Proinsulin (PI) is processed to mature insulin by prohormone convertases 1/3 (Pcsk1) and 2 (Pcsk2). In individuals with T1D and T2D, there is an increase in the circulating PI:insulin ratio. We hypothesized that beta-cell Pcsk1 deletion would result in beta-cell dysfunction and hyperglycemia.

Male and female Pcsk1flox/flox Ins1cre/+ (Pcsk1beta-KO) and Pcsk1+/+ Ins1cre/+ (Pcsk1beta-WT) mice were fed either a chow or a high fat diet (HFD; 45% fat) and monitored until 30 weeks of age. Despite an approximately 150-fold increase in fasting plasma PI (p < 0.001) and only immature insulin granules detectable by electron microscopy, chow-fed Pcsk1beta-KO male mice had normal glucose tolerance early in life and only developed glucose intolerance by 26 weeks of age (AUC: 934±294 vs. 597±223; p = 0.008). Histological analysis showed that male Pcsk1beta-KO mice displayed a trend toward increased beta-cell area (1.3±0.6 vs. 0.8±0.4%; p = 0.08). The unexpectedly mild hyperglycemia in Pcsk1beta-KO mice is likely due to incomplete disruption of proinsulin processing, as mass spectrometry and western blot analysis of Pcsk1beta-KO islets confirmed markedly elevated proinsulin, but detectable mature insulin. In HFD-fed cohorts, 3/10 Pcsk1beta-KO male mice developed sustained fasting hyperglycemia (>16 mM) after 19 weeks of diet. Chow and HFD-fed female Pcsk1beta-KO mice displayed no differences in glycemia or body weight from Pcsk1beta-WT controls. Deletion of both Pcsk1 and Pcsk2 in beta cells (Pcsk1flox/flox Pcsk2flox/flox Ins1cre/+) resulted in undetectable mature insulin in islets (western blot), and impaired glucose tolerance at 10 weeks of age in both chow-fed male and female mice.

Our results suggest that beta-cell Pcsk1 deficiency is not sufficient to drive diabetes development, but increases diabetes susceptibility in conditions of increased insulin secretory demand. Our data in mice support the idea that beta-cell prohormone processing errors likely contribute to pathogenesis of diabetes but not obesity.


A. Taylor: None. Y. Chen: None. B. Verchere: Advisory Panel; Self; Integrated Nanotherapeutics Inc., Sirona Biochem. Stock/Shareholder; Self; Integrated Nanotherapeutics Inc.


Canadian Institutes of Health Research (PJT153156)

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at