JS, Prata MM, Costa DV, Fonseca SG, Guedes MM, Soares AM, Brito GA, Havt A, Moore SR, Lima AA

Abstract
Undernutrition represents a major public health challenge for middle- and low-income countries. This study aimed to evaluate whether a multideficient Northeast Brazil regional basic diet (RBD) induces acute morphological and functional changes in the ileum of mice. Swiss mice (∼25 g) were allocated into two groups: i) control mice were fed a standard diet and II) undernourished mice were fed the RBD. After 7 days, mice were killed and the ileum collected for evaluation of electrophysiological parameters (Ussing chambers), transcription (RT-qPCR) and protein expression (western blotting) of intestinal transporters and tight junctions. Body weight gain was significantly decreased in the undernourished group, which also showed decreased crypt depth but no alterations in villus height. Electrophysiology measurements showed a reduced basal short circuit current (Isc) in the undernourished group, with no differences in transepithelial resistance. Specific substrate-evoked Isc related to affinity and efficacy (glutamine and alanyl-glutamine) were not different between groups, except for the maximum Isc (efficacy) induced by glucose. Transcription of Sglt1 and Pept1 was significantly higher in the undernourished group, while SN-2 transcription was decreased. No changes were found in transcription of CAT-1 and CFTR, while claudin-2 and occludin transcriptions were significantly increased in the undernourished group. Despite mRNA changes, SGLT-1, PEPT-1, claudin-2 and occludin protein expression showed no difference between groups. These results demonstrate early effects of the RBD on mice, which include reduced body weight and crypt depth in the absence of significant alterations to villus morphology, intestinal transporters and tight junction expression.

PMID: 27737316 [PubMed - in process]

Nab-paclitaxel+gemcitabine therapy for adenosquamous carcinoma of the pancreas: an autopsy case.

Wed, 10/12/2016 - 14:33

Nab-paclitaxel+gemcitabine therapy for adenosquamous carcinoma of the pancreas: an autopsy case.

Nihon Shokakibyo Gakkai Zasshi. 2016;113(10):1777-1784

Authors: Kataoka K, Matsubara H, Urano F, Okamura S, Maeda M

Abstract
A male patient aged over 60 years presented with abdominal pain. A solid lesion measuring 7cm was detected in the pancreatic body and tail, along with periaortic lymphadenopathy. Endoscopic ultrasound-guided fine-needle aspiration suggested squamous cell carcinoma. Nab-paclitaxel+gemcitabine therapy was effective;however, tumor progression was noted after the completion of the fourth course, and the patient died from the primary cancer 7 months after the initial consultation. Autopsy led to a definitive diagnosis of adenosquamous carcinoma of the pancreas. Non-resected adenosquamous carcinoma of the pancreas treated by chemotherapy is rare. Here, we report such an example in the present case study.

PMID: 27725467 [PubMed - in process]

Corrigendum: IRS1 deficiency protects β-cells against ER stress-induced apoptosis by modulating sXBP-1 stability and protein translation.

Wed, 10/12/2016 - 14:33
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Corrigendum: IRS1 deficiency protects β-cells against ER stress-induced apoptosis by modulating sXBP-1 stability and protein translation.

Sci Rep. 2016 Oct 10;6:34969

Authors: Takatani T, Shirakawa J, Roe MW, Leech CA, Maier BF, Mirmira RG, Kulkarni RN

PMID: 27721427 [PubMed - in process]

Endoplasmic reticulum stress in beta cells and autoimmune diabetes.

Sun, 10/09/2016 - 14:26
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Endoplasmic reticulum stress in beta cells and autoimmune diabetes.

Curr Opin Immunol. 2016 Oct 5;43:60-66

Authors: Clark AL, Urano F

Abstract
Type 1 diabetes results from the autoimmune destruction of pancreatic β cells, leading to insulin deficiency and hyperglycemia. Although multiple attempts have been made to slow the autoimmune process using immunosuppressive or immunomodulatory agents, there are still no effective treatments that can delay or reverse the progression of type 1 diabetes in humans. Recent studies support endoplasmic reticulum (ER) as a novel target for preventing the initiation of the autoimmune reaction, propagation of inflammation, and β cell death in type 1 diabetes. This review highlights recent findings on ER stress in β cells and development of type 1 diabetes and introduces potential new treatments targeting the ER to combat this disorder.

