Effects of Modulators of Gluconeogenesis, Glycogenolysis and Glucokinase Activity

Study Overview
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Brief Summary
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It has been shown that individuals with type 2 diabetes have higher blood sugar throughout the night than individuals without type 2 diabetes. However, it is still unknown if this rise in blood sugar can be controlled using medications. This study will examine the effects of three different diabetes treatments to determine if they improve night time blood sugars. Participants will be randomly assigned for 8 weeks to one of the following three groups: GROUP 1: Insulin. Participants will be instructed on self-injecting insulin glargine once-daily in the morning. The dose will be increased by the study team to avoid episodes of low blood sugar and to maintain fasting blood sugar concentrations between 70 to 180 mg/dl. GROUP 2: Metformin. Participants will start the drug (500 mg twice daily) with meals. After 72 hours and in the absence of side effects, they will increase the dose to 500 mg with breakfast and 1,000 mg with supper. After a further 72 hours and in the absence of side effects, they will increase the dose to 1,000 mg twice daily with meals and continue until the end of the trial. The dose will be adjusted by the study team to maintain fasting blood sugar concentrations between 70 to 180 mg/dl. GROUP 3: Dorzagliatin. This medication dose will be 75 mg twice daily. The investigators anticipate fasting glucose concentrations will be between 70 to 180 mg/dl since the dose of this medication cannot be titrated.

Official Title
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Effects of Modulators of Gluconeogenesis, Glycogenolysis and Glucokinase Activity on Endogenous Glucose Production in Type 2 Diabetes

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: Metformin
* Drug: Insulin Glargine
* Drug: Dorzagliatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BMI:25-40 kg/m2. HbA1C ≤ 9% on lifestyle therapy with or without monotherapy with metformin or sulphonylureas (SU); or combination therapies (metformin and SU, DPPIV inhibitors, only short acting GLP-1 analogues exenatide (Byeta) and liraglutide (Victoza). Exclusion Criteria: Insulin therapy SGLT2 inhibitors Long acting GLP-1 analogues TZDs Medications affecting GI motility (e.g., erythromycin, pramlintide). Medications that may affect glucose metabolism such as corticosteroids, tricyclic-antidepressants, benzodiazepines, opiates, barbiturates, and anticoagulants. Unstable diabetic retinopathy, microalbuminuria, macrovascular disease. Upper GI disorder/surgery, debilitating chronic disease, anemia, and symptoms of undiagnosed illnesses. History of alcoholism or substance abuse. Pregnancy or breast feeding, or other comorbidities precluding participation.

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 80 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Metformin<br> | Drug: Metformin<br>* 1500-2000 mg per day for 8 weeks<br>|
| Active Comparator: Insulin Glargine<br> | Drug: Insulin Glargine<br>* Long-acting insulin for 8 weeks<br>|
| Experimental: Dorzagliatin<br> | Drug: Dorzagliatin<br>* Oral Glucokinase Activator 75 mg twice daily for 8 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Contribution of gluconeogenesis (GNG) to endogenous glucose production (EGP) | Ratio of GNG to total EGP | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Contribution of glycogenolysis (GLY) to EGP | Ratio of GLY to total EGP | 8 weeks | 
| Glucokinase activity | UDP glucose flux | 8 weeks |