Loss of Slc39a5 in α-cells impairs glucose metabolism by chronically increasing glucagon.

INTRODUCTION

Glucagon is a critical regulator of glucose homeostasis by regulating liver glycogenolysis and gluconeogenesis. Hyperglucagonemia has been observed in patients with type 2 diabetes mellitus (T2DM). However, whether elevated glucagon is cause or consequence in the pathogenesis of T2DM is poorly investigated.

OBJECTIVES

This study aimed to investigate the metabolic effects of chronic glucagon elevation using a α-cells-specific Slc39a5 knockout mouse model.

METHODS

α-cells-specific Slc39a5 knockout mice (Slc39a5αKO) were generated using cre-loxP system to investigate the role of SLC39A5 in metabolic phenotypes. Islet morphology was assessed via hematoxylin-eosin (HE) and immunofluorescent staining. Glucagon secretion was measured in isolated islets from both Slc39a5αKO and control mice (Slc39a5fl/fl). Additionally, glucose and lipid metabolism-related gene expressions in the liver were measured using western blotting and RT-qPCR.

RESULTS

Compared with Slc39a5fl/fl mice, Slc39a5αKO mice exhibited a 40 % increase in fasting serum glucagon levels (28.17 pg/mL in Slc39a5fl/fl mice, and 39.67 pg/mL in Slc39a5αKO mice, respectively), accompanied by hyperglycemia and impaired insulin sensitivity. Islets isolated from Slc39a5αKO mice showed enhanced glucagon secretion under both basal (increasingfrom 3.27 pg/mL to 5.89 pg/mL) and low-glucose conditions (increasing from 7.49 pg/mL to 15.21 pg/mL). Additionally, the suppression of glucagon secretion by insulin was weakened. Furthermore, hepatic expression of phosphoenolpyruvate carboxykinase (Pepck) and glucose-6-phosphatase (G-6-Pase) was significantly upregulated. On a high-fat-diet, Slc39a5αKO mice developed pronouncedhepatic lipid accumulation.

CONCLUSIONS

These results demonstrate that Slc39a5 deficiency in α-cells leads to chronic glucagon elevation, which directly impairs hepatic glucose metabolism and promotes insulin resistance and hyperglycemia. This study thus establishes a causal role for α-cells Slc39a5 in prediabetes progression, highlighting sustained glucagon excess as a key contributor of metabolic dysfunction.