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

Recent Publications of BIIC Members - Thu, 12/07/2017 - 17:28
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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]

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

Recent Publications of BIIC Members - Wed, 11/29/2017 - 19:28
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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 SRM, 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 (VMHKO) have higher VMH 2-AG levels in conditions of endocannabinoid recruitment and fail to physiologically adapt to key metabolic challenges. VMHKO 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 - indexed for MEDLINE]

Considerations and guidelines for mouse metabolic phenotyping in diabetes research.

Recent Publications of BIIC Members - Sun, 11/19/2017 - 09:49
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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.

Recent Publications of BIIC Members - Wed, 11/15/2017 - 09:49
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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]

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

Recent Publications of BIIC Members - Wed, 11/15/2017 - 09:49
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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 - indexed for MEDLINE]

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.

Recent Publications of BIIC Members - Sat, 11/11/2017 - 09:49
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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.

Recent Publications of BIIC Members - Wed, 11/08/2017 - 09:49
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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]

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

Recent Publications of BIIC Members - Sun, 11/05/2017 - 08:49
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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 - indexed for MEDLINE]

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

Recent Publications of BIIC Members - Sun, 11/05/2017 - 08:49
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The P21-activated kinase PAK4 is implicated in fatty-acid potentiation of insulin secretion downstream of free fatty acid receptor 1.

Islets. 2016 Nov;8(6):157-164

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 β 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 - indexed for MEDLINE]

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