Download Stanley Schwartz, MD - Diabetes In Control

Diagnosing Diabetes In Adults–
Type 1, LADA, or Type 2?
Part 2 2
Stanley Schwartz MD, FACE, FACP
Affiliate Main Line Health
Emeritus, Clinical Assoc. Prof. of Medicine
Perlman School of Medicine, University of Pennsylvania
Struan F.A. Grant, Ph.D
Children’s Hospital of Philadelphia
Associate Professor, University of Pennsylvania
Vanessa Guy
Children’s Hospital of Philadelphia
Senior Clinical Research Coordinator
Co-Investigators NIH RO-1, Genes in LADA
PROPOSAL:
‘β-Cell Centric’
Classification of Diabetes
 Intuitively obvious approach
 Didn’t we know that all along! 
It can help define
diagnosis and therapy better,
especially as our knowledge-base increases
Pathogenic, β-Cell-Centric Construct for All Diabetes
Implications for Classification, Diagnosis, Prevention, Therapy, Research
E
P
I
G
E
N
I
T
I
C
S
Environmental Inflam. Triggers
eg: viral,endocrine disruptors, food AGE’s, biome
Resistance
inflammatory adipokines
Polygenic- other
Gene
E
P
I
G
E
N
I
T
I
C
S
Inflammatory;
Abnormal Immune
Modulation
Monogenic (HLA)
Polygenic
Monogenic - MODY
β-Cell PHENOTYPE
secretion/mass
− Mitochondrial
Resistance-FFA
Poor diet, inactivity
endocrine disruptors, food AGE’s ,biome
Environmental Triggers
Non
Inflammatory
Phenotypic Presentation, dependent on :
• The Age at presentation = tipping point when the combined Gene Effect
Environmental trigger is exposed as phenotypic hyperglycemia.
• The ‘Severity’ at presentation: Reflects the β-cell loss-function/massat presentation
• The Slope = Progressive ‘Natural History’ over time ie: = Rate of β-cell loss
100% −
−
−
−
% β−Cell −
Function −
−
Critical β−Cell
−
Mass
−
−
0% −I I I I I/ ≈ / I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I
Increasing Age
Phenotypic Presentation, dependent on :
• The Age at presentation = tipping point when the combined Gene Effect
Environmental trigger is exposed as phenotypic hyperglycemia.
• The ‘Severity’ at presentation: Reflects the β-cell loss-function/massat presentation
• The Slope = Progressive ‘Natural History’ over time ie: = Rate of β-cell loss
100% −
−
−
−
Pre-Diabetes = FBS ≥100, PPG ≥140
−
% β−Cell
Function −
T2D = FBS ≥126, PPG ≥200
−
Critical β−Cell
−
Mass
−
−
0% −I I I I I/ ≈ / I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I
Increasing Age
New β-Cell Centric Construct: Implications
Genetics 101 for Diabetes
Phenotype: is DEPENDENT ON
Genotype:
1. Number of Genes, which genes-their nature, even
Epigenetics
recent article on epigenetics in T1DM-DCCT/EDIC
ie: Genes influencing: insulin secretory dynamics, insulin
resistance, sites of susceptibility of β-Cell to destruction
by Endogenous/Exogenous Triggers eg: inflammation, etc.
i.e. Genetics is: Which genes,
how many different ones,
the ‘severity/intensity’ of expression!
Genotyping
Should Be a Standard Diagnostic Marker
to be obtained For DX of DM:
(Cost now $100)
eg: Pharmacogenetics
Pick right drug for right patient
• Find Gene action/ Function- Leads to understanding mechanisms
 eg: TCF7L2-Potential Therapy
 PARP-1 Inhibitor??, incretin
 Or Gene/Mechanism/ Therapy
 low BMR- results in morbid obesity
 Asian/ Eastern Europeansstore more Visceral Fat at Lower BMI
Genetics of ‘LADA’
R01DK085212
Typical age of onset
SPIDDM
Antibody + T2DM
40 yrs
~25-40 yrs
<10 yrs
Type 1 Diabetes
‘LADA’
Type 2 Diabetes
~60 genes
Late onset type 1 diabetes?
~60 genes
We are looking for
HLA LADA-Specific GenesTCF7L2
No genes in
common
New β-Cell Centric Construct: Implications
β-cell Issues
 Usual use of Glycemic Criteria
 Usual/Occasional Use of C-Peptide
 Try to Determine Mono-Genetic Causes
 Development of therapies aimed at
•
Improving β-cell function:
• Reduce Glucotoxicity
• Reduce Lipotoxicity
• Reduce IR
(treat inflammation, gut biome change)
Be aware of all the Secretory Dynamic Pathways involved,
AND GENES INVOLVED
New β-Cell Centric Construct: Implications
Inflammation Issues
Initiators of
inflammation
Glucose
Saturated
FFA
IL-1β
Cytokines (TNFα, IL-6, IL-12,
IL-1 α, IL-8)
12-HETE
IAPP
Yumi Imai1, Anca D. Dobrian2, Margaret A. Morris1,3, and Jerry L. NadlerIslet inflammation: a unifying target for diabetes treatment? Trends in Endocrinology and
Metabolism 2013:1-10 ;
Barbara Brooks-Worrell, Radhika Narla, and Jerry P. Palmer Biomarkers and immune-modulating therapies for Type 2 diabetes Trends in Immunology November
2012, Vol. 33, No. 11
New β-Cell Centric Construct: Implications
Inflammation Issues
Downstream
Effects
Yumi Imai1, Anca D. Dobrian2, Margaret A. Morris1,3, and Jerry L. NadlerIslet inflammation: a unifying target for diabetes treatment? Trends in Endocrinology and
Metabolism 2013:1-10 ;
Barbara Brooks-Worrell, Radhika Narla, and Jerry P. Palmer Biomarkers and immune-modulating therapies for Type 2 diabetes Trends in Immunology November
2012, Vol. 33, No. 11
Potential Immunomodulatory Therapy to
Prevent / Treat/Reverse Diabetes- (and not just Type 1DM)
www.thelancet.com Published online July 26, 2013
http://dx.doi.org/10.1016/SO140-6736(13)60591-7
A promising approach is the use of pharmacological agents, such as orally active chemical chaperones, which can stabilize protein conformation, improve
ER folding capacity,and facilitate the trafficking of mutant proteins.110–113 Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2014:7 25–34
CLAUDIA CAVELTI-WEDER, Effects of Gevokizumab on Glycemia and Inflammatory Markers in Type 2 DiabetesDiabetes Care 35:1654–1662, 2012
C. Levitan,,Proposal for generating new beta cells in a muted immune environment for type 1 diabetes [cyclosporin/PPI] Diabetes Metab Res Rev 2013; 29: 604