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GLP-1 is an important incretin, and the "GLP-1 pathway" is of great significance in the process of maintaining blood glucose homeostasis
.
Foreword Because of his outstanding contributions to the study of incretin, Dr.
Jens Juul Holst of the University of Copenhagen, Denmark, was awarded the 2021 American Diabetes Association (ADA) Banting Award (Figure 1) [1]
.
Figure 1 Dr.
Jens Juul Holst was awarded the 2021 American Diabetes Association (ADA) Banting Award So, what is incretin? After the human body takes in nutrients, the intestinal endocrine cells will synthesize and secrete a type of hormone that can promote insulin secretion and inhibit the secretion of glucagon to lower blood sugar.
This hormone is incretin, including glucose-dependent insulin releasing peptide (GIP) and glucagon-like peptide-1 (GLP-1) [2]
.
Among them, GLP-1 is secreted by L cells in the ileum and colon, which can promote the synthesis and secretion of insulin, and also has the effects of protecting β cells, suppressing appetite and glucagon release [2]
.
At present, drugs aimed at increasing the concentration of GLP-1 [2] have been widely used clinically
.
We know that the regulation of human blood glucose homeostasis mainly depends on the secretion of the glucose-controlling hormones insulin, glucagon and GLP-1, as well as the role of various target organs such as the liver.
The common key node in the above links is the blood glucose sensor— -Glucokinase (GK)
.
In the past, there was little research evidence on GLP-1 secretion by glucokinase activator (GKA)
.
At the 81st ADA Annual Scientific Meeting (ADA 2021), the results of a study of the world's first innovative drug glucokinase activator Dorzagliatin (Dorzagliatin) provided us with new evidence
.
Maintain blood glucose homeostasis: "GLP-1 pathway" attracts attention.
Glucokinase (GK) is mainly distributed in tissues and organs closely related to blood sugar regulation, such as the liver, pancreatic islets, and intestines.
It functions as a glucose sensor, and its activity is determined by the concentration of glucose.
To decide, and then by regulating the secretion of insulin and glucagon, as well as the synthesis and decomposition of liver glycogen, the blood sugar level is controlled within the target range of 4~6.
5 mmol/L [4,5]
.
In the process of maintaining glucose homeostasis, glucokinase (GK) is the core "component" (Figure 2)
.
When blood sugar is too high, the activity of glucokinase (GK) in pancreatic β-cells increases, which regulates the timely and appropriate secretion of insulin
.
Increased glucokinase (GK) activity in liver cells promotes liver glycogen synthesis; increased glucokinase (GK) activity in the intestines promotes the secretion of GLP-1, which in turn promotes the secretion of insulin by β cells; at the same time, glucokinase in α cells (GK) activity is enhanced, inhibiting the release of glucagon; when the blood sugar is too low, the activity of glucokinase (GK) in α cells decreases, and the timely secretion of glucagon is initiated.
The liver glycogen breaks down the glucose into the blood, causing the blood sugar to rise to Physiological target range
.
Figure 2 The sensing and execution system of the human blood glucose homeostasis balance regulation In the process of maintaining blood glucose homeostasis, the GLP-1 pathway attracts attention
.
If the function of glucokinase (GK) is impaired, the secretion of GLP-1 will also be impaired, leading to blood glucose imbalance
.
New proof: combined with dozaglietin to promote GLP-1 release and improve islet function.
At the 81st American Diabetes Association (ADA) Annual Scientific Meeting, Hua Medicine announced through oral reports and poster discussions.
Analysis data of multiple clinical studies of its world's first innovative drug for diabetes, glucokinase activator (GKA) dozaglietin
.
Among them, HMM0111, 0112 studies have confirmed that dozaglietin can promote GLP-1 secretion and improve islet function, which has attracted widespread attention
.
