A Model Approach

MATHEMATICAL MODELING PROVIDES AN INCREASINGLY CLEAR PICTURE OF

GLUCOSE AND NEURAL SYSTEMS.
Claudio Cobelli and Mauro Ursino | July 13, 2015 | 0 Comments

Mathematical modeling of physiological systems is a fundamental milestone of biomedical engineering.

Models allow for the quantitative understanding of the intimate functions of a biological system, estimating
parameters that are not accessible to direct measurement and performing in silico trials by simulating and
tracking a physiological system in case its function has been deranged. Modeling has always been central in
the Italian biomedical engineering community. Here, we review the progress in two areas: glucose and
neurocomputational modeling with an emphasis on their clinical impact.

GLUCOSE MODELING
The glucose system has received considerable interest in recent decades due to the growing prevalence of
diabetes [1].

Models to Measure: Minimal

Minimal (coarse-grained) modelsas opposed to maximal (fine-grained) models discussed laterare
parsimonious descriptions of the key components of the system and are capable of measuring the crucial
processes of glucose metabolism [2].
Glucose and Insulin Fixes
Glucose
Glucose production and utilization vary as an effect of a perturbation, e.g., a meal, due to endocrine and
nervous control mechanisms. Glucose tracers and models are needed to estimate the rate of appearance, Ra,
and disappearance, Rd, of glucose. New experimental guidelines for the accurate estimation of Ra and Rd have
been developed, particularly the tracer-to-tracee clamp technique with stable isotopes. Depending on the
question being asked, both dual and triple tracer protocols can be used.
Insulin
To quantitatively assess an insulin secretion profile after a glucose stimulus, a deconvolution method is needed.
However, it is not possible to reconstruct pancreatic secretion from plasma insulin concentration since insulin
is secreted in the portal vein and then degraded by the liver before appearing in circulation. This problem was
bypassed by using C-peptidesecreted equimolarly with insulin, but not extracted by the liverand the stateof-the-art method is the stochastic deconvolution.
Insulin and Glucose Control
Insulin
To assess insulin control, an intravenous glucose tolerance test (IVGTT), an oral glucose tolerance test
(OGTT), or a mixed-meal glucose tolerance test (MTT) must be used. Linear dynamic models are too
simplistic to describe insulin action. The concept of minimal parsimonious models was introduced and allowed

us to arrive at a nonlinear model with glucose kinetics described with one compartment and remote (with
respect to plasma) insulin controlling both the net hepatic glucose balance and the peripheral glucose disposal.
The model provides an index of insulin sensitivity, which was validated in numerous studies and employed in
more than 1,000 papers. This index does not account for how fast or slow insulin action takes place: A new
dynamic index was later introduced to also account for the timing of insulin action in addition to the
magnitude. Glucose kinetics requires at least a two-compartment model: Undermodeling the system
underestimates insulin sensitivity. An improved two-compartment glucose minimal model has been proposed
in a Bayesian maximum a posteriori (MAP) context.
IVGTT establishes glucose and insulin concentrations that are not seen in normal life. It is desirable to
measure insulin sensitivity in the presence of physiological conditions, e.g., during MTT or OGTT. For this
purpose, the oral glucose minimal model has been developed [Figure 1(a)] by using a parametric function
describing the rate of glucose appearance in plasma through the gastrointestinal tract. This added complexity
renders the model nonidentifiable, i.e., there is the need to assume some parameter values and to use a MAP
estimator. The model provides an index of insulin sensitivity, which has also been validated. Also for
MTT/OGTT, a dynamic insulin sensitivity index can be calculated.

FIGURE 1 The (a) glucose and (b) C-peptide oral minimal models. (c), (d) A schematic diagram to illustrate the importance of
expressing beta-cell responsivity in relation to insulin sensitivity by using the disposition index (DI) metric [i.e., the product of
beta-cell responsivity times insulin sensitivity (SI) is assumed to be a constant]. (c) A normal subject (state I) reacts to impaired
SI by increasing beta-cell responsivity (state II), while a subject with impaired tolerance does not (state 2). In state II, beta-cell
responsivity is increased but the disposition index (DI) is unchanged, and normal glucose tolerance is retained normal, while in
state 2, beta-cell responsivity is normal but not adequate to compensate for the decreased SI (state 2), and glucose intolerance is
developed. (d) Impaired glucose tolerance can arise due to defects of beta-cell responsivity and/or defects of SI. In this
hypothetical example, subject x is intolerant due to his poor beta-cell function, while subject y has poor SI. The ability to dissect
the underlying physiological defects (SI or beta-cell responsivity) allows us to optimize medical treatments, i.e., these two
individuals need opposite therapy vectors.

