Synergistic potent insulin release by combinations of weak secretagogues in pancreatic islets and INS-1 cells.

Synergistic potent insulin release by combinations of weak secretagogues in pancreatic islets and INS-1 cells. Research Abstract Details 

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Synergistic potent insulin release by combinations of weak secretagogues in pancreatic islets and INS-1 cells. Abstract Text:

Michael J MacDonald,

Insulin secretion by the beta cell depends on anaplerosis in which insulin secretagogues are metabolized by mitochondria into molecules that are most likely exported to the extramitochondrial space where they have signaling roles. However, very little is known about the products of anaplerosis. We discovered an experimental paradigm that has begun to provide new information about these products. When various intracellular metabolites were applied in combination to overnight-cultured rat or human pancreatic islets or to INS-1 832/13 cells, they interacted synergistically to strongly stimulate insulin release. When these same metabolites were applied individually to these cells, insulin stimulation was poor. Discerning the contributions of the individual compounds to metabolism has begun to allow us to dissect some of the pathways involved in insulin secretion, which was not possible from studying individual secretagogues. Monomethyl succinate (MMS) combined with a barely stimulatory concentration of alpha-ketoisocaproate (KIC) (2 mm) stimulated insulin release in cultured rat islets 18-fold (versus 21-fold for 16.7 mm glucose). MMS plus low glucose (2 mm) or pyruvate (5 mm) gave 11- and 9-fold stimulations. These agents also potentiated MMS-induced insulin release in fresh islets, and KIC plus MMS gave synergistic insulin release in cultured human islets. In INS-1 cells, neither MMS nor KIC (10 mm) was an insulin secretagogue, but when added together KIC (2 mm) and MMS stimulated insulin release 7-fold (versus 12-fold for glucose). In islets and INS-1 cells, conditions that stimulated insulin release caused large relative increases in acetoacetate, which is a precursor of pathways to short chain acyl-CoAs. Liquid chromatography-tandem mass spectrometry measurements of acetyl-CoA, acetoacetyl-CoA, succinyl-CoA, hydroxymethylglutaryl-CoA, and malonyl-CoA confirmed that they were increased by insulin secretagogues. The results suggest a new mechanism of insulin secretion in which anaplerosis increases short chain acyl-CoAs that have roles in insulin exocytosis.

Synergistic potent insulin release by combinations of weak secretagogues in pancreatic islets and INS-1 cells. Publishing Authors By Initials

MJ MacDonald,

For similar animals: chordata: vertebrates: mammals: rodentia: muridae: murinae: rats: rats, sprague-dawley research abstracts see: animals: chordata: vertebrates: mammals: rodentia: muridae: murinae: rats: rats, sprague-dawley research

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Synergistic potent insulin release by combinations of weak secretagogues in pancreatic islets and INS-1 cells. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: The Journal of biological chemistry

VOLUME: 282

Page Numbers: 6043-52

Journal Abbreviation: J. Biol. Chem.

ISSN: 0021-9258

DAY: 8

MONTH: 01

YEAR: 2007

Synergistic potent insulin release by combinations of weak secretagogues in pancreatic islets and INS-1 cells. Information

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LANGUAGE: eng

NlmUniqueID: 2985121

Synergistic potent insulin release by combinations of weak secretagogues in pancreatic islets and INS-1 cells. Keywords Mesh Terms:

KEYWORDS: Rats, Sprague-Dawley

MESH TERMS: secretion

Chemical & Substance for Abstract: Synergistic potent insulin release by combinations of weak secretagogues in pancreatic islets and INS-1 cells. Information

Substance Name: acetoacetic acid

Registry Number: 541-50-4

Grant and Affiliation Information for Synergistic potent insulin release by combinations of weak secretagogues in pancreatic islets and INS-1 cells.

AFFILIATION: Childrens Diabetes Center, University of Wisconsin Medical School, Madison, Wisconsin 53706, USA. mjmacdon@wisc.edu

Country: United States

AGENCY: United States NIDDK

GRANT: DK28348

ACRONYM: DK

MEDLINETA: J Biol Chem

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