AGI-1067, a novel antioxidant and anti-inflammatory agent, enhances insulin release and protects mouse islets

William S. Crim, Runpei Wu, Jeffrey D. Carter, Banumathi K. Cole, Anthony P. Trace, Raghavendra G. Mirmira, Charles Kunsch, Jerry L. Nadler, Craig S. Nunemaker

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

The antioxidant and anti-inflammatory compound AGI-1067 (succinobucol) has potential as an oral anti-diabetic agent. AGI-1067 reduces HbA1c, improves fasting plasma glucose, and reduces new-onset diabetes. We investigated AGI-1067 for possible effects on mouse pancreatic islets in vitro. Pretreatment with 10μM AGI-1067 increased glucose-stimulated insulin secretion (11mM) without affecting secretion in basal (3mM) glucose. AGI-1067 enhanced the intracellular calcium response to glucose stimulation in 7mM and 11mM glucose, but had no effect in 28mM or basal glucose. AGI-1067-pretreated islets also showed enhanced calcium responses to methyl pyruvate and alpha-ketoisocaproate at low doses, but not high doses. The AGI-1067-mediated effects on glucose-stimulated calcium were maintained during continuous diazoxide exposure, suggesting effects on the KATP-channel-independent pathway. AGI-1067 also reduced cytokine-induced islet cell death and expression of iNOS, a key component in cytokine signaling. This is the first report of direct stimulatory and protective effects of a first-in-class potential anti-diabetic agent on pancreatic islets.

Original languageEnglish (US)
Pages (from-to)246-255
Number of pages10
JournalMolecular and Cellular Endocrinology
Volume323
Issue number2
DOIs
StatePublished - Jul 2010

Keywords

  • Anti-inflammatory
  • Antioxidant
  • Beta cells
  • Beta-cell
  • Biphasic
  • Calcium
  • Cytokines
  • ER stress
  • Glucokinase
  • Glucose sensitivity
  • Inflammation
  • Insulin
  • K-channel
  • Oxidative stress
  • Probucol
  • Succinobucol

ASJC Scopus subject areas

  • Endocrinology
  • Molecular Biology
  • Biochemistry
  • Medicine(all)

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