The purpose of this study is to find new signs or signals in muscle cells that can help us understand when the body isn't responding well to insulin (a condition called insulin resistance).

The primary goal of this research is to look at gene expression changes to insulin stimulation in different cells and areas of skeletal muscle and how they are affected by obesity and insulin resistance. The investigators are studying sedentary men and women between the ages of 30 and 65 years with; either a body mass index (BMI) between 18-25 kg/m2 or 30-40 kg/m2

Inclusion Criteria:

• All Groups

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

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

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

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

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

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

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

Exclusion Criteria:

1. Clinically significant CVD including h/o MI, within the past year

2. Peripheral Vascular Disease

3. Diagnosed with Type I or Type II diabetes

4. Hepatic, renal, muscular/neuromuscular, or active hematologic/oncologic disease

5. Previous history of pulmonary emboli

6. Peripheral Neuropathy

7. Anemia (Hematocrit <34%, Hemoglobin < 14 gm/dL for men and <12.3 gm/dL for women) at screening

8. 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

9. Polycystic Ovarian Syndrome (PCOS) (self-report)

10. 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

11. Partial and/or full hysterectomy (self-report)

12. Not willing to archive biospecimens for future use

13. Any contraindications to exercise testing according to ACSM guidelines

14. Inability and/ or unwillingness to comply with the protocol as written

15. Active alcohol or substance abuse (Past 5 Years)

16. Positive toxicology result from screening visit or chronic use of Amphetamine, Barbiturate, Benzodiazepine, Cocaine, Methadone, Opiate, THC, Cannabis, Tricyclics, or Oxycodone.

17. Dyslipidemia (fasting triglycerides >500 mg/dL; low-density lipoprotein cholesterol (LDL-C) >190 mg/dL; total cholesterol >300 mg/dL);

18. 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

19. Proteinuria (defined as > 1+) at screening

20. Kidney disease (creatinine >1.6 mg/dl or estimated glomerular filtration rate <60 mL/min/1.73m2);

21. 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.

22. Receiving active treatment (including monoclonal antibodies) for autoimmune disorders within the last 6 months;

23. Hypothyroidism (sTSH>8) at screening or on thyroid replacement therapy

24. Abnormal bleeding or coagulopathy (self-report) or history of a bleeding disorder or clotting abnormality

25. 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;

26. Previous bariatric or other surgery for obesity

27. Females currently on hormone replacement therapy (HRT) less than 6 months

28. Females with an irregular menstrual cycle

29. Previous difficulty with lidocaine or other local anesthetic

30. 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.

31. 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.

32. 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.

The investigators are studying sedentary men and women between the ages of 30 and 65 years with; either a body mass index (BMI) between 18-25 kg/m2 or 30-40 kg/m2.