*It is only for medical professionals to read for reference.
It's time to look at T2DM from a different perspective
"Homeostasis", an important concept in physiology, was first proposed by American physiologist Cannon in 1926, revealing that the normal progress of life activities depends on the internal law of the relative stability of the internal environment
Cannon emphasized that homeostasis is not static.
On the contrary, it is a dynamic self-regulating system that involves the coordination of various systems and organs, enabling us to maintain the ability to survive in the face of ever-changing environmental demands
For example, no matter how the outside temperature fluctuates, the body temperature is always kept constant
In 2021, David Julius and Adem Pataptian also won the Nobel Prize in Physiology or Medicine for their discovery of temperature and tactile receptors
However, not only body temperature, but in order to ensure the normal operation of the body’s important organs, healthy people’s blood sugar can also be adjusted autonomously and kept within a normal range.
Diabetes patients’ blood sugar steady state is broken because of the impaired self-regulatory function.
In order to arouse the public's attention to diabetes prevention and care for patients with diabetes, the "medical community" sincerely invites Professor Li Yanbing from the First Affiliated Hospital of Sun Yat-sen University to talk with us about the autonomous regulation of blood glucose homeostasis
Firstly understand that blood glucose homeostasis autonomously regulates the human body has a complete set of sophisticated blood glucose regulation mechanisms to maintain the relative stability of blood glucose
Without any regulation, the body's blood sugar will rise beyond the normal physiological range after ingesting food
However, under normal physiological conditions, human blood sugar is always maintained at 3.
6 mmol/L (70~100mg/dL) under the coordination of all relevant organs of the body.
This relatively stable blood sugar state is called blood glucose homeostasis
A healthy body can always maintain blood sugar steady state without external interference, which shows that blood sugar steady state can be adjusted autonomously
The blood glucose regulation process that maintains blood glucose homeostasis mediated by glucose levels is the process of autonomously regulating blood glucose homeostasis
Blood glucose homeostasis is the basis for ensuring that cells such as the brain and red blood cells rely on glucose for energy to perform normal physiological functions [1-2]
Professor Li Yanbing pointed out that the blood glucose homeostasis system is composed of multiple organs involved in the regulation and utilization of glucose, including the brain, pancreatic islets, liver, intestine, muscle and fat
Among them, the liver, pancreas, and intestines are the three core organs for blood glucose regulation.
After sensing the changes in blood glucose levels, these organs autonomously regulate blood glucose through a series of actions according to the changed blood glucose levels, so as to maintain blood glucose steady state without the need.
Relying too much on the complex brain signal receiving-feedback process, which is called blood glucose homeostasis autonomous regulation
For example, the pancreas can release insulin or glucagon autonomously after sensing the fluctuation of blood sugar, the liver can store or release glucose; the intestine can release secretin, these mechanisms can regulate the body's uptake and utilization of glucose and glycogen Storage is carried out autonomously [1,3,4]
However, the core organs of blood glucose regulation are not always working, but need the glucose setting point as the "open point" for work
Only when the blood glucose level changes to the glucose set point, the blood glucose regulation core organ will "autonomously respond"
In addition, the glucose setting points of each sugar control mechanism are not consistent.
For example, when the glucose concentration is less than 4mmol/L, the islet α cells start to work and start the glucagon release mechanism; when the glucose concentration is more than 5mmol/L, the islet β The cells begin to work to initiate insulin secretion; when the glucose concentration reaches about 5.
5mmol/L, the intestinal L cells begin to secrete glucagon-like peptide-1 (GLP-1); and when the glucose concentration reaches 10mmol/L, The liver starts the synthesis of liver glycogen, and at this time, the output of liver glycogen is inhibited 
Glucokinase (GK) is the "chip" that plays a role in the core organs of blood sugar regulation.
It exists in the core organs of blood sugar regulation.
It is the first key enzyme for glucose metabolism in cells and the first step to turn on blood sugar regulation
When the blood glucose level changes beyond the threshold, GK changes the rate of glucose metabolism to convert the blood glucose signal into the secretion instruction of the glucose control core organs for blood glucose regulation, and initiates the subsequent hypoglycemic or hypoglycemic mechanism [1-5]
Professor Li Yanbing said: “It can be seen that the body has to mobilize the blood glucose control core organs in the system to perform their duties and cooperate with each other to respond autonomously to blood glucose changes, thereby maintaining blood glucose homeostasis.
The normal function of GK is very important
” From blood glucose Steady state looks at the pathogenesis of T2DM.
