Postprandial Fatty Acid Metabolism in the Natural History of Type 2 Diabetes (T2D)

NCT02808182 | Completed

• 1 other identifier: 2016-1196
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

Lipotoxicity-causing fatty acid overexposure and accretion in lean tissues leads to insulin resistance and impaired pancreatic β-cell function - the hallmarks of T2D - contributing to associated complications such as heart failure, kidney failure and microvascular diseases. Proper dietary fatty acid (DFA) storage in white adipose tissue (WAT) is now thought to prevent lean-tissue lipotoxicity. Using novel Positron-Emission Tomography (PET) and stable isotopic tracer methods which were developed in Sherbrooke, the investigator showed that WAT storage of DFA is impaired in people with pre-diabetes or T2D. The investigator also showed that this impairment is associated with greater cardiac DFA uptake, as well as subclinical left-ventricular systolic and diastolic dysfunction. Then, It has been found that modest weight loss in pre-diabetics, after a one-year lifestyle intervention, improved WAT DFA storage, curbed cardiac DFA uptake, and restored associated left-ventricular dysfunction. It has been also found that a 7-day low-saturated fat, low-calorie diet raised insulin sensitivity but did not restore WAT or cardiac DFA metabolism. Whether WAT DFA storage directly impacts cardiac DFA uptake is not known. Importantly, the investigator recently uncovered marked sex-specific differences in WAT DFA metabolism. These may explain, at least in part, sex-related differences in the cardiac DFA uptake, which occurs in pre-diabetes. Higher spillover of WAT DFA into circulating Non-Esterified Fatty Acid (NEFA) appears to be linked in women to greater cardiac DFA uptake, as opposed to direct cardiac chylomicron triglycerides (TG) uptake in men. Here, the investigator will isolate and compare organ-specific fatty acid uptake occurring postprandially from chylomicron-TG vs. NEFA pools, as well as the oxidative vs. non-oxidative intracellular metabolic pathways associated with increased cardiac DFA uptake in pre-diabetic men and women.

Conditions

Impaired Glucose Tolerance

Outcome Measures

Primary Outcomes (6)

• Plasma NEFA appearance rate

  NEFA appearance will be measured using i.v. administration of \[7,7,8,8-2H\]-palmitate (in 25% human albumin) from time -60 to +360 min, as slightly modified from previous descriptions, using Steele's non steady-state equations. Blood samples to measure plasma palmitate, oleate, linoleate, and total NEFA levels, \[7,7,8,8-2H\]-palmitate enrichments by GC/MS-MS.

  2 years

• Cardiac and hepatic uptake

  will be determined using 11C-palmitate PET/CT. 180 MBq will be administered by bolus injection at postprandial time 90min. After a transmission scan and regional CT (40mA), a 30-min dynamic list-mode PET acquisition will be performed starting at time 90 min on a 18 cm-high thoraco-abdominal segment to include the left cardiac ventricle and most of the liver on a Philips Gemini TOF PET/CT

  2 years

• WAT spillover NEFA appearance rates

  WAT spillover NEFA will be determined from oral administration of \[U-13C\]-palmitate. Blood samples to measure plasma \[U-13C\]-palmitate and chylomicron-TG \[U-13C\]-palmitate enrichment by GC/MS-MS

  2 years

• oxidative metabolism of NEFA

  will be assessed by using 13C-palmitate

  2 years

• cardiac and hepatic DFA uptake

  will be assessed using PET/CT method with oral administration of 18FTHA

  2 years

• whole-body organ-specific DFA partitioning

  will be determined by whole-body CT (16 mA) followed by PET acquisition of 18FTHA

  2 years

Secondary Outcomes (6)

• Insulin sensitivity

  2 years

• Insulin secretion rate

  2 years

• β-cell function

  2 years

• WAT size

  2 years

• hormonal response

  2 years

Study Arms (4)

A0: PET/scan with [11C] palmitate

OTHER

A bolus of 180 MBq of \[11C\]-acetate at time 90min and PET acquisition

Procedure: Biopsy; Other: liquid meal

A1: PET/scan with [11C] palmitate

OTHER

A bolus injection of 180 MBq of \[11C\]-acetate at time 90min, followed by PET acquisition

Drug: Nicotinic acid; Procedure: Biopsy; Other: liquid meal

B0: PET/scan with [18F]-FTHA

OTHER

At time 0, a standard liquid meal will be drunk over 20 minutes with 70 MBq of 18FTHA . PET acquisition at time 90 min.

Other: [7,7,8,8-2H]-palmitate; Other: [U-13C]-palmitate; Other: liquid meal

B1: PET/scan with [18F]-FTHA

OTHER

At time 0, a standard liquid meal will be drunk over 20 minutes with 70 MBq of 18FTHA followed by a PET acquisition at time 90 min.

