Determining Cell- and Spatially-distinct Skeletal Muscle Transcriptional Aberrations in Insulin Resistance

Inclusion Criteria

• All Groups

• 30 to 65 years of age
• Stable weight (No Gain/Loss of >10 lbs in 6 months)
• Sedentary (≤ 1 continuous exercise/week)
• Non-smoker
• Resting Blood Pressure ≤ 150mmHg systolic and ≤ 95 mmHg diastolic

Group A - Lean individuals with insulin sensitivity (IS-Lean)

• BMI 18-25 kg/m2
• Hemoglobin A1c ≤ 5.6% at screening
• Blood glucose level ≤ 140 mg/dL 2hr after a 75g oral glucose tolerance test

Group B - Individuals with obesity and insulin sensitivity (IS-Obesity)

• BMI 30-40 kg/m2
• Hemoglobin A1c ≤ 5.6% at screening
• Blood glucose level ≤ 140 mg/dL 2hr after a 75g oral glucose tolerance test

Group C - Individuals with obesity and insulin resistance (IR-Obesity)

• BMI 30-40 kg/m2
• Hemoglobin A1c ≤ 6.4 % at screening
• Blood glucose level 140-199 mg/dL 2hr after a 75g oral glucose tolerance test

Exclusion Criteria

• Clinically significant CVD including h/o MI, within the past year
• Peripheral Vascular Disease
• Diagnosed with Type I or Type II diabetes
• Hepatic, renal, muscular/neuromuscular, or active hematologic/oncologic disease
• Previous history of pulmonary emboli
• Peripheral Neuropathy
• Anemia (Hematocrit \<34%, Hemoglobin \< 14 gm/dL for men and \<12.3 gm/dL for women) at screening
• Currently pregnant (pregnancy test performed on day of DEXA scan in women of child-bearing potential); post-partum during the last 12 months; lactating during the last 12 months; planning to become pregnant during the participation period
• Polycystic Ovarian Syndrome (PCOS) (self-report)
• Hospitalization for COVID-19 infection in the past 12 months; individuals who tested positive for COVID-19 but were not hospitalized must be symptom-free at least 14 days
• Partial and/or full hysterectomy (self-report)
• Not willing to archive biospecimens for future use
• Any contraindications to exercise testing according to ACSM guidelines
• Inability and/ or unwillingness to comply with the protocol as written
• Active alcohol or substance abuse (Past 5 Years)
• Positive toxicology result from screening visit or chronic use of Amphetamine, Barbiturate, Benzodiazepine, Cocaine, Methadone, Opiate, THC, Cannabis, Tricyclics, or Oxycodone.
• Dyslipidemia (fasting triglycerides >500 mg/dL; low-density lipoprotein cholesterol (LDL-C) >190 mg/dL; total cholesterol >300 mg/dL);
• ALT >80, AST>80, Alk Phos >240 if a participant presents with liver functions out of these ranges at screening the MI or PI can give discretion to participate
• Proteinuria (defined as > 1+) at screening
• Kidney disease (creatinine >1.6 mg/dl or estimated glomerular filtration rate \<60 mL/min/1.73m2);
• Self-reported chronic, active, or latent infection requiring chronic antibiotic or anti-viral treatment; Human Immunodeficiency Virus (HIV); active hepatitis B or C undergoing antiviral therapy.
• Receiving active treatment (including monoclonal antibodies) for autoimmune disorders within the last 6 months;
• Hypothyroidism (sTSH>8) at screening or on thyroid replacement therapy
• Abnormal bleeding or coagulopathy (self-report) or history of a bleeding disorder or clotting abnormality
• History of cancer (other than non-melanoma skin cancer) within the last 5 years (not in remission); anti-hormonal therapy (e.g., for breast or prostate cancer) within the last 6 months;
• Previous bariatric or other surgery for obesity
• Females currently on hormone replacement therapy (HRT) less than 6 months
• Females with an irregular menstrual cycle
• Previous difficulty with lidocaine or other local anesthetic
• ACS symptoms:

• Positive ECG (> 2mm ST segment depression) without PCP cardiologist permission to participate
• Signs or symptoms of cardiovascular decomposition (eg. hypotensive response to exercise)
• Onset of angina or angina like symptoms, shortness of breath, change in heart rhythm, signs of poor perfusion (light-headedness), tightness.
• The following medication use is exclusionary;

• Dose change for any chronic-use drug in the last 3 months;
• Any medications that can alter glucose homeostasis (eg. steroids, glucocorticoids, nicotinic acid). Acute therapy (5-7 days) is not exclusionary however; participant must be agreeable to a washout period of 5-7 days prior to day of biopsy.
• Blood thinners such as Coumadin, Lovenox etc. Aspirin is not exclusionary however; participant must be agreeable to a washout period of > 10 days prior to day of biopsy
• All Weight loss medications including but not limited toGLP-1 agonists- Wegovy, liraglutide, semaglutide, Trulicity (dulaglutide), Phentermine and Contrave
• Cardiovascular: beta blockers and centrally acting anti-hypertensive drugs, anticoagulants, antiarrhythmics, and antiplatelet drugs (other than aspirin ≤100 mg/day);
• Psychiatric: chronic use of medium- or long-acting sedatives and hypnotics, including all benzodiazepines (short-acting non-benzodiazepine sedative-hypnotics are allowed), mood stabilizers, antiepileptic drugs, stimulants, Attention-Deficit/Hyperactivity Disorder (ADHD) drugs, anti-psychotic drugs, anti-depressant medication (e.g. Bupropion, selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine re-uptake inhibitors (SNRIs)).
• Pulmonary/Inflammation: chronic oral steroids (occasional use of inhaled steroids are allowed), burst/taper oral steroids more than once in the last 12 months, B2-agonists (allowed if on stable dose at least 3 months).
• Genitourinary: 5-alpha reductase inhibitors, daily use of phosphodiesterase type 5 inhibitor.
• Hormonal: androgenic anabolic steroids, anti-estrogens, anti-androgens, estrogens and/or progestins used for reasons other than birth control, growth hormone, insulin like growth factor-I, growth hormone releasing hormone,
• any drugs used to treat diabetes mellitus or lower blood glucose including metformin, thiazolidinediones, SGLT-2 inhibits or insulin
• any drugs used specifically to induce muscle growth/hypertrophy or augment exercise-induced muscle hypertrophy
• Pain/Inflammation: narcotics and narcotic receptor agonists, regular use of non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen, muscle relaxants ≥2 days per week
• Other: chronic systemic antimicrobials (antibiotic, antiviral, antifungal, antiparasite, etc.) for any reason, high-potency topical steroids if ≥10% surface area using rule of 9s, continuous/chronic use of antibiotics or other anti-infectives for treatment or prevention, monoclonal antibodies, anti-rejection medications/immune suppressants. Participants can be re-screened after a 3 month washout period if antimicrobial use is only used acutely \< 2 weeks.
• Presence of any condition that, in the opinion of the Investigator, compromises participant safety or data integrity or the participant's ability to complete the study.