In addition to hibernation, there is evidence that FBPase activity varies significantly between warm and cold seasons even for animals that do not hibernate. In rabbits exposed to cold temperatures, FBPase activity decreased throughout the duration of cold exposure, increasing when temperatures became warmer again. The mechanism of this FBPase inhibition is thought to be digestion of FBPase by lysosomal proteases, which are released at higher levels during colder periods. Inhibition of FBPase through proteolytic digestion decreases gluconeogenesis relative to glycolysis during cold periods, similar to hibernation. Fructose 1,6-bisphosphate aldolase is another temperature dependent enzyme that plays an important role in the regulation of glycolysis and gluconeogenesis during hibernation. Its main role is in glycolysis instead of gluconeogenesis, but its substrate is the same as FBPase's, so its activity affects that of FBPase in gluconeogenesis. Aldolase shows similar changes in activity to FBPase at colder temperatures, such as an upward shift in optimum pH at colder temperatures. This adaptation allows enzymes such as FBPase and fructose-1,6-bisphosphate aldolase to track intracellular pH changes in hibernating animals and match their activity ranges to these shifts. Aldolase also complements the activity of FBPase in anoxic conditions (discussed above) by increasing glycolytic output while FBPase inhibition decreases gluconeogenesis activity. Fructose 1,6-bisphosphatase is also a key player in treating type 2 diabetes. In this disease, hyperglycemia causes many serious problems, and treatments often focus on lowering blood sugar levels. Gluconeogenesis in the liver is a major cause of glucose overproduction in these patients, and so inhibition of gluconeogenesis is a reasonable way to treat type 2 diabetes. FBPase is a good enzyme to target in the gluconeogenesis pathway because it is rate-limiting and controls the incorporation of all three-carbon substrates into glucose but is not involved in glycogen breakdown and is removed from mitochondrial steps in the pathway. This means that altering its activity can have a large effect on gluconeogenesis while reducing the risk of hypoglycemia and other potential side effects from altering other enzymes in gluconeogenesis. Drug candidate have been developed that mimic the inhibitory activity of AMP on FBPase. Efforts were made to mimic the allosteric inhibitory effects of AMP while making the drug as structurally different from it as possible.