1. Diagnosing Diabetes In Adults– Type 1, LADA, or Type 2?
Stanley Schwartz MD, FACE, FACP
Affiliate Main Line Health
Emeritus, Clinical Assoc. Prof. of Medicine
Perlman School of Medicine, University of Pennsylvania
Part 4 of 4
Struan F.A. Grant, Ph.D Vanessa Guy
Children’s Hospital of Philadelphia Children’s Hospital of Philadelphia Associate Professor, University of Pennsylvania Senior Clinical Research Coordinator
Co-Investigators NIH RO-1, Genes in LADA

2. Egregious Eleven Defect Intervention / Therapy
β-Cell (Islet Cell) Classification Model- Implications for Therapy:
(Not Core Defects)-Targets for Therapies
Direct Effect on β-Cells
On #1-4 of ‘Egregious Eleven’
Egregious Eleven Defect
Intervention / Therapy 1
β-CELL
Incretin , Ranolazine 2
α-Cell Glucagon
Incretin, Pramlintide 3
↓INCRETIN EFFECT
Incretin 4
Inflammation
Incretin, ? Anti-inflammatory
Hierarchy of Medication Choice (a la AACE Guideline)(this and next slide) , not just reduction in HgA1c, but
Efficacy
Number of Targets of Therapy each drug addresses
Weight loss
Proven Reduction in CV outcomes

3. β-Cell (Islet Cell) Classification Model- Implications for Therapy:
(Not Core Defects)-Targets for Therapies
In-Direct Effect on β-Cells
On # of ‘Egregious Eleven’
Egregious Eleven
Target: Intervention / Therapy
5,6,7
Liver, Muscle, Fat
Insulin Resistance: MET, TZD, Bromocriptine-QR (wt. reduction agents– GLP-1 RA, SGLT-2 Inhibitors) 8
Kidney
Renal Threshold for Glucosuria: SGLT-2 Inhibitors 9
Brain
Appetite: Incretin
Centrally Controlled Peripheral IR: Bromocriptine-QR
Sympathetic Tone: Bromocriptine-QR 10
Stomach/Intestine
Rate of Appearance of Glucose in the blood:
AGI, GLP-1 RA, Pramlintide 11
Colon/Biome
Gut Biome:
? Probiotic (may improve IR, β-cell function, inflam.)
5-11 ALL Decrease Glucose/ Lipotoxicity

4. FOR ALL DM – potential CV benefit (ANTI-INFLAMMATORY)
Hedge your Bets: All get Incretins  DPP_4 Inh, GLP-1 RAs, [ or agents that increase GLP-1 e.g.: Metformin, Colesevalam, (TGR-5)]
Type 1- minimize brittle, dawn, unpredictable, variability, ? CV
benefits, Treat those ‘Type 2’ Genes’, ANTI-INFLAMMATORY
LADA = SPIDDM/ Autoimmune T2DM
Same- Slow , stabilize disease process, ANTI-INFLAMMATORY
Type 2- treats 7 MOA’s of DeFronzo’s Octet, or 9/11 EE 
Decreases oxidative stress, β-cell inflam., decreases lipo- and
gluco-toxicity, ?preserve mass, decreases appetite, treats IR via
wt. loss
MODY 3- recent report
FOR ALL DM – potential CV benefit (ANTI-INFLAMMATORY)

5. Reference list for last slide
 LADA
Zhao Y,et al . Dipeptidyl peptidase 4 inhibitor sitagliptin maintains β-cell function in patients with recent-onset latent autoimmune diabetes in adults: one year prospective study.,J Clin Endocrinol Metab Jan 16:jc
TYPE 1
Ellis et al, Effect of Sitagliptin on glucose control in Adult patients with Type 1 DM, Diabetic Medicine DOI: /j
Kielgast U., et al Treatment of Type ! Diabetic Patients with GLP-1 and GLP-1 Agonists, Current Diabetes Reviews,2009, 5:
TYPE 2
Ju-Young Kim,Exendin-4 Protects Against Sulfonylurea-Induced β-Cell Apoptosis, J Pharmacol Sci 118, 65 – 74 (2012)
Drucker DJ, Rosen CF. Glucagon-like peptide-1 (GLP-1) receptor agonists,
obesity and psoriasis: diabetes meets dermatology. Diabetologia 2011;54:2741–2744
Chaudhuri A, Ghanim H, Vora M, et al. Exenatide exerts a potent antiinflammatory effect. J Clin Endocrinol Metab 2012;97:198–207
Makdissi A, Ghanim H, Vora M, et al. Sitagliptin exerts an antinflammatory action. J Clin Endocrinol Metab 2012;97:3333–3341
Drucker, D., Incretin Action in the Pancreas: Potential Promise, Possible Perils, and Pathological PitfallsDiabetes 62:3316–3323, 2013
Shimoda M, Kanda Y, Hamamoto S, Tawaramoto K, Hashiramoto M, Matsuki M, Kaku K.The human glucagon-like peptide-1 analogue liraglutide preserves pancreatic beta cells via regulation of cell kinetics and suppression of oxidative and endoplasmic reticulum stress in a mouse model of diabetes.
Diabetologia May;54(5): doi: /s Epub 2011 Feb 22.
Kim JY, Lim DM, Moon CI, Jo KJ, Lee SK, Baik HW, Lee KH, Lee KW, Park KY, Kim BJ.Exendin-4 protects oxidative stress-induced β-cell apoptosis through reduced JNK and GSK3β activity.
J Korean Med Sci Nov;25(11): doi: /jkms Epub 2010 Oct 26.
Liu Z, Stanojevic V, Brindamour LJ, Habener GLP1-derived nonapeptide GLP1(28-36)amide protects pancreatic β-cells
from glucolipotoxicity. J Endocrinol May;213(2): doi: /JOE Epub 2012 Mar 13.
Glucagon-like peptide 1 analogue therapy directly modulates innate immune-mediated inflammation in individuals with type 2 diabetes mellitus Diabetologia - Clinical and Experimental Diabetes and Metabolism, 03/04/2014  Hogan AE,

