Glucose-regulated anaplerosis and cataplerosis in pancreatic beta-cells: possible implication of a pyruvate/citrate shuttle in insulin secretion.

Farfari, Salah; Schulz, Vera; Corkey, Barbara E.; Prentki, Marc

doi:10.2337/diabetes.49.5.718

Cited by 247 publications

(263 citation statements)

References 56 publications

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“…It has also been demonstrated that glucose carbon in acutely stimulated beta cells is incorporated into material extractable with organic solvents [14,15], consistent with the idea that secretagogue carbon is incorporated into lipid. One of the short chain acyl-CoAs that has been frequently shown to be increased by insulin secretagogues is malonyl-CoA [12][13][14][15][16][17]. Malonyl-CoA supplies the two-carbon units for fatty acid synthesis.…”

Section: Introductionsupporting

confidence: 60%

“…Methyl succinate by itself does not stimulate insulin release from INS-1 cells but it caused increases in some lipids (Supplemental Tables 1-8 Online) 1 . This may be because it provides NADPH [2,[12][13][14][15] which is used for fatty acid elongation and HMG-CoA synthesis. The relative increase in total CE induced by glucose was 17% and that induced by MMS plus KIC was 21% (Tables 2 and 3 and Supplemental Table 2).…”

Section: Measurement Of Lipidsmentioning

confidence: 99%

“…This idea came in part from the fact that certain lipid precursors, that is various short chain acyl-CoAs, are increased by insulin secretagogues in beta cells and the beta cell possesses several pathways for the transfer of acyl groups from the mitochondria to the cytosol, where lipid synthesis would take place [12,13]. It has also been demonstrated that glucose carbon in acutely stimulated beta cells is incorporated into material extractable with organic solvents [14,15], consistent with the idea that secretagogue carbon is incorporated into lipid. One of the short chain acyl-CoAs that has been frequently shown to be increased by insulin secretagogues is malonyl-CoA [12][13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

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The role of rapid lipogenesis in insulin secretion: Insulin secretagogues acutely alter lipid composition of INS-1 832/13 cells

MacDonald

Dobrzyń

Ntambi

et al. 2008

Archives of Biochemistry and Biophysics

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Pancreatic beta cell mitochondria convert insulin secretagogues into products that support insulin exocytosis. We explored the idea that lipids are some of these products formed from acyl group transfer out of mitochondria to the cytosol, the site of lipid synthesis. There are two isoforms of acetyl-CoA carboxylase, the enzyme that forms malonyl-CoA from which C 2 units for lipid synthesis are formed. We found that ACC1, the isoform seen in lipogenic tissues, is the only isoform present in human and rat pancreatic islets and INS-1 832/13 cells. Inhibitors of ACC and fatty acid synthase inhibited insulin release in islets and INS-1 cells. Carbon from glucose and pyruvate were rapidly incorporated into many lipid classes in INS-1 cells. Glucose and other insulin secretagogues acutely increased many lipids with C 14 -C 24 chains including individual cholesterol esters, phospholipids and fatty acids. Many phosphatidylcholines and phosphatidylserines were increased and many phosphatidylinositols and several phosphatidylethanolamines were decreased. The results suggest that lipid remodeling and rapid lipogenesis from secretagogue carbon support insulin secretion.

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Section: Introductionsupporting

confidence: 60%

Section: Measurement Of Lipidsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The role of rapid lipogenesis in insulin secretion: Insulin secretagogues acutely alter lipid composition of INS-1 832/13 cells

MacDonald

Dobrzyń

Ntambi

et al. 2008

Archives of Biochemistry and Biophysics

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“…In both cases, a clear induction of adipogenic transformation was observed upon the application of high-glucose culture conditions. The capacity of high glucose to partly activate an adipogenic differentiation program had already been noticed in pancreatic ␤ cells (13,14). In our case, the process consists in a full conversion into adipocytes, as verified by morphological and molecular criteria and the capacity of these cultured cell to form viable and vascularized adipose depots when implanted in vivo.…”

