Diabetes
Types 1 and 2
Darrell M Wilson, MD
dwilson@stanford.edu
Diabetes Mellitus
Insulin
dependent
IDDM
Juvenile onset
Brittle
Type 1
Non-insulin
dependent
NIDDM
Adult onset
Type 2
Atypical Diabetes
Costs Continue to Increase (U.S.)
(in Billions of Dollars)
$240
$192
$200
$156
$160
$138
$132
$109
$120
$92
$80
$40
$40
$47
$54
$0
Direct
Indirect
Diabetes Care 26:917-932, 2003
Total
2002
2010
2020
ADA Classification, 2004
MODY
MODY 1
hepatocyte nuclear factor-4-alpha
(600281)
MODY 2
glucokinase IV (125851)
MODY 3
hepatocyte nuclear factor-1-alpha
(600496)
Glucose Sensing
Glucose
Closes K+
channel
Opens Ca++
channel
Insulin
GLUT-2
Glucose
K+depolarizes
cell
Glucokinase
Glucose
6-phosphate
Glycolysis
ATP
Sulphonylurea
receptor closes
K+channel
Ca++granule
translocation
& exocytosis
Environmental
triggers
Genetics
Insulitis
Type 1 Diabetes
Diabetes Exposure
Renal
Eye
Complications Complications
Large
Vessels
Time Course of Diabetes
100
Percent
80
Trigger?
Clinical
Presentation
Demand
Mass
Function
60
40
20
Insulin
resistant
periods
0
Honeymoon
Time .....
Incidence – Europe
By Pediatric Age Group
Green Diabetol 2001
Travis, DM in Children, MPCP#29, 1987
Modes of Discovery
Incidental hyperglycemia
Incidentally discovered diabetes
routine sports PE
relative with diabetes
The polys, No DKA
Diabetic ketoacidosis
Symptoms and Signs
Total #
Polyuria
Polydipsia
Wgt loss
Polyphagia
Anorexia
Pittsburgh
Pre-1957
Rhode Island
Pre-1994
513
78%
76%
58%
49%
44%
75
93%
92%
57%
16%
20%
ADA Guidelines for Diabetes
1. Symptoms + casual glucose >200
2. Fasting plasma glucose >125
3. Glucose in OGTT @ 2 hr >200
OGTT not recommend for routine clinical
practice
in absence of metabolic decompensation,
must be repeated on a different day
Normal – fasting <100, 2 hr <140
Pitfalls in the Diagnosis of
Diabetes
Think diabetes
in flu season
polyuria
Never ignore a parent
Never ignore the diagnosis
delay is the deadliest form of denial
Initial Phases of Management
Diagnosis
Metabolic control
Patient and family
education
techniques
physiology
diet
Family support
Diabetic Emergencies
Diabetic Ketoacidosis (DKA)
recurrent DKA
Severe Hypoglycemia
Hyperosmolar Non-ketotic Coma (HNC)
What Kills Diabetics in DKA?
Cerebral edema (brain swelling)
Hyperkalemia
Hypokalemia
Dehydration
Treatment Goals
First order view
replace missing insulin
Second order view
do it correctly
avoid high blood glucose
avoid low blood glucose
continue to have a life
Limits of current technology
Insulin Replacement
Conventional insulin therapy
pump or injection
can be closed loop, but often fully open
loop
Transplants
Bio-sensing polymers
Glucose sensing mechanical pumps
The Core Compromise of
Diabetes
What Kills Diabetics?
Acute
DKA
brain swelling
metabolic
others
Hypoglycemia
Chronic
Complications
macrovascular
heart
lower extremities
microvascular
retinopathy
nephropathy
neuropathy
Historical Control Concepts
“Keep them sweet”
a bit of glucose in
the urine
Very limited
technology for
monitoring
Most pediatricians
(still) don’t have to
deal with
complications
http://jchemed.chem.wisc.edu/JCESoft/CCA/CCA5/MAIN/1ORGANIC/ORG18/TRAM18/B/1001311/PICTURE.HTM?3
Measurement of Glucose
Direct
Methods
meters
future sensors
Data analysis
average
variability
extremes
Measuring Glucose
Meters 2005
www.diabeteshealth.com
Data from Inpatient Accuracy Study Using the
Laboratory Glucoses as the Reference
Median RAD
20%
Ultra
Beckman/YSI/iStat
15%
10%
5%
0%
0
50
100
Reference Glucose (mg/dL)
150
Glucose
Data Analysis
Glucose
Data Analysis
Measurement of Glucose
Indirect
Glycated proteins
glycated hemoglobin
total glycated hemoglobin
hemoglobin A1c (HbA1c)
glycated albumin
glycated LDL
other glycated proteins
Hemoglobin A1c
http://www.cem.msu.edu/~cem252/sp97/ch18/ch18s20.GIF
Hemoglobin A1c
http://home.comcast.net/~creationsunltd/images/comparebsandhga1c.gif
DCCT
DCCT NEJM, 329:977,1993
Glucose Control
DCCT NEJM, 329:977,1993
Glucose Control
Glycosylated Hemoglobin
DCCT NEJM, 329:977,1993
Retinopathy
Primary Prevention
DCCT NEJM, 329:977,1993
Albuminuria
Primary Prevention
>300 mg/24hr
>40 mg/24hr
DCCT NEJM, 329:977,1993
D
C
C
T
D
a
t
a
8
1
0
0
6
8
0
4
6
0
2
SevreHypogly(cpeemri1a0pt/yr)
1
2
0
Progresion-Retinopath(yper10pt-yr)
1
0
4
0
0
2
0
5
.
