The purpose of this study is to establish the proof of concept for a brain serotonin pathway controlling blood glucose control in humans. We will examine whether activation of serotonin receptors by a single dose of sumatriptan (a drug used for the treatment of migraine) can lead to short term changes in blood glucose homeostasis. Thus far, this has been shown only in animal models but no study in humans has directly investigated this research question.

Briefly, in this study we will give a single dose of sumatriptan (100 mg) to each participant in a small sample (10 to 12) of overweight or obese, otherwise healthy humans. It will take place in the Translational Research Facility which is embedded in the Cambridge University Hospitals NHS Foundation Trust. The research staff have extensive experience and expertise in the procedures which will be used. The study will involve a screening visit and 2 subsequent visits at which sumatriptan/placebo will be taken and the glucose metabolism will be assessed using a Botnia clamp (3h procedure involving insulin and glucose infusions given intravenously with frequent blood sampling to assess insulin secretion and sensitivity). There will be about 60 days between screening visit and the last visit. The entire study (including the recruitment and data analysis) is expected to complete in about 12 months.

If sumatriptan alters glucose control, this might support future testing in disease models i.e. people with type 1 diabetes (T1D) and/or type 2 diabetes (T2D). Ultimately, if successful, either sumatriptan could be repurposed and/or other drugs from this group (triptans) could be developed for diabetes.

Inclusion Criteria:

1. Being able to provide a written informed consent
2. Age between 18 and 65 years
3. Body Mass Index (BMI) ≥25 kg/m2 and <30 kg/m2 for non-Asian individuals and BMI≥23 kg/m2 and <25 kg/m2 for Asian individuals according to the BMI classification by the World Health Organization (WHO)
4. HbA1C<48 mmol/mol at screening
5. Subject must not use any regular prescribed medications (this excludes simple analgesia used as needed)
6. Subject must not use any over the counter supplements targeting metabolism
7. Subject must not have any acute or chronic disease which in the opinion of the investigator may affect the study outcome
8. Subject must not be a current smoker
9. No history of substance abuse or excess alcohol consumption (>14 units/week)
10. Women of childbearing age must have a negative pregnancy test at screening and must not be breastfeeding
11. Women of childbearing age who are sexually active with a male partner must use highly effective contraceptive methods

Exclusion Criteria:

1. Use of any regular medications
2. Use of illicit drugs
3. Use of any over the counter supplements affecting metabolism
4. Diagnosis of any acute / chronic disease
5. Current smoking or excess alcohol consumption (>14 units/week)
6. Current pregnancy or lactation
7. Abnormal findings on physical exam or routine blood tests at screening (full blood count, urea and electrolytes, HbA1C, liver function tests)
8. Concurrent participation in another trial with an investigational product
9. History of anaphylaxis