PMID: 27718448 [PubMed - as supplied by publisher]

The P21-activated kinase PAK4 is implicated in fatty-acid potentiation of insulin secretion downstream of free fatty acid receptor 1.

Thu, 10/06/2016 - 13:18

The P21-activated kinase PAK4 is implicated in fatty-acid potentiation of insulin secretion downstream of free fatty acid receptor 1.

Islets. 2016 Oct 4;:0

Authors: Bergeron V, Ghislain J, Poitout V

Abstract
Free fatty acid receptor 1 (FFA1/GPR40) plays a key role in the potentiation of glucose-stimulated insulin secretion by fatty acids in pancreatic beta cells. We previously demonstrated that GPR40 signaling leads to cortical actin remodeling and potentiates the second phase of insulin secretion. In this study, we examined the role of p21 activated kinase 4 (PAK4), a known regulator of cytoskeletal dynamics, in GPR40-dependent potentiation of insulin secretion. The fatty acid oleate induced PAK4 phosphorylation in human islets, in isolated mouse islets and in the insulin secreting cell line INS832/13. However, oleate-induced PAK4 phosphorylation was not observed in GPR40-null mouse islets. siRNA-mediated knockdown of PAK4 in INS832/13 cells abrogated the potentiation of insulin secretion by oleate, whereas PAK7 knockdown had no effect. Our results indicate that PAK4 plays an important role in the potentiation of insulin secretion by fatty acids downstream of GPR40.

PMID: 27700527 [PubMed - as supplied by publisher]

The regulator of G-protein signaling RGS16 promotes insulin secretion and β-cell proliferation in rodent and human islets.

Mon, 10/03/2016 - 13:15
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The regulator of G-protein signaling RGS16 promotes insulin secretion and β-cell proliferation in rodent and human islets.

Mol Metab. 2016 Oct;5(10):988-96

Authors: Vivot K, Moullé VS, Zarrouki B, Tremblay C, Mancini AD, Maachi H, Ghislain J, Poitout V

Abstract
OBJECTIVE: G protein-coupled receptor (GPCR) signaling regulates insulin secretion and pancreatic β cell-proliferation. While much knowledge has been gained regarding how GPCRs are activated in β cells, less is known about the mechanisms controlling their deactivation. In many cell types, termination of GPCR signaling is controlled by the family of Regulators of G-protein Signaling (RGS). RGS proteins are expressed in most eukaryotic cells and ensure a timely return to the GPCR inactive state upon removal of the stimulus. The aims of this study were i) to determine if RGS16, the most highly enriched RGS protein in β cells, regulates insulin secretion and β-cell proliferation and, if so, ii) to elucidate the mechanisms underlying such effects.
METHODS: Mouse and human islets were infected with recombinant adenoviruses expressing shRNA or cDNA sequences to knock-down or overexpress RGS16, respectively. 60 h post-infection, insulin secretion and cAMP levels were measured in static incubations in the presence of glucose and various secretagogues. β-cell proliferation was measured in infected islets after 72 h in the presence of 16.7 mM glucose ± somatostatin and various inhibitors.
RESULTS: RGS16 mRNA levels are strongly up-regulated in islets of Langerhans under hyperglycemic conditions in vivo and ex vivo. RGS16 overexpression stimulated glucose-induced insulin secretion in isolated mouse and human islets while, conversely, insulin secretion was impaired following RGS16 knock-down. Insulin secretion was no longer affected by RGS16 knock-down when islets were pre-treated with pertussis toxin to inactivate Gαi/o proteins, or in the presence of a somatostatin receptor antagonist. RGS16 overexpression increased intracellular cAMP levels, and its effects were blocked by an adenylyl cyclase inhibitor. Finally, RGS16 overexpression prevented the inhibitory effect of somatostatin on insulin secretion and β-cell proliferation.
CONCLUSIONS: Our results identify RGS16 as a novel regulator of β-cell function that coordinately controls insulin secretion and proliferation by limiting the tonic inhibitory signal exerted by δ-cell-derived somatostatin in islets.

