Reduced platelet count in mice protects against glucose intolerance and beta cell loss during a long-term high-fat diet

INTRODUCTION: Platelets promote hemostasis and modulate different inflammatory and immunological processes. Recently, it was reported that platelets interact with pancreatic beta cells to increase insulin secretion. Inflammatory conditions and a lack of sufficient insulin secretion drive the pathogenesis of type 2 diabetes (T2D) in the context of obesity. However, the specific role of platelets during the development of obesity-related T2D has not yet been investigated. METHODS: Thrombopoietin receptor knockout (MPL(-/-)) mice displaying constant thrombocytopenia (approx. 90 % reduction in platelet count) or wild type (WT) mice were fed either a high-fat diet (HFD) or a control diet (CD) for 19 weeks, starting at 8 weeks of age. The mice were metabolically characterized at the end of the feeding period (metabolic caging, glucose and insulin tolerance testing, body and organ weight measurements, and gene expression analyses). Pancreatic tissue was histologically assessed via immunofluorescence, and circulating platelets were characterized by flow cytometry. RESULTS: After HFD feeding, obese MPL(-/-) mice showed a significantly improved glucose tolerance compared to WT mice. At the same time, MPL(-/-) mice tended to exhibit a more pronounced insulin resistance. The weight gain of MPL(-/-)and WT mice did not differ significantly after 19 weeks of feeding, but body weight was higher in MPL(-/-) between weeks 4 and 12. Likewise, the weight of adipose tissue depots was similar between both genotypes at the end of the study. In metabolic cages, obese MPL(-/-) mice showed less physical activity than WT, while other parameters like O2-consumption and heat dissipation were similar between the two groups. The expression of genes involved in glucose metabolism in muscle, liver, and epididymal adipose tissue did not show relevant differences between MPL(-/-) and WT mice. At the end of the study, a significantly higher insulin concentration was measured in the circulation of obese MPL(-/-) mice. This was accompanied by a higher proportion of pancreatic beta cells in the total analyzed tissue area. DISCUSSION: These results suggests that thrombocytopenia protects pancreatic beta cells in an obesity mouse model of T2D, thereby preserving insulin secretion and improving glucose tolerance.