To assure that this pathway was activated well before any confounding effects of hyperglycemia, we evaluated islets from HIP rats at 2.5 and 3.5 months of age, and found that PFKFB3 levels were already increased by 2.5 months of age, namely before frank hyperglycemia (Supplementary Fig. 1a–c and Supplementary Table 1). Here, PFKFB3 is linked to Hyperglycemia.