Carbohydrate restriction prevents postprandial hyperglycemia in Tbc1d4-deficient mice

Background and aims The two closely related Rab-GTPase activating proteins (RabGAPs) TBC1D4 (AS160) and TBC1D1 are key regulators of energy flux in skeletal muscle and adipose tissue. In previous studies, RabGAP-deficient mice showed decreased insulin- and contraction stimulated glucose uptake into skeletal muscle with concomitantly increased fatty acid oxidation (FAO). In addition, insulin-stimulated glucose transport into adipocytes is severely disturbed in Tbc1d4-knockout mice (D4KO). In humans, genetic variants of the two RabGAPs are associated with insulin resistance and obesity. In arctic populations, a common TBC1D4 p.Arg684Ter loss-of-function variant defines a specific subtype of T2D. This variant is hypothesized to be an evolutionary adaptation to a traditional high-fat low-carbohydrate diet of indigenous arctic populations.

Methods We generated different RabGAP-deficient mouse lines as models for genetically induced insulin resistance to analyze how nutrition affects metabolic flexibility and, as a consequence, insulin sensitivity. Therefore, these mice were subjected to high-fat diets differing in carbohydrate content to mimic a traditional arctic diet (high-fat low-carbohydrate) or a western diet (high-fat high-carbohydrate). Longitudinal analyses of skeletal muscle, adipocyte function and glycemic control in response to dietary interventions were performed.

Results Our findings indicate that a high-fat low-carbohydrate diet induces an impaired insulin response ex vivo in WAT and after insulin injection. Interestingly, Tbc1d4-deficient mice subjected to a low-carbohydrate diet show rescued postprandial hyperglycemia.

Conclusion Carbohydrate restriction rescues postprandial hyperglycemia in D4KO mice, therefore could prevent the onset of T2D in homozygous p.Arg684Ter variant carriers or serve as a potential treatment for this T2D subtype.

Publication History

Article published online:
26 May 2022