In this study we will investigate the intracellular metabolism and inflammatory state of CD14+ cells from blood and different adipose tissue depots in subjects with type 2diabetes mellitus compared to lean and obese healthy controls.
ID
Source
Brief title
Condition
- Diabetic complications
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To determine metabolic pathways important for inflammatory function of CD14+
cells from blood, visceral and subcutaneous adipose tissue by gene expression
analysis (human microarray platform by affymetrix) using a bioinformatics
approach.
To determine the intracellular metabolism of CD14+ cells from blood and adipose
tissue by measurements of metabolites in cell lysates or supernatants of the
(cultured) immune cells and by analysis of intracellular metabolic signalling
pathways on protein and gene expression level.
Secondary outcome
To determine the differences in inflammatory potential of CD14+ cells isolated
from lean, obese and diabetic subjects by histological assessment of adipocyte
size, macrophage infiltration and formation of crown-like structures in the
different adipose tissue depots and by measurements of plasma cytokines and
cytokines released upon stimulation of cultured cells isolated from the blood.
Background summary
The adipose tissue is a metabolically highly active tissue affecting many other
tissues such as the liver, skeletal muscle and vasculature. The adipose tissue
produces and secretes a wide variety of proteins. Adipose tissues can differ in
their metabolic characteristics dependent on their anatomical location, namely
the visceral and subcutaneous depots. Obesity is accompanied by an accumulation
of the adipose tissue mass as well as a hypertrophy and abnormal secretory
function of adipocytes. Furthermore, obesity is associated with an increased
infiltration of monocytes and macrophages into the adipose tissue, leading to
impaired lipid and glucose metabolism that is driven by an enhanced state of
inflammation. Therefore, the adipose tissue associated with a more
pro-inflammatory state is known to play a central role in the link between
obesity and insulin resistance. However, underlying mechanisms leading to
adipose tissue inflammation still remain elusive.
Recent research has revealed that the inflammatory function of macrophages is
determined by their metabolic status and is thereby influenced by the metabolic
environment that the cell is exposed to. Thus, different adipose tissue depots
might differentially influence the metabolism and thus inflammatory function of
monocytes and macrophages. Moreover, we hypothesize that the adverse metabolic
milieu in obese, insulin-resistant adipose tissue, i.e. high glucose levels
(hyperglycemia), hypoxia and elevated free fatty acid levels, is leading to a
shift in macrophage metabolism towards glycolysis and thereby dictates the
development of adipose tissue inflammation during obesity.
Study objective
In this study we will investigate the intracellular metabolism and inflammatory
state of CD14+ cells from blood and different adipose tissue depots in subjects
with type 2diabetes mellitus compared to lean and obese healthy controls.
Study design
In this case-control study, the intracellular metabolism and inflammatory
function of CD14+ cells isolates from the blood and the adipose tissue will be
characterized in lean and obese healthy human volunteers as well as in T2DM
patients. To this purpose, paired samples of visceral adipose tissue,
subcutaneous adipose tissue (each approximately 5g) and blood will be obtained
from 45 subjects undergoing elective abdominal surgery, such as
cholecystectomy. Prior to the surgical procedure, subjects will undergo
anthropometric measurements (BMI). Blood will be drawn to determine hsCRP,
plasma glucose, HbA1c, plasma insulin and plasma lipids and to isolate CD14+
cells for a detailed phenotypic characterization. During the surgery, adipose
tissue biopsies of approximately five grams will be obtained from both the
abdominal subcutaneous and omental visceral depots. Fractions of these biopsies
will immediately be stored in transport medium for further processing and
analysis at the laboratory of Internal Medicine.
Study burden and risks
The additional burden for the subjects associated with this study is minimal.
There is a small risk of bleeding at the place where the adipose tissue
biopsies will be obtained. This could directly be treated by the surgeon.
Moreover, a blood sample of 20 ml will be taken prior to the surgery when the
patient is already anaesthetized. Thus, there will be no extra physical or
psychological discomfort associated with the participation in the study and the
risks which are already associated with the surgery will not be increased.
This study is not directly beneficial for the individual subjects, but the
results obtained from this study might increase our understanding of innate
immune cells and their intracellular metabolism in relation to the development
of diabetes. This in turn, could be of great importance in developing future
therapeutics for obese patients with diabetes.
Geert Grooteplein Zuid 8
Nijmegen 6525GA
NL
Geert Grooteplein Zuid 8
Nijmegen 6525GA
NL
Listed location countries
Age
Inclusion criteria
group 1 (males and females): age: 35-75 years, body mass index (BMI) of 19-25 kg/m2;group 2 (males and females): age: 35-75 years, body mass index (BMI) of >25 kg/m2 ;group 3 (males and females): age: 35-75 years, body mass index (BMI) of >25 kg/m2, diagnosis of T2DM
Exclusion criteria
any presence of a chronic or acute inflammation and/or autoimmune disorder, any anti-inflammatory medication, metabolic diseases, endocrine diseases and chronic and/or acute inflammatory diseases (high sensitivity C-reactive protein > 1 mg/liter)
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 | NL55814.091.15 |