Post on 29-Jan-2016
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