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Introduction: A new type of liver-specific glucokinase activator-TTP399 is used in the adjuvant treatment of type 1 diabetes.
What is the effect and safety of the hypoglycemic effect? The latest research results are released.
Type 1 diabetes-except insulin, more treatment options are needed.
Although more new insulin analogues and treatment options [such as continuous subcutaneous insulin infusion (CSII) and continuous blood glucose monitoring (CGM)] have entered the clinic in recent years, they still There are many patients with type 1 diabetes who have poor blood sugar control and also worry about the risk of ketosis and insulin-related hypoglycemia.
Data show that more and more patients are hospitalized due to diabetic ketoacidosis (DKA) and hypoglycemia worldwide.
For type 1 diabetes, with the exception of insulin, more clinical treatment options are needed.
To this end, researchers explored the efficacy and safety of TTP399 (a new type of liver-specific glucokinase activator) for adjuvant treatment of type 1 diabetes, and whether it can improve blood sugar control without increasing the risk of hypoglycemia or ketosis.
.
The results of the study were recently published in Diabetes Care magazine.
A little strange? What is glucokinase activator and TTP399? In recent years, with the successive application of several new types of hypoglycemic drugs in the clinic, we are already very familiar with SGLT-2i, GLP-1RA, and DPP-4i.
Seeking the roots, the mechanism of action of these drugs is ultimately to activate or inhibit certain receptors.
In order to control blood sugar, similarly, glucokinase activator (GKa) can activate glucokinase (GK).
1.
In the blood glucose homeostasis system, GK plays an important role-in the normal physiological state of the glucose sensor, the human blood glucose level is stable at 3.
9-5.
6 mmol/L (steady state balance) to ensure that the brain, red blood cells, etc.
rely on glucose for energy The normal physiological function of the cells is called blood glucose homeostasis.It is essential for blood sugar to maintain a steady state: the brain relies on glucose as an energy source.
Insufficient glucose or low blood sugar can cause brain dysfunction, loss of consciousness, and even death in severe cases.
On the contrary, persistent hyperglycemia or diabetes can cause extensive metabolic disorders and damage important tissues and organs throughout the body.
If left unchecked, complications such as cardiovascular disease, blindness, and kidney failure will occur.
Steady-state regulation of blood glucose is mainly realized by the tissue cells such as pancreatic islets to sense the changes in glucose concentration, secrete blood glucose regulating hormones, and transmit the information to organs such as liver, muscle, fat and other organs for integrated treatment, which is achieved through highly systematic adjustment.
The body's regulation of glucose homeostasis mainly depends on insulin and glucagon, and the secretion of these two hormones is regulated by the concentration of glucose.
As a glucose sensor, GK can keenly sense changes in glucose concentration, timely regulate the secretion of insulin and glucagon, and maintain the body's glucose homeostasis.
If there is a problem with GK, the "sensor" cannot normally sense and transmit blood glucose concentration information, and the blood glucose steady state cannot be maintained, leading to disorder of glucose metabolism and eventually diabetes.
At low blood glucose concentrations, the liver-specific GK regulatory protein (GKRP) binds GK into an inactive form and sequesters it in the nucleus.
At high blood glucose concentrations, GKRP releases active GK into the cytoplasm, thereby limiting the liver's GK activity to the period of hyperglycemia.
In addition, the expression of liver GK also depends on insulin levels.
There is almost no endogenous insulin secretion in patients with type 1 diabetes, the portal vein insulin concentration is very low, GK expression is low, and the liver's glucose uptake and metabolism will be impaired.
Studies have shown that in mice with reduced insulin secretion, restoring the expression of GK in the liver can improve blood sugar control without increasing hypoglycemia or ketoacidosis.
2.
What is TTP399? TTP399, the protagonist of this study, belongs to a kind of GK activator, which can selectively target liver GK without destroying the GKRP/GK interaction. In animal models and patients with type 2 diabetes, TTP399 treatment can improve blood sugar control (mainly driven by lowering blood glucose levels after meals) without increasing the risk of hypoglycemia, elevated triglyceride levels, or liver fat.
What is the effect and safety of TTP399 in the adjuvant treatment of T1DM? The SimpliciT1 study results are released.
The SimpliciT1 study is a three-part phase 1b/2 proof-of-concept study, which aims to explore the effect of TTP399 as an adjuvant treatment for T1DM.