Both the IVGTT and MTT/OGTT minimal models provide a net effect measure of insulin action, i.e., the
ability of insulin to inhibit glucose production and stimulate glucose utilization. It is possible to dissect insulin
action into its two individual components by adding a glucose tracer to the IVGTT or MTT/OGTT. The labeled

IVGTT single-compartment model came first and was later improved by a two-compartment version. More
recently, a stable, labeled MTT/OGTT model was developed that provides validated indices of disposal and
liver insulin sensitivity.
While whole-body models can provide an overall measure of insulin action, it is important to measure insulin
action at the organ/tissue level, e.g., the skeletal muscle, by quantitating the effect of insulin on the individual
steps of glucose metabolism, i.e., transport from plasma to interstitium, transport from interstitium to cell, and
phosphorylation. Understanding which metabolic step is impaired can also guide a targeted therapeutic
strategy. Direct measurement of these individual steps is not possible, and the most recent model-based
approach is based on positron emission tomography (PET). A five-rate-constant model is needed for studying
glucose metabolism in the skeletal muscle from [18F]fluorodeoxyglucose ([18F]FDG) data. The model has
revealed inefficient transport and phosphorylation [18F]FDG rate constants in obesity and type 2 diabetes as
well as the plasticity of the system; i.e., defects can be substantially reversed with weight loss. From [18F]FDG
modeling, only glucose fractional uptake, not glucose transport and phosphorylation rate constants, can be
estimated. To this end, a multiple-tracer approach has been proposed with three different PET tracers injected
sequentially.
Insulin
A mechanistic description of pancreatic insulin secretion is needed to quantitate indices of beta-cell function.
This was first proposed for first- and second-phase IVGTT and later for MTT/OGTT. Two responsivity indices
were derived related to the dynamic (i.e., proportional to the rate of change) and the static (i.e., proportional to)
glucose control. Since the glucoseinsulin system is negative feedback, beta-cell function needs to be
interpreted in light of the prevailing insulin sensitivity. One possibility is to resort to a normalization of betacell function based on the disposition index (DI) paradigm. This concept is clearly illustrated above in Figure
1(c) and (d): Beta-cells ability to respond to a decrease in insulin sensitivity needs to be counteracted by an
increase of insulin secretion. The disposition paradigm allows for not only assessing whether the two phases of
beta-cell function are appropriate in light of the prevailing insulin sensitivity but also monitoring their
variations in time and quantifying the effect of different treatment strategies.

Models to Simulate: Maximal

Large-scale maximal (fine-grain) models are needed for simulation. These models are comprehensive
descriptions that attempt to fully implement the body of knowledge about a system into a generally large,
nonlinear model of high order with several parameters [3].
Theories of Insulin Secretion
The dynamics of insulin secretion was investigated in the 1960s and 1970s in the perfused pancreas mainly
from the rat. A model-based theory was proposed where insulin was located in packets. Recently, an update of
the model has been put forward based on data of cell-to-cell heterogeneity with respect to their activation
threshold. By using multiscale modeling, the relation between the subcellular events described in this model
and the beta-cell minimal model indices has been also investigated.

In Silico Experiments in Type 1 Diabetes

There are situations in which in silico experiments with large-scale models could be of enormous value. In
fact, it is often not possible, appropriate, convenient, or desirable to perform an experiment on a system
because it cannot be done at all or is too difficult, too dangerous, or unethical. In such cases, simulation offers
an alternative form of in silico experimentation on the system. A number of simulation models have been
published in the last four decades, but their impact has been very modest in the control of type 1 diabetes. In
fact, all these models were average, meaning that they are only able to simulate the average population
dynamics, not the interindividual variability. The average-model approach is not sufficient for realistic in silico
experimentation with control scenarios, where facing with intersubject variability is particularly challenging.
Building on the large-scale model developed in the healthy state from a rich triple tracer meal data set, a type 1
diabetes simulator has been developed that can realistically describe intersubject variability. This was a
paradigm change in the field of type 1 diabetes: For the first time, a computer model has been accepted by the
U.S. Food and Drug Administration as a substitute of animal trials for certain insulin treatments. In this
simulator, a virtual human is described as a combination of several glucose, insulin, and glucagon
subsystems (Figure 2).

FIGURE 2 A scheme of the model included in the U.S. Food and Drug Administration accepted type 1 diabetes simulator.

In summary, the model consists of 13 differential equations and 35 parameters for each subject. The simulator
is equipped with 100 virtual adults, 100 adolescents, and 100 children, spanning the variability of the type 1
diabetes population observed in vivo. Each virtual subject is represented by a model parameter vector, which is
randomly extracted from an appropriate joint parameter distribution. This simulator has been adopted by the
Juvenile Diabetes Research Foundation (JDRF) Artificial Pancreas Consortium and has allowed an important
acceleration of closed-loop studies with a number of regulatory approvals obtained based on simulation only.
The simulator has been used by 32 research groups in academia and by five companies active in the field of
diabetes and has led to 63 publications in peer-reviewed journals.

