how can we cure diabetes? clayton e. mathews, ph. d. department of pathology diabetes center of...
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How Can We Cure Diabetes?
Clayton E. Mathews, Ph. D.Department of Pathology
Diabetes Center of ExcellenceUniversity of Florida College of Medicine
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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
• $
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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
• $
![Page 4: How Can We Cure Diabetes? Clayton E. Mathews, Ph. D. Department of Pathology Diabetes Center of Excellence University of Florida College of Medicine](https://reader036.vdocuments.net/reader036/viewer/2022062500/5697bfba1a28abf838ca0148/html5/thumbnails/4.jpg)
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Glucose Production
Glucose Absorp
tion
BloodGlucose
Brain &Nervous System
GUT
LiverG
luco
se U
ptake
Glucose Uptake
Fat
Muscle
IsletPancreas
Regulation of Blood Glucose
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Glucose Production
Glucose Absorp
tion
Brain &Nervous System
GUT
LiverG
luco
se U
ptake
Glucose Uptake
Fat
Muscle
IsletPancreas
Regulation of Blood Glucose
BloodGlucose
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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
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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
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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
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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
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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 $
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Clinical Staff &
Physicians
Building a Diabetes Research Team
Clinical Trialists
ClinicalInvesti-gators
Basic Scientists
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Building a Diabetes Research Team
Clinical Staff &
Physicians
Clinical Trialists
ClinicalInvesti-gators
Basic Scientist
s
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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 $
![Page 14: How Can We Cure Diabetes? Clayton E. Mathews, Ph. D. Department of Pathology Diabetes Center of Excellence University of Florida College of Medicine](https://reader036.vdocuments.net/reader036/viewer/2022062500/5697bfba1a28abf838ca0148/html5/thumbnails/14.jpg)
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
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β cells dendritic cells CD8+ T cells
pLN
Infiltrated islets
INSULIN, CD8, CD4
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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
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Inherited Susceptibility Loci
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Stages in Human T1D DevelopmentB
eta
Cel
l M
ass
or
Bet
a C
ell
Fu
nct
ion
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Holst JJ & Gromada J, Amer J Physiol 2004, 287, E199-E206
Insulin Secretion by Pancreatic -cells
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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
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Metabolic / Endocrine Markers of T1D Risk
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When, Where, How B
eta
Cel
l M
ass
or
Bet
a C
ell
Fu
nct
ion
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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
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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
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INTERVENING IN TYPE 1 DIABETES INTERVENING IN TYPE 1 DIABETES
Control Autoimmunity
Beta CellRegeneration/
Transplantation
Protect BetaCell Mass
CurePrevention