This study will evaluate safety, tolerability, pharmacokinetic (PK) profile, and pharmacodynamic (PD) effects on GSBR-1290 in healthy overweight/obese volunteers (HOV) and Type 2 Diabetes Mellitus on Metformin (T2DM) This study includes 5 planned cohorts. Participants will receive multiple-ascending doses of GSBR-1290 or Placebo from Day 1 to Day 84

Inclusion Criteria cohorts 1-4:

1. Provided evidence of a signed consent
2. Age ≥ 18 and ≤ 75 years
3. Healthy overweight/obese adult men and women with body mass index ≥ 27 and ≤ 40 kg/m2
4. No nicotine use
5. Have a suitable venous access for blood sampling

Inclusion Criteria cohort 5:

1. Men and women with T2DM of ≥6 months duration
2. Age ≥ 18 and ≤ 75 years
3. BMI ≥ 27 and ≤ 40 kg/m2
4. Treated with stable doses of ≥500 mg of metformin with a duration ≥6 months and at stable doses for ≥2 months with a screening HbA1c ≥7.0% and ≤10.5%.

Exclusion Criteria:

1. History or presence of significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic or neurological disease, including any acute illness or major surgery within the major 3 months
2. A sitting BP after resting for 5 minutes > 160mm Hg systolic or > 100 mm Hg diastolic or an apical pulse rate <50 or >100 beats per minute.
3. Evidence of abnormality on the screening visit ECG, or a history of known arrhythmia or prolonged QTcF pr prolonged QRS interval
4. Liver function test results elevated > 2.0-fold above the ULN for gamma glutamyl transferase, alkaline phosphatase, aspartate aminotransferase or alanine aminotransferase. Bilirubin above the ULN
5. Estimated glomerular filtration rate < 60mL/min/1.73 m2 body surface area
6. Known hypersensitivity to any of the study drug ingredients
7. Any other condition or prior therapy that would make the participant unsuitable for this study

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request

Data sharing requests will be considered beginning 36 months after the study publication (manuscript accepted for publication) and either 1) the product have been granted marketing authorization in at least two regulatory jurisdictions, or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.

Researchers will submit a request containing the research objectives, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). Structure Therapeutics does not grant external requests for individual de-identified patient data for the following purposes:

• re-evaluating safety and efficacy end points already addressed in the product labelling,
• assessing safety or efficacy for an indication in current development

Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a panel of external advisors. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement.

This is a double-blind study in which the GSBR-1290 and the matching placebo are matching in appearance