How Can We Cure Diabetes?

Clayton E. Mathews, Ph. D.Department of Pathology

Diabetes Center of ExcellenceUniversity of Florida College of Medicine

What do you need to cure diabetes?

1. What is diabetes?

2. People & More People

3. $

4. Know how diabetes develops

• People

• $

5. Good/Great Ideas!

• People

• $

What do you need to cure diabetes?

1. What is diabetes?

2. People & More People

3. $

4. Know how diabetes develops

• People

• $

5. Good/Great Ideas!

• People

• $

-+

Glucose Production

Glucose Absorp

tion

BloodGlucose

Brain &Nervous System

GUT

LiverG

luco

se U

ptake

Glucose Uptake

Fat

Muscle

IsletPancreas

Regulation of Blood Glucose

-+

Glucose Production

Glucose Absorp

tion

Brain &Nervous System

GUT

LiverG

luco

se U

ptake

Glucose Uptake

Fat

Muscle

IsletPancreas

Regulation of Blood Glucose

BloodGlucose

What is Diabetes?• Type 1 diabetes

– Accounts for 10-15% of all people with the disease

• Monogenic autoimmune diabetes (i.e. APS1*, XLAAD)

• Latent autoimmune diabetes of adults (LADA)

– Adult onset T1D

• Type 2 diabetes– Affecting 85-90% of all people with the disease

– Atypical or ketosis-prone type 2 diabetes*

– Prediabetes: blood glucose levels are higher than normal

• Gestational diabetes mellitus (GDM)– Occurs in about 2%–10% of all pregnancies-improves after delivery

– About 20%–50% of affected women develop type 2 diabetes later

• Maturity onset diabetes of the young (MODY)

– Hereditary forms of diabetes: mutations in autosomal dominant genes

• Mitochondrial Diabetes (MIDD)

• Neonatal Diabetes– Congenital impairment in insulin secretion (GCK, KCNJ11, INS, ABCC8)

• Syndromes of Extreme Insulin Resistance

• CGL (congenital generalized lipodystrophy)– Severe Islet Amyloidosis

• Familial Partial Lipodystrophy, Dunnigan Variety (FPLD)– Adipose disorder (Laminin A)

Type 2

GDMType 1

American Diabetes Association. Diabetes Care January 2012 35:S1-S2*Requires confirmation by repeat testing

Symptoms of diabetes Polyuria, polydipsia, polyphagia, diabetic

plus ketoacidosis (DKA)

Random plasma glucose 200 mg/dL* (11mmol/L)

or

A1c 6.5%

or

Fasting plasma glucose (FPG) 126 mg/dL* (7.0mmol/L)

or

Oral glucose tolerancetest (OGTT) with 2-hour value 200 mg/dL* (11mmol/L)

and confirmed by

Presence of islet autoantibodies GADA, ICA, IA-2A, IAA

Making the Diagnosis of Type 1 Diabetes

Source: SEARCH for Diabetes in Youth Study NHW=non-Hispanic whites; NHB=non-Hispanic blacks; H=Hispanics/Latinos;API=Asian/Pacific Islander Americans; AI=American Indians

Who does Type 1 diabetes strike?

For the past few decades T1D incidence has been increasing at a rate of 3% per year: total populationThe incidence in the young (<5 years of age) has been increasing at a rate of 5.4% per year

TYPE 1 DIABETES 2012 STATUS QUO UNACCEPTABLE

• Epidemic worldwide

• Increasing burden to individual and society

• No recent improvement in early mortality

• No reduction in acute complications

• Potential benefits of improved glycemic control reaching a minority of patients

• Current ‘successful’ immune interventions of questionable translation

What do you need to cure diabetes?

1. What is diabetes?

2. People & More People

3. $

4. Know how diabetes develops

• People

• $

5. Good/Great Ideas!

• People

• Even more $

Clinical Staff &

Physicians

Building a Diabetes Research Team

Clinical Trialists

ClinicalInvesti-gators

Basic Scientists

Building a Diabetes Research Team

Clinical Staff &

Physicians

Clinical Trialists

ClinicalInvesti-gators

Basic Scientist

s

What do you need to cure diabetes?

1. What is diabetes?

2. People & More People

3. $

4. Know how diabetes

develops

• People

• $

5. Great Ideas!

• People

• Even more $

Pietropaolo M. et al. Diabetologia 45: 66-76, 2002

Cumulative risk of developing clinical Type 1 diabetes in relatives of T1DM probands using Ab markers alone (IAA, GAD65, IA-2, ICA)

1 Ab2 Abs3 Abs4 Abs

0 Abs

Log Rank

P < 0.00001

Per

cen

t T

1D-F

ree

β cells dendritic cells CD8+ T cells

pLN

Infiltrated islets

INSULIN, CD8, CD4

GeneticSusceptibility

No Disease

SubclinicalT1D

EnvironmentalExposure•Diet•Viral Infections•Maternal Environment•Lack of Environmental Exposure

ClinicalT1D

No Disease or Remission

Protective Factors

PromotingFactors•Low Vitamin D Status•Beta Cell Stress

Natural History of Type 1 Diabetes

Inherited Susceptibility Loci

Stages in Human T1D DevelopmentB

eta

Cel

l M

ass

or

Bet

a C

ell

Fu

nct

ion

Holst JJ & Gromada J, Amer J Physiol 2004, 287, E199-E206

Insulin Secretion by Pancreatic -cells

Loss of FPIR to glucose but not MMTT during T1D Progression

Pea

k C

-Pep

tid

e

Time (years) Before T1D Diagnosis

ivGTT

MMTT

OGTT

P<0.0001

Metabolic / Endocrine Markers of T1D Risk

When, Where, How B

eta

Cel

l M

ass

or

Bet

a C

ell

Fu

nct

ion

What do you need to cure diabetes?1. What is diabetes?

2. People & More People

3. $

4. Know how diabetes develops

• People

• $

5. Great Ideas!

• People

• Even more $

Modified from Bluestone et al : April 2010jdoi:10.1038/nature08933 with permissionModified from Bluestone et al : April 2010jdoi:10.1038/nature08933 with permission

Potential Diabetes Therapeutic TargetsPotential Diabetes Therapeutic Targets

G

enet

ic R

isk

“Pre

”-D

iab

etes

New-Onset Established Complications

An

tib

od

ies

OPPORTUNITIES FOR PREVENTION AND CURE

PREVENTION

INTERVENTIONCURE

WITHOUT PREVENTION THERE CAN NEVER BE A CURE

INTERVENING IN TYPE 1 DIABETES INTERVENING IN TYPE 1 DIABETES

Control Autoimmunity

Beta CellRegeneration/

Transplantation

Protect BetaCell Mass

CurePrevention