Visceral Adiposity and Diabetes: Translating Form to Function Using Imaging

January 22, 2020 updated by: Ian Neeland, University of Texas Southwestern Medical Center
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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

40

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Texas
      • Dallas, Texas, United States, 75390
        • University of Texas Southwestern Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

30 years to 65 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: PREVENTION
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: DOUBLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Empagliflozin
Empagliflozin 10 mg by mouth daily for 3 months.
Drug: [U-13C3] glycerol
Ingestion of [U-13C3] glycerol based on human's body weight such as (50 mg/kg body weight).
Other Names:
  • Glycerin
  • Glycerine
Drug: Empagliflozin
Active drug
Other Names:
  • EMPA
  • Jardiace
PLACEBO_COMPARATOR: Placebo
Placebo one tablet daily for 3 months
Drug: [U-13C3] glycerol
Ingestion of [U-13C3] glycerol based on human's body weight such as (50 mg/kg body weight).
Other Names:
  • Glycerin
  • Glycerine
Drug: Placebo (for Empagliflozin)
Placebo tablet manufactured to mimic EMPA 10 mg tablet.
Other Names:
  • Placebo
  • Sugar pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Glycerol Enrichment
Time Frame: 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.
3 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Texas Southwestern Medical Center

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

  • Principal Investigator: Ian Neeland, MD, UT Southwestern Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2016

Primary Completion (ACTUAL)

January 1, 2018

Study Completion (ACTUAL)

November 1, 2018

Study Registration Dates

First Submitted

July 5, 2016

First Submitted That Met QC Criteria

July 11, 2016

First Posted (ESTIMATE)

July 14, 2016

Study Record Updates

Last Update Posted (ACTUAL)

January 23, 2020

Last Update Submitted That Met QC Criteria

January 22, 2020

Last Verified

January 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • STU-012015-064
  • K23DK106520 (NIH)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

IPD sharing will be done upon reasonable request.

IPD Sharing Access Criteria

Email the PI with request.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • ANALYTIC_CODE

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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