Credit: Springer Nature Limited

Intracerebroventricular injection of fibroblast growth factor 1 (FGF1) in a rat model of type 2 diabetes mellitus (T2DM) induces sustained remission of hyperglycaemia independently of insulin-dependent glucose clearance reports a new study in Diabetes.

“We previously reported that a single dose of the growth factor FGF1 delivered directly into the brain causes sustained remission of hyperglycaemia across multiple rodent models of T2DM,” explains Michael Schwartz, corresponding author. “A key follow-up goal was to identify peripheral mechanisms mediating this effect.”

The researchers used the Zucker diabetic fatty fa/fa (ZDF) rat model of T2DM in their current study as it closely approximates human T2DM as both are characterized by progressive loss of β-cell function and mass over time.

In ZDF rats that received the intracerebroventricular injection of FGF1, the anticipated decline in β-cell function was delayed, corresponding to the time that hyperglycaemia was in remission. In addition, compared with control animals and baseline values, β-cell mass was increased in FGF1-treated animals 3 weeks after injection. However, after 7 weeks, β-cell mass decreased to match the values in control rats. Thus, FGF1 delays but does not prevent loss of β-cell function and diabetes mellitus relapse in ZDF rats.

Notably, a frequently sampled intravenous glucose tolerance test in a separate cohort of ZDF rats demonstrated that treatment with intracerebroventricular FGF1 had no effect on glucose-induced insulin secretion or insulin sensitivity. Furthermore, intravenous insulin injection had a reduced glucose-lowering effect in rats that received FGF1 compared with control rats. The researchers concluded that the sustained remission of hyperglycaemia induced by FGF1 must be insulin independent.

the sustained remission of hyperglycaemia induced by FGF1 must be insulin independent

Therefore, Schwartz and colleagues decided to focus on hepatic glucose uptake, which is insulin independent, as a possible mechanism contributing to remission of hyperglycaemia. They used a mathematical model to provide estimates of hepatic glucokinase activity (a key step in hepatic glucose uptake), which was reported to be doubled in ZDF rats that received FGF1. These estimates were in agreement with the twofold increases in hepatic Gck gene expression and GCK enzymatic activity measured biochemically in the livers of these rats. These data seem to confirm the researchers’ hypothesis that hepatic glucose uptake has a role in mediating the effects of FGF1 in ZDF rats.

“Our key goals are to determine if changes in autonomic input to the liver and pancreas account for our findings,” says Schwartz. “In addition, we are making progress identifying the brain area, cell types and signal transduction mechanisms that are responsible for this FGF1 effect.”