6. Follow current AACE GUIDELINE PRINCIPLES
Treat as many of the Egregious 11 Targets as needed, with least # of agents, to get lowest sugars/HgA1c as possible without undue weight gain or hypoglycemia
Early Combination Therapy
First Tier- Efficacy, (my add- CV event reduction, Weight Loss)
Treat with agents that address FBS AND PPG
Ideally agents will stabilize, preserve β-cells, the CORE DEFECT ( NO SU/GLINIDES)
Ideally agents will have potential to synergistically decrease in CV risk factors / outcomes

7. Summary: What do we do for Treatment
Which therapies to use will be based on:
New research as available
New guidelines to be developed
Each physicians assessment / comfort with
modalities at hand in an…
Evidence-Based PRACTICE approach
eg: I give incretins to (nearly) all (my) patients
with diabetes now (whenever possible), even ‘off-label’
‘Patient-centric approach’
PICK RIGHT DRUG FOR THE RIGHT PATIENT,
AND VICE-VERSA
Eg: no hesitation to use , for example TZD, SGLT-2, Incretins in ‘usual’ T1DM

8. Patient-Centric Diagnosis and Care/Therapy
Traditional Labs/Testing
FBS, RBS, HgA1c
Specific Therapy
At Risk
Individuals
Genes
Etiologic Diagnostic Markers:
β-Cell, IR, Inflam, Environment, Genes
Pre-Diabetes Rx
B = β-cell- (Incretin)
Br= Brain- (Bromo-QR)
I = Inflam- (Incretin, new)
R = Resistance- MET, Pio-
E = Environment- diet, exercise
Biome- (? Effects on IR, β-cell, Inflam)
(? Multiple- a la DeFronzo pilot)
Diabetes Rx
B = β-cell- Incretin, suppressing
glucagon agents, SGLT-2
Br = Brain- Bromo-QR, stomach, R
I = Inflam- Incretin, (New)
R = Resistance- MET, Pio, (New)
E = Environment- diet, exercise
Biome-(? Effects on IR, β-cell, Inflam)
Tempered by DATA- focus for future Research 
( ) = Not proven

9. Based on ‘New’ Classification: Recommended Process For Prevention, Diagnosis and Therapy, 2014
Convene ADA/EASD/WHO/AACE Committee :
Revising Classification of Diabetes Mellitus
Set Processes in Place
Increase current repositories-
JAEB, JDRI to include LADA patients, (but all ‘kinds of
hyperglycemic patient types), HDLI, Large Health Systems ( K-P)
Research- into these ideas/ approaches
EDUCATE MDs re :issues
Allan D. Sniderman et al The Necessity for Clinical Reasoning in the Era of Evidence-Based Medicine,Mayo Clin Proc. 2013;88(10):
THEN, use Evidence-Based Practice Approaches to DX & provide Therapy
Where evidence incomplete, But logic exists to help patients, apply appropriate
Clinical Reasoning,= Evidence Based Practice

10. So For Now, with Current Terminology, Cost- Driven
Diagnosis of Diabetes in Adults ‡
FH +
(-) Ketosis prone
Younger
BMI >30
Type 2
FH -
( +) ketosis prone
Younger
Type 1
‘LADA’
SPIDDM Autoimmune Type2
Antibody /HLA to Verify
BMI >30
Older
(-) Ketosis prone
FH+
BMI >30
Type 2
Genome to Clarify
<30 BMI
MODY
‘LADA’
SPIDDM Autoimmune Type2
BMI <30
Antibody /HLA to Verify
‡ BASED ON
FAMILY HX (GENES)
AGE, ?KETOSIS PRONE
BMI, ANTIBODIES
If cost ‘less of an Issue’- antibodies in all
Stanford Antibody Chip- fraction of cost of RAI
At some point ,NOW- genotype all 

