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

Not Applicable

Completed

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

• Registration Number: NCT02808182
• Lead Sponsor: Université de Sherbrooke

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2016-04-14
• Study First Submitted QC: 2016-06-16
• Study First Posted: 2016-06-21
• Study Start: 2017-01-17
• Primary Completion: 2020-12
• Study Completion: 2021-05
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-22
• Last Update Posted: 2025-01-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 50

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
B1: PET/scan with [18F]-FTHA	[7,7,8,8-2H]-palmitate	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.
B1: PET/scan with [18F]-FTHA	[U-13C]-palmitate	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.
A0: PET/scan with [11C] palmitate	Biopsy	A bolus of 180 MBq of \[11C\]-acetate at time 90min and PET acquisition
B0: PET/scan with [18F]-FTHA	[7,7,8,8-2H]-palmitate	At time 0, a standard liquid meal will be drunk over 20 minutes with 70 MBq of 18FTHA . PET acquisition at time 90 min.
A0: PET/scan with [11C] palmitate	liquid meal	A bolus of 180 MBq of \[11C\]-acetate at time 90min and PET acquisition
A1: PET/scan with [11C] palmitate	Biopsy	A bolus injection of 180 MBq of \[11C\]-acetate at time 90min, followed by PET acquisition
A1: PET/scan with [11C] palmitate	liquid meal	A bolus injection of 180 MBq of \[11C\]-acetate at time 90min, followed by PET acquisition
B0: PET/scan with [18F]-FTHA	[U-13C]-palmitate	At time 0, a standard liquid meal will be drunk over 20 minutes with 70 MBq of 18FTHA . PET acquisition at time 90 min.
B0: PET/scan with [18F]-FTHA	liquid meal	At time 0, a standard liquid meal will be drunk over 20 minutes with 70 MBq of 18FTHA . PET acquisition at time 90 min.
B1: PET/scan with [18F]-FTHA	Nicotinic acid	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.
B1: PET/scan with [18F]-FTHA	liquid meal	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.
A1: PET/scan with [11C] palmitate	Nicotinic acid	A bolus injection of 180 MBq of \[11C\]-acetate at time 90min, followed by PET acquisition

Primary Outcome Measures

Name	Time	Method
Cardiac and hepatic uptake	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
Plasma NEFA appearance rate	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.
WAT spillover NEFA appearance rates	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
whole-body organ-specific DFA partitioning	2 years	will be determined by whole-body CT (16 mA) followed by PET acquisition of 18FTHA
oxidative metabolism of NEFA	2 years	will be assessed by using 13C-palmitate
cardiac and hepatic DFA uptake	2 years	will be assessed using PET/CT method with oral administration of 18FTHA

Secondary Outcome Measures

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

Trial Locations

Locations (1)

centre de recherche du CHUS; 🇨🇦 Sherbrooke, Quebec, Canada