Neonatal hypoglycemia is a serious disease threatening the health and even life of newborns. Repeated severe hypoglycemia not only threatening life but can also causing permanent and irreversible damage to brain function and life-long disability. It has brought serious injuries and burdens to patients and families. The causes of hypoglycemia mainly are congenital hyperinsulinemia (CHI), the cause of the disease is complex (more than 11 pathogenic genes have been found). This disease has been included on the first list of rare diseases in China, as shown in the figure, the main pathogenic genes include:
❶: The key enzyme of amino acid metabolism, glutamate dehydrogenase (GDH) gain-of-function mutation ;
❷: The key enzyme of glucose metabolism, glucokinase (GK) gain-of-function mutation;
❸: ATP-dependent potassium channel (SUR1 and Kir6.2) loss-of-function mutation;
❹: The key enzyme of fatty acid metabolism (SCHAD) loss-off-function mutation, etc.
Glucokinase (GK): Neonatal Hypoglycemia caused by gain-of-function mutation and treatment of diabetes with glucokinase agonists Professor Franz Matschinsky, known as the father of GK, proposed the concept of GK as a glucose sensor more than 50 years ago. The discovery of these diseases related to GK function provides solid evidence for the hypothesis that GK is a glucose sensor, including Monogenic diabetes (MODY2) caused by GK loss-of-function mutation and Congenital Hyperinsulinemic Hypoglycemia(GK-CHI) caused by GK gain-of-function mutation. These findings confirm the theory that GK is a glucose sensor from the perspective of human physiology and pathology. The theoretical basis for the development of new drugs for the treatment of diabetes with glucokinase agonists (GKA) is based on GK as a glucose sensor principle. The change in GK activity caused by GK mutation directly determines the “set value” of the patient’s blood sugar, such as most MODY2, the fasting blood glucose of the patient is stable at ~8 mM, while the patient of GK-CHI is based on the activity of the mutant GK, especially the glucose S0.5 changes. There are different degrees of hypoglycemia performance. The application of GKA in diabetic patients can help patients correct “deviations”, the blood sugar setting value that has been changed which will return to the steady-state of blood sugar. Based on the new drug development concept of “the same target, from a rare disease to common disease”, Targets of insulin over-secretion which caused by genetic mutations not only can it cause CHI, but is also a target for new drug development in the fields of diabetes, fatty liver, and tumor metabolism. Started with a solid foundation for new drug research and development of New target from rare diseases, and has completed its extension to common diseases.