Variants close to theVPS13C/C2CD4A/C2CD4Blocus are associated with altered risk of type 2 diabetes in genome-wide association studies. Whilst previous functional work has suggested roles forVPS13CandC2CD4Ain disease development, none has explored the role ofC2CD4B. Here, we show that systemic inactivation ofC2cd4bin mice leads to marked, but highly sexually dimorphic, changes in body weight and glucose homeostasis. FemaleC2cd4bmice display unchanged body weight but abnormal glucose tolerance and defectivein vivo,but notin vitro,insulin secretion, associated with a marked decrease in follicle stimulating hormone levels. In sharp contrast, maleC2cd4bnull mice displayed normal glucose tolerance but an increase in body weight and fasting glycemia after maintenance on high fat diet. No metabolic disturbances were observed after global inactivation ofC2cd4ain mice, or in pancreatic β cell function at larval stages inC2cd4abnull zebrafish. These studies suggest thatC2cd4bmay act centrally to influence sex-dependent circuits which control pancreatic β cell function and glucose tolerance in rodents. However, the absence of sexual dimorphism in the impact of diabetes risk variants argues for additional roles forC2CD4AorVPS13Cin the control of glucose homeostasis in man.
Variants close to theVPS13C/C2CD4A/C2CD4Blocus are associated with altered risk of type 2 diabetes in genome-wide association studies. Whilst previous functional work has suggested roles forVPS13CandC2CD4Ain disease development, none has explored the role ofC2CD4B. Here, we show that systemic inactivation ofC2cd4bin mice leads to marked, but highly sexually dimorphic, changes in body weight and glucose homeostasis. FemaleC2cd4bmice display unchanged body weight but abnormal glucose tolerance and defectivein vivo,but notin vitro,insulin secretion, associated with a marked decrease in follicle stimulating hormone levels. In sharp contrast, maleC2cd4bnull mice displayed normal glucose tolerance but an increase in body weight and fasting glycemia after maintenance on high fat diet. No metabolic disturbances were observed after global inactivation ofC2cd4ain mice, or in pancreatic β cell function at larval stages inC2cd4abnull zebrafish. These studies suggest thatC2cd4bmay act centrally to influence sex-dependent circuits which control pancreatic β cell function and glucose tolerance in rodents. However, the absence of sexual dimorphism in the impact of diabetes risk variants argues for additional roles forC2CD4AorVPS13Cin the control of glucose homeostasis in man.
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