Visceral Adiposity and Diabetes: Translating Form to Function Using Imaging
Condition: Obesity, Visceral
MeSH terms: Obesity, Abdominal
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): [U-13C3] glycerol; Empagliflozin; Placebo (for Empagliflozin)
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Ingestion of [U-13C3] glycerol based on human's body weight such as (50 mg/kg body weight).; Active drug; Placebo tablet manufactured to mimic EMPA 10 mg tablet.
Other intervention name(s): Glycerine; Glycerin; EMPA; Jardiace; Placebo; Sugar pill
Intervention MeSH terms: Empagliflozin; Glycerol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Prevention
Keywords: Visceral; Obesity; Adipose; Diabetes