How Abnormal Function of Fat Tissue in Type 1 Diabetes Contributes to Fat in the Liver

N/ANot Yet RecruitingNCT07133854

Université de Sherbrooke32 enrolled

Overview

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.

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

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Enrollment

Conditions

Metabolic Dysfunction-Associated Steatotic Liver Disease Non-Alcoholic Steato-Hepatitis (NASH)

Interventions

Imaging PET/MRIDIAGNOSTIC_TEST

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.

Stable isotope infusionsDIAGNOSTIC_TEST

\[6,6 D2\]-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.

meal testDIAGNOSTIC_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.

Indirect calorimetryDIAGNOSTIC_TEST

Indirect calorimetry (Vmax Series from Vyaire medical, licence # 22536), measured during10 minutes, every hour.

Eligibility

Sex: ALLMin age: 21 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

hepatic NEFA uptake

using 11C-palmitate PET

Time frame: At baseline of Visit 2 (V2)

Secondary Outcomes

postprandial hepatic Dietary Fatty Acid uptake

using 18F-FTHA

Time frame: At V2 (from time 0 to +360 minutes)

Adipose Tissue DFA trapping and postprandial palmitate flux

Determined from the same static (whole-body) acquisition image using oral administration of \[18F\]-Fluoro-6-Thia- Heptadecanoic Acid (FTHA)

Time frame: At V2 (from time 0 to +360 minutes)

hepatic fatty acid oxidation, esterification and secretion into VLDL

\[11C\]-Palmitate PET. Calculated from the same multicompartmental equation using liver \[11C\]-palmitate kinetics

Time frame: At baseline

Hepatic triglyceride content

measured by MRI

Time frame: At V2 (-200 minutes)

Endogenous Glucose production and meal glucose systemic flux

Apparition rate (µmol/min) of glucose from multicompartimental equation using intravenous perfusion and oral stable isotope tracer

Time frame: At V2 (from time 0 to +360 minutes)

Insulin secretion

Determined by measuring C-peptide kinetics following the liquid meal

Time frame: At V2 (from time 0 to +360 minutes)

Insulin resistance/ sensitivity

Determined by measuring circulating glucose and insulin following the liquid meal: glucose and insulin will be combined to give insulin resistance/sensitivity

Time frame: At V2 (from time 0 to +360 minutes)

Glycerol turnover

calculated from \[1,1,2,3,3-2H\]-glycerol i.v.