Betatrophin was identified as a new hormone that could specifically increase b-cell mass in a novel pharmacological marine model of insulin resistance (IR). To explore the clinical relevance of betatrophin in humans, serum betatrophin levels were measured in age-, sex-, BMI- and blood lipids- matched subjects with normal glucose tolerance (n=137), isolated impaired fasting glucose (n=69), isolated impaired glucose tolerance (n=120) and newly diagnosed T2D (n=112). The results showed that circulating betatrophin levels are increased in patients with T2D and associated with indexes of IR (positively correlated with HOMA-IR; inversely correlated with QUICKI, ISIG and ISIM). Betatrophin was, therefore, considered as a biomarker for IR.
However, it remains largely unknown how betatrophin expression was regulated in IR condition. To study whether IR could regulate betatrophin expression and the corresponding molecular mechanisms, betatrophin expression were studied in 6 in vitro IR models which were established successfully using human hepatocytes L02 being treated with different agents, including tumor necrosis factor-α, interleukin-1β, dexamethasone, palmitate, high glucose and insulin. Although the IR was detected in all 6 models as showed that glucose uptake was dramatically decreased, betatrophin levels were elevated only in the insulin-treated cells. These results suggest that it is insulin, not IR that promotes betatrophin expression. In the meantime, PI3K/Akt pathway was activated by insulin and suppressed by above agents that caused IR. Insulin-upregulated betatrophin expression was suppressed by PI3K/Akt inhibitors and IR, suggesting that insulin upregulates and IR decreases betatrophin production through PI3K/Akt pathway. Consistently, the treatment of insulin in mice dose-dependently upregulated betatrophin levels, and the administration of metformin in IR mice also stimulated betatrophin production since published study showed metformin improved PI3K/Akt pathway and IR. In humans, compared with those without insulin treatment, serum betatrophin levels were increased in type 2 diabetic patients with insulin treatment.
In conclusion, insulin stimulates betatrophin secretion through PI3K/Akt pathway and IR may play an opposite role.