Postprandial Fatty Acid Metabolism in the Natural History of Type 2 Diabetes (T2D) (AGL11)

Postprandial Fatty Acid Metabolism in the Natural History of Type 2 Diabetes (T2D): Relative Contribution of Dietary vs Systemic Fatty Acids to Lean Tissue Fatty Acid Fluxes and Oxidative vs Non-oxidative Pathways

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.

Study Overview

• Status: Completed
• Conditions: Impaired Glucose Tolerance
• Intervention / Treatment: Procedure: Biopsy; Other: liquid meal; Drug: Nicotinic acid; Other: [7,7,8,8-2H]-palmitate; Other: [U-13C]-palmitate

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Centre de recherche du CHUS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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%

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: A0: PET/scan with [11C] palmitate; A bolus of 180 MBq of [11C]-acetate at time 90min and PET acquisition	Procedure: Biopsy; A subcutaneous abdominal 0.5-g adipose tissue biopsy will be performed at the end of protocols A0 and A1; Other: liquid meal; 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
Other: A1: PET/scan with [11C] palmitate; A bolus injection of 180 MBq of [11C]-acetate at time 90min, followed by PET acquisition	Procedure: Biopsy; A subcutaneous abdominal 0.5-g adipose tissue biopsy will be performed at the end of protocols A0 and A1; Other: liquid meal; 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; Drug: Nicotinic acid; oral administration of nicotinic acid (100mg at 0, 30, 60, 90, 120, 180, 240 and 300 min) to minimize WAT intracellular lipolysis; Other Names: Niacin
Other: B0: PET/scan with [18F]-FTHA; 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: liquid meal; 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; Other: [7,7,8,8-2H]-palmitate; using i.v. administration of [7,7,8,8-2H]-palmitate (in 25% human albumin) from time -60 to +360 min; Other: [U-13C]-palmitate; oral administration of [U-13C]-palmitate (0.2 g mixed into the liquid meal) at time 0 min
Other: B1: PET/scan with [18F]-FTHA; 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.	Other: liquid meal; 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; Drug: Nicotinic acid; oral administration of nicotinic acid (100mg at 0, 30, 60, 90, 120, 180, 240 and 300 min) to minimize WAT intracellular lipolysis; Other Names: Niacin; Other: [7,7,8,8-2H]-palmitate; using i.v. administration of [7,7,8,8-2H]-palmitate (in 25% human albumin) from time -60 to +360 min; Other: [U-13C]-palmitate; oral administration of [U-13C]-palmitate (0.2 g mixed into the liquid meal) at time 0 min

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin sensitivity	will be determined using the HOMA-IR (based on fasting insulin and glucose levels)	2 years
Insulin secretion rate	will be assessed using deconvolution of plasma C-peptide with standard C-peptide kinetic parameters	2 years
β-cell function	will be assessed by calculation of the disposition index (DI) that is insulin secretion in response to the ambient insulin	2 years
WAT size	by biopsy fixed in formalin	2 years
hormonal response	will be determined using a multiplex assay system	2 years
Lipoprotein lipase activity	will be assessed as on frozen 150-mg portions from biopsy	2 years

Collaborators and Investigators

• Sponsor: Université de Sherbrooke

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 17, 2017
• Primary Completion (Actual): December 1, 2020
• Study Completion (Actual): May 1, 2021

Study Registration Dates

• First Submitted: April 14, 2016
• First Submitted That Met QC Criteria: June 16, 2016
• First Posted (Estimate): June 21, 2016

Study Record Updates

• Last Update Posted (Actual): November 26, 2021
• Last Update Submitted That Met QC Criteria: November 16, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperglycemia; Glucose Intolerance; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Antimetabolites; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Vitamins; Vitamin B Complex; Nicotinic Acids; Niacinamide; Niacin
• Other Study ID Numbers: 2016-1196