11. So For Now, with Current Terminology, Cost- Driven
Diagnosis of Diabetes in Adults ‡
FH +
(-) Ketosis prone
Younger
BMI >30
Type 2
Older
(-) Ketosis prone
FH+
BMI >30
Type 2
Genome to Clarify
<30 BMI
MODY
‘LADA’
SPIDDM Autoimmune Type2
BMI <30
Antibody /HLA to Verify
‡ BASED ON
FAMILY HX (GENES)
AGE, ?KETOSIS PRONE
BMI, ANTIBODIES
If cost ‘less of an Issue’- antibodies in all
Stanford Antibody Chip- fraction of cost of RAI
At some point, NOW-genotype all 

12. So For Now, with Current Terminology, Cost- Driven
Diagnosis of Diabetes in Adults ‡
FH -
( +) ketosis prone
Younger
Type 1
‘LADA’
SPIDDM Autoimmune Type2
Antibody /HLA to Verify
BMI >30
‡ BASED ON
FAMILY HX (GENES)
AGE, ?KETOSIS PRONE
BMI, ANTIBODIES
If cost ‘less of an Issue’- antibodies in all
Stanford Antibody Chip- fraction of cost of RAI
At some point, NOW- genotype all 

13. So For Now, with Current Terminology, Cost- Driven
Diagnosis of Diabetes in Adults ‡
FH +
(-) Ketosis prone
Younger
BMI >30
Type 2
FH -
( +) ketosis prone
Younger
Type 1
‘LADA’
SPIDDM Autoimmune Type2
Antibody /HLA to Verify
BMI >30
Older
(-) Ketosis prone
FH+
BMI >30
Type 2
Genome to Clarify
<30 BMI
MODY
‘LADA’
SPIDDM Autoimmune Type2
BMI <30
Antibody /HLA to Verify
If cost ‘less of an Issue’- antibodies in all
Stanford Antibody Chip- fraction of cost of RAI
At some point, NOW- genotype all 
VOILA et MERCI
‡ BASED ON
FAMILY HX (GENES)
AGE, ?KETOSIS PRONE
BMI, ANTIBODIES

14. In Summary
Current Classification of Diabetes Types are unable to differentiate patients; inhibit appropriate use of all therapies that are available to us now , and in near future
New Classification that recognizes the Beta-cell as THE CORE DEFECT in ALL Diabetes, and describes the multiple causes for their dysfunction offers wonderful opportunities for Prevention, Therapy, Research and Education
In particular we must recognize that multiple types of therapy are, and will be available, to be used in any patient with diabetes, based on the causes of their dysfunction- genes, inflammation, insulin resistance, gut biome, central (brain) mechanisms;
defining markers, and processes of care in using them, will then allow appropriate patient-centric approaches- whether we choose to use old ie: current nomenclature or develop a new nomenclature. Eg : even at present it allows us to use, for example, incretins, insulin sensitivity agents, SGLT-2 inhibitors in T1DM, LADA patients etc.
More research always needed, but, in an evidence-based PRACTICE approach to care, we can START NOW

15. With Great Thanks!!
Dr. Richard Aguilar- Clinician, Educator, Collaborator,
A Best Friend!!
Our Mentors
• Arthur Rubenstein, David Rabin, Jesse Roth, Al
Weingrad, Oscar Crawford, John Williamson ,
Barabara Corkey, Lester Baker, Charles Stanley
• Hakon Hankerson

16. Acknowledgements: Our NIH Grant Collaborators
Action LADA Consortium T1D Exchange Institut de Biologie de Lille
David Leslie Carla Greenbaum Philippe Froguel
Mohammed Hawa Asa Davis Véronique Dhennin
Bernhard Boehm Kristen Kuhns Marianne Deweirder
Knud Yderstræde T1D Exchange Biobank Operations Center
Didac Mauricio Puente
Alberto Deleiva Geisinger Clinic Mayo Clinic
Charles Thivolet Ronald Harris Adrian Vella
Werner Scherbaum John Kennedy Paula Giesler
Nanette Schloot Rosemarie Delucca Jeanette Laugen
Mary Ann Ngoc Dang
National Disease Research Interchange University of Leicester Adventist Health System/Sunbelt
John Lonsdale Kamlesh Khunti Richard Pratley
Lee Ducat Melanie Davies Julie Clyatt Stephanie Goldby
University of Alabama at Birmingham Sian Hill University of Pennsylvania
Fernando Ovalle Michael Rickels
Kentress Davison Nora Rosenfeld
University of Washington Weill Cornell Medical College Health Diagnostic Laboratory, Inc.
Santica Marcovina David Brillon Steven Varvel
Jessica Harting Karen Hyams Joe McConnell