PMID: 27689011 [PubMed - in process]

A beta cell ATGL-lipolysis/adipose tissue axis controls energy homeostasis and body weight via insulin secretion in mice.

Fri, 09/30/2016 - 11:34
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A beta cell ATGL-lipolysis/adipose tissue axis controls energy homeostasis and body weight via insulin secretion in mice.

Diabetologia. 2016 Sep 27;

Authors: Attané C, Peyot ML, Lussier R, Poursharifi P, Zhao S, Zhang D, Morin J, Pineda M, Wang S, Dumortier O, Ruderman NB, Mitchell GA, Simons B, Madiraju SR, Joly E, Prentki M

Abstract
AIMS/HYPOTHESIS: To directly assess the role of beta cell lipolysis in insulin secretion and whole-body energy homeostasis, inducible beta cell-specific adipose triglyceride lipase (ATGL)-deficient (B-Atgl-KO) mice were studied under normal diet (ND) and high-fat diet (HFD) conditions.
METHODS: Atgl (flox/flox) mice were cross-bred with Mip-Cre-ERT mice to generate Mip-Cre-ERT(/+);Atgl (flox/flox) mice. At 8 weeks of age, these mice were injected with tamoxifen to induce deletion of beta cell-specific Atgl (also known as Pnpla2), and the mice were fed an ND or HFD.
RESULTS: ND-fed male B-Atgl-KO mice showed decreased insulinaemia and glucose-induced insulin secretion (GSIS) in vivo. Changes in GSIS correlated with the islet content of long-chain saturated monoacylglycerol (MAG) species that have been proposed to be metabolic coupling factors for insulin secretion. Exogenous MAGs restored GSIS in B-Atgl-KO islets. B-Atgl-KO male mice fed an HFD showed reduced insulinaemia, glycaemia in the fasted and fed states and after glucose challenge, as well as enhanced insulin sensitivity. Moreover, decreased insulinaemia in B-Atgl-KO mice was associated with increased energy expenditure, and lipid metabolism in brown (BAT) and white (WAT) adipose tissues, leading to reduced fat mass and body weight.
CONCLUSIONS/INTERPRETATION: ATGL in beta cells regulates insulin secretion via the production of signalling MAGs. Decreased insulinaemia due to lowered GSIS protects B-Atgl-KO mice from diet-induced obesity, improves insulin sensitivity, increases lipid mobilisation from WAT and causes BAT activation. The results support the concept that fuel excess can drive obesity and diabetes via hyperinsulinaemia, and that an islet beta cell ATGL-lipolysis/adipose tissue axis controls energy homeostasis and body weight via insulin secretion.

PMID: 27677764 [PubMed - as supplied by publisher]

Novel factors modulating human β-cell proliferation.

Thu, 09/15/2016 - 07:14
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Novel factors modulating human β-cell proliferation.

Diabetes Obes Metab. 2016 Sep;18 Suppl 1:71-7

Authors: Shirakawa J, Kulkarni RN

Abstract
β-Cell dysfunction in type 1 and type 2 diabetes is accompanied by a progressive loss of β-cells, and an understanding of the cellular mechanism(s) that regulate β-cell mass will enable approaches to enhance hormone secretion. It is becoming increasingly recognized that enhancement of human β-cell proliferation is one potential approach to restore β-cell mass to prevent and/or cure type 1 and type 2 diabetes. While several reports describe the factor(s) that enhance β-cell replication in animal models or cell lines, promoting effective human β-cell proliferation continues to be a challenge in the field. In this review, we discuss recent studies reporting successful human β-cell proliferation including WS6, an IkB kinase and EBP1 inhibitor; harmine and 5-IT, both DYRK1A inhibitors; GNF7156 and GNF4877, GSK-3β and DYRK1A inhibitors; osteoprotegrin and Denosmab, receptor activator of NF-kB (RANK) inhibitors; and SerpinB1, a protease inhibitor. These studies provide important examples of proteins and pathways that may prove useful for designing therapeutic strategies to counter the different forms of human diabetes.

