Background: Prolactin improves glucose homeostasis by increasing β-cell mass under certain conditions such as pregnancy, whereas hyperprolactinaemia due to a pituitary gland adenoma tumour exacerbates insulin resistance. However, previous studies have not evaluated how prolactin modulates β-cell function and insulin sensitivity at different dosages. Here, we determined that chronic intraperitoneal injections of different dosages of prolactin have opposite effects on insulin resistance and β-cell function and mass in 90% pancreatectomized diabetic male rats, and the mechanisms were explored.

Methods: Diabetic rats were divided into three groups according to the dose of intraperitoneally injected prolactin for 4 weeks: (1) low dose of prolactin (25 µg/kg bw/12 h), (2) high dose of prolactin (250 µg/kg bw/12 h), and (3) vehicle. As a non-diabetic control group, sham-operated rats were injected with vehicle.

Results: Chronic high- and low-dose prolactin injections elevated serum prolactin levels by 2.5- and 11.8-fold, respectively. Both dosages promoted β-cell mass by increasing β-cell proliferation and neogenesis through the potentiation of phosphorylation of signal transducer and activator of transcription 5 and decreased menin expression in diabetic rats. However, only the low-dose prolactin injection potentiated glucose-stimulated insulin secretion though glucokinase and glucose transporter 2 induction in the diabetic rats. In addition, low-dose prolactin decreased hepatic glucose output in hyperinsulinaemic states, indicating an improvement in hepatic insulin resistance. However, the high-dose prolactin injection exacerbated whole-body and hepatic insulin resistance in diabetic rats.

Conclusions: In contrast to the normal adaptive increases in glucose-stimulated insulin secretion through expanded β-cell mass and insulin sensitivity realized with moderately increased prolactin levels, high levels of prolactin exacerbate insulin resistance and impair the insulin-secretory capacity in diabetic mice.