How Can We Cure Diabetes?
Clayton E. Mathews, Ph. D.
Department of Pathology
Diabetes Center of Excellence
University 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
•
$
Regulation of Blood Glucose
Islet
Pancreas
Muscle
GUT
-
Blood
Glucose
+
Fat
Liver
Brain &
Nervous System
Regulation of Blood Glucose
Pancreas
Islet
Muscle
GUT
-
Blood +
Glucose
Fat
Liver
Brain &
Nervous System
• Type 1 diabetes
•
•
What is 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
Type 1
GDM
• 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
–
•
•
Syndromes of Extreme Insulin Resistance
CGL (congenital generalized lipodystrophy)
–
•
Congenital impairment in insulin secretion (GCK, KCNJ11, INS, ABCC8)
Severe Islet Amyloidosis
Familial Partial Lipodystrophy, Dunnigan Variety (FPLD)
–
Adipose disorder (Laminin A)
Type 2
Making the Diagnosis of Type 1 Diabetes
Symptoms of diabetes
Polyuria, polydipsia,
polyphagia, diabetic
ketoacidosis (DKA)
plus
200 mg/dL* (11mmol/L)
Random plasma glucose
or
 6.5%
A1c
or
126 mg/dL* (7.0mmol/L)
Fasting plasma glucose (FPG)
or
Oral glucose tolerance
test (OGTT) with 2-hour value
and confirmed by
200 mg/dL* (11mmol/L)
Presence of islet autoantibodies
GADA, ICA, IA-2A, IAA
*Requires confirmation by repeat testing
American Diabetes Association. Diabetes Care January 2012 35:S1-S2
Who does Type 1 diabetes strike?
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
For the past few decades T1D incidence has been increasing at a rate of 3% per year: total population
The 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 $
Building a Diabetes Research Team
Clinical
Investigators
Clinical
Staff &
Physicians
Clinical
Trialists
Basic
Scientists
Building a Diabetes Research Team
Clinical
Staff &
Physicians
Clinical
Investigators
Clinical
Trialists
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
Percent IDDM-free
T1D-Free
Percent
Cumulative risk of developing clinical Type 1 diabetes in relatives
of T1DM probands using Ab markers alone (IAA, GAD65, IA-2, ICA)
100
0Series1
Abs
1Series2
Ab
2Series3
Abs
3Series4
Abs
4Series5
Abs
80
60
40
20
0
0
5
10
15
20
Years Follow up
Pietropaolo M. et al. Diabetologia 45: 66-76, 2002
Log Rank
P < 0.00001
Infiltrated islets
pLN
INSULIN, CD8, CD4
β cells
dendritic cells
CD8+ T cells
Natural History of Type 1 Diabetes
No Disease
Genetic
Susceptibility
No Disease or
Remission
Protective Factors
Subclinical
Clinical
T1D
T1D
Environmental
Exposure
• Diet
• Viral Infections
• Maternal Environment
• Lack of Environmental
Exposure
Promoting
Factors
• Low Vitamin D Status
• Beta Cell Stress
Inherited Susceptibility Loci
Beta Cell Mass
or
Beta Cell Function
Stages in Human T1D Development
Insulin Secretion by Pancreatic b-cells
Holst JJ & Gromada J, Amer J Physiol 2004, 287, E199-E206
Loss of FPIR to glucose but not MMTT during T1D Progression
ivGTT
P<0.0001
Peak C-Peptide
MMTT
OGTT
Time (years) Before T1D Diagnosis
Metabolic / Endocrine Markers of T1D Risk
Beta Cell Mass
or
Beta Cell Function
When, Where, How
What do you need to cure diabetes?
1. What is diabetes?
2. People & More People
3. $
4. Know how diabetes develops
•
People
•
$
Potential Diabetes
Therapeutic Targets
5. Great Ideas!
•
People
•
Even more $
Modified from Bluestone et al : April 2010jdoi:10.1038/nature08933 with permission
OPPORTUNITIES FOR PREVENTION AND
CURE
“Pre”-Diabetes
Antibodies
Genetic Risk
INTERVENTION
PREVENTION
CURE
WITHOUT PREVENTION THERE
CAN NEVER BE A CURE
NewOnset
Established
Complications
INTERVENING IN TYPE 1 DIABETES
Beta Cell
Regeneration/
Transplantation
Control
Autoimmunity
Protect Beta
Cell Mass
Prevention
Cure