Download Stanley Schwartz, MD - Diabetes In Control

Diagnosing Diabetes In Adults–
Type 1, LADA, or Type 2?
Part 1 of 4
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
OR
Since Confusion Abounds,
Isn’t it Time for…
A New Classification/Approach to
the Diagnosis of Diabetes
Disclosures
• Vanessa Guy- none
• Struan Grant- None
• Stanley Schwartz
– Ad boards- Janssen, Merck, Santarus, AZ-BMS, BI-Lilly
– Speaker’s Bureaus- Takeda, Janssen, Merck, Novo, Salix,
BI-LILLY
Purely Clinical Answer
Empiric, Pragmatic Approach
At this point in time,
it doesn’t matter which label is applied 
• Insulin Requiring
 DKA: ketosis prone, die without insulin
• Everyone else – Independent of Age,
 “Label” Patient, ‘best guess’
 Treat ‘as needed’ to get glycemic control
But Need to be More Than Pragmatic!!
’Diagnosis’: Has Many Functions
 Plan care − eg: imply ‘cause-specific’ studies and
therapies
 Predict − who else might get disease
 Prevent − disease development and progression
 Proliferate Scientific Knowledge − about diabetes
Current Diabetes Classification
 Note the OVERLAP
 Diagnosis is Often IMPRECISE
Definitions: T1D, ‘LADA’, T2D
Won’t belabor typical definitions- T1D and T2D!
• ‘LADA’ use – ambiguous
Includes:
 Later age, therefore, SPIDDM- Slowly progressive T1D
• ‘slower’ destruction of β-cells than T1D
 Antibody positive T2D = ‘T1.5D’
• ‘faster’ destruction of β-cells than in T2D
 T-cell abnormal SPIDDM
• antibody negative
‘Definitions of LADA’
A. The Immunology of Diabetes Society –LADA, and Action LADA
1. 30 years of age
2. Positive for at least one of the four antibodies commonly found in T1D
3. Not treated with insulin within the first 6 months after diagnosis
Implies: antibody positive adults, that may be on insulin,
but may not be insulin dependent
B. ADA recognizes LADA as a variation of T1DM
1. Also called:
 Type 1.5
 ‘Slowly’ progressive Type 1D
 Latent-onset Type 1D
Implies: insulin-dependent antibody-positive adults
Visualization of the Overlap
IMMUNITY
AGE
GENES
BMI
INSULIN THERAPY
T1DM
In children
Strong
+++
child
HLA++
low
Intermediate
Immediate
T1DM
In adults
++
adult
HLA+
normal
Immediate
LADA
+
adult
HLA
normal
Variable
T2DM
weak
adult
?
high
Infrequent
Adapted from Leslie et al. Diabetes Metab Res Rev. 2008 Oct;24(7):511-9
Characteristics Frequently Overlap
‘LADA’
T1D
Typical Age of Onset All Ages
% of all Diabetes
T2D
Usually Age >30
10%
MODY
Adults
10%
Usually Age <25
75%
Mostly Overweight or
Obese
All
5%
Typical BMI
Ethnicity
Mostly Normal or
Mostly Normal or Thin Overweight
All
All
Progression to
insulin Dependence
Fast (Days/Week)
Latent (Months/Years) Slow (Years)
Depends on MODY
type
Insulin Resistance
Mostly no; ~10% ,yes
Some
Yes
Depends on MODY
type
Presence of
Autoantibodies
Yes (ICA, IA2, GAD65, Yes (mostly GAD65),
IAA)
Some not
No
No
T cell reponses to
islet proteins
Yes
Yes
No
No
Insulin/ C-peptides
Level at diagnosis
Ketoacidosis
Insulin Secretion
Islet Inflammation
HLA Link
TCF7L2 Link
Undectable or
extermely low
Yes
Low/null
Chronic Inflammation
High
None
Low
Yes, many not all
Varies
Chronic Inflammation
Low
Greater than T2DM
Normal to High
Rare
Varies
Chronic Inflammation
None
?5%
Normal
Rare
Varies
None
None
None
PTPN22; INS; CTLA4;
PPARG; JAZF1;
KCNJ11; NOTCH2;
WFS1; IGF2BP2; FTO;
SLC30A8; HHEX
Non-Insulin,
Insulin required,
Non-Insulin or insulin, diet & increased
diet & exercise helpful diet & exercise helpful activity
Other Genes Involved CCR5; FOXP3;
PTPN22; INS
HNF1A; IL2RA; IL6;
ITPR3; OAS1; SUMO4
Early Treatment
Late Treatment
Insulin, diet, exercise
Insulin, pills, diet,
exercise
Insulin, pills, diet,
exercise
Mostly normal
All
HNF4A; GCK; HNF1A;
IPF1; HNF1B;
NEUROD1
Gene Specific
Gene Specific
Characteristics Frequently Overlap
‘LADA’
T1D
Typical Age of Onset All Ages
% of all Diabetes
Typical BMI
Ethnicity
T2D
Usually Age >30
Adults
Usually Age <25
10%
75%
T1D
‘LADA’
T2D
Mostly Normal or
Mostly Overweight or
10%
Mostly Normal or Thin Overweight
All
All
Insulin
Secretion
Progression
to
MODY
Obese
All
Low/null
Varies
Mostly normal
All
Varies
insulin Dependence
Fast (Days/Week)
Latent (Months/Years) Slow (Years)
Depends on MODY
type
Insulin Resistance
Mostly no; ~10% ,yes
Some
Depends on MODY
type
Presence of
Autoantibodies
Yes (ICA, IA2, GAD65, Yes (mostly GAD65),
IAA)
Some not
T cell reponses to
islet proteins
Yes
T1D
Yes
Chronic
Insulin/ C-peptides
Undectable or
Islet Inflammation
Level at diagnosis
extermely Inflammation
low
Low
Ketoacidosis
Insulin Secretion
Islet Inflammation
HLA Link
TCF7L2 Link
Yes
Low/null
Chronic Inflammation
High
None
Early Treatment
Late Treatment
No
‘LADA’
No
T2D
No
T1D
Rare
Varies
Chronic Inflammation
None
?5%
‘LADA’
PPARG; JAZF1;
Rare
Varies
None
None
None
Insulin, diet, exercise
Greater than
T2DM
Insulin, pills, diet,
exercise
Insulin, pills, diet,
exercise
Varies
MODY
None
T2D
MODY
? 5%
None
HNF4A; GCK; HNF1A;
KCNJ11; NOTCH2;
IPF1; HNF1B;
WFS1; IGF2BP2; FTO; NEUROD1
SLC30A8; HHEX
Non-Insulin,
Insulin required,
Non-Insulin or insulin, diet & increased
diet & exercise helpful diet & exercise helpful activity
Gene Specific
None
MODY
No
Chronic
Chronic
Normal to High
Normal
Inflammation
Inflammation
Yes, many not all
Varies
Chronic Inflammation
Low
Greater than T2DM
PTPN22; INS; CTLA4;
Other Genes Involved CCR5; FOXP3;
PTPN22; INS
HNF1A; IL2RA; IL6;
ITPR3; OAS1; SUMO4
TCF7L2 Link
Yes
5%
Gene Specific
•
•
•
•
Summary
Definitions are Imprecise, Ambiguous
Exceptions to ‘typical’ presentations
Overlapping Characteristics (eg: T1 with T2 parents)
They don’t take into account various causes of
hyperglycemia that we know exist.
CONCLUSION: We need to bring
Nomenclature of Classification and Diagnosis
in line with therapies: current and future,
and vice versa