The HMM0111 study-the DDI study of dozagliptin and DPP-4i sitagliptin-showed [6]: the combination of dozagliptin and sitagliptin can regulate the GLP of patients with type 2 diabetes- 1 Synergistic effect on secretion: Compared with dozagliflozin alone, the AUEC of active GLP-1 at 0～4h after treatment with sitagliptin is significantly increased by 94.
9%; combined with dozagliflozin Compared with sitagliptin, the area under the total GLP-1 concentration-time curve (AUEC0-4h) increased by 103.
6% in patients with type 2 diabetes after monotherapy with dozagliflechtin and the maximum total GLP-1 concentration Increased by 141%
.
From the mechanism point of view, dozaglietin promotes the increase of the secretion of active GLP-1 by repairing the function of glucokinase (GK) in the intestine of patients with type 2 diabetes; sitagliptin acts as dipeptidyl peptidase-4 (DPP) -4) Inhibitors, which block the activity of DPP-4 enzyme, thereby reducing the inactivation of GLP-1 in the body and increasing the level of endogenous GLP-1 [7], dozagliptin combined with sitagliptin Afterwards, it has a synergistic effect and jointly promotes the increase in the concentration of active GLP-1
.
In addition to acting on the GLP-1 pathway, dozagliflozin combined with DPP-4 inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors can also improve pancreatic β-cell function: compared to dozagliflozin alone The combination of dozagliptin and sitagliptin can increase the level of C-peptide, AUEC0-4h increased by 46.
6% (P<0.
01), and Cmax increased by 52.
5% (P<0.
01) compared with single use of Enpagliflozin , C-peptide secretion AUEC0-4h increased by 30.
3% (p<0.
05), Cmax increased by 31% (p<0.
01), glucose AUEC0-4h decreased by 37.
6%, maximum glucose concentration after dozaglifledin combined with empagliflozin treatment A decrease of 27.
8%
.
Dozagliptin can repair the glucose sensor glucokinase (GK) function on the islet β and α cells, restore the blood glucose regulation ability of patients with type 2 diabetes, and then improve the islet function; SGLT2 inhibitors can also promote β cell proliferation and inhibit inflammation , Apoptosis, and dedifferentiation can improve β cells[9], and the combination of the two also has a synergistic effect to improve the function of islets
.
The new research result of dozagliflozin improving the secretion of GLP-1 in patients with type 2 diabetes may not only lead to further attention to glucokinase activator (GKA) drugs in the field of diabetes drug development, but also for the development of dozagliflozin.
The combination of Itin and GLP-1 agonists or the development of fixed compound preparations lay the foundation to better play the role of the two in promoting GLP-1 secretion, and give patients multiple benefits
.
Summary GLP-1 is an important incretin, "GLP-1 pathway" is of great significance in the process of maintaining blood glucose homeostasis
.
If the function of glucokinase (GK) is impaired, the secretion of GLP-1 will be impaired, which is one of the important causes of blood glucose imbalance
.
Dozagliptin can repair the function of glucokinase (GK) in the intestinal cells of patients with type 2 diabetes and promote the increase of the secretion of active GLP-1.
It has a synergistic effect in combination with DPP-4 inhibitors and jointly promotes active GLP-1.
The concentration further increased [6]
.
In addition, whether dozaglietin combined with DPP-4 inhibitor or SGLT2 inhibitor, can effectively improve the function of pancreatic β-cells [8]
.
Therefore, the combination therapy of hypoglycemic drugs based on dozaglietin has a bright future
.
In April 2021, the new drug application (NDA) application for dozaglifledetin has been accepted by the National Medical Products Administration (NMPA), becoming the first glucokinase activator (GKA) product in the world to submit an NDA, and it has also become The undisputed leading product under this new mechanism
.
297-300.
Source: Medical Editor: Tian Dongliang Proofreader: Zang Hengjia Plate-making: Xue Jiao's wonderful review of the past evening news | Medical institutions "Natural Index" top 100 list released | China's first "intestinal flora" academic branch established ADA : Controlling blood sugar, dinner time is the key to a higher risk of cancer in diabetic patients? ADA issued a warning
.
