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.

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.

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).

MOTS-c and placebo are identical in appearance and packaging. Randomization codes are held by an unblinded pharmacist/interactive response system; participants, site staff, investigators, and outcome assessors remain blinded until database lock (except for emergency unblinding).