Obesity, VisceralPhase 4NCT02833415
Visceral Adiposity and Diabetes: Translating Form to Function Using Imaging
A Phase 4 study testing [U-13C3] glycerol and Empagliflozin in people with Obesity, Visceral, run by University of Texas Southwestern Medical Center at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 30 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Obesity, Visceral
- What is being tested?
- [U-13C3] glycerol and Empagliflozin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 40 participants
- Where
- 1 siteUnited States
- Study dates
- Mar 2016to Nov 2018
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 30 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 9Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Texas Southwestern Medical Center
Dallas, Texas, 75390
About this study
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.
Read the 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.
- Conditions
- Obesity, Visceral
- Being tested
- [U-13C3] glycerol, Empagliflozin, Placebo (for Empagliflozin)
- Keywords
- Visceral, Obesity, Adipose, Diabetes
- Medical subject headings
- Obesity, Abdominal, Obesity, Diabetes Mellitus
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
[U-13C3] glycerolDrug
Also called Glycerine, Glycerin
Ingestion of [U-13C3] glycerol based on human's body weight such as (50 mg/kg body weight).
EmpagliflozinDrug
Also called EMPA, Jardiace
Active drug
Placebo (for Empagliflozin)Drug
Also called Placebo, Sugar pill
Placebo tablet manufactured to mimic EMPA 10 mg tablet.
| Study group | Role | What they receive |
|---|---|---|
| Empagliflozin | Experimental | Empagliflozin 10 mg by mouth daily for 3 months. Receives: Drug: [U-13C3] glycerol; Drug: Empagliflozin |
| Placebo | Placebo comparator | Placebo one tablet daily for 3 months Receives: Drug: [U-13C3] glycerol; Drug: Placebo (for Empagliflozin) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 3 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Jul 2016 (estimated)
- Study startMar 2016
- Primary completionJan 2018
- Study completionNov 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Obesity, VisceralStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Texas Southwestern Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Ian Neeland, University of Texas Southwestern Medical Center
- Investigators
- Ian Neeland, MD, Principal investigator, University of Texas Southwestern Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02833415
- Sponsor's protocol ID
- STU-012015-064
- Other IDs
- K23DK106520
- Status last verified
- Jan 2020
- First submitted
- 5 Jul 2016
- Last updated
- 23 Jan 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- Yes: IPD sharing will be done upon reasonable request.
Publications
Neeland IJ, Ayers CR, Rohatgi AK, Turer AT, Berry JD, Das SR, Vega GL, Khera A, McGuire DK, Grundy SM, de Lemos JA. Associations of visceral and abdominal subcutaneous adipose tissue with markers of cardiac and metabolic risk in obese adults. Obesity (Silver Spring). 2013 Sep;21(9):E439-47. doi: 10.1002/oby.20135. Epub 2013 May 19.
PubMed 23687099Neeland IJ, Turer AT, Ayers CR, Powell-Wiley TM, Vega GL, Farzaneh-Far R, Grundy SM, Khera A, McGuire DK, de Lemos JA. Dysfunctional adiposity and the risk of prediabetes and type 2 diabetes in obese adults. JAMA. 2012 Sep 19;308(11):1150-9. doi: 10.1001/2012.jama.11132.
PubMed 22990274Nurjhan N, Kennedy F, Consoli A, Martin C, Miles J, Gerich J. Quantification of the glycolytic origin of plasma glycerol: implications for the use of the rate of appearance of plasma glycerol as an index of lipolysis in vivo. Metabolism. 1988 Apr;37(4):386-9. doi: 10.1016/0026-0495(88)90140-0.
PubMed 3357420Baba H, Zhang XJ, Wolfe RR. Glycerol gluconeogenesis in fasting humans. Nutrition. 1995 Mar-Apr;11(2):149-53.
PubMed 7647479Jin ES, Sherry AD, Malloy CR. Interaction between the pentose phosphate pathway and gluconeogenesis from glycerol in the liver. J Biol Chem. 2014 Nov 21;289(47):32593-603. doi: 10.1074/jbc.M114.577692. Epub 2014 Oct 6.
PubMed 25288790Neeland IJ, de Albuquerque Rocha N, Hughes C, Ayers CR, Malloy CR, Jin ES. Effects of Empagliflozin Treatment on Glycerol-Derived Hepatic Gluconeogenesis in Adults with Obesity: A Randomized Clinical Trial. Obesity (Silver Spring). 2020 Jul;28(7):1254-1262. doi: 10.1002/oby.22854.
