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 H(b)A1c, improves fasting plasma glucose, and reduces new-onset diabetes. We investigated AGI-1067 for possible effects on mouse pancreatic islets in vitro. Pretreatment with 10 microM AGI-1067 increased glucose-stimulated insulin secretion (11 mM) without affecting secretion in basal (3 mM) glucose. AGI-1067 enhanced the intracellular calcium response to glucose stimulation in 7 mM and 11 mM glucose, but had no effect in 28 mM 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 K(ATP)-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.
authors.affiliation: Department of Medicine, University of Virginia, VA 22908, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Crim
authors.forename: Runpei
authors.initials: R
authors.lastname: Wu
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Carter
authors.forename: Banumathi K
authors.initials: BK
authors.lastname: Cole
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Trace
authors.forename: Raghavendra G
authors.initials: RG
authors.lastname: Mirmira
authors.forename: Charles
authors.initials: C
authors.lastname: Kunsch
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Nadler
authors.forename: Craig S
authors.initials: CS
authors.lastname: Nunemaker
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D007651:Keto Acids / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D011341:Probucol / Q000031:analogs & derivatives* / Q000494:pharmacology; D014044:Tolbutamide / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D000959:Antihypertensive Agents; D000975:Antioxidants; D016207:Cytokines; D007004:Hypoglycemic Agents; D007328:Insulin; D007651:Keto Acids; D015221:Potassium Channels; C013082:alpha-ketoisocaproic acid; D014044:Tolbutamide; D052247:Nitric Oxide Synthase Type II; D005947:Glucose; C471047:succinobucol; D003981:Diazoxide; D011341:Probucol; D002118:Calcium