Models to Control
A patient with type 1 diabetes faces a lifelong behavior-controlled optimization problem: The administration of
external insulin to control glycemia enters a stochastic scenario where hyperglycemia and hypoglycemia may
not be easily prevented by standard open-loop therapy. To restore the missing loop, a system combining a
glucose sensor, a control algorithm, and an insulin infusion device is needed: the so-called artificial pancreas
(AP). Recently, thanks to technological progress in both subcutaneous (SC) glucose sensing and insulin
delivery, the development of new controllers known as model-predictive control (MPC) and the possibility of
performing in silico trials have resulted in an increase in AP research, which is also facilitated by support from
several bodies, including the JDRF, the National Institutes of Health, and the European Union.
The new wave of SC AP based on MPC uses prediction of glucose dynamics by using a model of the patient
and, as a result, appears better suited for mitigation of time delays due to SC glucose sensing and insulin
infusion. MPC also allows us to incorporate constraints on the insulin delivery rate and glucose values that
safeguard against insulin overdose or extreme BG fluctuations and can cope with inter- and intrapatient
variability. Another important design element is the concept of the modular approach to AP design, which has
the advantage of allowing sequential development, clinical testing, and ambulatory acceptance of elements
(modules) of the closed-loop system. The various modules have different responsibilities, such as the
prevention of hypoglycemia, postprandial insulin correction boluses, basal rate control, and administration of
premeal boluses, and act on different time scales. This modular MPC algorithm has been successfully
employed in two hospital trials, showing reduced average glucose without increasing patients risk for
hypoglycemia.
However, none of these previous systems had an AP system suitable for outpatient use. The critical missing
features were portability and a user interface designed to be operated by the patient. The AP transition to
portability and ambulatory use began in 2011 with the introduction of the Diabetes Assistant (DiAs)the first
portable outpatient AP platform, which uses an Android smartphone as a computational platform (Figure 3). In
October 2011, the wearable DiAs-based AP was used in two outpatient pilot trials done simultaneously at the
universities of Padova, Italy, and Montpellier, France. These two-day trials enabled a series of feasibility and
efficacy studies of ambulatory closed-loop control conducted at the universities of Virginia, Padova, and
Montpellier, and at Sansum Diabetes Research Institute, Santa Barbara, California. Recently, an outpatient

multinight bedside closed-loop control study has been completed, showing a significant improvement in
morning and overnight glucose levels and time in the target range. At present, multisite randomized crossover
trials of two months are being conducted in an outpatient setting.

FIGURE 3 The outpatient wearable AP system.

NEUROCOMPUTATIONAL MODELING
The study of neural mechanisms with mathematical models (a subject often named computational
neuroscience) is a relatively new discipline that is becoming crucially important within the field of
neuroscience. It aims at providing a better understanding of brain function and converting this knowledge into
neurological clinical applications. For the sake of simplicity, in the following sections, three main problems
will be considered within the domain of computational neuroscience, although this distinction is often more
didactical than real.

Connectivity
A classical problem in modern neuroscience consists in finding the connectivity patterns among brain regions
during specific cognitive tasks. The basic idea is that the brain can be described as a network, i.e., a connected
system of units (representing specialized regions in the brain) linked via communication pathways. In fact,
even the solution of simple cognitive problems requires the participation of many different specialized regions

that are recruited during the task and reciprocally exchange information in a temporally dependent way so that
the activity in one region is influenced by the temporal activity in the others. The use of connectivity graphs is
fundamental to summarize this information-exchange process and to follow its alterations in neurological
disorders.
Astolfi et al. used time-varying multivariate autoregressive models to describe the interactions among cortical
areas based on Granger causality, starting from high-resolution electroencephalography (EEG) recordings [4].
They demonstrated that this approach allows for the estimation of rapidly changing influences between the
cortical areas during simple motor tasks. An important aspect of most connectivity studies is that the cortical
activities in the regions of interest (from which the autoregressive models are estimated) are reconstructed
from scalp EEG using a realistic geometry head volume conduction model. Data obtained with the previous
models are generally summarized using the graph theory for which a large body of indexes and tools are
available in the literature: The final network is represented by means of an oriented graph from which the main
connectivity parameters can be assessed in objective quantitative terms. These techniques may have important
clinical applications since connectivity patterns are altered in neurological pathologies such as schizophrenia,
brain reorganization after a stroke, or following motor imagery-based braincomputer interface training.