Section: Discussionmentioning

confidence: 83%

High glucose induces adipogenic differentiation of muscle-derived stem cells

Aguiari

Leo

Zavan

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

251

178

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Regeneration of mesenchymal tissues depends on a resident stem cell population, that in most cases remains elusive in terms of cellular identity and differentiation signals. We here show that primary cell cultures derived from adipose tissue or skeletal muscle differentiate into adipocytes when cultured in high glucose. High glucose induces ROS production and PKC␤ activation. These two events appear crucial steps in this differentiation process that can be directly induced by oxidizing agents and inhibited by PKC␤ siRNA silencing. The differentiated adipocytes, when implanted in vivo, form viable and vascularized adipose tissue. Overall, the data highlight a previously uncharacterized differentiation route triggered by high glucose that drives not only resident stem cells of the adipose tissue but also uncommitted precursors present in muscle cells to form adipose depots. This process may represent a feed-forward cycle between the regional increase in adiposity and insulin resistance that plays a key role in the pathogenesis of diabetes mellitus.adipocyte ͉ hyperglycemia ͉ PKC ͉ ROS

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“…However, the kinetics of insulin release and of proinsulin biosynthesis, and the metabolic signals mediating these processes, are not identical [3,8]. In fact, the role of various glycolytic and TCA cycle intermediates in glucose-stimulated insulin secretion is controversial [7,[9][10][11][12][13][14][15][16], and even less is known about the metabolic signals for glucose-stimulated insulin production. A previous report by Alarcon et al suggested that succinate is the key signal for glucose stimulation of preproinsulin mRNA translation [3].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial regulation of insulin production in rat pancreatic islets

Leibowitz

Khaldi²,

Shauer

et al. 2005

Diabetologia

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Aims/hypothesis: The study was designed to identify the key metabolic signals of glucose-stimulated proinsulin gene transcription and translation, focusing on the mechanism of succinate stimulation of insulin production. Methods: Wistar rat islets were incubated in 3.3 mmol/l glucose with and without esters of different mitochondrial metabolites or with 16.7 mmol/l glucose. Proinsulin biosynthesis was analysed by tritiated leucine incorporation into newly synthesised proinsulin. Preproinsulin gene transcription was evaluated following transduction with adenoviral vectors expressing the luciferase reporter gene under the control of the rat I preproinsulin promoter. Steady-state preproinsulin mRNA was determined using relative quantitative PCR. The mitochondrial membrane potential was measured by microspectrofluorimetry using rhodamine-123. Results: Succinic acid monomethyl ester, but not other mitochondrial metabolites, stimulated preproinsulin gene transcription and translation. Similarly to glucose, succinate increased specific preproinsulin gene transcription and biosynthesis. The inhibitor of succinate dehydrogenase (SDH), 3-nitropropionate, abolished glucose-and succinate-stimulated mitochondrial membrane hyperpolarisation and proinsulin biosynthesis, indicating that stimulation of proinsulin translation depends on SDH activity. Partial inhibition of SDH activity by exposure to fumaric acid monomethyl ester abolished the stimulation of preproinsulin gene transcription, but only partially inhibited the stimulation of proinsulin biosynthesis by glucose and succinate, suggesting that SDH activity is particularly important for the transcriptional response to glucose. Conclusions/interpretation: Succinate is a key metabolic mediator of glucose-stimulated preproinsulin gene transcription and translation. Moreover, succinate stimulation of insulin production depends on its metabolism via SDH. The differential effect of fumarate on preproinsulin gene transcription and translation suggests that these processes have different sensitivities to metabolic signals.

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Glucose-regulated anaplerosis and cataplerosis in pancreatic beta-cells: possible implication of a pyruvate/citrate shuttle in insulin secretion.

Cited by 247 publications

References 56 publications

The role of rapid lipogenesis in insulin secretion: Insulin secretagogues acutely alter lipid composition of INS-1 832/13 cells

The role of rapid lipogenesis in insulin secretion: Insulin secretagogues acutely alter lipid composition of INS-1 832/13 cells

High glucose induces adipogenic differentiation of muscle-derived stem cells

Mitochondrial regulation of insulin production in rat pancreatic islets

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