Each subject will participate in the following visits:~Visit v1 (screening) - for each patient, fasting venous blood will be collected and an oral glucose tolerance test (OGTT) will be performed - with blood samples taken 30, 60, 90 and 120 minutes after drinking the glucose solution. Fasting blood samples will be used to measure basic metabolic parameters (including glucose, lipid profile, HbA1c, AST, ALT, GGTP, electrolytes, blood count, the presence of antibodies against beta-cell antigens, TSH), and from blood collected at each time point during the OGTT glucose and insulin concentrations will be measured. Each patient will also undergo a detailed body composition analysis using bioimpedance and DXA. In addition, during the visit, each participant will receive a continuous glucose monitoring system (CGM) and an accelerometer to measure physical activity for a period of 10-14 days.~Visit v2 (1-3 days after v1)- during the visit, each patient will undergo a mixed meal tolerance test (MMTT) along with a non-invasive measurement of resting energy expenditure (RMR). After the end of the test, the patient will receive semaglutide in two marked doses: 3 mg and 7 mg, along with instructions on how to take them and a diary in which the drug intake and occurrence of side effects will be recorded. During the visit, an elastography examination of the liver will also be performed for the non-invasive assessment of fatty liver and fibrosis.~Visit v3 - four weeks after starting the semaglutide treatment. During the visit, fasting venous blood will be collected to measure basic metabolic parameters. Each patient will undergo a detailed body composition analysis using bioimpedance and DXA. During the visit, patients will receive semaglutide in the dose of 14 mg, along with instructions on how to take them and a diary in which the drug intake and occurrence of side effects will be recorded.~Visit v4 - after eight weeks of treatment with 14 mg of semaglutide. Similar to visit 1 (OGTT).~Visit v5 - after eight weeks of treatment with 14 mg of semaglutide. Similar to visit 2 (MMTT).~Additionally, a random 20% of the study group will participate in additional visits:~Visit A.1 (between visits v1 and v2) and A.2 (+ 1-5 days from visit v5) - during the visit, biological material will be collected for each patient in the form of a biopsy of the vastus lateralis muscle and subcutaneous adipose tissue.~Visit B.1 (between visits v1 and v2) and B.2 (+ 1-5 days from visit v5) - during the visit, patients will undergo an abdominal MRI scan to assess the steatosis of the liver, muscle and pancreas.~Visit v6 (follow-up visit) - after twelve weeks of ending the semaglutide treatment. Similar to visit 1 (OGTT).
The study aims to investigate the genetic basis of the response to short-term (3 months) orally administered semaglutide treatment, in terms of improving metabolic parameters, including the hormonal response to a standardized meal, and changes in body composition and liver steatosis. In the study, parameters such as fasting and 2-hour glucose during OGTT, HbA1c, body fat mass, body weight, total cholesterol, HDL and LDL, triglycerides, HOMA-IR, Matsuda Index and liver steatosis will be assessed. All the patients will undergo genome-wide genotyping. Moreover, in a subset of participants, muscle and fat biopsies will be performed, before and after the treatment, and liver, muscle and pancreas fat content will be assessed using MRI.