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%
• Provision of signed and dated informed consent form
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Male or (pre-menopausal) female, aged 25-55 years
• Body mass index (BMI) between 25 and 45 kg/m2
• Sedentary (1 day or less per week of structured exercise)
• Type 2 diabetes mellitus: HbA1c ≥7.5%
• Liver fat ≥5.6% based on MRI
• Weight stable (± 2 kg) for prior 3 months Inclusion criteria for lean, healthy controls
• Provision of signed and dated informed consent form
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Male or (pre-menopausal) female, aged 25-55 years
• Body mass index (BMI) between 18.5 and 27.5 kg/m2
• Normal liver fat (FibroScan CAP \<249dB/m, \<5.6% liver fat based on MRI)
• Weight stable (± 2 kg) for prior 3 months
• Active (≥3 day/week of structured exercise)

Exclusion criteria

• Any change in glucose-lowering medications within the previous three months.
• Inability to stop any medications which interfere with glucose metabolism for visits 4 and 7.
• Resting blood pressure ≥ 160/100 mm Hg
• Triglycerides ≥ 500 mg/dL
• 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
• Any significant disease or unstable medical condition (i.e., coronary heart disease, chronic renal failure, chronic hepatic disease, severe pulmonary disease)
• Presence of clinically significant abnormalities on electrocardiogram (ECG) that is a contra-indication to exercise testing
• Cancer (active malignancy with or without concurrent chemotherapy; except for basal cell carcinoma)
• Pregnancy during the previous 6 months, lactating, or planned pregnancy in the next 6 months
• Post- or peri-menopausal women
• Partial and/or full hysterectomy (self-report)
• Use of drugs known to affect energy metabolism or body weight: including, but not limited to orlistat, sibutramine, ephedrine, phenylpropanolamine, corticosterone, etc
• 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
• Current treatment with blood thinners or anti-platelet medications that cannot be safely stopped for testing procedures
• New onset (\<3 months on a stable regime) hormone replacement therapy
• Current use of beta-adrenergic blocking agents
• Major surgery on the abdomen, pelvis, or lower extremities within previous 3 months
• Previous bariatric or other surgery for obesity
• 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
• Current smokers (smoking within the past 3 months prior to screening visit, including any/all tobacco products)
• Current drug or alcohol abuse/dependence, or positive urine toxicology screen
• 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)
• Metal implants (pacemaker, aneurysm clips) based on investigator's judgment at screening
• Not physically capable of performing the exercise required of the study protocols
• 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.
• Unable to tolerate MRI or claustrophobia.
• Diagnosed psychotic or psychiatric conditions prohibiting adherence to study protocol; hospitalization for any psychotic or psychiatric condition within one year
• 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
• Unable or unwilling to communicate with staff or to provide written informed consent Exclusion criteria for lean, healthy controls
• Currently taking insulin, injectable incretin mimetics, and/or thiazolidinediones
• Taking glucose-lowering medications
• HbA1c ≥ 5.7%; pre-diabetes, type 2 diabetes, or type 1 diabetes
• Resting blood pressure ≥ 160/100 mm Hg
• Triglycerides ≥ 500 mg/dL
• 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
• Any significant disease or unstable medical condition (i.e., coronary heart disease, chronic renal failure, chronic hepatic disease, severe pulmonary disease)
• Presence of clinically significant abnormalities on electrocardiogram (ECG) that is a contra-indication to exercise testing
• Cancer (active malignancy with or without concurrent chemotherapy; except for basal cell carcinoma)
• Pregnancy during the previous 6 months, lactating, or planned pregnancy in the next year
• Post- or peri-menopausal women
• Partial and/or full hysterectomy (self-report)
• Use of drugs known to affect energy metabolism or body weight: including, but not limited to orlistat, sibutramine, ephedrine, phenylpropanolamine, corticosterone, etc
• 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
• Current treatment with blood thinners or anti-platelet medications that cannot be safely stopped for testing procedures
• New onset (\<3 months on a stable regime) hormone replacement therapy
• Current use of beta-adrenergic blocking agents
• Major surgery on the abdomen, pelvis, or lower extremities within previous 3 months
• Previous bariatric or other surgery for obesity
• Increased liver function tests (AST/ALT/GGT/or alkaline phosphatase greater than 2.5 times the upper limit of normal)
• 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
• Current smokers (smoking within the past 3 months prior to screening visit, including any/all tobacco products)
• Current drug or alcohol abuse/dependence, or positive urine toxicology screen
• 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)
• Metal implants (pacemaker, aneurysm clips) based on investigator's judgment at screening
• Not physically capable of performing the exercise required of the study protocols
• 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.
• Unable to tolerate MRI or claustrophobia.
• Diagnosed psychotic or psychiatric conditions prohibiting adherence to study protocol; hospitalization for any psychotic or psychiatric condition within one year
• 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
• Unable or unwilling to communicate with staff or to provide written informed consent