Computational Modeling of Glucose

Toxicity in Pancreatic -cells as a

Development Factor in Type II Diabetes

Abraham E. Torres Coln

Danilo T. Prez Rivera
Vernica L. Torres Torres
Mentor: Dr. Mayte Cruz Aponte

OUTLINE
Introduction of Type II Diabetes
Literature Review
o Biological Model of the Beta Cell Dynamic

Mathematical Model Review

o Propose Schematic of the Mathematical Model

Research Question
Objectives
References

What is Type II Diabetes?

Diabetes is a polygenic disease that is characterized by
the inability to metabolize glucose properly.
With type II diabetes, your body either resists the effects
of insulin or doesn't produce enough insulin to maintain
glucose homeostasis.
This phenomenon is known as insulin resistance.

Type-2 Diabetes
G
G
G
G
G
G
G

Glucose

Insulin

Recent Research on Type II Diabetes

Recent research has proven that there is a marked
difference between the states glucose toxicity and
glucose desensitization.
The ladder implies a short temporary state of
defective insulin secretion that is reversible either by
regulating glucose or by introduction of exogenous
insulin.
Glucose toxicity implies an irreversible state where
prolonged exposure to high concentrations of glucose
coupled with ROS decrease insulin synthesis and -cell
mass.

Lowered
Glucose Intake

Persistantly High
Glucose Levels

-cell
Exhaustion

Healthy
-cells

Glucose
Desensitization

Glucose
Toxicity
Insulin Inhibition
Elevated Glucose Levels

Adverse Effects of Chronic

Hyperglycemia on -cell Function

Proposed Mechanism for -cell

Mass Depletion
Accumulation of Metabolites
from Fatty Acid Esterification

Inhibited Fatty Acid

Processing in Mitochondria
Accumulation of Fatty Acids
as Long-chain Fatty acyl CoAs

Lipotoxicity

-cell
Apoptosis

Glucose
Toxicity

Autoxidation
Oxidative
Phosphorilation
Glycosylation
Glucosamine

Oxidative
Stress
Presence of peroxides

Sustained Rate of
-cell Replication
Increased Rate of
-cell Apoptosis

Decreased
-cell Mass

Recent Research in Mathematical Models

Building off an electrophysiological and biophysical
model of Keizer and Magnus (1989), Han et al. (2012)
have further defined the significance of Ca2+-induced
bursting of Beta Cells.
These models both bridged the experimental setting and
mathematical settings to be able to explain phenomena
from the electrical coupling of beta cells, to system-level
availability of glucose.

Recent Research in Mathematical Models

1. Basic Action Potential

2. Contribution of Ca2+
current.

3. Result and Impact on

Glucose-Insulin Concentrations

Recent Research in Mathematical Models

Equations

Hodgkin-Huxley type equations.

More than 10 differential equations,
including time-delays and gating
variables.
Highly non-linear relationships,
resisting most analytical treatment.
Numerical solutions obtained by 5th
order Runge-Kutta method.
Tracks changes in ith Beta cell and
outputs significance into compartment.

Main Research Question

Can a threshold level for glucose toxicity, beta cell mass, and
insulin be detected through computational modeling that will
allow assessment of the reversibility of Type 2 Diabetes
progression?

Objectives
To create a mathematical model that will allow us to
track the progression of this condition and that is
consistent with the observed biological behavior of the cell.
To determine to what extent Type II Diabetes deleterious
effects are reversible.

References
Butler, A. Janson, J. Bonner-Weir, S. Ritzel, R. Rizza, R. Butler, P. Cell Deficit and Increased -cell Apoptosis in Humans with
Type 2 Diabetes. [Online] 2002
Prentki M, Corkey BE 1996 Are the -cell signaling molecules malonyl
CoA and cytosylic long-chain acyl-CoA implicated in the multiple
tissue defects of obesity and NIDDM? Daibetes 45:273-283
Robertson, R. Harmon, J. Tran, P. Poitout, V. -Cell Glucose Toxicity,
Lipotoxicity, and Chronic and Chronic Oxidative Stress in Type 2
Diabetes [Online] 2003
Robertson, R. Poitout, V. Minireview Secondary -cell Failure in Type 2
Diabetes-A Convergence of Glucotoxicity and Lipotoxocity
[Online] 2002
Kyungreem Han, Hyuk Kangb, M.Y. Choic, Jinwoong Kima
and Myung-Shik, Lee. Mathematical model of the glucose
insulin regulatory system: From the bursting electrical activity in
pancreatic -cells to the glucose dynamics in the whole body.
2012.

Acknowledgments
We thank the BRIC program and the University of Puerto
Rico at Cayey for the opportunity to conduct this research
and our mentor Dr. Mayte Cruz-Aponte for guiding us.

Questions?