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Completed

NCT Number: NCT02808182

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

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.

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Key information

Conditions

Impaired Glucose Tolerance Glucose Intolerance Glucose Metabolism Disorders Hyperglycemia Metabolic Diseases Nutritional and Metabolic Diseases

Age range

45 year–80 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

centre de recherche du CHUS

Sherbrooke, Quebec, J1H 5N4, Canada

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

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

Other names: Niacin

[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

[U-13C]-palmitate

Other

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

Biopsy

Procedure

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

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

Primary outcomes

  1. Plasma NEFA appearance rate

    Time frame: 2 years

    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. Cardiac and hepatic uptake

    Time frame: 2 years

    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

  3. WAT spillover NEFA appearance rates

    Time frame: 2 years

    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

  4. oxidative metabolism of NEFA

    Time frame: 2 years

    will be assessed by using 13C-palmitate

  5. cardiac and hepatic DFA uptake

    Time frame: 2 years

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

  6. whole-body organ-specific DFA partitioning

    Time frame: 2 years

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

Secondary outcomes

  1. Insulin sensitivity

    Time frame: 2 years

    will be determined using the HOMA-IR (based on fasting insulin and glucose levels)

  2. Insulin secretion rate

    Time frame: 2 years

    will be assessed using deconvolution of plasma C-peptide with standard C-peptide kinetic parameters

  3. β-cell function

    Time frame: 2 years

    will be assessed by calculation of the disposition index (DI) that is insulin secretion in response to the ambient insulin

  4. WAT size

    Time frame: 2 years

    by biopsy fixed in formalin

  5. hormonal response

    Time frame: 2 years

    will be determined using a multiplex assay system

  6. Lipoprotein lipase activity

    Time frame: 2 years

    will be assessed as on frozen 150-mg portions from biopsy

Sponsors and collaborators

Lead sponsor

Université de Sherbrooke

Other

Registry information

Official study title

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

Acronym: AGL11

Important dates

Study start
2017
Primary completion
2020
Study completion
2021
First posted
Jun 21, 2016
Registry last updated
Jan 27, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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