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

NCT ID: NCT02808182

Last Updated: 2025-01-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-01-17
• Study Completion Date: 2021-05-31

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

A0: PET/scan with [11C] palmitate

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

Group Type: OTHER

Biopsy

Intervention Type: PROCEDURE

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

liquid meal

Intervention Type: 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

A1: PET/scan with [11C] palmitate

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

Group Type: OTHER

Nicotinic acid

Intervention Type: DRUG

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

Biopsy

Intervention Type: PROCEDURE

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

liquid meal

Intervention Type: 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

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.

Group Type: OTHER

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

Intervention Type: OTHER

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

[U-13C]-palmitate

Intervention Type: OTHER

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

liquid meal

Intervention Type: 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

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.

Group Type: OTHER

Nicotinic acid

Intervention Type: DRUG

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

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

Intervention Type: OTHER

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

[U-13C]-palmitate

Intervention Type: OTHER

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

liquid meal

Intervention Type: 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

Interventions

Nicotinic acid

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

Intervention Type: DRUG

[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

Intervention Type: OTHER

[U-13C]-palmitate

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

Intervention Type: OTHER

Biopsy

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

Intervention Type: PROCEDURE

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

Intervention Type: OTHER

Other Intervention Names

Niacin

Eligibility Criteria

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

• Minimum Eligible Age: 45 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Université de Sherbrooke

OTHER

Sponsor Role: lead

Responsible Party

André Carpentier

Tenured Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

centre de recherche du CHUS

Sherbrooke, Quebec, Canada

Countries

Canada

References

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.

Reference Type: DERIVED

PMID: 40157702 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35748318 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33870714 (View on PubMed)

Related Links

https://pubmed.ncbi.nlm.nih.gov/35748318/

Total Postprandial Hepatic Nonesterified and Dietary Fatty Acid Uptake Is Increased and Insufficiently Curbed by Adipose Tissue Fatty Acid Trapping in Prediabetes With Overweight

https://pubmed.ncbi.nlm.nih.gov/33870714/

Increased postprandial nonesterified fatty acid efflux from adipose tissue in prediabetes is offset by enhanced dietary fatty acid adipose trapping

Other Identifiers

2016-1196

Identifier Type: -

Identifier Source: org_study_id