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.