Overexpression of monocarboxylate transporter and lactate dehydrogenase alters insulin secretory responses to pyruvate and lactate in β cells

Ishihara, Hideharu; Wang, Haiyan; Drewes, Lester R.; Wollheim, Claes B.

doi:10.1172/jci7515

Cited by 174 publications

(211 citation statements)

References 39 publications

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“…Acute exercise as well as an overnight fast are both physiological states in which insulin secretion must be avoided. This is consistent with the low expression of monocarboxylate transporter in beta cells, which avoids pyruvate and lactate-induced insulin release [64]. Clinical significance of such undesired secretory responses has recently been reported in the form of an autosomal trait characterised by abnormal pyruvate-induced insulin release and exercise-induced hyperinsulinaemic hypoglycaemia [65].…”

Section: Discussionsupporting

confidence: 73%

Insulin secretion profiles are modified by overexpression of glutamate dehydrogenase in pancreatic islets

Carobbio¹,

Ishihara²,

Fernández-Pascual

et al. 2004

Diabetologia

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Aims/hypothesis. Glutamate dehydrogenase (GDH) is a mitochondrial enzyme playing a key role in the control of insulin secretion. However, it is not known whether GDH expression levels in beta cells are ratelimiting for the secretory response to glucose. GDH also controls glutamine and glutamate oxidative metabolism, which is only weak in islets if GDH is not allosterically activated by L-leucine or (+/−)-2-aminobicyclo-[2,2,1]heptane-2-carboxylic acid (BCH). Methods. We constructed an adenovirus encoding for GDH to overexpress the enzyme in the beta-cell line INS-1E, as well as in isolated rat and mouse pancreatic islets. The secretory responses to glucose and glutamine were studied in static and perifusion experiments. Amino acid concentrations and metabolic parameters were measured in parallel.Results. GDH overexpression in rat islets did not change insulin release at basal or intermediate glucose (2.8 and 8.3 mmol/l respectively), but potentiated the secretory response at high glucose concentrations (16.7 mmol/l) compared to controls (+35%). Control islets exposed to 5 mmol/l glutamine at basal glucose did not increase insulin release, unless BCH was added with a resulting 2.5-fold response. In islets overexpressing GDH glutamine alone stimulated insulin secretion (2.7-fold), which was potentiated 2.2-fold by adding BCH. The secretory responses evoked by glutamine under these conditions correlated with enhanced cellular metabolism. Conclusions/interpretation. GDH could be rate-limiting in glucose-induced insulin secretion, as GDH overexpression enhanced secretory responses. Moreover, GDH overexpression made islets responsive to glutamine, indicating that under physiological conditions this enzyme acts as a gatekeeper to prevent amino acids from being inappropriate efficient secretagogues. [Diabetologia (2004) 47:266-276]

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Section: Discussionsupporting

confidence: 73%

Insulin secretion profiles are modified by overexpression of glutamate dehydrogenase in pancreatic islets

Carobbio¹,

Ishihara²,

Fernández-Pascual

et al. 2004

Diabetologia

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“…That Vhlh −/− ␤ cells have undergone such a shift in glucose metabolism is supported by the presence of enhanced lactate secretion from Vhlh −/− islets as well as the constitutive production of ATP at low glucose. That mitochondrial activity is critical for normal insulin secretion is further supported by previous work demonstrating that depletion of mitochondrial DNA inhibits glucose-stimulated insulin secretion and that manipulating the activities of LDHA or PDH in ␤-cell lines or isolated rat islets likewise affects pyruvate metabolism with consequent effects on insulin secretion (Kennedy et al 1998;Tsuruzoe et al 1998;Ishihara et al 1999;Ainscow et al 2000;Nicholls et al 2002).…”

Section: Pvhl-hif Regulates Insulin Secretion Genes and Development 3141mentioning

confidence: 72%

pVHL is a regulator of glucose metabolism and insulin secretion in pancreatic β cells

Zehetner¹,

Danzer²,

Collins³

et al. 2008

Genes Dev.

108

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Insulin secretion from pancreatic ␤ cells is stimulated by glucose metabolism. However, the relative importance of metabolizing glucose via mitochondrial oxidative phosphorylation versus glycolysis for insulin secretion remains unclear. von Hippel-Lindau (VHL) tumor suppressor protein, pVHL, negatively regulates hypoxia-inducible factor HIF1␣, a transcription factor implicated in promoting a glycolytic form of metabolism. Here we report a central role for the pVHL-HIF1␣ pathway in the control of ␤-cell glucose utilization, insulin secretion, and glucose homeostasis. Conditional inactivation of Vhlh in ␤ cells promoted a diversion of glucose away from mitochondria into lactate production, causing cells to produce high levels of glycolytically derived ATP and to secrete elevated levels of insulin at low glucose concentrations. Vhlh-deficient mice exhibited diminished glucose-stimulated changes in cytoplasmic Ca 2+ concentration, electrical activity, and insulin secretion, which culminate in impaired systemic glucose tolerance. Importantly, combined deletion of Vhlh and Hif1␣ rescued these phenotypes, implying that they are the result of HIF1␣ activation. Together, these results identify pVHL and HIF1␣ as key regulators of insulin secretion from pancreatic ␤ cells. They further suggest that changes in the metabolic strategy of glucose metabolism in ␤ cells have profound effects on whole-body glucose homeostasis.[Keywords: HIF; VHL; glucose intolerance; islet; pancreas] Supplemental material is available at http://www.genesdev.org. Received July 14, 2008; revised version accepted September 5, 2008. During adulthood, cell type-specific growth that exceeds the normal physiological constraints is a common feature of adaptive processes of tissues to changes in metabolic homeostasis and underlies the development of many human diseases, including cancer, heart disease, and diabetes (De Boer et al. 2003;Bouwens and Rooman 2005). Adaptive cell mass expansion, whether neoplastic or nonneoplastic, creates a requirement for compensatory neovascularization to supply oxygen, metabolic substances, and growth/survival factors to the growing tissue (Marti 2005). Therefore, adaptive cell growth responses are generally accompanied, at least initially, by relative states of hypoxia as a result of a mismatch between oxygen demand caused by tissue expansion and oxygen supply provided by the vasculature. An immediate consequence of decreased tissue oxygen availability is that cells shift cellular fuel metabolism from mitochondrial respiration to glycolysis and activate an angiogenic program to increase oxygen delivery in order to overcome the imbalance between tissue mass and vascularization (Semenza 2001;Brahimi-Horn et al. 2007). In this way, tissue function is supported and further mass expansion can occur.At the molecular level, the central regulators of the cellular response to low-oxygen availability are the hypoxia-inducible transcription factors (HIF). HIF are heterodimeric transcription factors composed of HIF1␣, HIF2␣, or HI...

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“…14 C incorporation into FFA and diglycerides was increased to a smaller extent. Pyruvate is a potent stimulant of insulin release in INS-1 cells [12,13,37,38]. 14 C incorporation into lipids in the presence of both concentrations of pyruvate was also increased, but not quite to the extent of 14 C incorporation from glucose (Table 4).…”

Section: Measurement Of Lipidsmentioning

confidence: 96%

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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Overexpression of monocarboxylate transporter and lactate dehydrogenase alters insulin secretory responses to pyruvate and lactate in β cells

Cited by 174 publications

References 39 publications

Insulin secretion profiles are modified by overexpression of glutamate dehydrogenase in pancreatic islets

Insulin secretion profiles are modified by overexpression of glutamate dehydrogenase in pancreatic islets

pVHL is a regulator of glucose metabolism and insulin secretion in pancreatic β cells

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

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