Overweight and Obesity, PreDiabetes, Prediabetic State
Conditions
Brief summary
The overall purpose of this study is to identify how empagliflozin (a drug commonly used to treat type 2 diabetes) impacts skeletal muscle metabolic health among adults with prediabetes. Our aims are to: 1) Test the ability of empagliflozin to improve regulation of glucose metabolism (i.e., blood sugar) among overweight and obese individuals at risk for diabetes, and 2) Identify mechanisms to explain how empagliflozin may improve skeletal muscle glucose metabolism. We hypothesize empagliflozin will improve regulation of glucose metabolism due to changes in whole-body and skeletal muscle metabolism (e.g., increased rates of whole-body fat oxidation, evidence of impaired skeletal muscle mitochondrial respiratory function and increased energetic stress, lower accumulation of skeletal muscle lipids and improved skeletal muscle insulin signaling compared with placebo treatment).
Detailed description
The overall study design is a 13-week, double-blind, placebo-controlled intervention trial, testing the ability of empagliflozin to improve glucose metabolism among overweight and obese individuals at risk for diabetes (compared with a multivitamin-placebo). The study involves metabolic testing before and during the intervention to identify changes in outcomes as a function of the intervention and to ensure participant safety. The study involves 9 visits to the Samaritan Athletic Medicine Center on the campus of Oregon State University in Corvallis, Oregon. Full completion of the study is anticipated to take \ 4 months. The project is being completed in collaboration with physicians at Samaritan Health Services.
Interventions
DRUGEmpagliflozin
Participants will take 10mg empagliflozin per day for 2 weeks. Absent contraindications, dosing will be increased to 25 mg empagliflozin per day for the next 11 weeks.
DRUGMultivitamin-Placebo
Participants will take 1 multivitamin per day for 13 weeks.
Sponsors
Oregon State University
Samaritan Health Services
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Pills will be prepared and dispensed by a pharmacy to blind participants and investigators.
Eligibility
Sex/Gender
ALL
Age
18 Years to 59 Years
Healthy volunteers
No
Inclusion criteria
* BMI 26-45 kg/m2 * Weight stable (± 10 lbs in previous 3 months) * Fasting blood glucose \<126 mg/dL or HbA1c \<6.5% (\<48mmol/mol)
Exclusion criteria
* Regular moderate-vigorous exercise (≥30 min/session on ≥2 days per week) * Pregnancy, planning to become pregnant or nursing * Lidocaine allergy * Current or recent smoking or nicotine use (≤ 1-year abstention) * Medications including glucose lowering medications and supplements (SGLT2 inhibitors, GLP1 agonists, sulfonylurea, insulin, TZDs); mono-amine oxidase inhibitors; beta-blockers; diuretics * Major metabolic or cardiovascular conditions (e.g., type 1 diabetes, Crohn's disease, untreated hypo- or hyperthyroid, cancer, coronary artery disease, tachycardia, prior bariatric surgery, peripheral vascular disease, liver diseases (e.g., cirrhosis) * Diagnosed type 2 diabetes. In absence of diagnosis, two separate samples with test results of fasting blood glucose ≥126 mg/dL or HbA1c ≥6.5% (48 mmol/mol). * Contraindications/precautions for empagliflozin (impaired renal function (EGR\<60), history of: empagliflozin hypersensitivity, ketoacidosis, hypotension, recurring urinary tract or genital mycotic infections, amputation)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin-stimulated glucose disposal | Insulin-stimulated glucose disposal is measured before the start of the intervention (baseline) and during week 13 of the intervention. | The glucose infusion rate to maintain glycemia during insulin clamp, using plasma enrichment of glucose isotope tracer to determine changes in rates of insulin-stimulated glucose disposal |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Oral glucose tolerance | Oral glucose tolerance is measured before the start of the intervention (baseline) and during week 12 of the intervention. | The change in blood glucose concentration in response to a 75g glucose beverage |
| Fasting plasma glucose concentration | Fasting plasma glucose is measured before the start of the intervention (baseline) and during week 13 of the intervention. | The change in fasting plasma glucose concentration |
| Whole-body fat oxidation | Whole-body fat oxidation is measured before the start of the intervention (baseline) and during week 13 of the intervention. | Indirect calorimetry will be used to determine the change in whole-body rate of fat oxidation during basal and insulin-stimulated conditions |
| Skeletal muscle insulin signaling | Skeletal muscle insulin signaling is measured before the start of the intervention (baseline) and during week 13 of the intervention. | Immunoblotting to determine the change in activation of insulin signaling proteins in skeletal muscle collected at basal and during insulin-stimulated conditions |
| Skeletal muscle lipids | Skeletal muscle lipids are measured before the start of the intervention (baseline) and during week 13 of the intervention. | Mass spectrometry lipidomic analysis of skeletal muscle to determine changes in muscle lipid content |
| Skeletal muscle mitochondrial respiratory function | Skeletal muscle mitochondrial respiratory function is measured before the start of the intervention (baseline) and during week 13 of the intervention. | Changes in skeletal muscle mitochondrial respiratory capacity measured using high-resolution respirometry |
| Skeletal muscle energetic stress | Skeletal muscle energetic stress is measured before the start of the intervention (baseline) and during week 13 of the intervention. | Immunoblotting to determine changes in activation of AMPK and related signaling proteins pathways |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORSean A Newsom, Ph.D.
Oregon State University
Outcome results
None listed