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

Pépin, Émilie; Al‐Mass, Anfal; Attané, Camille; Zhang, Kezhuo; Lamontagne, Julien; Lussier, Roxane; Joly, Etienne; Ruderman, Neil B.; Sladek, Robert; Prentki, Marc; Peyot, Marie‐Line

doi:10.1371/journal.pone.0153017

Cited by 24 publications

(20 citation statements)

References 54 publications

(80 reference statements)

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“…In accordance with the observation that an important fate of glucose in the ␤-cell is cholesterol, the first intermediate in the pathway of cholesterol biosynthesis, hydroxymethylglutaryl-CoA (HMG-CoA) ( Fig. 5I), was reduced perhaps due to HMG-CoA reductase activa-tion due to AMP kinase inhibition at elevated glucose (50). We found a significant reduction in aspartate ( Fig.…”

Section: Changes In the Levels Of Metabolites In Response To Glucose supporting

confidence: 90%

“…Because cholesterol can be secreted from cells and CE are considered as a biologically inert storage (detoxification) form of cholesterol and because inhibition of cholesterol efflux causes ␤-cell dysfunction, this pathway is also potentially involved in excess-fuel detoxification in the ␤-cell. This is not to dismiss that chronic accumulation of free cholesterol in the ␤-cell contributes to ␤-cell failure in diabetes (50,65).…”

Section: Discussionmentioning

confidence: 99%

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

Mugabo

Zhao

Lamontagne

et al. 2017

Journal of Biological Chemistry

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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 INS-1(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.

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Section: Changes In the Levels Of Metabolites In Response To Glucose supporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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

Mugabo

Zhao

Lamontagne

et al. 2017

Journal of Biological Chemistry

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“…and the quest for such agents is ongoing (8,18). Notably, AMPK appears to ensure both normal β cell glucose sensing and glucose-stimulated insulin secretion (GSIS), and reduced AMPK activity has been associated with β cell dysfunction in diet-induced obese (DIO) mice (19)(20)(21)(22)(23). Moreover, AMPK stimulates macroautophagy, herein referred to as autophagy, which not only is important for β cell function and survival (24,25), but which -by clearing aggregating proteins (26,27) -also may prevent accumulation of toxic islet amyloid polypeptide (IAPP) aggregates/amyloid in β cells (28)(29)(30).…”

Section: Introductionmentioning

confidence: 99%

PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients

Steneberg¹,

Lindahl²,

Dahl³

et al. 2018

JCI Insight

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AMPK activated protein kinase (AMPK), a master regulator of energy homeostasis, is activated in response to an energy shortage imposed by physical activity and caloric restriction. We here report on the identification of PAN-AMPK activator O304, which - in diet-induced obese mice - increased glucose uptake in skeletal muscle, reduced β cell stress, and promoted β cell rest. Accordingly, O304 reduced fasting plasma glucose levels and homeostasis model assessment of insulin resistance (HOMA-IR) in a proof-of-concept phase IIa clinical trial in type 2 diabetes (T2D) patients on Metformin. T2D is associated with devastating micro- and macrovascular complications, and O304 improved peripheral microvascular perfusion and reduced blood pressure both in animals and T2D patients. Moreover, like exercise, O304 activated AMPK in the heart, increased cardiac glucose uptake, reduced cardiac glycogen levels, and improved left ventricular stroke volume in mice, but it did not increase heart weight in mice or rats. Thus, O304 exhibits a great potential as a novel drug to treat T2D and associated cardiovascular complications.

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“…1 ). Of these differentially expressed genes, 21.2% overlapped with those previously identified by microarray [31] . We also detected 1761 UCSC annotated lncRNAs (23 upregulated and 104 downregulated) and 1996 non-annotated UCSC lncRNA genes (4303 transcripts), of which, 39 were upregulated and 107 downregulated ( Figure 1 B, Supplemental Tables 4 and 5 ).…”

Section: Resultsmentioning

confidence: 77%

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

Motterle

Gattesco

Peyot³

et al. 2017

Molecular Metabolism

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ObjectiveNon-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.MethodsNovel 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.ResultsWe 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.ConclusionsTaken 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.

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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

Cited by 24 publications

References 54 publications

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

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

PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients

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

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