Biology Reference
In-Depth Information
taking advantage of the high signal strength of water resonances, commonly
used in MRI experiments but which are being increasingly applied to measuring
metabolic parameters, such as oxygen consumption and energy production.
The future will also require advances in the theories of metabolic control,
which presently guide and interpret experimentation. A most promising study
of 'Control in Multi-level Reaction Networks' by Hofmeyr and Westerhoff
(Hofmeyr and Westerhoff, 2001) is relevant for extending the experimental
results discussed above. They have developed a formal framework for expressing
the control of the whole system in terms of its component modules. In our exper-
iments, the pathway of glycogenesis would be one such module and the area of
systemic physiology of glucose would be identified as another module. The the-
ory also allowed for the modular properties to change as a result of interactions
with other elements of the whole system. The modules are not necessarily at the
same level of organization so that the physiological and biochemical levels of our
experiment would be suitable inputs for this framework. Interactions between the
modules are 'only by means of regulatory or catalytic effects - a chemical species
in one module may affect the rate of a reaction in another module by binding to an
enzyme or a transport system or by acting as a catalyst'. In our experiments inter-
actions between physiological and biochemical modules are effected by glucose.
2. FROM MOLECULES TO DIABETES VIA METABOLISM AND
SYSTEMIC PHYSIOLOGY
Experiments using these methods have extended the physiological understanding
to explain the control of glucose metabolism in Non-Insulin-Dependent Diabetes
(NIDD). In NIDD, the pancreas secretes insulin but the body does not use
it effectively to remove glucose from the blood. The disease has a genetic
component, as evidenced by family histories and by its high concordance in
identical twins. We know that it also has life style contributions, as a controlled
diet and active exercise can contribute to delaying or ultimately avoiding the
high blood glucose and its harmful consequences. In early life, the pancreas
overproduces insulin which compensates for its ineffectiveness, so that blood
glucose concentrations are maintained in the normal range. However, in later
life, the overproduction may cease, creating high concentrations of blood glucose
that will subsequently damage eyes, muscle, or other organs. On the basis of
these properties and the definition of the disease by centuries of medical science,
and armed by earlier biochemical studies, we studied this disease in humans by
13
C MRS experiments. (for review see Shulman & Rothman, 2001 and 2005,
Shulman & Schafer, 2005). We located the particular chemical step in the
pathway of glycogen synthesis in NIDD patients that is responsible for the slower
clearance of glucose under insulin stimulation (Fig. 3). The MRS experiments
