In vivo targeted delivery of ANGPTL8 gene for beta cell regeneration in rats.

ABSTRACT

AIMS/HYPOTHESIS: ANGPTL8 is a circulatory hormone secreted from liver and adipose tissue that promotes pancreatic beta cell proliferation and interferes with triacylglycerol metabolism in mice. The clinical significance of its effects on inducing beta cell proliferation is limited because it causes severe hypertriacylglycerolaemia. METHODS: We employed ultrasound-targeted microbubble destruction (UTMD) to deliver human ANGPTL8 gene plasmids to the pancreas, liver and skeletal muscle of normal adult rats. RESULTS: Human ANGPTL8 was consistently detected in the circulation 1 month after UTMD. ANGPTL8 gene delivery promoted the proliferation of adult and aged beta cells, expanded the beta cell mass, improved glucose tolerance and increased the fasting blood insulin level after UTMD treatment without causing severe hypertriacylglycerolaemia. ANGPTL8 gene therapy significantly alleviated but did not totally reverse STZ-induced diabetes in a rat model. CONCLUSIONS/INTERPRETATION: ANGPTL8 induced adult and aged beta cell regeneration in a rat model.