Downregulation of Carnitine Acyl-Carnitine Translocase by miRNAs 132 and 212 Amplifies Glucose-Stimulated Insulin Secretion

Soni, Mufaddal; Rabaglia, Mary E.; Bhatnagar, Sushant; Shang, Jin; Ilkayeva, Olga; Mynatt, Randall L.; Zhou, Yunping; Schadt, Eric E.; Thornberry, Nancy A.; Muoio, Deborah M.; Keller, Mark P.; Attie, Alan D.

doi:10.2337/db13-1677

Cited by 44 publications

(37 citation statements)

References 57 publications

(83 reference statements)

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“…The key finding of the present study is the decrease of lipid utilization by purified islets in the presence of elevated glucose. These findings can be explained by several concurrent features of the gene expression analysis: (i) the strong inhibition of Ppar␥ and C/ebps with feeding; (ii) Cd36 is decreased, as are Cpt1␣ and -␤; (iii) Chrebp is increased and so is its target gene AldoB, which would funnel more glucose toward oxidation; (iv) AldoB is normally inhibited by Ppar␣ activation when lipid oxidation is favored over glucose oxidation (38); (v) the decrease of the Slc25 family and specifically the carnitine/acylcarnitine carrier is consistent with the observation that these carriers are increased in cells exposed to glucose and lipotoxicity (28) and that inhibition of carnitine translocase enhances insulin secretion (29). Thus, the ability of 6KR to tune down expression of solute carriers might be part of a protective function.…”

Section: Discussionsupporting

confidence: 57%

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FoxO1 Deacetylation Decreases Fatty Acid Oxidation in β-Cells and Sustains Insulin Secretion in Diabetes

Kim-Muller

Kim

Fan

et al. 2016

Journal of Biological Chemistry

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Pancreatic ␤-cell dysfunction contributes to onset and progression of type 2 diabetes. In this state ␤-cells become metabolically inflexible, losing the ability to select between carbohydrates and lipids as substrates for mitochondrial oxidation. These changes lead to ␤-cell dedifferentiation. We have proposed that FoxO proteins are activated through deacetylationdependent nuclear translocation to forestall the progression of these abnormalities. However, how deacetylated FoxO exert their actions remains unclear. To address this question, we analyzed islet function in mice homozygous for knock-in alleles encoding deacetylated FoxO1 (6KR). Islets expressing 6KR mutant FoxO1 have enhanced insulin secretion in vivo and ex vivo and decreased fatty acid oxidation ex vivo. Remarkably, the gene expression signature associated with FoxO1 deacetylation differs from wild type by only ϳ2% of the >4000 genes regulated in response to re-feeding. But this narrow swath includes key genes required for ␤-cell identity, lipid metabolism, and mitochondrial fatty acid and solute transport. The data support the notion that deacetylated FoxO1 protects ␤-cell function by limiting mitochondrial lipid utilization and raise the possibility that inhibition of fatty acid oxidation in ␤-cells is beneficial to diabetes treatment.

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Section: Discussionsupporting

confidence: 57%

“…secretion (29). The fact that they are decreased in 6KR islets raises the interesting possibility that reducing substrate flux into the mitochondrial inner core protects against mitochondrial dysfunction.…”

Section: Foxo1 Deacetylation and Lipid Oxidation In ␤-Cellsmentioning

confidence: 99%

FoxO1 Deacetylation Decreases Fatty Acid Oxidation in β-Cells and Sustains Insulin Secretion in Diabetes

Kim-Muller

Kim

Fan

et al. 2016

Journal of Biological Chemistry

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“…Under conditions of insulin resistance, the expression of several miRNAs including miR-7, miR-132, miR-184 and miR-338-3p and possibly miR-375 is modified in order to promote compensatory β-cell mass expansion and amplification of insulin secretion [18,31,49,50].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, overexpression of miR-132 amplified the amount of insulin secreted in response to glucose without affecting insulin content and promoted β-cell proliferation in dispersed rat islet cells. The beneficial effect of miR-132 on insulin release has been suggested to be mediated by direct down-regulation of carnitine acyl-carnitine translocase (CACT), a mitochondrial protein important for β-oxidation [49]. Down-regulation of miR-184 also increased β-cell proliferation [31].…”

