st step of long-chain FA -oxidation. Transduction of INS-1E cells and isolated rat islets with AdCA-aralar1 increases aralar1 protein levels.43 In INS-1E cells, overexpression of aralar1 potentiated metabolism-secretion coupling stimulated by high glucose in association with increased NADH generation, mitochondrial membrane hyperpolarization, ATP get Butein levels and glucose oxidation, and suppressed lactate production.43 Similarly, overexpressing aralar1 in rat islets enhanced insulin secretion at high glucose.43 Overexpression of the aralar1 in BRIN-BD11 cells increases acute and long-term glucose- and amino-acid-stimulated insulin secretion and enhances glucose, L-alanine and L-glutamine metabolism, leading to the suggestion that increased malateaspartate shuttle activity positively shifts -cell metabolism to enhance insulin secretion.44,45 Conversely, inhibition of the malate-aspartate shuttle impairs glucose metabolism and i nsulin secretion.45 Knockdown of aralar1 by adenovirusmediated delivery of shRNA in INS-1E cells impairs glucose oxidation and increases lactate production.46 This highlights the role of aralar1 and the malate/aspartate shuttle in regenerating NAD + if cells express low levels of LDH. Knockdown of aralar1 was also associated with impaired GSIS at high glucose. AGC1 knockdown in rat islets did not affect their secretory response. Irrespective of these potential interactions and mechanisms, it is interesting that the low expression of LDH in the -cell not only funnels pyruvate into the mitochondrion via the PC and PDC reactions but also, if FADH 2 and NADH generated by PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19817875 the glycerol-3-phosphate and malate-aspartate shuttles are used to fuel oxidative phosphorylation, produces a large amount of mitochondrial ATP. 
This can be used to enhance GSIS in concert with augmented glycolytic flux. The role of glutamate in the operation of the malate/aspartate shuttle is also of interest. There is evidence that glutamate has a regulatory role in insulin secretion, but how it exerts its effects remains uncertain.47,48 -cell-specific deletion of glutamate dehydrogenase results in lowered GSIS in pancreatic perfusions, a response that is reversed by adenovirus-mediated re-expression of GDH in Glud1 islets.49 Constitutive or acute adenovirusmediated knockout of GDH in islets also lowers GSIS.49 In vivo, Glud1 mice exhibit lower plasma insulin levels in response to both feeding and a glucose load.49 The mitochondrial glutamate carrier is expressed in both INS-1E -cells and rat islets. Silencing of GC1 in INS-1E cells by adenoviral delivery of short hairpin RNA lowers mitochondrial glutamate transport by approximately 50% and impairs GSIS at high, but not low, glucose.50 The impairment of GSIS was reversed by cell-permeant glutamate.50 Silencing of GC1 in rat islets impaired first and second phase GSIS during islet perifusions,50 demonstrating that the recently-identified GC1 is important for maximal glucose response. A recent study 51 has shown that ornithine aminotransferase, an enzyme lying on the pathway for conversion of glutamate to ornithine, like LDH, is selectively repressed in pancreatic -cells. Thus, adequate availability of glutamate is important for maintaining GSIS in part through facilitating the operation of the malate/aspartate shuttle to regenerate cytoplasmic NAD + required for continued glycolysis. Metabolic Coupling Factors that Enhance GSIS Require PC, PDC and Pyruvate Cycling Mitochondrial metabolism has previously be
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