Nature; doi:10.1038/nature12724

Blood glucose levels must be carefully regulated in response to nutritional status, as disruption of this homeostasis can result in hyperglycemia, a hallmark of type II diabetes. Glucose production and utilization are controlled by enzymes such as glucokinase (GK), which phosphorylates glucose and promotes glucose uptake into tissues. Under fasting conditions, GK is sequestered in the nucleus and rendered inactive through direct interactions with glucokinase regulatory protein (GKRP). A rise in blood glucose concentration triggers GK activation by promoting cytoplasmic translocation. Stimulating GK activity in cases of rampant hyperglycemia could therefore relieve the metabolic defects associated with type II diabetes through lowering of blood glucose levels. However, the compounds that have been developed to directly activate GK reduce blood glucose to dangerously low levels, making them unsafe for use. An alternative approach is to target GKRP activity. Lloyd et al. identified two small molecules (AMG-1694 and AMG-3969) that disrupt GK-GKRP interactions by binding an allosteric site on GKRP, resulting in redistribution of GK to the cytoplasm to promote cellular glucose uptake. Interestingly, treatment of diabetic rats and mice with either compound could reduce blood glucose levels but had no effect on normoglycemic animals. These compounds represent a new strategy to treat type II diabetes by lowering the amount of blood glucose to a manageable level.