Use of Empagliflozin to Treat Prediabetes

Oregon State University60 enrolled

Overview

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).

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

QUADRUPLE

Enrollment

Conditions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 59 Years

Medical Language ↔ Plain English

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)

Outcomes

Primary Outcomes

Insulin-stimulated glucose disposal

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

Time frame: Insulin-stimulated glucose disposal is measured before the start of the intervention (baseline) and during week 13 of the intervention.

Secondary Outcomes

Oral glucose tolerance

The change in blood glucose concentration in response to a 75g glucose beverage

Time frame: Oral glucose tolerance is measured before the start of the intervention (baseline) and during week 12 of the intervention.

Fasting plasma glucose concentration

The change in fasting plasma glucose concentration

Time frame: Fasting plasma glucose is measured before the start of the intervention (baseline) and during week 13 of the intervention.

Whole-body fat oxidation

Indirect calorimetry will be used to determine the change in whole-body rate of fat oxidation during basal and insulin-stimulated conditions

Time frame: Whole-body fat oxidation is measured before the start of the intervention (baseline) and during week 13 of the intervention.

Skeletal muscle insulin signaling

Immunoblotting to determine the change in activation of insulin signaling proteins in skeletal muscle collected at basal and during insulin-stimulated conditions

Time frame: Skeletal muscle insulin signaling is measured before the start of the intervention (baseline) and during week 13 of the intervention.

Skeletal muscle lipids

Mass spectrometry lipidomic analysis of skeletal muscle to determine changes in muscle lipid content

Time frame: Skeletal muscle lipids are measured before the start of the intervention (baseline) and during week 13 of the intervention.

Skeletal muscle mitochondrial respiratory function

Changes in skeletal muscle mitochondrial respiratory capacity measured using high-resolution respirometry

Time frame: Skeletal muscle mitochondrial respiratory function is measured before the start of the intervention (baseline) and during week 13 of the intervention.

Skeletal muscle energetic stress

Immunoblotting to determine changes in activation of AMPK and related signaling proteins pathways

Time frame: Skeletal muscle energetic stress is measured before the start of the intervention (baseline) and during week 13 of the intervention.