Lipoprotein Lipase Deficiency
Conditions
Brief summary
Lipoprotein lipase (LPL) is an enzyme that plays an important role in removing triglycerides (TG) (molecules that transport dietary fat) from the blood. Patients with LPL deficiency (LPLD) display during their whole life very high plasma TG levels often associated with episodes of postprandial abdominal pain, malaise, blurred vision, dizziness (hyperchylomicronemia syndrome) that may lead to recurrent pancreatitis episodes. Because of their very slow clearance in blood of their chylomicron-TG, these patients need to severely restrict their dietary fat intake to avoid these complications. Fortunately, novel treatments are being developed to circumvent LPL deficiency (LPLD) metabolic effect on chylomicron-TG clearance. However, there is no data on how LPLD affect organ-specific dietary fatty acid metabolism nor how the novel therapeutic agents may change this metabolism. For example, it is currently not understood how subjects with LPLD store their DFA into adipose tissues and whether they are able to use DFA as a fuel to sustain their cardiac metabolism, as healthy individuals do. This study aims to better understand theses two questions.
Detailed description
The study protocol includes 3 visits: the screening visit and 2 postprandial metabolic studies performed in random order at an interval of 7 to 14 days, and performed with (A1) and without (A0) an intravenous (i.v.) heparin bolus followed by 250 IU/h i.v during 6 hours. Each metabolic study will last 9 hours (with 6 hours postprandial) and will include PET and stable isotopic tracer methods. At time 0, a low fat liquid meal will be ingested over 20 minutes.
Interventions
DRUGHeparin
an intravenous (i.v.) heparin bolus (50 IU/kg i.v.) followed by 250 IU/h i.v. during 6 hours, starting 15 minutes before ingestion of liquid meal
DIETARY_SUPPLEMENTliquid meal
low fat meal: (500 mL, 898 Kcal, 13% fat, 20.3% protein and 62.3% carbohydrates) will be ingested over 20 minutes
Sponsors
Université de Sherbrooke
Institut de Recherches Cliniques de Montreal
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* 8 healthy LPL-deficient individuals (LPLD subjects) with history of fasting TG \> 5 mmol/l and homozygote or compound heterozygote for a LPL-gene mutation; * 8 control subjects (fasting glucose \< 5.6, 2-hour post 75g OGTT glucose \< 7.8 mmol/l and HbA1c \< 5.8%; fasting TG \< 1.5 mmol/l); * age 18 to 75 yo; * To be willing and able to adhere to the specifications of the protocol; * To have signed an informed consent document indicating that they understood the purpose
Exclusion criteria
* age \< 18 yo; * 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); * Treatment with anti-hypertensive medication (only for LPL-deficient individuals); * presence of liver or renal disease; uncontrolled thyroid disorder; * previous diagnosis of heparin-induced thrombocytopenia; * Treatment with oral anticoagulation medication or platelet aggregation inhibiting drugs; * A history of major hemorrhagic event; * smoking (\>1 cigarette/day) and/or consumption of \>2 alcoholic beverages per day;; * Female of child-bearing potential who is pregnant, breast feeding or intends to become pregnant or pre-menopausal female with a positive serum pregnancy test at the time of enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Organ-specific Dietary Fatty Acid (DFA) partitioning | 2 months | will be determined using oral administration of \[18F \]-Fluoro-6-Thia- Heptadecanoic Acid (FTHA ) during whole-body acquisition. |
| Myocardial DFA uptake | 2 months | will be assessed using oral administration of \[18F\]-FTHA during dynamic PET acquisition. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Myocardial nonesterified fatty acids (NEFA) metabolism | 2 months | will be determined using \[11C\]-palmitate during dynamic PET acquisition. |
| Dietary fatty acid oxidation rate | 6 months | will be measured using breath \[13C\]-carbon dioxide enrichment |
| Total oxidation rate | 2 months | will be determined by indirect calorimetry |
| postprandial plasma NEFA turnover | 6 months | will be determined using stable isotope tracers of fatty acids |
| postprandial plasma glucose turnover | 6 months | will be determined using stable isotope tracers of glucose |
| Left ventricular function by Positron Emitting Positron (PET) ventriculography | 2 months | will be determined using \[11C\]-acetate PET/CT. 180 megabecquerel (MBq) will be administered by bolus injection |
| Myocardial oxidative metabolism | 2 months | will be determined using i.v. \[11C\]-acetate during dynamic PET/CT scanning. |
| Insulin sensitivity | 6 months | will be determined using a multiplex ELISA which will measure multiple analytes in a single experiment. |
| Liver nonesterified fatty acids (NEFA) metabolism | 2 months | will be determined using \[11C\]-palmitate during dynamic PET acquisition. |
| Metabolites distribution in plasma | 2 months | will be determined using oral administration of \[18F\]-FTHA |
Countries
Canada
Contacts
CONTACTFrédérique Frisch
PRINCIPAL_INVESTIGATORAndré Carpentier
Université de Sherbrooke
Outcome results
None listed