Effects of Modulators of Gluconeogenesis, Glycogenolysis and Glucokinase Activity

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Metformin; Drug: Insulin Glargine; Drug: Dorzagliatin

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Rita Basu
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study record dates

Study Major Dates

• Study Start (Actual): March 7, 2022
• Primary Completion (Actual): July 29, 2025
• Study Completion (Estimated): July 29, 2026

Study Registration Dates

• First Submitted: October 8, 2021
• First Submitted That Met QC Criteria: October 26, 2021
• First Posted (Actual): October 28, 2021

Study Record Updates

• Last Update Posted (Actual): July 30, 2025
• Last Update Submitted That Met QC Criteria: July 29, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Diabetes Mellitus, Type 2; Physiological Effects of Drugs; Hypoglycemic Agents; Insulin Glargine; Metformin
• Other Study ID Numbers: 210395; R01DK029953 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No