PMID: 27615134 [PubMed - in process]

NAD(P)H-dependent Quinone Oxidoreductase 1 (NQO1) and Cytochrome P450 Oxidoreductase (CYP450OR) differentially regulate menadione-mediated alterations in redox status, survival and metabolism in pancreatic β-cells.

Sun, 08/28/2016 - 03:44
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NAD(P)H-dependent Quinone Oxidoreductase 1 (NQO1) and Cytochrome P450 Oxidoreductase (CYP450OR) differentially regulate menadione-mediated alterations in redox status, survival and metabolism in pancreatic β-cells.

Toxicol Lett. 2016 Aug 21;

Authors: Gray JP, Karandrea S, Burgos DZ, Jaiswal AA, Heart EA

Abstract
NQO1 (NAD(P)H-quinone oxidoreductase 1) reduces quinones and xenobiotics to less-reactive compounds via 2-electron reduction, one feature responsible for the role of NQO1 in antioxidant defense in several tissues. In contrast, NADPH cytochrome P450 oxidoreductase (CYP450OR), catalyzes the 1-electron reduction of quinones and xenobiotics, resulting in enhanced superoxide formation. However, to date, the roles of NQO1 and CYP450OR in pancreatic β-cell metabolism under basal conditions and oxidant challenge have not been characterized. Using NQO1 inhibition, over-expression and knock out, we have demonstrated that, in addition to protection of β-cells from toxic concentrations of the redox cycling quinone menadione, NQO1 also regulates the basal level of reduced-to-oxidized nucleotides, suggesting other role(s) beside that of an antioxidant enzyme. In contrast, over-expression of NADPH cytochrome P450 oxidoreductase (CYP450OR) resulted in enhanced redox cycling activity and decreased cellular viability, consistent with the enhanced generation of superoxide and H2O2. Basal expression of NQO1 and CYP450OR was comparable in isolated islets and liver. However, NQO1, but not CYP450OR, was strongly induced in β-cells exposed to menadione. NQO1 and CYP450OR exhibited a reciprocal preference for reducing equivalents in β-cells: while CYP450OR preferentially utilized NADPH, NQO1 primarily utilized NADH. Together, these results demonstrate that NQO1 and CYP450OR reciprocally regulate oxidant metabolism in pancreatic β-cells.

PMID: 27558805 [PubMed - as supplied by publisher]

Pancreatic β-Cell Dysfunction in Diet-Induced Obese Mice: Roles of AMP-Kinase, Protein Kinase Cε, Mitochondrial and Cholesterol Metabolism, and Alterations in Gene Expression.

Mon, 08/22/2016 - 03:24
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Pancreatic β-Cell Dysfunction in Diet-Induced Obese Mice: Roles of AMP-Kinase, Protein Kinase Cε, Mitochondrial and Cholesterol Metabolism, and Alterations in Gene Expression.

PLoS One. 2016;11(4):e0153017

Authors: Pepin É, Al-Mass A, Attané C, Zhang K, Lamontagne J, Lussier R, Madiraju SR, Joly E, Ruderman NB, Sladek R, Prentki M, Peyot ML