Foreword Because of his outstanding contributions to the study of incretin, Dr.
Jens Juul Holst of the University of Copenhagen, Denmark, was awarded the 2021 American Diabetes Association (ADA) Banting Award (Figure 1) [1]
.
Figure 1 Dr.
Jens Juul Holst was awarded the 2021 American Diabetes Association (ADA) Banting Award So, what is incretin? After the human body takes in nutrients, the intestinal endocrine cells will synthesize and secrete a type of hormone that can promote insulin secretion and inhibit the secretion of glucagon to lower blood sugar.
This hormone is incretin, including glucose-dependent insulin releasing peptide (GIP) and glucagon-like peptide-1 (GLP-1) [2]
.
Among them, GLP-1 is secreted by L cells in the ileum and colon, which can promote the synthesis and secretion of insulin, and also has the effects of protecting β cells, suppressing appetite and glucagon release [2]
.
At present, drugs aimed at increasing the concentration of GLP-1 [2] have been widely used clinically
.
We know that the regulation of human blood glucose homeostasis mainly depends on the secretion of the glucose-controlling hormones insulin, glucagon and GLP-1, as well as the role of various target organs such as the liver.
The common key node in the above links is the blood glucose sensor— -Glucokinase (GK)
.
In the past, there was little research evidence on GLP-1 secretion by glucokinase activator (GKA)
.
At the 81st ADA Annual Scientific Meeting (ADA 2021), the results of a study of the world's first innovative drug glucokinase activator Dorzagliatin (Dorzagliatin) provided us with new evidence
.
Maintain blood glucose homeostasis: "GLP-1 pathway" attracts attention.
Glucokinase (GK) is mainly distributed in tissues and organs closely related to blood sugar regulation, such as the liver, pancreatic islets, and intestines.
It functions as a glucose sensor, and its activity is determined by the concentration of glucose.
To decide, and then by regulating the secretion of insulin and glucagon, as well as the synthesis and decomposition of liver glycogen, the blood sugar level is controlled within the target range of 4~6.
5 mmol/L [4,5]
.
In the process of maintaining glucose homeostasis, glucokinase (GK) is the core "component" (Figure 2)
.
When blood sugar is too high, the activity of glucokinase (GK) in pancreatic β-cells increases, which regulates the timely and appropriate secretion of insulin
.
Increased glucokinase (GK) activity in liver cells promotes liver glycogen synthesis; increased glucokinase (GK) activity in the intestines promotes the secretion of GLP-1, which in turn promotes the secretion of insulin by β cells; at the same time, glucokinase in α cells (GK) activity is enhanced, inhibiting the release of glucagon; when the blood sugar is too low, the activity of glucokinase (GK) in α cells decreases, and the timely secretion of glucagon is initiated.
The liver glycogen breaks down the glucose into the blood, causing the blood sugar to rise to Physiological target range
.
Figure 2 The sensing and execution system of the human blood glucose homeostasis balance regulation In the process of maintaining blood glucose homeostasis, the GLP-1 pathway attracts attention
.
If the function of glucokinase (GK) is impaired, the secretion of GLP-1 will also be impaired, leading to blood glucose imbalance
.
New proof: combined with dozaglietin to promote GLP-1 release and improve islet function.
At the 81st American Diabetes Association (ADA) Annual Scientific Meeting, Hua Medicine announced through oral reports and poster discussions.
Analysis data of multiple clinical studies of its world's first innovative drug for diabetes, glucokinase activator (GKA) dozaglietin
.
Among them, HMM0111, 0112 studies have confirmed that dozaglietin can promote GLP-1 secretion and improve islet function, which has attracted widespread attention
.
The HMM0111 study-the DDI study of dozagliptin and DPP-4i sitagliptin-showed [6]: the combination of dozagliptin and sitagliptin can regulate the GLP of patients with type 2 diabetes- 1 Synergistic effect on secretion: Compared with dozagliflozin alone, the AUEC of active GLP-1 at 0～4h after treatment with sitagliptin is significantly increased by 94.
