Visceral Adiposity and Diabetes: Translating Form to Function Using Imaging

• Sponsor: University of Texas Southwestern Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT02833415
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 40
• Location: 1
• Arms: 2
• Duration (Months): 32
• Patients Per Site Per Month: 1.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Obesity, Visceral	Drug: [U-13C3] glycerol; Drug: Empagliflozin; Drug: Placebo (for Empagliflozin)	Phase 4

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

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: Visceral Adiposity and Diabetes: Translating Form to Function Using Imaging
• Study Start Date: Mar 1, 2016
• Actual Primary Completion Date: Jan 1, 2018
• Actual Study Completion Date: Nov 1, 2018

Arms and Interventions

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: Glycerine Glycerin ; 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: Glycerine Glycerin ; Drug: Placebo (for Empagliflozin); Placebo tablet manufactured to mimic EMPA 10 mg tablet.; Other Names: Placebo Sugar pill

Outcome Measures

Primary Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390

Sponsors and Collaborators

• University of Texas Southwestern Medical Center
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 13, 2017

More Information

Publications

• Baba H, Zhang XJ, Wolfe RR. Glycerol gluconeogenesis in fasting humans. Nutrition. 1995 Mar-Apr;11(2):149-53.
• Jin 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.
• 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.
• Neeland 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.
• Nurjhan 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.

• Responsible Party: Ian Neeland, M.D., University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT02833415
• Other Study ID Numbers: STU-012015-064; K23DK106520
• First Posted: Jul 14, 2016
• Last Update Posted: Jan 23, 2020
• Last Verified: Jan 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Ian Neeland, M.D., University of Texas Southwestern Medical Center: Visceral; Obesity; Adipose; Diabetes
• Additional relevant MeSH terms: Obesity, Abdominal; Empagliflozin; Glycerol

Study Results

Participant Flow

Arm/Group Title	Empagliflozin	Placebo
Arm/Group Description	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	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.
Period Title: Overall Study
STARTED	20	20
COMPLETED	18	17
NOT COMPLETED	2	3

Baseline Characteristics

Arm/Group Title	Empagliflozin	Placebo	Total
Arm/Group Description	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	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.	Total of all reporting groups
Overall Participants	18	17	35
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	50.5	54	53
Sex: Female, Male (Count of Participants)
Female	11 61.1%	11 64.7%	22 62.9%
Male	7 38.9%	6 35.3%	13 37.1%
Race/Ethnicity, Customized (participants) [Number]
African-American	5 27.8%	7 41.2%	12 34.3%
Systolic Blood Pressure (mmHg) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mmHg]	126	132	130
Hemoglobin A1C (percent of glycosylated hemoglobin) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [percent of glycosylated hemoglobin]	5.6	5.9	5.8
Body Mass Index (kg/m^2) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg/m^2]	36.8	35.3	35.5
Visceral Fat (kg) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg]	5.4	4.3	5.4

Outcome Measures

1. Primary Outcome

Title	Change in Glycerol Enrichment
Description	[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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Empagliflozin	Placebo
Arm/Group Description	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	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.
Measure Participants	18	17
Number [Percentage change]	6.5	1.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empagliflozin
	Comments	Baseline to Followup
	Type of Statistical Test	Other
	Comments	Differences of Least Squares Means
Statistical Test of Hypothesis	p-Value	0.0053
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Differences of Least Squares Means
	Estimated Value	0.9398
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.2941
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	Baseline to Followup
	Type of Statistical Test	Other
	Comments	Differences of Least Squares Means
Statistical Test of Hypothesis	p-Value	0.5394
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Differences of Least Squares Means
	Estimated Value	0.1520
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.2424
	Estimation Comments

Adverse Events

Time Frame	3 months
Adverse Event Reporting Description	Adverse Events Definition: Any untoward or unfavorable medical occurrence in a participant, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participant's participation in the research, whether or not considered related to the participant's participation in the research.
Arm/Group Title	Empagliflozin		Placebo
Arm/Group Description	Empagliflozin 10 mg daily by mouth		Placebo daily by mouth
All Cause Mortality
	Empagliflozin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)
Serious Adverse Events
	Empagliflozin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Empagliflozin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/20 (5%)		0/20 (0%)
Renal and urinary disorders
Urinary Tract Infection	1/20 (5%)	1	0/20 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.