Researchers hypothesize that it can help improve blood glucose control in patients with T1DM.
Will increase the risk of hypoglycemia or ketoacidosis.
1.
What is a phase 1b/2 study? ➤Phase 1b of the study is also called the sentinel phase.
The purpose is to determine the safe dose of TTP399 without placebo control; ➤Phase 2 study is divided into two parts: Part 1 aims to determine the feasibility of the trial and includes 20 people The subjects were randomly assigned to receive CSII or CGM; Part 2 randomly assigned 85 subjects to receive CSII or CGM, during which the subjects were randomized to receive 800 mg TTP399 or placebo for 12 weeks.
The primary endpoint of the study was the change in HbA1c from baseline to week 12.
2.
Research results released: TTP399 can improve blood sugar control without increasing the risk of hypoglycemia or ketoacidosis.
From baseline to week 12, the HbA1c change between TTP399 and placebo was -0.
7 in the first part of the phase 2 study % (95%CI -1.
3~-0.
07), in Part 2 it is -0.
21% (95%CI -0.
39~-0.
04).
Moreover, although the HbA1c of patients in the TTP399 group was significantly reduced, compared with the placebo group, the incidence of severe/symptomatic hypoglycemia was reduced by 40%.
During the treatment period, the plasma β-hydroxybutyric acid and urine ketones of the patients in the TTP399 group were lower than those in the placebo group.
Placebo group.
Summary This study shows that as an adjuvant therapy for insulin, TTP399 can reduce HbA1c levels and the incidence of hypoglycemia in patients with T1DM, without increasing the risk of ketosis.
In the end, whether it can enter the clinic, it needs further evaluation in the future.
References: [1]Klara R.
Klein,Jennifer LR Freeman,Imogene Dunn,et al.
The SimpliciT1 Study: A Randomized, Double-Blind, Placebo-Controlled Phase 1b/2 Adaptive Study of TTP399, a Hepatoselective Glucokinase Activator, for Adjunctive Treatment of Type 1 Diabetes[J].
Diabetes Care 2021 Apr; 44(4): 960-968.
[2]Li Xiaoying.
The core role of glucokinase in glucose homeostasis[J].
DIABETES JOURNAL.
2019/7 Volume 11, Issue 7.
Introduction: A new type of liver-specific glucokinase activator-TTP399 is used in the adjuvant treatment of type 1 diabetes.
What is the effect and safety of the hypoglycemic effect? The latest research results are released.
Type 1 diabetes-except insulin, more treatment options are needed.
Although more new insulin analogues and treatment options [such as continuous subcutaneous insulin infusion (CSII) and continuous blood glucose monitoring (CGM)] have entered the clinic in recent years, they still There are many patients with type 1 diabetes who have poor blood sugar control and also worry about the risk of ketosis and insulin-related hypoglycemia.
Data show that more and more patients are hospitalized due to diabetic ketoacidosis (DKA) and hypoglycemia worldwide.
For type 1 diabetes, with the exception of insulin, more clinical treatment options are needed.
To this end, researchers explored the efficacy and safety of TTP399 (a new type of liver-specific glucokinase activator) for adjuvant treatment of type 1 diabetes, and whether it can improve blood sugar control without increasing the risk of hypoglycemia or ketosis.
.
The results of the study were recently published in Diabetes Care magazine.
A little strange? What is glucokinase activator and TTP399? In recent years, with the successive application of several new types of hypoglycemic drugs in the clinic, we are already very familiar with SGLT-2i, GLP-1RA, and DPP-4i.
Seeking the roots, the mechanism of action of these drugs is ultimately to activate or inhibit certain receptors.
In order to control blood sugar, similarly, glucokinase activator (GKa) can activate glucokinase (GK).
1.
In the blood glucose homeostasis system, GK plays an important role-in the normal physiological state of the glucose sensor, the human blood glucose level is stable at 3.
9-5.
6 mmol/L (steady state balance) to ensure that the brain, red blood cells, etc.
rely on glucose for energy The normal physiological function of the cells is called blood glucose homeostasis.It is essential for blood sugar to maintain a steady state: the brain relies on glucose as an energy source.
Insufficient glucose or low blood sugar can cause brain dysfunction, loss of consciousness, and even death in severe cases.
On the contrary, persistent hyperglycemia or diabetes can cause extensive metabolic disorders and damage important tissues and organs throughout the body.
If left unchecked, complications such as cardiovascular disease, blindness, and kidney failure will occur.
