Overview
This Phase 2a study evaluates whether 12 weeks of treatment with investigational MOTS-c improves insulin sensitivity compared with placebo in adults with prediabetes and overweight/obesity.
Participants are randomized 1:1 to MOTS-c or placebo, receive standardized lifestyle counseling, and are followed for safety through Week 16.
Description
Mitochondrial-derived peptides (MDPs) are small peptides encoded by mitochondrial DNA that can act as signaling molecules. MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) has been reported to regulate insulin sensitivity and metabolic homeostasis in preclinical studies, with skeletal muscle identified as a key target tissue and AMPK activation proposed as a downstream mechanism. Based on these findings, this trial is designed to test the hypothesis that MOTS-c can improve insulin sensitivity and cardiometabolic risk markers in humans with early metabolic dysfunction. The study includes a screening period (up to 4 weeks), a 12-week double-blind treatment period, and a 4-week post-treatment safety follow-up. Efficacy is assessed using a 75 g oral glucose tolerance test (OGTT)-derived insulin sensitivity index and standard metabolic endpoints (HbA1c, fasting glucose, lipids, body weight, and waist circumference). Safety assessments include adverse events, vital signs, ECG, and laboratory testing.
Eligibility
Inclusion Criteria:
- Age 18 to 65 years at the time of consent.
- Body mass index (BMI) 27.0 to 40.0 kg/m\^2.
- Prediabetes documented at screening by any of the following: (a) HbA1c 5.7% to 6.4%; (b) fasting plasma glucose 100 to 125 mg/dL; or (c) 2-hour plasma glucose 140 to 199 mg/dL during a 75 g OGTT.
- Stable body weight (less than 5% change) for at least 3 months prior to screening.
- Willingness to maintain stable diet and physical activity patterns during the 12-week treatment period.
- For participants of childbearing potential: agreement to use highly effective contraception for the study duration and for a protocol-specified period after last dose.
- Ability to understand and sign informed consent.
Exclusion Criteria:
- Diabetes mellitus (e.g., HbA1c 6.5% or higher, fasting plasma glucose 126 mg/dL or higher, or 2-hour glucose 200 mg/dL or higher at screening).
- Use of glucose-lowering medications (including metformin, GLP-1 receptor agonists, SGLT2 inhibitors) within 3 months prior to screening.
- History of bariatric surgery or planned weight-loss surgery during the study period.
- Clinically significant cardiovascular disease within 6 months (e.g., myocardial infarction, stroke, unstable angina) or uncontrolled hypertension.
- Estimated glomerular filtration rate (eGFR) \< 60 mL/min/1.73 m\^2, clinically significant hepatic disease, or ALT/AST \> 2.5x upper limit of normal at screening.
- Active malignancy requiring treatment (except adequately treated non-melanoma skin cancer).
- Pregnant, breastfeeding, or planning pregnancy during the study period.
- Known hypersensitivity to peptide therapeutics or any component of the investigational product formulation.
- Any condition that, in the investigator's judgment, would interfere with study participation or interpretation of results (e.g., inability to comply with study procedures).