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Computational Modeling of Glucose

Toxicity in Pancreatic β-cells as a

Development Factor in Type II Diabetes

bra!am "# Torres Col$n

Danilo T# P%re& 'ivera

(er$nica )# Torres Torres

Mentor* Dr# Mayte% Cru& ponte

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3!at is Type II Diabetes4

• Diabetes is a polygenic disease t!at is

c!aracteri&ed by t!e inability to metaboli&e

glucose properly#

• 3it! type II diabetes5 your body eit!er resists t!e

effects of insulin or doesn6t produce enoug!

insulin to maintain glucose !omeostasis#

 – T!is p!enomenon is 7no.n as insulin

resistance#

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 Type-2 Diabetes

G

G

G

G

G

G

G

G

G

G

G

G

G

G

G

G

G

G

G

G

G

G

G

G   IGlucose   Insulin

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'ecent 'esearc! on Type II Diabetes

• 'ecent researc! !as proven t!at t!ere is a mar7ed

difference bet.een t!e states glucose toxicity and

glucose desensiti&ation#

• T!e ladder implies a s!ort temporary state of defective

insulin secretion t!at is reversible eit!er by regulating

glucose or by introduction of exogenous insulin#

•

 Glucose toxicity implies an irreversible state .!ere prolonged exposure to !ig! concentrations of glucose

coupled .it! '+2 decrease insulin synt!esis and β-cell

mass#

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8ealt!y

β-cells

Insulin In!ibition

Glucose

Desensiti&ation

"levated Glucose )evels

9-cell

"x!austion

Glucose

Toxicity

Persistantly 8ig!

Glucose )evels

dverse "ffects of C!ronic

8yperglycemia on β-cell Function

)o.ered

Glucose Inta7e

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Glucose

Toxicity

In!ibited Fatty cid

Processing in Mitoc!ondria

ccumulation of Fatty cids

as )ong-c!ain Fatty acyl Cos

)ipotoxicity

β-cell

poptosis

Decreased

β-cell Mass

2ustained 'ate of

β-cell 'eplication

Increased 'ate of

β-cell poptosis

Proposed Mec!anism for β-cell

Mass Depletion

+xidative

2tress

• utoxidation

• +xidative

P!osp!orilation• Glycosylation• Glucosamine

Presence of peroxides

ccumulation of Metabolites

from Fatty cid "sterification

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Main 'esearc! 0uestion

Can a t!res!old level for glucose toxicity5 beta cell mass5 and

insulin be detected t!roug! computational modeling t!at .illallo. t!e assessment of t!e reversibility of Type : Diabetes

 progression4

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+b1ectives

• To create a mat!ematical model t!at .ill allo. us to trac7

t!e progression of t!is condition and t!at is consistent

.it! t!e observed biological be!avior of t!e β-cell#

• To determine to .!at extent Type II Diabetes; deleterious

effects are reversible#

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2implified 2ystem Dynamics

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Proposed Mat!ematical ModelGlucose from

Glycogen /rea7do.n

Glucose Metaboli&ed

due to Insulin 'elease

Insulin 'eleased in

'esponse to "xcess Glucose

Insulin Decay

β-cell loss due to 8yperglycemia

Glucose "limination

t!roug! +xidation

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2imulations

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Future Plans• s a s!ort-term goal5 .e plan to incorporate !o. fatty acid

accumulation could exacerbate t!e loss of glucose !omeostasis

 by promoting insluin resistance in our mat!ematical model#• T!e follo.ing differential e

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0uestions4