Acute Exercise and Endogenous Glucose Production in Type 2 Diabetes: Implications for Glycemic Control and Treatment of Hepatic Steatosis

Inclusion criteria for individuals with T2D and elevated liver fat ≥5.6% 1. Provision of signed and dated informed consent form 2. Stated willingness to comply with all study procedures and availability for the duration of the study 3. Male or (pre-menopausal) female, aged 25-55 years 4. Body mass index (BMI) between 25 and 45 kg/m2 5. Sedentary (1 day or less per week of structured exercise) 6. Type 2 diabetes mellitus: HbA1c ≥7.5% 7. Liver fat ≥5.6% based on MRI 8. Weight stable (± 2 kg) for prior 3 months Inclusion criteria for lean, healthy controls 1. Provision of signed and dated informed consent form 2. Stated willingness to comply with all study procedures and availability for the duration of the study 3. Male or (pre-menopausal) female, aged 25-55 years 4. Body mass index (BMI) between 18.5 and 27.5 kg/m2 5. Normal liver fat (FibroScan CAP \<249dB/m, \<5.6% liver fat based on MRI) 6. Weight stable (± 2 kg) for prior 3 months 7. Active (≥3 day/week of structured exercise) Exclusion Criteria 1. Exclusion criteria for individuals with T2D and elevated liver fat ≥5.6% Currently taking insulin, incretin mimetics, and/or thiazolidinediones 2. Any change in glucose-lowering medications within the previous three months. 3. Inability to stop any medications which interfere with glucose metabolism for visits 4 and 7. 4. Resting blood pressure ≥ 160/100 mm Hg 5. Triglycerides ≥ 500 mg/dL 6. Any renal, cardiac, liver, lung, or neurological disease that in the opinion of the principal investigator would compromise participant safety or the participants' ability to complete the exercise protocol 7. Any significant disease or unstable medical condition (i.e., coronary heart disease, chronic renal failure, chronic hepatic disease, severe pulmonary disease) 8. Presence of clinically significant abnormalities on electrocardiogram (ECG) that is a contra-indication to exercise testing 9. Cancer (active malignancy with or without concurrent chemotherapy; except for basal cell carcinoma) 10. Pregnancy during the previous 6 months, lactating, or planned pregnancy in the next 6 months 11. Post- or peri-menopausal women 12. Partial and/or full hysterectomy (self-report) 13. Use of drugs known to affect energy metabolism or body weight: including, but not limited to orlistat, sibutramine, ephedrine, phenylpropanolamine, corticosterone, etc 14. Hyperthyroidism including those with normal TSH (0.35-4.5) on pharmacological treatment; individuals with hypothyroidism may be referred to their primary care provider for evaluation and retested; any medication change for hypothyroidism must be stable for ≥3 months prior to retesting 15. Current treatment with blood thinners or anti-platelet medications that cannot be safely stopped for testing procedures 16. New onset (\<3 months on a stable regime) hormone replacement therapy 17. Current use of beta-adrenergic blocking agents 18. Major surgery on the abdomen, pelvis, or lower extremities within previous 3 months 19. Previous bariatric or other surgery for obesity 20. Abnormal blood count/anemia (hemoglobin \<12 g/dl in men or 11 g/dl in women; Hct \<34%), blood transfusion or blood donation within the last 2 months 21. Current smokers (smoking within the past 3 months prior to screening visit, including any/all tobacco products) 22. Current drug or alcohol abuse/dependence, or positive urine toxicology screen 23. Alcohol consumption \>7 drinks per week for women or 14 drinks per week for men or history of binge drinking (≥5 drinks for males or 4 drinks for females in a 2-hour period more than once per month) 24. Metal implants (pacemaker, aneurysm clips) based on investigator's judgment at screening 25. Not physically capable of performing the exercise required of the study protocols 26. Unable to participate in Magnetic Resonance Imaging (MRI) assessments due to physical limitations of equipment tolerances (e.g. MRI bore size) based on investigator's judgment at screening. 27. Unable to tolerate MRI or claustrophobia. 28. Diagnosed psychotic or psychiatric conditions prohibiting adherence to study protocol; hospitalization for any psychotic or psychiatric condition within one year 29. 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 30. Unable or unwilling to communicate with staff or to provide written informed consent Exclusion criteria for lean, healthy controls 1. Currently taking insulin, injectable incretin mimetics, and/or thiazolidinediones 2. Taking glucose-lowering medications 3. HbA1c ≥ 5.7%; pre-diabetes, type 2 diabetes, or type 1 diabetes 4. Resting blood pressure ≥ 160/100 mm Hg 5. Triglycerides ≥ 500 mg/dL 6. Any renal, cardiac, liver, lung, or neurological disease that in the opinion of the principal investigator would compromise participant safety or the participants' ability to complete the exercise protocol 7. Any significant disease or unstable medical condition (i.e., coronary heart disease, chronic renal failure, chronic hepatic disease, severe pulmonary disease) 8. Presence of clinically significant abnormalities on electrocardiogram (ECG) that is a contra-indication to exercise testing 9. Cancer (active malignancy with or without concurrent chemotherapy; except for basal cell carcinoma) 10. Pregnancy during the previous 6 months, lactating, or planned pregnancy in the next year 11. Post- or peri-menopausal women 12. Partial and/or full hysterectomy (self-report) 13. Use of drugs known to affect energy metabolism or body weight: including, but not limited to orlistat, sibutramine, ephedrine, phenylpropanolamine, corticosterone, etc 14. Hyperthyroidism including those with normal TSH (0.35-4.5) on pharmacological treatment; individuals with hypothyroidism may be referred to their primary care provider for evaluation and retested; any medication change for hypothyroidism must be stable for ≥3 months prior to retesting 15. Current treatment with blood thinners or anti-platelet medications that cannot be safely stopped for testing procedures 16. New onset (\<3 months on a stable regime) hormone replacement therapy 17. Current use of beta-adrenergic blocking agents 18. Major surgery on the abdomen, pelvis, or lower extremities within previous 3 months 19. Previous bariatric or other surgery for obesity 20. Increased liver function tests (AST/ALT/GGT/or alkaline phosphatase greater than 2.5 times the upper limit of normal) 21. Abnormal blood count/anemia (hemoglobin \<12 g/dl in men or 11 g/dl in women; Hct \<34%), blood transfusion or blood donation within the last 2 months 22. Current smokers (smoking within the past 3 months prior to screening visit, including any/all tobacco products) 23. Current drug or alcohol abuse/dependence, or positive urine toxicology screen 24. Alcohol consumption \>7 drinks per week for women or 14 drinks per week for men or history of binge drinking (≥5 drinks for males or 4 drinks for females in a 2-hour period more than once per month) 25. Metal implants (pacemaker, aneurysm clips) based on investigator's judgment at screening 26. Not physically capable of performing the exercise required of the study protocols 27. Unable to participate in Magnetic Resonance Imaging (MRI) assessments due to physical limitations of equipment tolerances (e.g. MRI bore size) based on investigator's judgment at screening. 28. Unable to tolerate MRI or claustrophobia. 29. Diagnosed psychotic or psychiatric conditions prohibiting adherence to study protocol; hospitalization for any psychotic or psychiatric condition within one year 30. 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 31. Unable or unwilling to communicate with staff or to provide written informed consent