Obesity, Type2diabetes
Conditions
Keywords
VLCD, Exercise, Type 2 diabetes, hepatokines, Hepatic steatosis, Liver fat
Brief summary
The aim of this randomized trial is to determine whether liver fat depletion via a short-term (i.e., two weeks) very-low calorie diet will restore the normal exercise-induced secretion of a signaling protein (fibroblast growth factor 21) from the liver in people living with type 2 diabetes. Participants will have their liver fat, body composition, and various markers of metabolic health assessed and then will be randomized to either the very-low calorie diet intervention or a free-living control group for two weeks. Upon completion of the two-week intervention period, participants will redo all of the pre-intervention assessments. The changes in the assessments from before vs. after the intervention period will be compared between the two intervention groups (i.e., the very-low calorie diet group vs. the free living control group).
Detailed description
Fibroblast growth factor 21 (FGF21) is a hepatokine that confers multiple beneficial effects when signaling to other tissues in the body. This is particularly true in adipose tissue, where it improves insulin sensitivity and leads to adiponectin production/secretion. In healthy individuals, FGF21 secretion is induced by exercise: however, this effect is absent in people living with type 2 diabetes (T2D). Aberrant secretion of FGF21 and other hepatokines is associated with increases in ectopic fat in the liver, but it is unknown if depletion of ectopic liver fat ameliorate this effect. 42 participants living with T2D will be recruited for this parallel randomized controlled trial. At baseline, participants will have their liver fat assessed via magnetic resonance imaging, exercise-induced FGF21 incremental area under the curve (following \ 1 hour of exercise on a cycle ergometer at a workload equivalent to 60% VO2peak) as well as anthropometrics and outcomes relating to cardiometabolic health. Participants will then be randomized to either 1) two weeks of a very-low calorie diet (VLCD; \ 800 kcal/day) or 2) two weeks of free living control (CON). Following the two week intervention period, participants will repeat the baseline outcome assessment. The primary objective of this trial is to determine whether diet-induced liver fat depletion will restore exercise-induced FGF21 secretion in people living with T2D. Secondary objectives include determining the effect of diet-induced liver fat depletion on fasting levels of circulating FGF21 and expression of FGF21 receptor/co-receptors and downstream signals in adipose tissue, as well as other cardiometabolic outcomes.
Interventions
BEHAVIORALVery-low calorie diet
\ 800 kcal/day delivered via commercially available diet plan (NUPO).
Sponsors
Diabetesforeningen
Canadian Institutes of Health Research (CIHR)
Region Hovedstadens Forskningsfond
Rigshospitalet, Denmark
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Two arm open-label parallel group randomized controlled trial
Eligibility
Sex/Gender
ALL
Age
30 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Men and women 30-70 years of age * The target population is persons with type 2 diabetes. I.e., persons are eligible if they are diagnosed with type 2 diabetes either only with metformin for managing glucose or without use of glucose lowering medications. Persons with a HbA1c ≥ 48 mmol/mol with or without the use of glucose lowering medications are also eligible. Any glucose lowering medications other than metformin are disallowed (described under
Exclusion criteria
, below) * Diabetes duration \< 7 years * Body Mass Index (BMI) ≥ 30 kg/m2 and ≤ 40 kg/m2 * Accepts medical regulation by the study endocrinologist * Inactivity, defined as \< 1,5 hours of structured physical activity pr. week at moderate intensity and cycling \< 30 minutes/5 km pr. day at moderate intensity (moderate intensity = out of breath but able to speak)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in change in FGF21 incremental area-under-the-curve | 4 weeks | The difference in change between groups of FGF21 incremental area-under-the-curve in plasma following an exercise bout (continuous cycling at an intensity equivalent to 60% VO2peak for a gross energy expenditure of \ 2500 kJ) from baseline to follow-up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Difference in change in fasting and post exercise plasma glucagon | 4 weeks | The difference in change between groups in fasting pre- and post-exercise glucagon in plasma following an exercise bout from baseline to follow-up. |
