β‐Cell glucokinase expression was increased in type 2 diabetes subjects with better glycemic control.

Background: Type 2 diabetes (T2D) is characterized by a progressive deterioration of β‐cell function with a continuous decline in insulin secretion. Glucokinase (GCK) facilitates the rate‐limiting step of glycolysis in pancreatic β‐cells, to acquire the proper glucose‐stimulated insulin secretion. Multiple glucokinase activators (GKAs) have been developed and clinically tested. However, the dynamic change of human pancreatic GCK expression during T2D progression has not been investigated. Methods: We evaluated GCK expression by measuring the average immunoreactivity of GCK in insulin+ or glucagon+ cells from pancreatic sections of 11 nondiabetic subjects (ND), 10 subjects with impaired fasting glucose (IFG), 9 with well‐controlled T2D (wT2D), and 5 individuals with poorly controlled T2D (uT2D). We also assessed the relationship between GCK expression and adaptive unfolded protein response (UPR) in human diabetic β‐cells. Results: We did not detect changes of GCK expression in IFG islets. However, we found β‐cell GCK levels were significantly increased in T2D with adequate glucose control (wT2D) but not in T2D with poor glucose control (uT2D). Furthermore, there was a strong positive correlation between GCK expression and adaptive UPR (spliced X‐box binding protein 1 [XBP1s] and activating transcription factor 4 [ATF4]), as well as functional maturity marker (urocortin‐3 [UCN3]) in human diabetic β‐cells. Conclusions: Our study demonstrates that inductions of GCK enhanced adaptive UPR and UCN3 in human β‐cells, which might be an adaptive mechanism during T2D progression. This finding provides a rationale for exploring novel molecules that activate β‐cell GCK and thereby improve pharmacological treatment of T2D. [ABSTRACT FROM AUTHOR]