Effects of Modulators of Gluconeogenesis, Glycogenolysis and Glucokinase Activity

Conditions

Type 2 Diabetes

Brief summary

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.

Chen L, Zhang J, Sun Y, Zhao Y, Liu X, Fang Z, Feng L, He B, Zou Q, Tracey GJ.

2023-03-149 citations

10.1038/s41467-023-36946-7

Dorzagliatin add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial.

Yang W, Zhu D, Gan S, Dong X, Su J, Li W, Jiang H, Zhao W, Yao M, Song W, Lu Y, Zhang X, Li H, Wang G, Qiu W, Yuan G, Ma J, Li W, Li Z, Wang X, Zeng J, Yang Z, Liu J, Liang Y, Lu S, Zhang H, Liu H, Liu P, Fan K, Jiang X, Li Y, Su Q, Ning T, Tan H, An Z, Jiang Z, Liu L, Zhou Z, Zhang Q, Li X, Shan Z, Xue Y, Mao H, Shi L, Ye S, Zhang X, Sun J, Li P, Yang T, Li F, Lin J, Zhang Z, Zhao Y, Li R, Guo X, Yao Q, Lu W, Qu S, Li H, Tan L, Wang W, Yao Y, Chen D, Li Y, Gao J, Hu W, Fei X, Wu T, Dong S, Jin W, Li C, Zhao D, Feng B, Zhao Y, Zhang Y, Li X, Chen L.

2022-05-1253 citations

10.1038/s41591-022-01803-5

Interventions

DRUGMetformin

1500-2000 mg per day for 8 weeks

DRUGInsulin Glargine

Long-acting insulin for 8 weeks

DRUGDorzagliatin

Oral Glucokinase Activator 75 mg twice daily for 8 weeks

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

OTHER

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

25 Years to 80 Years

Healthy volunteers

No

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.

Design outcomes

Primary

Measure	Time frame	Description
Contribution of gluconeogenesis (GNG) to endogenous glucose production (EGP)	8 weeks	Ratio of GNG to total EGP

Secondary

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

Countries

United States

Outcome results

None listed