Abstract
Diet induced obese (DIO) mice can be stratified according to their weight gain in response to high fat diet as low responders (LDR) and high responders (HDR). This allows the study of β-cell failure and the transitions to prediabetes (LDR) and early diabetes (HDR). C57BL/6N mice were fed for 8 weeks with a normal chow diet (ND) or a high fat diet and stratified as LDR and HDR. Freshly isolated islets from ND, LDR and HDR mice were studied ex-vivo for mitochondrial metabolism, AMPK activity and signalling, the expression and activity of key enzymes of energy metabolism, cholesterol synthesis, and mRNA profiling. Severely compromised glucose-induced insulin secretion in HDR islets, as compared to ND and LDR islets, was associated with suppressed AMP-kinase activity. HDR islets also showed reduced acetyl-CoA carboxylase activity and enhanced activity of 3-hydroxy-3-methylglutaryl-CoA reductase, which led respectively to elevated fatty acid oxidation and increased cholesterol biosynthesis. HDR islets also displayed mitochondrial membrane hyperpolarization and reduced ATP turnover in the presence of elevated glucose. Expression of protein kinase Cε, which reduces both lipolysis and production of signals for insulin secretion, was elevated in DIO islets. Genes whose expression increased or decreased by more than 1.2-fold were minor between LDR and ND islets (17 differentially expressed), but were prominent between HDR and ND islets (1508 differentially expressed). In HDR islets, particularly affected genes were related to cell cycle and proliferation, AMPK signaling, mitochondrial metabolism and cholesterol metabolism. In conclusion, chronically reduced AMPK activity, mitochondrial dysfunction, elevated cholesterol biosynthesis in islets, and substantial alterations in gene expression accompany β-cell failure in HDR islets. The β-cell compensation process in the prediabetic state (LDR) is largely independent of transcriptional adaptive changes, whereas the transition to early diabetes (HDR) is associated with major alterations in gene expression.

PMID: 27043434 [PubMed - indexed for MEDLINE]

Amyrins from Protium heptaphyllum Reduce High-Fat Diet-Induced Obesity in Mice via Modulation of Enzymatic, Hormonal And Inflammatory Responses.

Fri, 08/19/2016 - 03:13
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Amyrins from Protium heptaphyllum Reduce High-Fat Diet-Induced Obesity in Mice via Modulation of Enzymatic, Hormonal And Inflammatory Responses.

Planta Med. 2016 Aug 15;

Authors: Carvalho KM, de Melo TS, de Melo KM, Quinderé AL, de Oliveira FT, Viana AF, Nunes PI, Quetz JD, Viana DA, da Silva AA, Havt A, Fonseca SG, Chaves MH, Rao VS, Santos FA

Abstract
Obesity remains a global problem. In search of phytochemicals that have antiobesity potential, this study evaluated α,β-amyrin, a triterpenoid mixture from Protium heptaphyllum, on high-fat diet-induced obesity in mice. Groups of mice (n = 8) were fed a normal diet or a high-fat diet, and were orally treated or not treated with either α,β-amyrin (10 or 20 mg/kg) or sibutramine (10 mg/kg) for 15 weeks. Variables measured at termination were body weight, visceral fat accumulation, adipocyte surface area, peroxisome proliferator-activated receptor gamma, and lipoprotein lipase expressions in adipose tissue, the levels of plasma glucose and insulin, the satiety hormones ghrelin and leptin, the digestive enzymes amylase and lipase, and the inflammatory mediators TNF-α, interleukin-6, and MCP-1. Results showed that α,β-amyrin treatment resulted in lower high-fat diet-induced increases in body weight, visceral fat content, adipocyte surface area, peroxisome proliferator-activated receptor gamma, and lipoprotein lipase expressions, and blood glucose and insulin levels. Additionally, the markedly elevated leptin and decreased ghrelin levels seen in the high-fat diet-fed control mice were significantly modulated by α,β-amyrin treatment. Furthermore, α,β-amyrin decreased serum TNF-α and MCP-1. These results suggest that α,β-amyrin could be beneficial in reducing high-fat diet-induced obesity and associated disorders via modulation of enzymatic, hormonal, and inflammatory responses.

PMID: 27525508 [PubMed - as supplied by publisher]

Urea impairs β cell glycolysis and insulin secretion in chronic kidney disease.

Fri, 08/19/2016 - 03:13
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Urea impairs β cell glycolysis and insulin secretion in chronic kidney disease.

