Imaging in Semaglutide Study

Type 2 diabetes (T2D),characterized by insulin resistance and abnormal metabolic functions, is the most prevalent metabolic syndrome disease (1). Excess weight gain is the number one risk factor for development of T2D, in which 85% of individuals with T2D are either overweight or obese (2). While weight management through diet and exercise is foundational for treatment, genetic and environmental factors pose challenges (3). Recently, once-weekly subcutaneous semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), and tirzepatide, a gastric inhibitory peptide/glucagon-like peptide-1 dual receptor agonist (GIP/GLP-1RA), were approved for the treatment of T2D as well as obesity (4, 5). They have displayed significant efficacy in improving glycemic control and weight reduction in both individuals with overweight or obesity with or without T2D (6). However, the significant weight loss associated with these medications is not only related to reduction in body fat mass, but also loss of body lean mass, as observed in previous clinical studies (7). Indeed, this raises concern in older individuals for the development of sarcopenic obesity, a medical condition defined by the presence of both sarcopenia (loss of muscle) and obesity, a condition associated with poor morbidity and mortality (7, 8). However, it remains unclear whether the substantial reduction in body fat and lean mass is directly associated with changes in skeletal muscle volume, strength, quality and metabolic function. This proposal aims to address this gap by evaluating the longitudinal effect of semaglutide treatment on skeletal muscle metabolic function in individuals with T2D and obesity. The study will evaluate skeletal muscle strength of the patients of T2D and obesity undergoing semaglutide therapy and leverage MRI and phosphorus-31 magnetic resonance spectroscopy (31P-MRS) to assess changes in skeletal muscle volume, quality and metabolic functions pertaining to muscle mitochondria.

Inclusion criteria

• Gender: men and women
• Ethnicity: all ethnic groups
• Age between 45 and 75 years
• BMI ≥ 30 kg/m2 and BMI < 45 kg/m2
• Diagnosis of Type 2 Diabetes (T2D) with HbA1c levels between 7% and 10.5%.
• Starting subcutaneous semaglutide for clinically indicated T2D management.
• Ability and willingness to participate in the study for its full duration.
• Provision of informed consent for participation in research.

Exclusion criteria

• Previous intolerance or allergy to any semaglutide-based therapy.
• History of prior intolerance to any GLP-1RA or GIP/GLP-1RA.
• Unwillingness or uncertainty to commit to the duration of the study.
• Contraindication to MRI (e.g. claustrophobia, implanted devices including cardiac pacemaker and cardioverter-defibrillators), circumference of largest calf > 17inch/43cm (max size to fit into the MR coil).
• History of myocardial infarction or coronary revascularization (percutaneous intervention or coronary artery bypass) within 30 days prior to screening.
• History of hospitalization for heart failure within the past 30 days, or NYHA class IV
• Current use of glucocorticoid therapy (≥5 mg prednisone or equivalent).
• Self-reported weight loss > 10 lbs in the 90 days prior to screening.
• Use of other mediation, on or off-label, for the primary intent of weight loss within 90 days prior to screening.
• Secondary etiologies for sarcopenia (e.g., gastrointestinal malabsorption, myopathies, severe neurological conditions).
• Glomerular Filtration Rate (eGFR) within the past 120 days is not available.
• Mental incapacity or language barriers preventing informed consent and compliance.
• Pregnancy, plans for pregnancy in the next 12 months, or lactating/nursing females.
• History of bariatric or metabolic surgery or related procedures.
• Prior participation in the Endocrinology and Metabolism Institute's Integrated Weight Management Program within the past 3 months.
• Active smoking.
• Excessive alcohol consumption, defined as ≥3 drinks per day.
• Uncontrolled lung disease (e.g., severe asthma or COPD).
• Uncontrolled thyroid disease.
• Personal commitments that may limit optimal participation (e.g., work, travel, caregiving responsibilities).
• History of malabsorptive disorders, such as celiac disease or Crohn's disease.
• Cholestatic liver disease or inadequate hepatic function (AST/ALT > 3.0 x ULN).
• Liver cirrhosis.
• Conductive implanted devices (e.g., cardiac pacemaker, cardioverter-defibrillators).
• Major surgical procedures or significant traumatic injury within 30 days prior to the enrollment date.
• Any medical or surgical condition that, in the opinion of the principal investigator, may make the participant unfit for the trial (e.g., psychiatric disorders, malignancy).
• Any condition, unwillingness, or inability, not otherwise covered by exclusion criteria, which might jeopardize the subject's safety or compliance with the protocol.
• Presence of metal in the eye