Obesity, Visceral
Conditions
Keywords
Visceral, Obesity, Adipose, Diabetes
Brief summary
This study is a clinical study to investigate the gluconeogenesis pathway related to visceral adipose tissue (VAT) in obese individuals without type 2 diabetes and the effects of empagliflozin (EMPA) on glucose homeostasis in viscerally-obese individuals using functional studies of glycerol metabolism in hepatic gluconeogenesis using a well-validated nuclear magnetic resonance (NMR) spectroscopy platform.
Detailed description
Diabetes mellitus type II is the consequence of insulin resistance and pancreatic beta cell failure resulting from a variety of metabolic insults, one of which is excess body adiposity/obesity. In the diabetic individual, hepatic gluconeogenesis may go uninhibited due to failure of the body's normal feedback mechanisms to appropriately incorporate glucose into cells via insulin signaling, leading to excess gluconeogenesis and hyperglycemia. The substrate for this excess glucose derives from multiple sources in the liver including dietary glycerol, adipose-derived glycerol from lipolysis, and substrates from the citric acid cycle. In the normal state, lipolysis is maintained at a steady state in equilibrium between stored dietary triglycerides and free fatty acids. However, in situations of triglyceride excess (e.g. in the obese state), lipolysis may become overactive resulting in increased free fatty acids and adipose-derived glycerol. This excess glycerol drives hepatic gluconeogenesis and is incorporated into glucose and released into the blood, leading to hyperglycemia, and ultimately diabetes and its clinical sequelae. A popular hypothesis linking visceral fat with excess gluconeogenesis is delivery of glycerol arising from mesenteric triglyceride turnover directly into the portal circulation and to the liver. Glycerol is a primary substrate for gluconeogenesis in the liver. Under normal conditions, hepatic gluconeogenesis begins from glycerol ingested in the diet which is converted to glycerol-3-phosphate and subsequently dihydroxyacetone phosphate (DHAP) in the liver. DHAP is converted to fructose-1,6-bisphosphate which undergoes a series of reactions to become a single 6-carbon glucose molecule. Adipocytes contribute glycerol to hepatic gluconeogenesis through lipolysis of triglyceride stores. Although glycerol-gluconeogenesis has been extensively studied in animals, the traditional reliance on radioactive tracers makes translation to humans difficult for many reasons. We aim to use new techniques to explore the mechanisms behind altered glucose metabolism related to excess visceral adiposity in obese adults by quantifying the relative contributions of varying substrates to liver-derived glucose. One such method uses 13C3 labeled glycerol to trace the incorporation of glycerol from dietary sources to hepatic gluconeogenesis. This technology utilizes nuclear magnetic resonance (NMR) spectroscopy, a technique that does not require ionizing radiation and has been extensively validated, to analyze the NMR spectra of plasma glucose and quantify the percent enrichment of the circulating glucose molecules with labeled glycerol. In turn, differences in enrichment reflect variability in hepatic glucose metabolism as it relates to the contribution of glycerol from visceral adipose tissue to gluconeogenesis. The rationale of this project is to utilize existing technology to investigate the impact of excess visceral adiposity on glycerol metabolism in hepatic gluconeogenesis in obese adults without diabetes and to explore the effects of treatment with EMPA on visceral adiposity related glucose homeostasis.
Interventions
DRUG[U-13C3] glycerol
Ingestion of \[U-13C3\] glycerol based on human's body weight such as (50 mg/kg body weight).
DRUGEmpagliflozin
Active drug
DRUGPlacebo (for Empagliflozin)
Placebo tablet manufactured to mimic EMPA 10 mg tablet.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Texas Southwestern Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
30 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Obese, defined as BMI ≥ 30 kg/m2, at both time of abdominal fat imaging and at study entry. * Ages 30-65 * No prevalent diagnosis of type 2 diabetes mellitus, either at the time of abdominal fat imaging or at study entry. * Previous abdominal fat quantification by magnetic resonance imaging in the Dallas Heart Study or possible neck-to-knee MRI for VAT measurement may be performed.
Exclusion criteria
* Pregnant or breastfeeding * Incarcerated * Chronic kidney or liver disease * History of frequent (\>2/year) urinary tract infections * Non-obese either at time of abdominal fat imaging or at present. * Greater than 10% change in body weight (kg) between time of abdominal fat imaging and present. * Has donated blood within last 6 weeks * Cannot give informed consent, understand the protocol, or tolerate any aspect of the protocol * If undergoing MRI, persons with metal implants contraindicated for 3Tesla MRI exams will be excluded. Severe claustrophobia will also be assessed prior to an MRI exam.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glycerol Enrichment | 3 months | \[U-13C3\] glycerol enrichment in plasma blood glucose over time will be measured by nuclear magnetic resonance spectroscopy. This is a percentage change from baseline to follow up in the percent enrichment of exogenous glycerol in blood glucose. We are unable to report a measure of central tendency and dispersion as the outcome is a percent change in the area under the enrichment curve for each group between baseline and follow-up. There is no measure of central tendency for these measurements without bootstrapping, which was not performed. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Empagliflozin Empagliflozin 10 mg by mouth daily for 3 months.
\[U-13C3\] glycerol: Ingestion of \[U-13C3\] glycerol based on human's body weight such as (50 mg/kg body weight).
Empagliflozin: Active drug | 18 |
| Placebo Placebo one tablet daily for 3 months
\[U-13C3\] glycerol: Ingestion of \[U-13C3\] glycerol based on human's body weight such as (50 mg/kg body weight).
Placebo (for Empagliflozin): Placebo tablet manufactured to mimic EMPA 10 mg tablet. | 17 |
| Total | 35 |
Baseline characteristics
| Characteristic | Empagliflozin | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 50.5 years | 53 years | 54 years |
| Body Mass Index | 36.8 kg/m^2 | 35.5 kg/m^2 | 35.3 kg/m^2 |
| Hemoglobin A1C | 5.6 percent of glycosylated hemoglobin | 5.8 percent of glycosylated hemoglobin | 5.9 percent of glycosylated hemoglobin |
| Race/Ethnicity, Customized African-American | 5 participants | 12 participants | 7 participants |
| Sex: Female, Male Female | 11 Participants | 22 Participants | 11 Participants |
| Sex: Female, Male Male | 7 Participants | 13 Participants | 6 Participants |
| Systolic Blood Pressure | 126 mmHg | 130 mmHg | 132 mmHg |
| Visceral Fat | 5.4 kg | 5.4 kg | 4.3 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 1 / 20 | 0 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
Primary
Change in Glycerol Enrichment
\[U-13C3\] glycerol enrichment in plasma blood glucose over time will be measured by nuclear magnetic resonance spectroscopy. This is a percentage change from baseline to follow up in the percent enrichment of exogenous glycerol in blood glucose. We are unable to report a measure of central tendency and dispersion as the outcome is a percent change in the area under the enrichment curve for each group between baseline and follow-up. There is no measure of central tendency for these measurements without bootstrapping, which was not performed.
Time frame: 3 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Empagliflozin | Change in Glycerol Enrichment | 6.5 Percentage change |
| Placebo | Change in Glycerol Enrichment | 1.4 Percentage change |
Comparison: Baseline to Followupp-value: 0.0053Mixed Models Analysis
Comparison: Baseline to Followupp-value: 0.5394Mixed Models Analysis