Section: Contribution Of Other Mirnas To Compensatory β-Cell Mass Expmentioning

confidence: 99%

MicroRNAs and the functional β cell mass: For better or worse

Guay

Regazzi

2015

Diabetes & Metabolism

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Insulin secretion from pancreatic β-cells plays a central role in the control of blood glucose levels. The amount of insulin released by β-cells is precisely adjusted to match the organism requirements. A number of conditions occurring during life, including pregnancy and obesity, can result in a decrease in the sensitivity of insulin target tissues and in the consequent rise in the insulin needs. To preserve glucose homeostasis, the augmented insulin demand requires a compensatory expansion of the mass of pancreatic β-cells and an increase in their secretory activity. This compensatory process is known to be accompanied by modifications in β-cell gene expression but the molecular mechanisms underlying this phenomenon are still poorly understood. Emerging evidence indicate that at least part of these compensatory events may be orchestrated by changes in the level of a novel class of gene regulators, the microRNAs.Indeed, several of these small non-coding RNAs have either positive or negative impacts on β-cell proliferation and survival. The studies reviewed in this paper suggest that the balance between the actions of these two groups of microRNAs with opposing functional effects determines whether β-cells expand sufficiently to maintain blood glucose levels in the normal range or fail to meet the insulin demand with a consequent progression toward diabetes manifestation. A better understanding of the mechanisms governing the changes in the microRNA profile will open the way for the development of new strategies to prevent and/or treat type 2 and gestational diabetes.

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“…However, not all the changes in microRNA levels detected in the islets of diabetic animals have deleterious effects on beta cell activities. Indeed, reduction of miR-184 and miR-338-3p or a rise of miR-132 was found to trigger beta cell proliferation and improve survival and/or insulin release [20,21,31,33]. This suggests that these changes contribute to physiological processes that attempt to compensate for insulin resistance rather than to pathological events causing the appearance of diabetes.…”

Section: Inappropriate Islet Microrna Expression As a Potential Causementioning

confidence: 99%

Role of islet microRNAs in diabetes: which model for which question?

Guay

Regazzi

2014

Diabetologia

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MicroRNAs are important regulators of gene expression. The vast majority of the cells in our body rely on hundreds of these tiny non-coding RNA molecules to precisely adjust their protein repertoire and faithfully accomplish their tasks. Indeed, alterations in the microRNA profile can lead to cellular dysfunction that favours the appearance of several diseases. A specific set of microRNAs plays a crucial role in pancreatic beta cell differentiation and is essential for the fine-tuning of insulin secretion and for compensatory beta cell mass expansion in response to insulin resistance. Recently, several independent studies reported alterations in microRNA levels in the islets of animal models of diabetes and in islets isolated from diabetic patients. Surprisingly, many of the changes in microRNA expression observed in animal models of diabetes were not detected in the islets of diabetic patients and vice versa. These findings are unlikely to merely reflect species differences because microRNAs are highly conserved in mammals. These puzzling results are most probably explained by fundamental differences in the experimental approaches which selectively highlight the microRNAs directly contributing to diabetes development, the microRNAs predisposing individuals to the disease or the microRNAs displaying expression changes subsequent to the development of diabetes. In this review we will highlight the suitability of the different models for addressing each of these questions and propose future strategies that should allow us to obtain a better understanding of the contribution of microRNAs to the development of diabetes mellitus in humans.Keywords Animal models of Diabetes . Diabetes . Human islet donors . Insulin . Islets of Langerhans . MicroRNAs . Pancreatic beta cells . Review MicroRNAs as regulators of beta cell differentiation and functionType 2 diabetes is a chronic metabolic disorder characterised by major alterations in gene expression, which affects several organs, including the islets of Langerhans. A growing number of studies demonstrate that these changes are not only caused by deregulation of key transcription factors such as v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (avian) (MafA) or pancreatic and duodenal homeobox 1 (PDX1) but are also driven by modifications in the level of another group of molecules regulating gene expression, the microRNAs [1][2][3][4]. MicroRNAs are small non-coding RNAs (typically 21-23 nucleotides long) that pair to the 3′ untranslated region of target mRNAs leading to translational repression and/or a decrease in messenger stability [5].The importance of the microRNA regulatory network for proper differentiation and function of beta cells is highlighted by the phenotypic traits of mice lacking Dicer1, an enzyme essential for the generation of most microRNAs [5]. Deletion of Dicer1 at different stages of pancreas development or of the pancreatic endocrine lineage results in a dramatic loss of microRNAs, accompanied by severe defects in pancreas m...

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Downregulation of Carnitine Acyl-Carnitine Translocase by miRNAs 132 and 212 Amplifies Glucose-Stimulated Insulin Secretion

Cited by 44 publications

References 57 publications

FoxO1 Deacetylation Decreases Fatty Acid Oxidation in β-Cells and Sustains Insulin Secretion in Diabetes

FoxO1 Deacetylation Decreases Fatty Acid Oxidation in β-Cells and Sustains Insulin Secretion in Diabetes

MicroRNAs and the functional β cell mass: For better or worse

Role of islet microRNAs in diabetes: which model for which question?

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