Introduction
The consistent finding of reduced functional pancreatic beta cell mass (BCM) not only in type 1 diabetes but also in type 2 diabetes has increased the focus on finding new treatments that may increase and/or cause regeneration of functional BCM. Gastrin has been shown to increase proliferation of human and rodent duct-like pancreatic cells in culture, and administration of gastrin stimulates beta cell neogenesis and expansion of the BCM in rodents [
1,
2]. During treatment with proton pump inhibitors (PPIs), endogenous gastrin levels are increased in humans and rodents, and in a recent publication Suarez-Pinzon et al. showed that PPI treatment of mice in a model of type 1 diabetes resulted in an almost threefold increase in endogenous gastrin levels and improvement in glycaemia [
3].
Since no data have been published on the effect of gastrin or PPIs in type 2 diabetes, we decided to investigate whether treatment with the PPI lansoprazole would have beneficial effects on glycaemic control in a type 2 diabetes animal model, the gerbil
Psammomys obesus. When this gerbil is fed a high-energy diet, morning blood glucose (mBG) levels are distinctly increased, with subsequent/concomitant loss of beta cell function and mass [
4].
Results
In a subsequent study, primarily focusing on pancreas histology and a higher dose of lansoprazole, similar results were obtained (Fig.
1c, d). There was no reduction in mBG in the vehicle-treated group (
n = 8); mBG at end of study was 13.6 ± 1.5 mmol/l. In the lansoprazole 10 mg/kg group mBG was significantly reduced to 5.0 ± 1.4 (
p < 0.001) and in the 15 mg/kg group to 6.1 ± 2.3 mmol/l (
p < 0.001 compared with vehicle) (Fig.
1c). Likewise, HbA
1c in the animals treated with 10 and 15 mg/kg of lansoprazole was significantly lower (6.9 ± 0.3% and 7.0 ± 0.3% respectively,
p < 0.01) than in the vehicle-treated animals (10.4 ± 0.7%; Fig.
1d).
Discussion
Our results show that the PPI lansoprazole increases endogenous gastrin levels in
P. obesus, glycaemic control is almost normalised and BCM and insulin content of the pancreas are increased. Several studies have shown that PPIs elevate gastrin levels in both rodents and humans, and in this study we show this also to be the case in
P. obesus. It has been shown that treatment with gastrin alone can induce formation of new beta cells under different conditions [
1,
2]; however, from the present study we cannot determine whether the increased beta cell mass is due to an increase in neogenesis and/or proliferation or a decrease in apoptosis. Further studies that directly address these mechanisms are warranted also in light of the possibility that rodents have a higher capacity for regeneration of BCM than humans.
Although we did not directly measure beta cell function, there was a significant reduction in mBG and HbA1c, which are both clinically relevant variables to measure for any agent that influences beta cell function or BCM.
Even though it is known that PPIs stimulate gastrin production, treatment with PPIs will result in very different pharmacokinetic profiles as compared with gastrin injections. Therefore, it could not be expected that PPIs would have the same effect on expansion of beta cell mass and function as has previously been demonstrated with gastrin. Whereas gastrin, in the doses used in the in vivo rodent studies, has a short half-life in rodents (less than 10 min; T. B. Bödvarsdóttir, L. Pridal, unpublished results), which results in a high exposure for a short time period, PPI treatment, in contrast, will result in a chronic elevation of gastrin levels to a few times above normal. A direct comparison of gastrin and PPIs is needed in order to clarify whether PPI treatment is superior to gastrin or vice versa. But, since PPIs are readily available as oral agents with a long-standing record of safety, the data presented here from lansoprazole-treated P. obesus warrant further studies of the clinical benefits of PPIs in type 2 diabetes.
In conclusion, the PPI lansoprazole has significant glucose-lowering effects in an animal model of type 2 diabetes, and thus PPIs might have the potential to become a new class of safe glucose-lowering agents, provided these findings can be extrapolated to other PPIs and humans.
Acknowledgements
We thank H. Jensen-Holm, M. Jorgensen, S. Primdahl, P. Rothe and A. Hansen, Novo Nordisk Diabetes & Obesity Pharmacology, Måløv, Denmark for expert technical assistance and J. Rehfeld, University Hospital, Copenhagen, Denmark for the kind provision of gastrin antibodies.
Open AccessThis is an open access article distributed under the terms of the Creative Commons Attribution Noncommercial License (
https://creativecommons.org/licenses/by-nc/2.0), which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.