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
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
β-Cell (Islet Cell) Classification ModelImplications 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
1. Efficacy
2. Number of Targets of Therapy each drug addresses
3. Weight loss
4. Proven Reduction in CV outcomes
β-Cell (Islet Cell) Classification ModelImplications for Therapy:
(Not Core Defects)-Targets for Therapies
In-Direct Effect on β-Cells
On #5-11 of ‘Egregious Eleven’
Egregious Eleven
5,6,7
Liver, Muscle, Fat
Target: Intervention / Therapy
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
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)
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. 2014 Jan 16:jc20133633.
TYPE 1
Ellis et al, Effect of Sitagliptin on glucose control in Adult patients with Type 1 DM, Diabetic Medicine DOI: 10.1111/j.1464-5491.2011.03331
Kielgast U., et al Treatment of Type ! Diabetic Patients with GLP-1 and GLP-1 Agonists, Current Diabetes Reviews,2009, 5:266-275
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. 2011 May;54(5):1098-108. doi: 10.1007/s00125-011-2069-9. 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. 2010 Nov;25(11):1626-32. doi: 10.3346/jkms.2010.25.11.1626. 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. 2012 May;213(2):143-54. doi: 10.1530/JOE-11-0328. 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,
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
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
Patient-Centric Diagnosis and Care/Therapy
Specific Therapy
Traditional Labs/Testing
FBS, RBS, HgA1c
At Risk
Individuals
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, PioE = Environment- diet, exercise
Genes
Diabetes Rx
• B = β-cell- Incretin, suppressing
glucagon agents, SGLT-2
Biome- (? Effects on IR, β-cell, Inflam)
•
•
•
•
Br=
I =
R =
E =
(? Multiple- a la DeFronzo pilot)
•
Biome-(? Effects on IR, β-cell, Inflam)
Tempered by DATA- focus for future Research 
Brain- Bromo-QR, stomach, R
Inflam- Incretin, (New)
Resistance- MET, Pio, (New)
Environment- diet, exercise
( ) = Not proven
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 repositoriesJAEB, 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
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
•
Allan D. Sniderman et al The Necessity for Clinical Reasoning in the Era of Evidence-Based Medicine,Mayo Clin Proc. 2013;88(10):1108-1114
So For Now, with Current Terminology, Cost- Driven
Diagnosis of Diabetes in Adults ‡
FH +
(-) Ketosis prone
Younger
FH ( +) ketosis prone
FH+
(-) Ketosis prone
Older
Younger
BMI >30
BMI >30 <30 BMI
BMI <30
BMI >30
‘LADA’
Type 2
MODY
Genome
to Clarify
‡ BASED ON
FAMILY HX (GENES)
AGE, ?KETOSIS PRONE
BMI, ANTIBODIES
Type 1
SPIDDM
Autoimmune Type2
Type 2
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 
So For Now, with Current Terminology, Cost- Driven
Diagnosis of Diabetes in Adults ‡
FH +
(-) Ketosis prone
FH+
(-) Ketosis prone
Older
Younger
BMI <30
BMI >30 <30 BMI
BMI >30
‘LADA’
Type 2
MODY
Genome
to Clarify
‡ BASED ON
FAMILY HX (GENES)
AGE, ?KETOSIS PRONE
BMI, ANTIBODIES
SPIDDM
Autoimmune Type2
Type 2
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 
So For Now, with Current Terminology, Cost- Driven
Diagnosis of Diabetes in Adults ‡
FH ( +) ketosis prone
Younger
BMI >30
‘LADA’
Type 1
SPIDDM
Autoimmune Type2
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 
So For Now, with Current Terminology, Cost- Driven
Diagnosis of Diabetes in Adults ‡
FH +
(-) Ketosis prone
Younger
FH ( +) ketosis prone
FH+
(-) Ketosis prone
Older
Younger
BMI >30
BMI >30 <30 BMI
BMI <30
BMI >30
‘LADA’
Type 2
MODY
Genome
to Clarify
‡ BASED ON
FAMILY HX (GENES)
AGE, ?KETOSIS PRONE
BMI, ANTIBODIES
Type 1
SPIDDM
Autoimmune Type2
Type 2
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
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
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
Acknowledgements:
Our NIH Grant Collaborators
Action LADA Consortium
T1D Exchange
Institut de Biologie de Lille
David Leslie
Mohammed Hawa
Bernhard Boehm
Knud Yderstræde
Didac Mauricio Puente
Carla Greenbaum
Asa Davis
Kristen Kuhns
T1D Exchange Biobank Operations Center
Philippe Froguel
Véronique Dhennin
Marianne Deweirder
Alberto Deleiva
Charles Thivolet
Werner Scherbaum
Nanette Schloot
Mary Ann Ngoc Dang
Geisinger Clinic
Mayo Clinic
Ronald Harris
John Kennedy
Rosemarie Delucca
Adrian Vella
Paula Giesler
Jeanette Laugen
National Disease Research Interchange
University of Leicester
Adventist Health System/Sunbelt
John Lonsdale
Kamlesh Khunti
Richard Pratley
Lee Ducat
Melanie Davies
Stephanie Goldby
Julie Clyatt
University of Alabama at Birmingham
Sian Hill
University of Pennsylvania
Fernando Ovalle
Kentress Davison
Michael Rickels
Nora Rosenfeld
University of Washington
Weill Cornell Medical College
Santica Marcovina
Jessica Harting
David Brillon
Karen Hyams
Health Diagnostic Laboratory, Inc.
Steven Varvel
Joe McConnell