Steady-state regulation of blood glucose is mainly realized by the tissue cells such as pancreatic islets to sense the changes in glucose concentration, secrete blood glucose regulating hormones, and transmit the information to organs such as liver, muscle, fat and other organs for integrated treatment, which is achieved through highly systematic adjustment.
The body's regulation of glucose homeostasis mainly depends on insulin and glucagon, and the secretion of these two hormones is regulated by the concentration of glucose.
As a glucose sensor, GK can keenly sense changes in glucose concentration, timely regulate the secretion of insulin and glucagon, and maintain the body's glucose homeostasis.
If there is a problem with GK, the "sensor" cannot normally sense and transmit blood glucose concentration information, and the blood glucose steady state cannot be maintained, leading to disorder of glucose metabolism and eventually diabetes.
At low blood glucose concentrations, the liver-specific GK regulatory protein (GKRP) binds GK into an inactive form and sequesters it in the nucleus.
At high blood glucose concentrations, GKRP releases active GK into the cytoplasm, thereby limiting the liver's GK activity to the period of hyperglycemia.
In addition, the expression of liver GK also depends on insulin levels.
There is almost no endogenous insulin secretion in patients with type 1 diabetes, the portal vein insulin concentration is very low, GK expression is low, and the liver's glucose uptake and metabolism will be impaired.
Studies have shown that in mice with reduced insulin secretion, restoring the expression of GK in the liver can improve blood sugar control without increasing hypoglycemia or ketoacidosis.
2.
What is TTP399? TTP399, the protagonist of this study, belongs to a kind of GK activator, which can selectively target liver GK without destroying the GKRP/GK interaction. In animal models and patients with type 2 diabetes, TTP399 treatment can improve blood sugar control (mainly driven by lowering blood glucose levels after meals) without increasing the risk of hypoglycemia, elevated triglyceride levels, or liver fat.
What is the effect and safety of TTP399 in the adjuvant treatment of T1DM? The SimpliciT1 study results are released.
The SimpliciT1 study is a three-part phase 1b/2 proof-of-concept study, which aims to explore the effect of TTP399 as an adjuvant treatment for T1DM.
Researchers hypothesize that it can help improve blood glucose control in patients with T1DM.
Will increase the risk of hypoglycemia or ketoacidosis.
1.
What is a phase 1b/2 study? ➤Phase 1b of the study is also called the sentinel phase.
The purpose is to determine the safe dose of TTP399 without placebo control; ➤Phase 2 study is divided into two parts: Part 1 aims to determine the feasibility of the trial and includes 20 people The subjects were randomly assigned to receive CSII or CGM; Part 2 randomly assigned 85 subjects to receive CSII or CGM, during which the subjects were randomized to receive 800 mg TTP399 or placebo for 12 weeks.
The primary endpoint of the study was the change in HbA1c from baseline to week 12.
2.
Research results released: TTP399 can improve blood sugar control without increasing the risk of hypoglycemia or ketoacidosis.
From baseline to week 12, the HbA1c change between TTP399 and placebo was -0.
7 in the first part of the phase 2 study % (95%CI -1.
3~-0.
07), in Part 2 it is -0.
21% (95%CI -0.
39~-0.
04).
Moreover, although the HbA1c of patients in the TTP399 group was significantly reduced, compared with the placebo group, the incidence of severe/symptomatic hypoglycemia was reduced by 40%.
During the treatment period, the plasma β-hydroxybutyric acid and urine ketones of the patients in the TTP399 group were lower than those in the placebo group.
Placebo group.
Summary This study shows that as an adjuvant therapy for insulin, TTP399 can reduce HbA1c levels and the incidence of hypoglycemia in patients with T1DM, without increasing the risk of ketosis.
In the end, whether it can enter the clinic, it needs further evaluation in the future.
References: [1]Klara R.
Klein,Jennifer LR Freeman,Imogene Dunn,et al.
The SimpliciT1 Study: A Randomized, Double-Blind, Placebo-Controlled Phase 1b/2 Adaptive Study of TTP399, a Hepatoselective Glucokinase Activator, for Adjunctive Treatment of Type 1 Diabetes[J].
Diabetes Care 2021 Apr; 44(4): 960-968.
[2]Li Xiaoying.
The core role of glucokinase in glucose homeostasis[J].
DIABETES JOURNAL.
2019/7 Volume 11, Issue 7.