Centre for Medical Systems Biology
Jan Bert van Klinken, LUMC
Introduction
Aim
Development of a mathematical model of whole-body
metabolism, in relation to metabolic syndrome
(obesity, dyslipidemia, high blood pressure, insulin resistance,...)
At LUMC focus on whole-body level.
?
At TU/e focus on cellular level.
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The hyperinsulinemic-euglycemic clamp
Insulin resistance: a condition in which normal amounts of insulin are
inadequate to produce a normal insulin response in muscle, liver and
fat cells
LIVER
Plasma glucose
GLUCOSE INFUSION
-
+
PERIPHERAL
TISSUES
INSULIN INFUSION
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Indirect Calorimetry
Metabolic flexibility: the ability to adapt fuel selection to fuel availability
C6H12O6 + 6O2  6CO2 + 6H2O
glucose
tripalmitin
RER 
2 C51H98O6 + 145O2  102CO2 + 98H2O
VCO 2
1
Carb
VO 2
RER = 1.0
RER = 0.7
Fat
0.7
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Modelling Approach
Mathematical model will be based on that of Hall, which explains at
a macrolevel how changes in body weight and composition result
from changes in food intake.
Existing model will be extended with more detailed regulation
mechanisms for glucose and fat homeostasis and organ specificity.
Hall (2006) Am J Physiol
Endocrinol Metab
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Modelling Approach
In order to be better able to validate the mathematical model,
existing experimental techniques and methods for data analysis
are being optimised.
- relate time patterns in variables measured by metabolic cage
(food intake, physical activity, O2 and CO2 exchange) by means
of digital signal processing techniques.
- refine calculations of macronutrient oxidation rates (from O2
and CO2 exchange) for specific diet compositions, such that
whole-body energy balance can be deduced.
- perform clamp and other tracer experiments with stable
isotopes in order to get a more comprehensive picture of
macronutrient flows and their regulation.
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Summary
*
Main focus in our Systems Biology approach lies on quantitative
understanding
*
Dynamic mathematical models simple (typically few dynamic
variables)
*
Heterogeneous experimental data: metabolic cage, dexa scan,
clamp, tracer experiments, Western blot
*
Broad range of analysis techniques: digital signal processing,
statistics, stoichiometric analysis (simulation, control analysis)
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