EEG and fMRI Fusion

A second important modeling problem in computational neuroscience concerns the relationship between EEG
and functional magnetic resonance imaging (fMRI). The two techniques, in fact, are mutually complementary:
EEG exhibits a good temporal resolution but poor spatial precision; conversely, fMRI exhibits very good
spatial resolution but poor temporal discrimination capacity. Furthermore, the two techniques measure different
quantities (i.e., EEG measures electrical activity and fMRI measures metabolism changes). The best way to
fuse data from the two techniques is to build mathematical models that are able to integrate both aspects in a
coherent framework. In this regard, some authors used autoregressive models estimated from cortical sources
derived from EEG data: Determination of the priors in the resolution of the linear inverse problem can be
performed with the use of information from the hemodynamic responses, as revealed in the cortical areas by
fMRI. Another approach makes use of neural mass models; in these, individual components of the network
consist of oscillatory circuits that are able to simulate EEG waves and relate them with metabolic neuron
activity. A possible clinical application of these models concerns not only the interpretation of EEG patterns
and their relation with fMRI but also the study of brain waves, such as those occurring during epilepsy, sleep,
or high cognitive tasks.

Biologically Inspired Neural Networks

FIGURE 4 A synthesis of the fundamental elements that should be incorporated in biologically inspired neurocomputational
models.

Finally, an important research field concerns the construction of biologically inspired neural networks. Their
aim is to gain a deeper understanding of the neurophysiological mechanisms underlying some cognitive
processes, such as memory, perception, and attention. In these models, as shown in Figure 4, the activity of
individual neural groups is described using equations inspired by the physiology (either using spiking neurons
or rate neurons, i.e., neurons whose output is proportional to the firing rate) connected via reliable synapses;
emphasis is given to the topology of the network and to the synaptic relationships (excitatory or inhibitory)
among neurons.
The results can be used to not only simulate physiological data but also mimic behavioral experiments. These
models differ from those summarized previously in two main aspects. First, the individual neurons and their
connections must have a clear neurophysiological counterpart (although largely simplified); i.e., the topology
is established a priori on the basis of neurophysiological knowledge rather than being derived a posteriori from
data. Second, synapses are plastic and can be trained using physiological learning rules to simulate the
emergence of cognitive behavior from experience. Several authors have employed these models to simulate
different cognitive processes. Some used a neural network model to simulate semantic memory and its
relationship with language or to study the foundation of human mathematical learning [5].

The clinical benefits of these models lie in the possibility to understand the origin of neurological semantic
disorders in which patients show the inability to recognize objects belonging to individual categories. Another
crucial problem on which many modeling efforts are presently devoted concerns multisensory integration, i.e.,
the ability of the brain to link information from different sensory modalities (i.e., visual, auditory, or tactile) to
improve the perception of external events in difficult or noisy conditions [6]. In neurology, multisensory
models can be exploited to design or optimize clinical procedures for the rehabilitation of neurological patients
with individual sensory deficits. (For instance, patients with visual deficits can be helped by the use of
congruent multisensory audiovisual stimuli.)
A part of the brain that has been extensively investigated with mathematical models is the hippocampus, a
bilateral subcortical temporal region implicated in individual episodic memory and in allocentric spatial
navigation. A peculiarity of hippocampal circuits consists in the strong feedback connections among neurons,
which self-organize during storage, resulting in a typical attractor dynamics. The dynamics of these models is
further complicated by the presence of oscillating patterns (such as theta waves in the range of 47 Hz), which
flexibly coordinate the hippocampal regions. Models explain how such waves support a flexible associative
memory formation and retrieval and allow for the memorization of a list of items, such as during the recovery
of a whole trajectory in a spatial navigation task. In clinics, these models may help understanding important
neurological deficits such as schizophrenia and, above all, Alzheimers disease, in which the hippocampus is
one of the first regions to be damaged, resulting in memory loss and disorientation.
Lastly, the basal ganglia, a brain structure implicated in action selection and in the initiation and termination of
movements, has received much modeling attention in the past due to its crucial role in Parkinsons disease. In
particular, dopamine depletion in the basal ganglia of Parkinsons patients gives rise to both motor and postural
as well as learning impairments. Cellular-based models of the basal ganglia allow the analysis of the role of
deep brain stimulation for the treatment of these patients. The results are comparable with clinical and
experimental evidence on the effect of deep brain stimulation.
In summary, it is ever more apparent that mathematical modeling is having an influence on clinical practice in
situations where direct measurement would otherwise be impossible. In the future, it is likely that our
understanding of physiological systems will continue to improve as modeling systems become more
sophisticated, leading to a commensurate advance in treatment options for patients with diabetes or
neurological deficits.

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