lung cells, in pancreatic islet cells, and in periventricular neurons of the hypothalamus in rats, but physiological function and significance in these organs are unknown. Species differences GKRP was originally discovered in rat liver. GKRP was found to serve a similar function in livers of mice and humans as well as other animals. Cats are unusual in lacking GK activity, and have also been found to lack GKRP, though the genes for both GK and GKRP can be identified in the feline genome. Clinical significance Many mutant forms of human GK are associated with impaired or amplified insulin secretion or action, resulting in higher or lower blood glucose levels, and either diabetes (MODY2) or hyperinsulinemic hypoglycemia, respectively. Some of these variants have altered interaction with GKRP, which may contribute to the hyperglycemia. The glucokinase of "knockout mice" who lack GKRP has a reduced expression and is entirely found in the cytoplasm. The knockout mice do not respond rapidly to glucose, exhibiting impaired glucose tolerance. Mutations of the GKRP gene (GCKR) in humans have been sought as possible causes of monogenic diabetes (MODY), but no examples have yet been discovered. However, variant forms of GCKR have been found to be associated with small differences in levels of glucose, insulin, triglycerides, C-reactive protein, and higher or lower risks for type 2 diabetes mellitus. Activators of GK are being investigated as possible medicines for type 2 diabetes. One of the mechanisms of activation may be protection from binding by GKRP. References Proteins