Drug: Nicotinic acid; Other: [7,7,8,8-2H]-palmitate; Other: [U-13C]-palmitate; Other: liquid meal

Interventions

Nicotinic acid DRUG

oral administration of nicotinic acid (100mg at 0, 30, 60, 90, 120, 180, 240 and 300 min) to minimize WAT intracellular lipolysis

Also known as: Niacin

A1: PET/scan with [11C] palmitate; B1: PET/scan with [18F]-FTHA

[7,7,8,8-2H]-palmitate OTHER

using i.v. administration of \[7,7,8,8-2H\]-palmitate (in 25% human albumin) from time -60 to +360 min

B0: PET/scan with [18F]-FTHA; B1: PET/scan with [18F]-FTHA

[U-13C]-palmitate OTHER

oral administration of \[U-13C\]-palmitate (0.2 g mixed into the liquid meal) at time 0 min

B0: PET/scan with [18F]-FTHA; B1: PET/scan with [18F]-FTHA

Biopsy PROCEDURE

A subcutaneous abdominal 0.5-g adipose tissue biopsy will be performed at the end of protocols A0 and A1

A0: PET/scan with [11C] palmitate; A1: PET/scan with [11C] palmitate

liquid meal OTHER

At time 0, a standard liquid meal (400 mL, 906 kcal, 33g-fat/34g-protein/101g-carbohydrates i.e. 33%/17%/50% calories) will be drunk over 20 minutes

A0: PET/scan with [11C] palmitate; A1: PET/scan with [11C] palmitate; B0: PET/scan with [18F]-FTHA; B1: PET/scan with [18F]-FTHA

Eligibility Criteria

• Age: 45 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• For healthy subjects: fasting glucose \< 5.6, 2-hour post 75g Oral Glucose Tolerance Test (OGTT) glucose \< 7.8 mmol/l and HbA1c \< 5.8%
• For subject with glucose intolerance (IGT): 2-hour post 75g OGTT glucose at 7.8-11.1 mmol/l on two separate occasions and HbA1c of 6.0 to 6.4%

You may not qualify if:

• overt cardiovascular disease as assessed by medical history, physical exam, and abnormal ECG
• treatment with a fibrate, thiazolidinedione, beta-blocker or other drug known to affect lipid or carbohydrate metabolism (except statins, metformin, and other antihypertensive agents that can be safely interrupted)
• presence of liver or renal disease, uncontrolled thyroid disorder, previous pancreatitis, bleeding disorder, or other major illness
• smoking (\>1 cigarette/day) and/or consumption of \>2 alcoholic beverages per day
• prior history or current fasting plasma cholesterol level \> 7 mmol/l or fasting TG \> 6 mmol/l
• any other contraindication to temporarily interrupt current meds for lipids or hypertension
• being pregnant
• not be barren

Sponsors & Collaborators

• Université de Sherbrooke: lead

Study Sites (1)

centre de recherche du CHUS

Sherbrooke, Quebec, J1H 5N4, Canada

Location

Related Publications (3)

• Montastier E, Ye RZ, Noll C, Amrani M, Frisch F, Fortin M, Bouffard L, Phoenix S, Sarrhini O, Cunnane SC, Guerin B, Turcotte EE, Carpentier AC. Nicotinic acid increases adipose tissue dietary fatty acid trapping and reduces postprandial hepatic and cardiac fatty acid uptake in prediabetes. Eur J Pharmacol. 2025 Jul 5;998:177563. doi: 10.1016/j.ejphar.2025.177563. Epub 2025 Mar 27.

  PMID: 40157702 DERIVED

• Ye RZ, Montastier E, Noll C, Frisch F, Fortin M, Bouffard L, Phoenix S, Guerin B, Turcotte EE, Carpentier AC. Total Postprandial Hepatic Nonesterified and Dietary Fatty Acid Uptake Is Increased and Insufficiently Curbed by Adipose Tissue Fatty Acid Trapping in Prediabetes With Overweight. Diabetes. 2022 Sep 1;71(9):1891-1901. doi: 10.2337/db21-1097.

  PMID: 35748318 DERIVED

• Montastier E, Ye RZ, Noll C, Bouffard L, Fortin M, Frisch F, Phoenix S, Guerin B, Turcotte EE, Lewis GF, Carpentier AC. Increased postprandial nonesterified fatty acid efflux from adipose tissue in prediabetes is offset by enhanced dietary fatty acid adipose trapping. Am J Physiol Endocrinol Metab. 2021 Jun 1;320(6):E1093-E1106. doi: 10.1152/ajpendo.00619.2020. Epub 2021 Apr 19.

  PMID: 33870714 DERIVED

Related Links

• Total Postprandial Hepatic Nonesterified and Dietary Fatty Acid Uptake Is Increased and Insufficiently Curbed by Adipose Tissue Fatty Acid Trapping in Prediabetes With Overweight
• Increased postprandial nonesterified fatty acid efflux from adipose tissue in prediabetes is offset by enhanced dietary fatty acid adipose trapping

MeSH Terms

Conditions

Glucose Intolerance

Interventions

Niacin; Biopsy

Condition Hierarchy (Ancestors)

Hyperglycemia; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Specimen Handling; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Tenured Professor

Study Record Dates

• First Submitted: April 14, 2016
• First Posted: June 21, 2016
• Study Start: January 17, 2017
• Primary Completion: December 1, 2020
• Study Completion: May 1, 2021
• Last Updated: January 27, 2025

Record last verified: 2025-01

Locations

CA (1)