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Transcript of Diabetes Types 1 and 2 Darrell M Wilson, MD [email protected].
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Diabetes Mellitus
Insulin dependent
IDDMJuvenile onsetBrittle
Type 1
Non-insulin dependent
NIDDMAdult onset
Type 2
Atypical Diabetes
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$92
$109
$138
$40$47
$54
$132
$156
$192
$0
$40
$80
$120
$160
$200
$240
Direct Indirect Total
2002
2010
2020
Diabetes Care 26:917-932, 2003
Costs Continue to Increase (U.S.)(in Billions of Dollars)
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ADA Classification, 2004
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MODY
MODY 1hepatocyte nuclear factor-4-alpha (600281)
MODY 2glucokinase IV (125851)
MODY 3hepatocyte nuclear factor-1-alpha (600496)
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Glucose Sensing
Glucose
Glucose
Glucose6-phosphate
Glucokinase
GLUT-2
ATP
Glycolysis
Closes K+
channel
K+depolarizes cell
Opens Ca++
channel
Ca++granule translocation& exocytosis
Insulin
Sulphonylurea receptor closes
K+channel
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GeneticsEnvironmental
triggers
Insulitis
Type 1 Diabetes
Diabetes Exposure
RenalComplications
EyeComplications
LargeVessels
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Time Course of Diabetes
Time .....0
20
40
60
80
100
Pe
rce
nt
DemandMassFunction
Trigger?
Insulinresistantperiods
ClinicalPresentation
Honeymoon
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Incidence – EuropeBy Pediatric Age Group
Green Diabetol 2001
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Travis, DM in Children, MPCP#29, 1987
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Modes of Discovery
Incidental hyperglycemiaIncidentally discovered diabetes
routine sports PErelative with diabetes
The polys, No DKADiabetic ketoacidosis
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Symptoms and Signs
Pittsburgh Pre-1957
Rhode Island Pre-1994
Total # 513 75 Polyuria 78% 93%
Polydipsia 76% 92% Wgt loss 58% 57%
Polyphagia 49% 16% Anorexia 44% 20%
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ADA Guidelines for Diabetes
1. Symptoms + casual glucose >2002. Fasting plasma glucose >1253. 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
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Pitfalls in the Diagnosis of Diabetes
Think diabetesin flu seasonpolyuria
Never ignore a parentNever ignore the diagnosis
delay is the deadliest form of denial
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Initial Phases of Management
DiagnosisMetabolic controlPatient and family
educationtechniquesphysiologydiet
Family support
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Diabetic Emergencies
Diabetic Ketoacidosis (DKA)recurrent DKA
Severe HypoglycemiaHyperosmolar Non-ketotic Coma (HNC)
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What Kills Diabetics in DKA?
Cerebral edema (brain swelling)HyperkalemiaHypokalemiaDehydration
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Treatment Goals
First order viewreplace missing insulin
Second order viewdo it correctly
avoid high blood glucoseavoid low blood glucosecontinue to have a life
Limits of current technology
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Insulin Replacement
Conventional insulin therapypump or injectioncan be closed loop, but often fully open
loop
TransplantsBio-sensing polymersGlucose sensing mechanical pumps
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The Core Compromise of Diabetes
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What Kills Diabetics?
AcuteDKA
brain swellingmetabolic others
Hypoglycemia
Chronic Complicationsmacrovascular
heartlower extremities
microvascularretinopathynephropathyneuropathy
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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
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Measurement of Glucose
DirectMethods
metersfuture sensors
Data analysisaveragevariabilityextremes
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www.diabeteshealth.com
Measuring GlucoseMeters 2005
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Data from Inpatient Accuracy Study Using the Laboratory Glucoses as the Reference
0%
5%
10%
15%
20%
0 50 100 150
Reference Glucose (mg/dL)
Me
dia
n R
AD
UltraBeckman/YSI/iStat
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GlucoseData Analysis
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GlucoseData Analysis
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Burmeister DTT 2:12, 2000
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Measurement of Glucose
IndirectGlycated proteins
glycated hemoglobintotal glycated hemoglobinhemoglobin A1c (HbA1c)
glycated albuminglycated LDLother glycated proteins
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Hemoglobin A1c
http://www.cem.msu.edu/~cem252/sp97/ch18/ch18s20.GIF
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Hemoglobin A1c
http://home.comcast.net/~creationsunltd/images/comparebsandhga1c.gif
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DCCT
DCCT NEJM, 329:977,1993
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Glucose Control
DCCT NEJM, 329:977,1993
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Glucose ControlGlycosylated Hemoglobin
DCCT NEJM, 329:977,1993
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RetinopathyPrimary Prevention
DCCT NEJM, 329:977,1993
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AlbuminuriaPrimary Prevention
DCCT NEJM, 329:977,1993>40 mg/24hr
>300 mg/24hr
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DCCT Data
Glycosylated Hemoglobin (%)5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5
Pro
gre
ssio
n -
Ret
ino
pat
hy
(per
100
pt-
yr)
0
2
4
6
8
10
Sev
ere
Hyp
og
lyce
mia
(per
100
pt/
yr)
20
40
60
80
100
120
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Who Gets Complications?
