Metabolic Dysfunction-Associated Steatotic Liver Disease, Non-Alcoholic Steato-Hepatitis (NASH), Type 1 Diabetes Mellitus
Conditions
Keywords
abdominal obesity, Adipose tissue insulin resistance
Brief summary
Steatotic liver disease associated with metabolic dysfunction (MASLD) is a disease caused by excess fat storage in the liver. Excessive fat delivery to the liver and MASLD typically occurs in people with abdominal obesity and type 2 diabetes. Type 1 diabetes (T1D) is also associated with a marked increase in the release of fat from adipose tissues and MASLD is increased in T1D and significantly increases the risk of heart, kidney and eye diseases.
Detailed description
It is a parallel study design between T1D and controls. The outcomes will be assessed between T1D vs. controls during the metabolic visit. The metabolic visit will last 9 hours: it will be a test meal with perfusion of stable tracers, blood sampling, PET acquisitions using radiopharmaceuticals (18FTHA and 11C-palmitate) and MRI acquisitions. In total, 32 participants will be recruited: * 16 living with T1D and abdominal obesity * 16 with normoglycemia
Interventions
DIAGNOSTIC_TESTImaging PET/MRI
MRI using 1H-MRS and Dixon sequences on a 3 T clinical MRI system (Ingenia, Philips Healthcare, Best, the Netherlands) will be performed. \[11C\]-palmitate: 1 x i.v. injection of 175 MBq followed by TEP imaging. \[18F\]-FTHA: oral administration of 75 MBq followed by TEP imaging.
DIAGNOSTIC_TESTStable isotope infusions
\[6,6 D2\]-glucose infusion (0.22 µmol/kg/min, preceded by a bolus of 22 µmol/kg) will start from -180 until time + 360. \[1,1,2,3,3-2H\]-glycerol (0.05 µmol/kg/min.) and of \[7,7,8,8-2H\] palmitate (0.01 µmol/kg/min) will start from time -60 until time +360.
DIAGNOSTIC_TESTmeal test
A liquid meal will be administered at time 0. The liquid meal (400 ml) energy breakdown is 50% (101g) from glucose, 33% (31g) from fat, and 17% (40g) from protein; participants will consume the 400 ml in 4 aliquots of 100 ml over 20 min, supplemented with 0.9 g of U-\[13C\]-glucose and 9 μmol/kg lean mass of \[U-13C\]-palmitate.
DIAGNOSTIC_TESTIndirect calorimetry
Indirect calorimetry (Vmax Series from Vyaire medical, licence # 22536), measured during10 minutes, every hour.
Sponsors
Centre de recherche du Centre hospitalier universitaire de Sherbrooke
Université de Sherbrooke
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* 16 individuals living with T1D and abdominal obesity, as defined by the International Diabetes Federation country/ethnic group-specific criteria (https://www.idf.org/e-library/consensus-statements/60- \[1\]. Treatment for T1D will be intensive insulin therapy on continuous pump perfusion with continuous glucose monitoring. * 16 individuals with normoglycemia (i.e., HbA1c below 6.0%) matched for sex, age (± 5 years), waist circumference (± 3 cm), and menopausal status.
Exclusion criteria
* less than 70% of time in glycemic range (for T1D); * history of primary dyslipidemia (LDL-cholesterol over 5 mmol/L or TG over 10 mmol/L) or uncontrolled high blood pressure (over 160/100 mmHg) precluding the withdrawal of lipid lowering and anti-hypertensive agents as per protocol; * presence of overt cardiovascular, liver or renal disease (except microalbuminuria without reduced kidney function), or other uncontrolled medical conditions; * use of any medication other than insulin that may affect lipid or carbohydrate metabolism and that cannot be stopped prior to testing; * current or planned pregnancy within the next 6 months; * any contraindication to MRI. * Being allergic to eggs * Smoking (\>1 cigarette/day) and/or consumption of \>2 alcoholic beverages per day * Having participated to a research study with exposure to radiation in the last year before the start of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| hepatic NEFA uptake | At baseline of Visit 2 (V2) | using 11C-palmitate PET |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adipose Tissue DFA trapping and postprandial palmitate flux | At V2 (from time 0 to +360 minutes) | Determined from the same static (whole-body) acquisition image using oral administration of \[18F\]-Fluoro-6-Thia- Heptadecanoic Acid (FTHA) |
| hepatic fatty acid oxidation, esterification and secretion into VLDL | At baseline | \[11C\]-Palmitate PET. Calculated from the same multicompartmental equation using liver \[11C\]-palmitate kinetics |
| Hepatic triglyceride content | At V2 (-200 minutes) | measured by MRI |
| Endogenous Glucose production and meal glucose systemic flux | At V2 (from time 0 to +360 minutes) | Apparition rate (µmol/min) of glucose from multicompartimental equation using intravenous perfusion and oral stable isotope tracer |
| Insulin secretion | At V2 (from time 0 to +360 minutes) | Determined by measuring C-peptide kinetics following the liquid meal |
| Insulin resistance/ sensitivity | At V2 (from time 0 to +360 minutes) | Determined by measuring circulating glucose and insulin following the liquid meal: glucose and insulin will be combined to give insulin resistance/sensitivity |
| postprandial hepatic Dietary Fatty Acid uptake | At V2 (from time 0 to +360 minutes) | using 18F-FTHA |
| Total substrate utilisation | At visit 2 (from time 0 to +360 minutes). | measured by using indirect calorimetry |
| metabolite response | At visit 2 (from time 0 to +360 minutes) | Colorimetric assay |
| hormonal response | At visit 2 (from time 0 to +360 minutes) | Multiplex assay |
| plasma NEFA NEFA flux | At visit 2 (from time 0 to +360 minutes) | calculated from i.v. stable isotope tracer (mass spectrometry). |
| plasma distribution of DFA metabolites | At visit 2 (from time 0 to +360 minutes) | calculated from i.v. and oral stable isotope tracers (mass spectrometry) incorporated into triglyceride-rich lipoproteins and NEFA. |
| Adipose tissue Insulin Resistance index | At visit 2 (from time 0 to +360 minutes) | is calculated from measurement of postabsorptive concentrations of FFAs and insulin. |
| Glycerol turnover | At visit 2 (from time 0 to +360 minutes) | calculated from \[1,1,2,3,3-2H\]-glycerol i.v. |
Countries
Canada
Contacts
Primary ContactFrédérique Frisch
Outcome results
None listed