Effects of Dorzagliatin on 1st Phase Insulin and Beta-cell Glucose Sensitivity in T2D and Monogenic Diabetes

Study Overview
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Brief Summary
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Diabetes is a disorder of energy energy metabolism. Glucose is the main energy substrate for generation of ATP to maintain cellular metabolism, structure and function. Glucokinase (GK) serves as a glucose sensor for the initiation of the energy generation.for energy metabolism. Dorzagliatin is a novel, first-in-class, dual-acting allosteric GK activator (GKA). It increases the affinity of GK for glucose by directly binding a pocket distal to its active site, thus lowering the set point for glucose-stimulated insulin secretion in the beta-cell. Dorzagliatin is a new drug which acts as GK sensor activator (GKA). It can restore the sensitivity of the pancreas cells to glucose and improve glucose control. The drug has been trialled in healthy volunteers and in individuals with type 2 diabetes. The aim of this study is to understand the way in which dorzagliatin works to improve blood sugar control in people with diabetes. The study will look at how dorzagliatin affects insulin secretion and the sensitivity of the pancreas to changes in blood sugar levels. We will examine whether dorzagliatin can restore the function of this GK sensor in patients with known mutations. In a cross-over study, we will evaluate the effects of dorzagliatin, a specific GKA versus placebo in terms of insulin secretion and beta-cell glucose sensitivity in patients with newly-diagnosed T2D and patients who are known heterozygous carriers of GK mutations.

Official Title
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Effects of Dorzagliatin on 1st Phase Insulin and Beta-cell Glucose Sensitivity in Individuals With Recent-onset Type 2 Diabetes and Monogenic Diabetes

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Dorzagliatin
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals aged ≥ 18 years but < 65years Male or female Body mass index of over 18 kg/m2 and < 30 kg/m2 Additional Inclusion criteria for recent-onset T2D group Diagnosis of T2D for at least 3 months and less than 2 years On diet control only HbA1c>6.5 % and <8% Additional Inclusion criteria for GK MODY-2 group Abnormal fasting plasma glucose >5.6 mmol/l and known heterozygous carrier of pathogenic GK mutation Exclusion Criteria: Subjects who do not agree to participate in this study. Country of birth is unknown Body weight less than 45kg Acute phase of cerebrovascular and cardiovascular diseases (within 6 months of recruitment). Subjects with severe renal dysfunction as defined by eGFR <30 ml/min/1.73m2 or patients receiving renal dialysis (such as haemodialysis or continuous ambulatory peritoneal dialysis). Severe hepatic dysfunction as defined by AST and/or ALT > 3 times upper limit of normal Severe cardiovascular disease, history of stroke, heart failure (NYHA III or IV) or history of myocardial infarction within last 12 months History of drug abuse or excessive alcohol intake based on investigator judgment Severe hypoglycaemia resulting in seizure/unconsciousness/coma/hospitalization in the last 3 months before screening Diagnosis with Type 1 Diabetes Mellitus (T1DM) or any previous episodes of diabetic ketoacidosis. Dehydration, diarrhoea or vomiting at the time of recruitment Subjects with severe infection, in perioperative period or with serious injury at the time of recruitment Subjects with anaemia (Haemoglobin <9.0mg/dL) Pregnant or lactating or intending to become pregnant within 30 days after last dose of study drug. Participation in a clinical trial within 30 days before enrolment Donation or loss of blood (excluding the volume of blood that will be drawn during screening procedures) as follows: >=300 mL of blood within 30 days prior to study drug administration. Subjects judged unsuitable for the study based on investigator judgment Use of metformin, sulfonylureas, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 [GLP-1] agonists, sodium glucose transporter 2 inhibitors, insulin, thiazolidinediones, acarbose in the 3 months prior to study enrolment will not be permitted. Use of strong or moderate CYP3A4 inhibitors or inducers and cannot be discontinued Unwilling or unable to follow protocol requirements.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Group 1<br>receive a single oral dose of dorzagliatin 75mg tablet on visit 2 and receive one placebo tablet on visit 3 | Drug: Dorzagliatin<br>* tablet<br>Drug: placebo<br>* placebo<br>|
| Other: Group 2<br>receive a single oral dose of one placebo tablet on visit 2 and receive dorzagliatin 75mg tablet on visit 3 | Drug: Dorzagliatin<br>* tablet<br>Drug: placebo<br>* placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| first phase insulin response to glucose | measure insulin between 0 to 10 minutes | 10 mins | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| First phase C-peptide responses to glucose | measure C peptide between 0 to 10 minutes | 10 mins | 
| Maximum concentration (Cmax) 1st phase insulin between 0 to 10 minutes | measure insulin between 0 to 10 minutes | 10 mins | 
| Time to maximum (Tmax) of acute phase insulin response between 0 to 10 minutes | measure insulin between 0 to 10 minutes | 10 mins | 
| Second phase insulin response | measure insulin at last 40 mins of hyperglycemic clamp | 40 mins | 
| Beta cell glucose sensitivity | insulin secretion in last 40 minutes of hyperglycemic clamp | 40 mins | 
| Insulin sensitivity index | glucose infusion rate in last 40 minutes of hyperglycemic clamp | 40 mins | 
| Area under curve of glucagon levels | measure glucagon from 0-120 mins | 120 mins | 
| Area under curve of GLP-1 levels | measure GLP-1 from 0-120 mins | 120 mins |