diabetes types 1 and 2 darrell m wilson, md [email protected]
TRANSCRIPT
Diabetes Mellitus
Insulin dependent
IDDMJuvenile onsetBrittle
Type 1
Non-insulin dependent
NIDDMAdult onset
Type 2
Atypical Diabetes
$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)
ADA Classification, 2004
MODY
MODY 1hepatocyte nuclear factor-4-alpha (600281)
MODY 2glucokinase IV (125851)
MODY 3hepatocyte nuclear factor-1-alpha (600496)
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
GeneticsEnvironmental
triggers
Insulitis
Type 1 Diabetes
Diabetes Exposure
RenalComplications
EyeComplications
LargeVessels
Time Course of Diabetes
Time .....0
20
40
60
80
100
Pe
rce
nt
DemandMassFunction
Trigger?
Insulinresistantperiods
ClinicalPresentation
Honeymoon
Incidence – EuropeBy Pediatric Age Group
Green Diabetol 2001
Travis, DM in Children, MPCP#29, 1987
Modes of Discovery
Incidental hyperglycemiaIncidentally discovered diabetes
routine sports PErelative with diabetes
The polys, No DKADiabetic ketoacidosis
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%
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
Pitfalls in the Diagnosis of Diabetes
Think diabetesin flu seasonpolyuria
Never ignore a parentNever ignore the diagnosis
delay is the deadliest form of denial
Initial Phases of Management
DiagnosisMetabolic controlPatient and family
educationtechniquesphysiologydiet
Family support
Diabetic Emergencies
Diabetic Ketoacidosis (DKA)recurrent DKA
Severe HypoglycemiaHyperosmolar Non-ketotic Coma (HNC)
What Kills Diabetics in DKA?
Cerebral edema (brain swelling)HyperkalemiaHypokalemiaDehydration
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
Insulin Replacement
Conventional insulin therapypump or injectioncan be closed loop, but often fully open
loop
TransplantsBio-sensing polymersGlucose sensing mechanical pumps
The Core Compromise of Diabetes
What Kills Diabetics?
AcuteDKA
brain swellingmetabolic others
Hypoglycemia
Chronic Complicationsmacrovascular
heartlower extremities
microvascularretinopathynephropathyneuropathy
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
DirectMethods
metersfuture sensors
Data analysisaveragevariabilityextremes
www.diabeteshealth.com
Measuring GlucoseMeters 2005
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
GlucoseData Analysis
GlucoseData Analysis
Burmeister DTT 2:12, 2000
Measurement of Glucose
IndirectGlycated proteins
glycated hemoglobintotal glycated hemoglobinhemoglobin A1c (HbA1c)
glycated albuminglycated LDLother 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 ControlGlycosylated Hemoglobin
DCCT NEJM, 329:977,1993
RetinopathyPrimary Prevention
DCCT NEJM, 329:977,1993
AlbuminuriaPrimary Prevention
DCCT NEJM, 329:977,1993>40 mg/24hr
>300 mg/24hr
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
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.
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)
Other Factors Associated with Complications
HypertensionLipidsSmokingAgeSexEthnicity SES
Risk Modifiers
Direct treatmentlaser treatment of retinopathykidney transplantCVS
Risks of Tight Control
Hypoglycemiarelationship to agepermanent damageperformance impairmentdetection
often missed, frequently at night
Symptoms of Hypoglycemia
Neurogenicadrenergic
anxietytremorpalpitationsincreased HR
cholinergicsweatinghungerparaesthesias
Neuroglycopenicchanges in
mentationcomararely focal seizuresdeath
Driving While Low
0
1
2
3
4
5
6
Swerving Spinning Over Line Off Road
115
65
47
Cox, Diabetes, 42:239, 1993
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
How Low Should We Go?
Current answer - As low as possible without significant hypoglycemiaactual glycemic goals vary:
agepersonalityfamily supportmedical supportetc
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)
Current Practice
As low as possible without (significant) hypoglycemiaLimited by technologyLimited by family timeLimited by professional time
Insulin Types
Very short actingLispro, Insulin aspart, insulin glulisine
Short actingRegular, Semi-lente
Intermediate actingNPH, Lente
Long actinginsulin detemir, Ultralente
Very long actingGlargine
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
Insulin Action Curves
Hours
0 5 10 15 20 25 30
Act
ion
0
20
40
60
80
100 LisproRegularNPH & LenteUltra
Insulin Action Curves
Hours
0 1 2 3 4 5 6
Act
ion
0
20
40
60
80
100LisproRegular
New Age Two Shots
Time
0 4 8 12 16 20 24
Act
ion
0
20
40
60
80
100
Three Shots
Time
0 4 8 12 16 20 24
Act
ion
Pumps
What do they do?Basal(s) ratesMeal bolusesCorrection bolusWhat don't they do?Still open loopRequire a great deal of attention to detail
Pump Example
Time
0 4 8 12 16 20 24
Act
ion
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 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
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
Transplants
Pancreasworks but
need to prevent rejectionneed to prevent autoimmune destructionneed organ sourceusually associated with kidney transplant
Islet celllots of research on going
Carbon vs Silicon
Transplantssource of materialrejectionautoimmune
MechanicalLag associated with glucose sensor and
insulin actionFDA approval
Diabetes Summer Camps2009
Teen Cruise CampCamp Sequoia Lake Camp De los Ninos www.diabetessociety.org/