To study the mechanisms underlying ectopic fat accumulation (i.e. in liver or muscle) by excess intake of added sugars in long-term obestiy in relation to insulin resistance and metabolic complications.
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
- Lipid metabolism disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Differences in regulation of lipogenic pathways in insulin-sensitive tissues by
fructose versus glucose intake in obese humans with or without hepatic
steatosis.
Secondary outcome
-regulation of de novo lipogenesis (lipid flux) in response to oral fructose or
glucose
-the role of important lipogenic enzymes (such as ChREBP-*/* and FGF21) in de
novo lipogenesis, fat distribution and ectopic fat accumulation
-the role of these pathways in peripheral and hepatic insulin resistance and
endogenous glucose production-differences in lipid species composition in relation to gene expression
profiles and lipid and glucose fluxes
-differences in de novo lipogenesis, fat distribution and ectopic fat
accumulation in relation to systemic and hepatic insulin resistance
Background summary
Obesity and insulin resistance/type 2 diabetes are an increasing threat to
public health worldwide. The mechanisms underlying insulin resistance are
partly elucidated. In long-term obesity, de novo lipogenesis (DNL) in white
adipose tissue (WAT) is eventually decreased, and lipids accumulate in ectopic
sites such as liver and muscle. Altered lipid metabolism and storage is
implicated in the development of insulin resistance and the metabolic syndrome.
Excessive dietary carbohydrate intake is linked with altered DNL and hepatic
steatosis. There appears to be a broad variety between overweight individuals
with respect to metabolic handling of caloric/carbohydrate excess, resulting in
metabolically healthy and metabolically unhealthy subtypes of obesity. By
studying the interactions between intake of (fruit) sugar, lipid and sugar
metabolism as well as accumulation of liver fat in different subtypes of
obesity, we hope to gain more insight into the pathophysiologic mechanisms
underlying metabolic disease and find novel therapeutic targets.
Study objective
To study the mechanisms underlying ectopic fat accumulation (i.e. in liver or
muscle) by excess intake of added sugars in long-term obestiy in relation to
insulin resistance and metabolic complications.
Study design
Observational study with cross-sectional design
Study burden and risks
Subjects will visit the metabolic unit on three occasions (screening, study day
1, study day 2). Lipid and glucose fluxes will be measured using stable isotope
tracers that behave like their natural substrates and have been previously used
without adverse effects when infused or ingested. Liver fat will be assessed
during MRS, which is harmless. Fructose and glucose drinks will be used
preoperatively to assess their effect on carbohydrate and lipid metabolism
pathways. Risks associated with participation (hypoglycaemia during the
hyperinsulinemic clamp, bleeding from the biopsy sites) will be kept to minimum
by frequent bedside glucose monitoring and several measures to check for and
promote haemostasis. We believe that the scientific value of our findings will
outweigh the burden and risks associated with participation.
Meibergdreef 9
Amsterdam 1105AZ
NL
Meibergdreef 9
Amsterdam 1105AZ
NL
Listed location countries
Age
Inclusion criteria
-eligible and scheduled for bariatric surgery (gastric bypass)
-18-65 years of age
-ability to provide informed consent
-stable weight 3 months prior to inclusion
-willingness to stop lipid lowering medication 4 weeks prior to start
Exclusion criteria
-primary lipid disorder
-childhood onset obesity (i.e. <12 years of age)
-use of exogenous insulin, GLP1 agonists or DDP4 inhibitors
-all medica! and psychiatric conditions except for obesity-related diseases
-coagulation disorders
-uncontrolled hypertension (blood pressure >150/95 mmHg)
-renal insufficiency (plasma creatinin >150 umol/l)
-excessive alcohol intake (>14 units/week)
-pregnancy, breastfeeding
-contraindication to MR scanning (e.g. pacemaker, metallic foreign body, claustrophobia)
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL49576.018.14 |