0
5
.
5
6
.
0
6
.
5
7
.
0
7
.
5
8
.
0
8
.
5
9
.
0
9
.
5
1
0
.
0
1
0
.
5
G
l
y
c
o
s
y
l
a
t
e
d
H
e
m
o
g
l
o
b
i
n
(
%
)
Who Gets Complications?
Only about 50% of diabetics appear to
be at high risk for complications
Potential risk areas
Lipoprotein metabolism
Glycation pathways
Oxidation pathways
The hemostatic cascade
Other candidate genes.
Mechanisms of Complications
The “glucose hypothesis”
acute/reversible
increased polyols (sugar alcohols)
 sorbitol in insulin independent tissues
 increase in NADH/NAD+ ratios
decreased myoinositol
early glycation products
chronic/irreversible
advanced glycation end-products (AGE)
Other Factors Associated with
Complications
Hypertension
Lipids
Smoking
Age
Sex
Ethnicity
SES
Risk Modifiers
Direct treatment
laser treatment of retinopathy
kidney transplant
CVS
Risks of Tight Control
Hypoglycemia
relationship to age
permanent damage
performance impairment
detection
often missed, frequently at night
Symptoms of Hypoglycemia
Neurogenic
adrenergic
anxiety
tremor
palpitations
increased HR
cholinergic
sweating
hunger
paraesthesias
Neuroglycopenic
changes in
mentation
coma
rarely focal
seizures
death
Driving While Low
6
5
4
115
65
47
3
2
1
0
Swerving
Spinning
Over Line
Off Road
Cox, Diabetes, 42:239, 1993
Seizures Are Bad (Duh!)
16 children, 7 years, 9 had seizures
lower perceptual, motor, memory,
attention
Rovet, J Peds, 134:503, 1999
55 children, 2.6 years, 8 had seizures
decreased memory skills
Kaufman, J Diab Compli, 13:31, 1999
How Low Should We Go?
Current answer - As low as possible
without significant hypoglycemia
actual glycemic goals vary:
age
personality
family support
medical support
etc
The Era of Attempted Tight
Control
Hyperglycemia causes (correlates with)
complications
DCCT data (among others)
New technology
blood glucose meters
glycated hemoglobin
insulin delivery systems
pumps
inhaled insulin
insulin analogs (eg lispro)
Current Practice
As low as possible without (significant)
hypoglycemia
Limited by technology
Limited by family time
Limited by professional time
Insulin Types
Very short acting
Lispro, Insulin aspart, insulin glulisine
Short acting
Regular, Semi-lente
Intermediate acting
NPH, Lente
Long acting
insulin detemir, Ultralente
Very long acting
Glargine
Insulin Action
(hours)
Onset
Peak
Duration
¼
1
4
Regular
½
2
6
NPH/Lente
2
6
14
Ultralente
6
15
24+
Lispro
Insulin Aspart
Glargine
Flat for ~ 24 hours
Insulin Action Curves
100
Lispro
Regular
NPH & Lente
Ultra
Action
80
60
40
20
0
0
5
10
15
Hours
20
25
30
Insulin Action Curves
100
Lispro
Regular
Action
80
60
40
20
0
0
1
2
3
Hours
4
5
6
New Age Two Shots
100
Action
80
60
40
20
0
0
4
8
12
Time
16
20
24
Action
Three Shots
0
4
8
12
Time
16
20
24
Pumps
What do they do?
Basal(s) rates
Meal boluses
Correction bolus
What don't they do?
Still open loop
Require a great deal of attention to detail
Action
Pump Example
0
4
8
12
Time
16
20
24
Long-term Follow-up
 Every 3 months
 glycosylated hemoglobin
 glucose meter/sensor/pump download
 Every year
 TSH
 flu vaccine
 Every so often
 celiac disease
 Every year (after 5-10 years of duration)
 ophthalmologist
 microalbuminuria
The Next Steps
Type 1 Diabetes
TrialNet (NIH)
14 center clinical
research group to
conduct trials to
prevent, delay,
reverse Type 1
diabetes
Selection of Test Populations
New Onset vs At Risk
New onset diabetics
At risk for diabetes
Easy to find
Further along in the
disease process
Very difficult to find
Earlier in the disease
process
May limit efficacy
Allows for a more
intense intervention
May enhance efficacy
Limits intensity of
intervention
Screening methods
General population
TrialNet Natural History Study
& Oral Insulin Study
Looking for relatives of Type 1
diabetics
Screening for anti-islet cell antibodies
1st degree relatives – 45 yo or less
2nd degree relatives – 20 yo or less
Contacts
Stanford – dped.stanford.edu
National - www.diabetestrialnet.org
Transplants
Pancreas
works but
need to prevent rejection
need to prevent autoimmune destruction
need organ source
usually associated with kidney transplant
Islet cell
lots of research on going
Carbon vs Silicon
Transplants
source of material
rejection
autoimmune
Mechanical
Lag associated with glucose sensor and
insulin action
FDA approval
Diabetes Summer Camps
2009
Teen Cruise Camp
Camp Sequoia Lake
Camp De los Ninos
 www.diabetessociety.org/