Transcript Stanley Schwartz, MD - Diabetes In Control

Diagnosing Diabetes In Adults–
Type 1, LADA, or Type 2?
Part 3
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
New β-Cell Centric Construct: Implications
Insulin Resistance Exposes and Exacerbates the
Core β-Cell Defect
 Genetically- Based
 Exacerbated by Environmental issues- Diet, Activity, Biome
 Includes Brain-Directed, Peripheral Insulin Resistance
Loss of Dopa- Surge in SCN
 IR Impairs β-Cell Function by:
• Lipo and gluco-toxicity
• Inflammatory Mechanisms
• Adipocytokine effect on β-cell
 IR is NOT a Core Defect (as only ~1/3 of IR patients have Diabetes)
(but CLEARLY, IR is a focus of therapy in patients with
vulnerable β-cells)
Simplistic Inflammatory and Non-Inflammatory Effects
of Insulin Resistance
IAPP boosts islet macrophage IL-1 in type 2 diabetes : Nature ...www.nature.com
Multiple Causes IRMultiple Potential Therapies
Weight Reduction
Biome
ProIR
Biotics,
Pre-Biotics
Central IR/
Appetite
Peripheral
IR
TZD (Pio-) ,
Metformin
Bromocriptine-QR
Inflammation
IR
AntiInflam.
New β-Cell Centric Construct: Implications
Environmental Risk Factors in
T1D/T2D,
?
‘LADA’
T1D
 Seasonality at diagnosis
 Migrants assume risk of host country
 Risk factors from case-control studies
•
•
•
•
•
Hormones
• Vitamin D
Stress
• Cow’s Milk
Improved Hygiene
• Gut-microbial Balance – Biome
Infant/childhood diet
• Lack of Physical Activity
Viruses – exposures as early as in utero
T2D
LADA
 Obesity-Diet
 Coffee
 More Educated
 Lack of Physical Activity
 AGE ingestion
Going Forward: New Focus of Care:
Primary Prevention: ? For All DM in New Classification
 Genetic / antibody screening 1
effort to identify eligible subjects
 Potential Immune Modulators 2
 Environmental Modulation 3
– Especially as we learn morevaccination, endocrine disruptors,
diet, exercise
 Intervention needs to be
2
extremely safe
 Defining risk factors will facilitate
primary prevention studies
Atkinson, Eisenbarth,THE LANCET • Vol 358 • July 21, 2001 225
1
3
APPLY MODEL TO ALL DM
New β-Cell Centric Construct: Implications
Diagnosis Markers
By Virtue of Family History ‘DM”, Physiogomy, hyperglycemia
in Prediabetic and diabetic range
 Genes
• Family History
• Genotype- HLA, TCF7L2, etc
 β-Cell
• FBS, 2hr ppg, HgA1c, ? C-peptide, ?other
 Inflammation
• Antibodies, Inflammatory Markers, T-Cell function, ?other
 Insulin Resistance
• BMI, Adiponectin, Adipocytokines, ? Other
Abilities to get what/which above data will be cost-dependenteach patient, insurers, formulary, government
Current Terminology
Should Reflect the β-Cell Centric Approach;
or,…we need to Develop a New Terminology
Older
Younger
‘LADA’
T2D
MODY,
monogenic
T1D
SPIDDM
Autoimmune
T2D
T2D
+,which
+,which
+,which
+,which
+
+
+
+/-
Genes
- mono
+,which
- poly
+,which
Inflammation
+/-
Resistance
+/-
+/-
─
+/-
+/-
+,which
+,which
+,which
+,which
+,which
Environment
─
Implications for Therapy
β-Cell (Islet Cell) Classification ModelImplications for Therapy:
(Not Core Defects)-Targets for Therapies
GIVES US ‘PERMISSION’ TO USE ANY LOGICAL THERAPY for
ANY DIABETIC ‘TYPE”
Egregious Eleven
1.
2.
3.
4.
β-CELL
α cell Glucagon defect
↓ INCRETIN EFFECT-Incretin
Inflammation
5. Liver
6. Muscle
7. Fat
8. Kidney
9. Brain
10. Stomach/Intestine
11. Colon- Biome
With Appropriate , on bent-knee, thanks and appreciation, to my (Renal fellow
when I was an intern) friend and collaborator, Dr. Ralph DeFronzo
β-Cell (Islet Cell) Classification ModelImplications for Therapy:
Egregious
Eleven
1. β- Cell
2. α- Cell
3. Incretin
4. Inflammation
inflammation
5. Liver
6. Muscle
7. Fat
8. Kidney
9. Brain
10. Stomach/Intestine
11. Colon/Biome
BRAIN
Gene(s)
↑Appetite
SCN
INSURES it’s GETTING ENOUGH
GLUCOSE TO WORK!!
Cells ‘complain’ not getting
enough glucose
↓Dopa surge
Inflammation
Insulin resistance
Lipotoxicity
Gene/
Envir
interAction!!
Environment
↑Glucagon
↓ Amylin
↓ Incretin effect
↑ GLP-1 resistance
↓ β-Cell function
↓ β-Cell mass
↓Insulin
PPG-HYPERGLYCEMIA
Glucotoxicity
β-Cell Centric Construct
For Pathogenesis of All Diabetes:
Implications for RX- EGREGIOUS ELEVEN
CORE ISSUES
Teach CROSSTALK
BRAIN
Gene(s)
↑Appetite
SCN
INSURES it’s GETTING ENOUGH
GLUCOSE TO WORK!!
Cells ‘complain’ not getting
enough glucose
↓Dopa surge
Inflammation
Fat
Liver Muscle
Insulin resistance
Lipotoxicity
Gene/
Envir
interAction!!
Environment
↑Glucagon
↓ Amylin
↓ Incretin effect
↑ GLP-1 resistance
↓ β-Cell function
↓ β-Cell mass
↓Insulin
PPG-HYPERGLYCEMIA
Glucotoxicity
β-Cell Centric Construct
For Pathogenesis of All Diabetes:
Implications for RX- EGREGIOUS ELEVEN
CORE + IR ISSUES
BRAIN
↑Appetite
SCN
Gene(s)
INSURES it’s GETTING ENOUGH
GLUCOSE TO WORK!!
Cells ‘complain’ not getting
enough glucose
↓Dopa surge
Inflammation
Fat
Liver Muscle
Insulin resistance
Lipotoxicity
Gene/
Envir
interAction!!
↑Glucagon
Colon
biome
Environment
↓ Amylin
↓ Incretin effect
↑ GLP-1 resistance
↓ β-Cell function
↓ β-Cell mass
↓Insulin
Stomach
Fast emptying
PPG-HYPERGLYCEMIA
Glucotoxicity
Up-regulates
SGLT-2
β-Cell Centric Construct
For Pathogenesis of All Diabetes:
Implications for RX- EGREGIOUS ELEVEN
Kidney
ALL ISSUES