9%; combined with dozagliflozin Compared with sitagliptin, the area under the total GLP-1 concentration-time curve (AUEC0-4h) increased by 103.
6% in patients with type 2 diabetes after monotherapy with dozagliflechtin and the maximum total GLP-1 concentration Increased by 141%
.
From the mechanism point of view, dozaglietin promotes the increase of the secretion of active GLP-1 by repairing the function of glucokinase (GK) in the intestine of patients with type 2 diabetes; sitagliptin acts as dipeptidyl peptidase-4 (DPP) -4) Inhibitors, which block the activity of DPP-4 enzyme, thereby reducing the inactivation of GLP-1 in the body and increasing the level of endogenous GLP-1 [7], dozagliptin combined with sitagliptin Afterwards, it has a synergistic effect and jointly promotes the increase in the concentration of active GLP-1
.
In addition to acting on the GLP-1 pathway, dozagliflozin combined with DPP-4 inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors can also improve pancreatic β-cell function: compared to dozagliflozin alone The combination of dozagliptin and sitagliptin can increase the level of C-peptide, AUEC0-4h increased by 46.
6% (P<0.
01), and Cmax increased by 52.
5% (P<0.
01) compared with single use of Enpagliflozin , C-peptide secretion AUEC0-4h increased by 30.
3% (p<0.
05), Cmax increased by 31% (p<0.
01), glucose AUEC0-4h decreased by 37.
6%, maximum glucose concentration after dozaglifledin combined with empagliflozin treatment A decrease of 27.
8%
.
Dozagliptin can repair the glucose sensor glucokinase (GK) function on the islet β and α cells, restore the blood glucose regulation ability of patients with type 2 diabetes, and then improve the islet function; SGLT2 inhibitors can also promote β cell proliferation and inhibit inflammation , Apoptosis, and dedifferentiation can improve β cells[9], and the combination of the two also has a synergistic effect to improve the function of islets
.
The new research result of dozagliflozin improving the secretion of GLP-1 in patients with type 2 diabetes may not only lead to further attention to glucokinase activator (GKA) drugs in the field of diabetes drug development, but also for the development of dozagliflozin.
The combination of Itin and GLP-1 agonists or the development of fixed compound preparations lay the foundation to better play the role of the two in promoting GLP-1 secretion, and give patients multiple benefits
.
Summary GLP-1 is an important incretin, "GLP-1 pathway" is of great significance in the process of maintaining blood glucose homeostasis
.
If the function of glucokinase (GK) is impaired, the secretion of GLP-1 will be impaired, which is one of the important causes of blood glucose imbalance
.
Dozagliptin can repair the function of glucokinase (GK) in the intestinal cells of patients with type 2 diabetes and promote the increase of the secretion of active GLP-1.
It has a synergistic effect in combination with DPP-4 inhibitors and jointly promotes active GLP-1.
The concentration further increased [6]
.
In addition, whether dozaglietin combined with DPP-4 inhibitor or SGLT2 inhibitor, can effectively improve the function of pancreatic β-cells [8]
.
Therefore, the combination therapy of hypoglycemic drugs based on dozaglietin has a bright future
.
In April 2021, the new drug application (NDA) application for dozaglifledetin has been accepted by the National Medical Products Administration (NMPA), becoming the first glucokinase activator (GKA) product in the world to submit an NDA, and it has also become The undisputed leading product under this new mechanism
.
297-300.
Source: Medical Editor: Tian Dongliang Proofreader: Zang Hengjia Plate-making: Xue Jiao's wonderful review of the past evening news | Medical institutions "Natural Index" top 100 list released | China's first "intestinal flora" academic branch established ADA : Controlling blood sugar, dinner time is the key to a higher risk of cancer in diabetic patients? ADA issued a warning