J Clin Invest. 2016 Aug 15;

Authors: Koppe L, Nyam E, Vivot K, Manning Fox JE, Dai XQ, Nguyen BN, Trudel D, Attané C, Moullé VS, MacDonald PE, Ghislain J, Poitout V

Abstract
Disorders of glucose homeostasis are common in chronic kidney disease (CKD) and are associated with increased mortality, but the mechanisms of impaired insulin secretion in this disease remain unclear. Here, we tested the hypothesis that defective insulin secretion in CKD is caused by a direct effect of urea on pancreatic β cells. In a murine model in which CKD is induced by 5/6 nephrectomy (CKD mice), we observed defects in glucose-stimulated insulin secretion in vivo and in isolated islets. Similarly, insulin secretion was impaired in normal mouse and human islets that were cultured with disease-relevant concentrations of urea and in islets from normal mice treated orally with urea for 3 weeks. In CKD mouse islets as well as urea-exposed normal islets, we observed an increase in oxidative stress and protein O-GlcNAcylation. Protein O-GlcNAcylation was also observed in pancreatic sections from CKD patients. Impairment of insulin secretion in both CKD mouse and urea-exposed islets was associated with reduced glucose utilization and activity of phosphofructokinase 1 (PFK-1), which could be reversed by inhibiting O-GlcNAcylation. Inhibition of O-GlcNAcylation also restored insulin secretion in both mouse models. These results suggest that insulin secretory defects associated with CKD arise from elevated circulating levels of urea that increase islet protein O-GlcNAcylation and impair glycolysis.

PMID: 27525435 [PubMed - as supplied by publisher]

Response to Comment on Schwartz et al. The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of the β-Cell-Centric Classification Schema. Diabetes Care 2016;39:179-186.

Fri, 07/29/2016 - 02:02
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Response to Comment on Schwartz et al. The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of the β-Cell-Centric Classification Schema. Diabetes Care 2016;39:179-186.

Diabetes Care. 2016 Aug;39(8):e129-30

Authors: Schwartz SS, Epstein S, Corkey BE, Grant SF, Gavin JR, Aguilar RB

PMID: 27457644 [PubMed - in process]

Differential Insulin Secretion of High-Fat Diet-Fed C57BL/6NN and C57BL/6NJ Mice: Implications of Mixed Genetic Background in Metabolic Studies.

Thu, 07/14/2016 - 01:06

Differential Insulin Secretion of High-Fat Diet-Fed C57BL/6NN and C57BL/6NJ Mice: Implications of Mixed Genetic Background in Metabolic Studies.

PLoS One. 2016;11(7):e0159165

Authors: Attané C, Peyot ML, Lussier R, Zhang D, Joly E, Madiraju SR, Prentki M

Abstract
Many metabolic studies employ tissue-specific gene knockout mice, which requires breeding of floxed gene mice, available mostly on C57BL/6N (NN) genetic background, with cre or Flp recombinase-expressing mice, available on C57BL/6J (JJ) background, resulting in the generation of mixed C57BL/6NJ (NJ) genetic background mice. Recent awareness of many genetic differences between NN and JJ strains including the deletion of nicotinamide nucleotide transhydrogenase (nnt), necessitates examination of the consequence of mixed NJ background on glucose tolerance, beta cell function and other metabolic parameters. Male mice with NN and NJ genetic background were fed with normal or high fat diets (HFD) for 12 weeks and glucose and insulin homeostasis were studied. Genotype had no effect on body weight and food intake in mice fed normal or high fat diets. Insulinemia in the fed and fasted states and after a glucose challenge was lower in HFD-fed NJ mice, even though their glycemia and insulin sensitivity were similar to NN mice. NJ mice showed mild glucose intolerance. Moreover, glucose- but not KCl-stimulated insulin secretion in isolated islets was decreased in HFD-fed NJ vs NN mice without changes in insulin content and beta cell mass. Under normal diet, besides reduced fed insulinemia, NN and NJ mice presented similar metabolic parameters. However, HFD-fed NJ mice displayed lower fed and fasted insulinemia and glucose-induced insulin secretion in vivo and ex vivo, as compared to NN mice. These results strongly caution against using unmatched mixed genetic background C57BL/6 mice for comparisons, particularly under HFD conditions.

PMID: 27403868 [PubMed - in process]

Physiology: Pancreatic β-cell heterogeneity revisited.

Thu, 07/14/2016 - 01:06

Physiology: Pancreatic β-cell heterogeneity revisited.

Nature. 2016 Jul 11;

Authors: Bonner-Weir S, Aguayo-Mazzucato C

PMID: 27398615 [PubMed - as supplied by publisher]

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