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 Dynamics

Research Question and Objectives

Proposed Schematic of the Mathematical Model
Future Plans

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 Glucose
G
G
G
G

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

Healthy
-cells

Glucose
Desensitization

-cell
Exhaustion

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

Main Research Question

Can a threshold level for glucose toxicity, beta cell mass, and
insulin be detected through computational modeling that will
allow the 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.

Simplified System Dynamics

Proposed Mathematical Model

Glucose from
Glycogen Breakdown

Glucose Elimination
through Oxidation

Glucose Metabolized
due to Insulin Release
Insulin Decay

Insulin Released in
Response to Excess Glucose

-cell loss due to Hyperglycemia

Simulations

Future Plans
As a short-term goal, we plan to incorporate how fatty acid
accumulation could exacerbate the loss of glucose homeostasis
by promoting insluin resistance in our mathematical model.
The following differential equations have currently been
proposed:

Furthermore, we aim to include other variables that could refine

our modeling of the -cell dynamics in a state of glucotoxicity
like the effects of reactive oxidative species in the cell count.

Questions?