PubMed 32568464
Study at a glance
From the registry record, last updated by the sponsor on 23 Jan 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Visceral Adiposity and Diabetes: Translating Form to Function Using Imaging
- ClinicalTrials.gov ID
- NCT02833415
- Acronym / sponsor ID
- STU-012015-064
- Conditions
- Obesity, Visceral
- Keywords
- Visceral, Obesity, Adipose, Diabetes
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 40 participants (actual)
- Lead sponsor
- University of Texas Southwestern Medical CenterUniversity, hospital or other
- Collaborators
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Study start
- Mar 2016
- Primary completion
- Jan 2018 (actual)
- Study completion
- Nov 2018 (actual)
- First posted
- 14 Jul 2016 (estimated)
- Results
- Posted 2 May 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Empagliflozin | Experimental | Drug: [U-13C3] glycerol, Drug: EmpagliflozinEmpagliflozin 10 mg by mouth daily for 3 months. |
| Placebo | Placebo comparator | Drug: [U-13C3] glycerol, Drug: Placebo (for Empagliflozin)Placebo one tablet daily for 3 months |
Who may qualify
- Ages
- 30 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (9 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| [U-13C3] glycerolAlso: Glycerine, GlycerinIngestion of [U-13C3] glycerol based on human's body weight such as (50 mg/kg body weight). | Drug | Empagliflozin, Placebo |
| EmpagliflozinAlso: EMPA, JardiaceActive drug | Drug | Empagliflozin |
| Placebo (for Empagliflozin)Also: Placebo, Sugar pillPlacebo tablet manufactured to mimic EMPA 10 mg tablet. | Drug | Placebo |
Primary outcome
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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Jan 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 23687099Neeland IJ, Ayers CR, Rohatgi AK, Turer AT, Berry JD, Das SR, Vega GL, Khera A, McGuire DK, Grundy SM, de Lemos JA. Associations of visceral and abdominal subcutaneous adipose tissue with markers of cardiac and metabolic risk in obese adults. Obesity (Silver Spring). 2013 Sep;21(9):E439-47. doi: 10.1002/oby.20135. Epub 2013 May 19.
- Background: PubMed 22990274Neeland IJ, Turer AT, Ayers CR, Powell-Wiley TM, Vega GL, Farzaneh-Far R, Grundy SM, Khera A, McGuire DK, de Lemos JA. Dysfunctional adiposity and the risk of prediabetes and type 2 diabetes in obese adults. JAMA. 2012 Sep 19;308(11):1150-9. doi: 10.1001/2012.jama.11132.
- Background: PubMed 3357420Nurjhan N, Kennedy F, Consoli A, Martin C, Miles J, Gerich J. Quantification of the glycolytic origin of plasma glycerol: implications for the use of the rate of appearance of plasma glycerol as an index of lipolysis in vivo. Metabolism. 1988 Apr;37(4):386-9. doi: 10.1016/0026-0495(88)90140-0.
- Background: PubMed 7647479Baba H, Zhang XJ, Wolfe RR. Glycerol gluconeogenesis in fasting humans. Nutrition. 1995 Mar-Apr;11(2):149-53.
- Background: PubMed 25288790Jin ES, Sherry AD, Malloy CR. Interaction between the pentose phosphate pathway and gluconeogenesis from glycerol in the liver. J Biol Chem. 2014 Nov 21;289(47):32593-603. doi: 10.1074/jbc.M114.577692. Epub 2014 Oct 6.
- Derived from this study: PubMed 32568464Neeland IJ, de Albuquerque Rocha N, Hughes C, Ayers CR, Malloy CR, Jin ES. Effects of Empagliflozin Treatment on Glycerol-Derived Hepatic Gluconeogenesis in Adults with Obesity: A Randomized Clinical Trial. Obesity (Silver Spring). 2020 Jul;28(7):1254-1262. doi: 10.1002/oby.22854.
- Individual participant dataSharing planned: Yes. IPD sharing will be done upon reasonable request.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ian Neeland, MD principal investigator
University of Texas Southwestern Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing [U-13C3] glycerol and Empagliflozin in people with Obesity, Visceral, run by University of Texas Southwestern Medical Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 23 Jan 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 2 May 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Glycerol Enrichment (time frame: 3 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02833415, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jan 2020.