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

Impaired Glucose Tolerance Clinical Trial

— AGL11  

Official 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02808182
• Other study ID #: 2016-1196
• Status: Completed
• Phase: N/A
• Start date: January 17, 2017
• Est. completion date: May 2021

Study information

• Verified date: November 2021
• Source: Université de Sherbrooke
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: May 2021
• Est. primary completion date: December 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 45 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Glucose Intolerance
• Impaired Glucose Tolerance

Intervention

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

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

Locations

Country	Name	City	State
Canada	centre de recherche du CHUS	Sherbrooke	Quebec

Sponsors (1)

Lead Sponsor	Collaborator
Université de Sherbrooke

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	oxidative metabolism of NEFA	will be assessed by using 13C-palmitate	2 years
Primary	cardiac and hepatic DFA uptake	will be assessed using PET/CT method with oral administration of 18FTHA	2 years
Primary	whole-body organ-specific DFA partitioning	will be determined by whole-body CT (16 mA) followed by PET acquisition of 18FTHA	2 years
Secondary	Insulin sensitivity	will be determined using the HOMA-IR (based on fasting insulin and glucose levels)	2 years
Secondary	Insulin secretion rate	will be assessed using deconvolution of plasma C-peptide with standard C-peptide kinetic parameters	2 years
Secondary	ß-cell function	will be assessed by calculation of the disposition index (DI) that is insulin secretion in response to the ambient insulin	2 years
Secondary	WAT size	by biopsy fixed in formalin	2 years
Secondary	hormonal response	will be determined using a multiplex assay system	2 years
Secondary	Lipoprotein lipase activity	will be assessed as on frozen 150-mg portions from biopsy	2 years