Hua Medicine 1
Glucokinase: 50 Years of Research
50 years ago, scientists discovered a glucose metabolism enzyme in mice pancreas, which showed very different enzyme kinetic property from known hexokinase, a glucose process enzyme. Glucokinase, as a glucose sensor, plays a central role in glucose homeostasis, which controls the human blood glucose level in a very narrow range of 4-6.5 mmol/L. Glucokinase controls the set point of blood in the body and regulates it through a threshold control. It augments the secretion of Hormones that regulates the glucose disposition and metabolisms through its function in pancreas, intestine and liver.
Advances in our understanding of genetics have given us much more insight into the way Glucokinase works. Activating mutations (eg. PHHI gene) are shown to cause hypoglycaemia, while deactivating mutations (eg. MODY-2 gene) cause hyperglycemia. Disruption of Hepatic Glucokinase or Glucokinase regulatory protein by gene mutations has also shown to be related to abnormal blood glucose level and dyslipidemia. It’s also been shown that gene expression of Glucokinase is regulated by insulin and glucose, with the reduction of Glucokinase expression associated with aging, abnormal blood glucose level and Type 2 Diabetes (T2D).
The key pathophysiological factor in T2D is the disfunction of early phase insulin secretion in response to glucose change – this contributes to a loss of glucose and insulin sensitivity. At the same time, impaired Glucokinase expression and function in T2D patients has been closely associated with the delay of early phase insulin secretion, hepatic insulin resistance and elevated blood glucose. Based on this understanding, researchers developed Dorzagliatin, a glucokinase activator. Dorzagliatin improves the glucose sensor function in T2D patients and improves glucose sensitivity ultimately leading to the repair of disfunction in insulin sensitivity.