Genetic Control of Pancreatic Islet Resistance to Autoimmune Attack

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How Can We Cure Diabetes?
Clayton E. Mathews, Ph. D. Department of
Pathology Diabetes Center of Excellence University
of Florida College of Medicine
2
What do you need to cure diabetes?

• What is diabetes?
• People More People
• Know how diabetes develops
• People
• Good/Great Ideas!
• People

3
What do you need to cure diabetes?

• What is diabetes?
• People More People
• Know how diabetes develops
• People
• Good/Great Ideas!
• People

4
Regulation of Blood Glucose
Islet
Pancreas
Glucose Absorption
Muscle
GUT
Glucose Uptake
Blood Glucose
-
Glucose Uptake
Glucose Production
Fat
Brain Nervous System
Liver
5
Regulation of Blood Glucose
Islet
Pancreas
Glucose Absorption
Muscle
GUT
Glucose Uptake
Blood Glucose
-
Glucose Uptake
Glucose Production
Fat
Brain Nervous System
Liver
6
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 210 of all pregnancies-improves
  after delivery
• About 2050 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)

GDM
Type 1
Type 2
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Making the Diagnosis of Type 1 Diabetes
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
Requires confirmation by repeat testing
American Diabetes Association. Diabetes Care
January 2012 35S1-S2
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Who does Type 1 diabetes strike?
Source SEARCH for Diabetes in Youth Study
NHWnon-Hispanic whites NHBnon-Hispanic
blacks HHispanics/LatinosAPIAsian/Pacific
Islander Americans AIAmerican Indians
For the past few decades T1D incidence has been
increasing at a rate of 3 per year total
population The incidence in the young (lt5 years
of age) has been increasing at a rate of 5.4 per
year
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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

10
What do you need to cure diabetes?

• What is diabetes?
• People More People
• Know how diabetes develops
• People
• Good/Great Ideas!
• People
• Even more

11
Building a Diabetes Research Team
Clinical Investi-gators
Clinical Staff Physicians
Clinical Trialists
Basic Scientists
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Building a Diabetes Research Team
Clinical Staff Physicians
Clinical Investi-gators
Basic Scientists
Clinical Trialists
13
What do you need to cure diabetes?

• What is diabetes?
• People More People
• Know how diabetes develops
• People
• Great Ideas!
• People
• Even more

14
Cumulative risk of developing clinical Type 1
diabetes in relatives of T1DM probands using
Ab markers alone (IAA, GAD65, IA-2, ICA)
Percent T1D-Free
Pietropaolo M. et al. Diabetologia 45 66-76,
2002
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(No Transcript)
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Infiltrated islets
pLN
INSULIN, CD8, CD4
ß cells
dendritic cells
CD8 T cells
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Natural History of Type 1 Diabetes
No Disease or Remission
No Disease
Protective Factors
Genetic Susceptibility
Subclinical T1D
Clinical T1D

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

• Promoting
• Factors
• Low Vitamin D Status
• Beta Cell Stress

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Inherited Susceptibility Loci
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Stages in Human T1D Development
Beta Cell Mass or Beta Cell Function
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Insulin Secretion by Pancreatic b-cells
Holst JJ Gromada J, Amer J Physiol 2004, 287,
E199-E206
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Loss of FPIR to glucose but not MMTT during T1D
Progression
Plt0.0001
ivGTT
MMTT
OGTT
Peak C-Peptide
Time (years) Before T1D Diagnosis
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Metabolic / Endocrine Markers of T1D Risk
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When, Where, How
Beta Cell Mass or Beta Cell Function
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What do you need to cure diabetes?

• What is diabetes?
• People More People
• Know how diabetes develops
• People
• Great Ideas!
• People
• Even more

Potential Diabetes Therapeutic Targets
Modified from Bluestone et al April
2010jdoi10.1038/nature08933 with permission
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OPPORTUNITIES FOR PREVENTION AND CURE
INTERVENTION
CURE
WITHOUT PREVENTION THERE CAN NEVER BE A CURE
PREVENTION
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INTERVENING IN TYPE 1 DIABETES
Control Autoimmunity
Beta Cell Regeneration/ Transplantation
Protect Beta Cell Mass
Cure
Prevention