The stimulatory effect of HI 129, a novel indole derivative, on glucose-induced insulin secretion

Indole derivatives exhibit a broad spectrum of beneficial effects, encompassing anti-inflammatory, antiviral, antimalarial, anti-diabetic, antioxidant, anti-hepatitis, and antidepressant properties. Here, we describe the potentiation of insulin secretion in pancreatic islets and INS-1 cells through methyl 2-(2-ethoxy-1-hydroxy-2-oxoethyl)-1-(pyrimidine-2-yl)-1H-indole-3-carboxylate (HI 129), a novel indole derivative. Treatment with HI 129 led to notably decreased ADP/ATP ratios in pancreatic islets and INS-1 cells compared with those in the vehicle-treated controls, indicating a shift in cellular ATP production. Moreover, the augmentation of insulin secretion by HI 129 was closely correlated with its ability to enhance the mitochondrial membrane potential and respiration, partly by reducing the phosphorylation levels of AMP-activated protein kinase (AMPK). Mechanistically, HI 129 enhanced the association between AMPK and β-arrestin-1, critical molecules for glucose-induced insulin secretion. Furthermore, β-arrestin-1 depletion attenuated the effect of HI 129 on glucose-induced insulin secretion, suggesting that HI 129 potentiates insulin secretion via β-arrestin-1/AMPK signaling. These results collectively underscore the potential of HI 129 in enhancing insulin secretion as a novel candidate for improving glucose homeostasis in type 2 diabetes.