Clinical trial NCT02833415: Visceral Adiposity and Diabetes: Translating Form to Function Using Imaging
Official title: Visceral Adiposity and Diabetes: Translating Form to Function Using Imaging
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Obesity, Visceral
Keywords: Visceral
Obesity
Adipose
Diabetes
Lead sponsor: University of Texas Southwestern Medical Center
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2016-07-14
Enrollment: 40
Sex: ALL
Minimum age (years): 30
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in Glycerol Enrichment
timeFrame: 3 months
Secondary outcomes:
Other outcomes:
Locations:
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
Study officials:
affiliation: UT Southwestern Medical Center
name: Ian Neeland, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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. doi: 10.1001/2012.jama.11132.
citation: 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. doi: 10.1016/0026-0495(88)90140-0.
citation: Baba H, Zhang XJ, Wolfe RR. Glycerol gluconeogenesis in fasting humans. Nutrition. 1995 Mar-Apr;11(2):149-53.
citation: 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.
citation: Neeland 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.