Only about 50% of diabetics appear to be at high risk for complications
Potential risk areasLipoprotein metabolismGlycation pathwaysOxidation pathwaysThe hemostatic cascadeOther candidate genes.
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Mechanisms of Complications
The “glucose hypothesis”acute/reversible
increased polyols (sugar alcohols)sorbitol in insulin independent tissuesincrease in NADH/NAD+ ratios
decreased myoinositolearly glycation products
chronic/irreversibleadvanced glycation end-products (AGE)
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Other Factors Associated with Complications
HypertensionLipidsSmokingAgeSexEthnicity SES
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Risk Modifiers
Direct treatmentlaser treatment of retinopathykidney transplantCVS
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Risks of Tight Control
Hypoglycemiarelationship to agepermanent damageperformance impairmentdetection
often missed, frequently at night
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Symptoms of Hypoglycemia
Neurogenicadrenergic
anxietytremorpalpitationsincreased HR
cholinergicsweatinghungerparaesthesias
Neuroglycopenicchanges in
mentationcomararely focal seizuresdeath
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Driving While Low
0
1
2
3
4
5
6
Swerving Spinning Over Line Off Road
115
65
47
Cox, Diabetes, 42:239, 1993
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Seizures Are Bad (Duh!)
16 children, 7 years, 9 had seizureslower perceptual, motor, memory,
attentionRovet, J Peds, 134:503, 1999
55 children, 2.6 years, 8 had seizuresdecreased memory skills
Kaufman, J Diab Compli, 13:31, 1999
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How Low Should We Go?
Current answer - As low as possible without significant hypoglycemiaactual glycemic goals vary:
agepersonalityfamily supportmedical supportetc
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The Era of Attempted Tight Control
Hyperglycemia causes (correlates with) complicationsDCCT data (among others)
New technologyblood glucose metersglycated hemoglobininsulin delivery systems
pumpsinhaled insulin
insulin analogs (eg lispro)
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Current Practice
As low as possible without (significant) hypoglycemiaLimited by technologyLimited by family timeLimited by professional time
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Insulin Types
Very short actingLispro, Insulin aspart, insulin glulisine
Short actingRegular, Semi-lente
Intermediate actingNPH, Lente
Long actinginsulin detemir, Ultralente
Very long actingGlargine
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Insulin Action(hours)
Onset Peak Duration
LisproInsulin Aspart
¼ 1 4
Regular ½ 2 6
NPH/Lente 2 6 14
Ultralente 6 15 24+
Glargine Flat for ~ 24 hours
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Insulin Action Curves
Hours
0 5 10 15 20 25 30
Act
ion
0
20
40
60
80
100 LisproRegularNPH & LenteUltra
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Insulin Action Curves
Hours
0 1 2 3 4 5 6
Act
ion
0
20
40
60
80
100LisproRegular
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New Age Two Shots
Time
0 4 8 12 16 20 24
Act
ion
0
20
40
60
80
100
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Three Shots
Time
0 4 8 12 16 20 24
Act
ion
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Pumps
What do they do?Basal(s) ratesMeal bolusesCorrection bolusWhat don't they do?Still open loopRequire a great deal of attention to detail
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Pump Example
Time
0 4 8 12 16 20 24
Act
ion
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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
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The Next Steps
Type 1 Diabetes TrialNet (NIH)14 center clinical
research group to conduct trials to prevent, delay, reverse Type 1 diabetes
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Selection of Test PopulationsNew Onset vs At Risk
New onset diabeticsEasy to findFurther along in the
disease processMay limit efficacyAllows for a more
intense intervention
At risk for diabetesVery difficult to findEarlier in the disease
processMay enhance efficacyLimits intensity of
intervention
Screening methodsGeneral population
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TrialNet Natural History Study& Oral Insulin Study
Looking for relatives of Type 1 diabetics
Screening for anti-islet cell antibodies1st degree relatives – 45 yo or less2nd degree relatives – 20 yo or less
ContactsStanford – dped.stanford.eduNational - www.diabetestrialnet.org
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Transplants
Pancreasworks but
need to prevent rejectionneed to prevent autoimmune destructionneed organ sourceusually associated with kidney transplant
Islet celllots of research on going
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Carbon vs Silicon
Transplantssource of materialrejectionautoimmune
MechanicalLag associated with glucose sensor and
insulin actionFDA approval
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Diabetes Summer Camps2009
Teen Cruise CampCamp Sequoia Lake Camp De los Ninos www.diabetessociety.org/