The pathogenesis of diabetes with decreased glucose sensitivity due to impaired GK is very complex, but blood glucose instability is a common feature of the complex pathogenesis of T2DM
GK plays a central role in the autonomous regulation of blood glucose homeostasis, and GK expression in patients with T2DM is generally severely reduced, which results in a decrease in the sensitivity of the steady-state system to blood glucose changes and an increase in blood glucose [6,7,8]
Take the example of GK regulating insulin release in pancreatic β cells.
Under normal circumstances, as the blood glucose concentration rises, when the glucose setting point of β cells is reached, GK is activated, opening the door to a series of subsequent reactions, and these reactions eventually promote Insulin is released outside the cell through exocytosis [5,9]
After GK is damaged, the sensitivity of pancreatic β-cells to glucose decreases, and insulin secretion decreases 
Similarly, under normal circumstances, GK can also inhibit the release of glucagon in pancreatic islet α cells through a series of mechanisms , promote the release of GLP-1 from intestinal cells , and promote glycogen synthesis in liver cells  , Thereby reducing blood sugar
Damage to GK leads to increased secretion of glucagon in alpha cells , the release of insulin, GLP-1 and glycogen synthesis in liver cells are reduced [11,13], so a series of blood glucose instability manifestations
It is precisely because of the impact of GK damage on T2DM.
When asked whether it is possible to repair the function of GK, reshape the blood glucose homeostasis autonomous regulation function of T2DM patients, and then achieve the goal of diabetes treatment, Professor Li Yanbing expressed this For sure
"Since GK was first discovered in the liver in 1963, scientists have been researching and exploring the GK pathway for nearly sixty years, trying to help patients rebuild blood glucose homeostasis through the development of a glucokinase activator (GKA) based on this pathway.
Autonomous regulation 
As mentioned earlier, GK is the first key enzyme for glucose metabolism in cells, and it is also the first step to turn on blood sugar regulation,” Professor Li Yanbing emphasized, “GK damage is common in diabetic patients, and GK activity decreases.
The role of GKA is the first step-through the combination or dissociation of GKA and GK as the glucose concentration changes, the glucose-dependent dynamic regulation is realized, the body's "observation of blood sugar changes" is restored, and the blood sugar steady state autonomy is restored.
"In 2020, Professor Matschinsky, the father of GK, won the global "Nobel Prize" in the field of endocrinology and metabolism-Rolf Luft Award  for his outstanding contributions in GK research and promotion of GKA research and development, It can be seen that the GK pathway plays an important role in diabetes and even the entire endocrine and metabolism fields
At present, research on GKA is still in full swing
In 2021, the world's first GKA, which is also the original research GKA in China-Dopagliflozin has submitted a new drug marketing application and is waiting to enter the clinical use stage
Professor Li Yanbing also expressed his eager expectation that this GKA drug can bring new hope to the treatment of T2DM patients
Summary: The human body has a complete set of sophisticated blood glucose regulation mechanisms to maintain the relative stability of blood glucose.
The pancreas, liver, and intestine are the core organs for blood glucose regulation, and the coordination of the blood glucose regulation core organs is initiated by GK
GK damage is common in patients with T2DM, and the latter can cause blood glucose instability by affecting a series of subsequent glucose-regulating mechanisms
The deep cultivation of the GK pathway and the research and development of GKA drugs is a great innovation in the field of diabetes treatment.
A new perspective on this disease that has been entangled with mankind for thousands of years
Doxagliptin stands out among GKA drugs and is waiting to enter the clinical use stage
Expert profile Professor Li Yanbing, PhD in endocrinology, doctoral supervisor, director of the Department of Endocrinology, Sun Yat-sen University's famous doctor, the First Affiliated Hospital of Sun Yat-sen University, Director of the Key Laboratory of Endocrinology, Guangdong Provincial Department of Health, Chairman of the Endocrinology Branch of the Guangdong Medical Association, Member of the Endocrinology Branch of the Chinese Medical Association, Deputy Leader of the Pituitary Science Group Leader of the Chinese Insulin Secretion Research Group Leader of the National Key Specialized Chronic Diseases in Guangdong Province, National Leading Medical Talent of Guangdong Province J Diabetes Res Guest Editor-in-Chief, Diabetes Metab Res Rev Guest Editor, Editorial Board Member of Chinese Journal of Diabetes, Chinese Endocrinology and Metabolism Member of the editorial board of the journal, deputy editor of the Chinese Electronic Journal of Obesity and Metabolic Diseases, Chairman of the third session of the Diabetes Branch of the Guangdong Medical Association Chairman of the Metabolism and Endocrine Professional Committee of the Guangdong Health Management Society Member of the Guangdong Provincial Cadre Health Expert Group, and Chief Expert of Guangdong Health Education References:  Biochemistry and Molecular Biology 9th Edition.
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