| Difference in change in OGTT derived insulin secretion. | 4 weeks | The difference in change between groups in OGTT derived insulin secretion (area-under-the-curve for the ratio of insulin/glucose) from baseline to follow-up. |
| Difference in change in OGTT derived beta-cell function | 4 weeks | The difference in change between groups in OGTT derived beta cell function (disposition index calculated via the Matsuda index multiplied by the area-under-the-curve for the ratio of insulin/glucose) from baseline to follow-up. |
| Difference in change in fasting plasma gamma-glutamyl transferase | 4 weeks | The difference in change between groups in fasting levels of circulating gamma-glutamyl transferase (GGT) from baseline to follow-up. |
| Difference in change in fasting plasma aspartate aminotransferase | 4 weeks | The difference in change between groups in fasting levels of circulating aspartate aminotransferase (AST) from baseline to follow-up. |
| Difference in change in fasting plasma alanine aminotransferase | 4 weeks | The difference in change between groups in fasting levels of circulating alanine aminotransferase (ALT) from baseline to follow-up. |
| Difference in change in fasting plasma FGF21 | 4 weeks | The difference in change between groups in fasting plasma FGF21 from baseline to follow-up. |
| Difference in change in liver fat fraction | 4 weeks | The difference in change between groups in liver fat fraction (assessed via MRI) from baseline to follow-up. |
| Difference in change in fasting and post exercise plasma adiponectin | 4 weeks | The difference in change between groups in fasting pre- and post-exercise adiponectin in plasma following an exercise bout from baseline to follow-up. |
| Difference in change in adipose tissue mRNA targets relating to FGF21 signaling | 4 weeks | Difference in change between groups in expression of the genes encoding adiponectin, FGFR1c, FGFR3c, and β-Klotho in subcutaneous adipose tissue from baseline to follow-up. |
| Difference in change in fasting and post exercise plasma glucose | 4 weeks | The difference in change between groups in fasting pre- and post-exercise glucose in plasma following an exercise bout from baseline to follow-up. |
| Difference in change in fasting and post exercise plasma insulin | 4 weeks | The difference in change between groups in fasting pre- and post-exercise insulin in plasma following an exercise bout from baseline to follow-up. |
| Difference in change in the ratio of glucagon to insulin | 4 weeks | The difference in change between groups in the fasting and post-exercise glucagon-to-insulin ratio in plasma from baseline to follow-up. |
| Difference in change in fasting and post exercise plasma free fatty acids | 4 weeks | The difference in change between groups in fasting pre- and post-exercise free fatty acids in plasma following an exercise bout from baseline to follow-up. |
| Difference in change in HOMA indices | 4 weeks | The difference in change between groups in homeostatic model assessment of insulin resistance and beta-cell function from baseline to follow-up. |
| Difference in change in OGTT derived insulin sensitivity. | 4 weeks | The difference in change between groups in OGTT derived insulin sensitivity (Matsuda index) from baseline to follow-up. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Difference in change in FIB4 index | 4 weeks | The difference in change between groups in FIB4 from baseline to follow-up. |
| Difference in change in hunger | 4 weeks | Difference in change between groups in appetite and hunger (assessed via a visual analog scale) from baseline to follow-up. The higher scores indicate greater appetite and hunger compared to lower scores. |
| Difference in change in lipid parameters | 4 weeks | Difference in change between groups in traditional lipid parameters (i.e., total cholesterol, HDL-C, LDL-C, and triglycerides) from baseline to follow-up. |
| Difference in change in fatty liver index | 4 weeks | The difference in change between groups in fatty liver index from baseline to follow-up. |
| Difference in change in hepatic steatosis index | 4 weeks | The difference in change between groups in hepatis steatosis index from baseline to follow-up. |
Countries
Denmark
Contacts
Primary ContactCody G Durrer, Ph.D.
Outcome results
None listed