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

作者：Crim William S; Wu Runpei; Carter Jeffrey D; Cole Banumathi K; Trace Anthony P; Mirmira Raghavendra G; Kunsch Charles; Nadler Jerry L; Nunemaker Craig S^*

来源：Molecular and Cellular Endocrinology, 2010, 323(2): 246-255.

DOI：10.1016/j.mce.2010.02.041

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

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 mu M 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.

• 出版日期2010-7-29