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, Raghu Mirmira, Charles Kunsch, Jerry L. Nadler, Craig S. Nunemaker

Research output: Contribution to journalArticle

12 Citations (Scopus)

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

Fingerprint

Anti-Inflammatory Agents
Antioxidants
Insulin
Glucose
Islets of Langerhans
Calcium
Cytokines
Diazoxide
succinobucol
KATP Channels
Cell death
Medical problems
Fasting
Cell Death
Plasmas

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)

Cite this

AGI-1067, a novel antioxidant and anti-inflammatory agent, enhances insulin release and protects mouse islets. / Crim, William S.; Wu, Runpei; Carter, Jeffrey D.; Cole, Banumathi K.; Trace, Anthony P.; Mirmira, Raghu; Kunsch, Charles; Nadler, Jerry L.; Nunemaker, Craig S.

In: Molecular and Cellular Endocrinology, Vol. 323, No. 2, 07.2010, p. 246-255.

Research output: Contribution to journalArticle

Crim, William S. ; Wu, Runpei ; Carter, Jeffrey D. ; Cole, Banumathi K. ; Trace, Anthony P. ; Mirmira, Raghu ; Kunsch, Charles ; Nadler, Jerry L. ; Nunemaker, Craig S. / AGI-1067, a novel antioxidant and anti-inflammatory agent, enhances insulin release and protects mouse islets. In: Molecular and Cellular Endocrinology. 2010 ; Vol. 323, No. 2. pp. 246-255.
@article{0fb126dd241645c89c64b66b211e52f0,
title = "AGI-1067, a novel antioxidant and anti-inflammatory agent, enhances insulin release and protects mouse islets",
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.",
keywords = "Anti-inflammatory, Antioxidant, Beta cells, Beta-cell, Biphasic, Calcium, Cytokines, ER stress, Glucokinase, Glucose sensitivity, Inflammation, Insulin, K-channel, Oxidative stress, Probucol, Succinobucol",
author = "Crim, {William S.} and Runpei Wu and Carter, {Jeffrey D.} and Cole, {Banumathi K.} and Trace, {Anthony P.} and Raghu Mirmira and Charles Kunsch and Nadler, {Jerry L.} and Nunemaker, {Craig S.}",
year = "2010",
month = "7",
doi = "10.1016/j.mce.2010.02.041",
language = "English",
volume = "323",
pages = "246--255",
journal = "Molecular and Cellular Endocrinology",
issn = "0303-7207",
publisher = "Elsevier Ireland Ltd",
number = "2",

}

TY - JOUR

T1 - AGI-1067, a novel antioxidant and anti-inflammatory agent, enhances insulin release and protects mouse islets

AU - Crim, William S.

AU - Wu, Runpei

AU - Carter, Jeffrey D.

AU - Cole, Banumathi K.

AU - Trace, Anthony P.

AU - Mirmira, Raghu

AU - Kunsch, Charles

AU - Nadler, Jerry L.

AU - Nunemaker, Craig S.

PY - 2010/7

Y1 - 2010/7

N2 - 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.

AB - 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.

KW - Anti-inflammatory

KW - Antioxidant

KW - Beta cells

KW - Beta-cell

KW - Biphasic

KW - Calcium

KW - Cytokines

KW - ER stress

KW - Glucokinase

KW - Glucose sensitivity

KW - Inflammation

KW - Insulin

KW - K-channel

KW - Oxidative stress

KW - Probucol

KW - Succinobucol

UR - http://www.scopus.com/inward/record.url?scp=77952954397&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77952954397&partnerID=8YFLogxK

U2 - 10.1016/j.mce.2010.02.041

DO - 10.1016/j.mce.2010.02.041

M3 - Article

VL - 323

SP - 246

EP - 255

JO - Molecular and Cellular Endocrinology

JF - Molecular and Cellular Endocrinology

SN - 0303-7207

IS - 2

ER -