Impact of different dietary compositions on energy substrate metabolism in diabetes relevant tissues in RabGAP-deficient mice

Background The RabGTPase-activating protein (RabGAP) TBC1D4 plays a crucial role in glucose metabolism. A muscle-specific TBC1D4 p.Arg684Ter loss-of-function variant has been associated with postprandial hyperglycemia and increased risk of type 2 diabetes in arctic populations. We speculate that TBC1D4-deficiency represents an evolutionary adaptation to a diet rich in unsaturated lipids and proteins with low carbohydrate content. This project aims to clarify the impact of dietary compositions on whole-body glycemia and insulin-responsive tissues in Tbc1d4-deficient (D4KO) mice.

Methods D4KO mice were subjected to high-fat diets differing in their carbohydrate-to-protein ratio (Arctic diet: low-carbohydrate, high-protein vs. Western diet: high-carbohydrate, low-protein). Whole-body glycemia and expression levels of key factors for glucose metabolism were analyzed.

Results D4KO mice present substantial improvements in postprandial hyperglycemia and insulin-stimulated glucose uptake into oxidative Soleus muscle after carbohydrate restriction. In the liver from wildtype (WT) but not D4KO mice, we observe increased phosphoenolpyruvate carboxykinase 1 (PEPCK) and decreased glycogen synthase (GS) abundance after carbohydrate restriction. On the Western diet, D4KO mice show reduced expression levels of browning markers in subcutaneous white adipose tissue (scWAT) compared to WT mice.

Conclusion Arctic diet-feeding promotes protection from hepatic and muscular insulin resistance and improves postprandial glycemia in D4KO mice. In contrast, Western diet-feeding leads to a potentially reduced mitochondrial activity in scWAT from D4KO mice. Our results suggest a complex interplay between insulin-responsive tissues in promoting protective effects of an Arctic diet on TBC1D4-deficiency and have the potential to improve future precision medicine approaches.

Publication History

Article published online:
02 May 2023