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Diabetes Types 1 and 2

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Diabetes Types 1 and 2 Darrell M Wilson, MD dwilson_at_stanford.edu * * * * Glucose Control Glycosylated Hemoglobin DCCT NEJM, 329:977,1993 Retinopathy Primary ... – PowerPoint PPT presentation

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Title: Diabetes Types 1 and 2


1
DiabetesTypes 1 and 2
  • Darrell M Wilson, MD
  • dwilson_at_stanford.edu

2
Diabetes Mellitus
  • Insulin dependent
  • IDDM
  • Juvenile onset
  • Brittle
  • Type 1
  • Non-insulin dependent
  • NIDDM
  • Adult onset
  • Type 2

Atypical Diabetes
3
Costs Continue to Increase (U.S.)(in Billions of
Dollars)
Diabetes Care 26917-932, 2003
4
ADA Classification, 2004
5
MODY
  • MODY 1
  • hepatocyte nuclear factor-4-alpha (600281)
  • MODY 2
  • glucokinase IV (125851)
  • MODY 3
  • hepatocyte nuclear factor-1-alpha (600496)

6
Glucose Sensing
Closes K channel
Opens Ca channel
Glucose
Insulin
GLUT-2
Cagranule translocation exocytosis
Kdepolarizes cell
Glucose
Glucokinase
Glucose 6-phosphate
Sulphonylurea receptor closes Kchannel
Glycolysis
ATP
7
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8
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9
Incidence EuropeBy Pediatric Age Group
Green Diabetol 2001
10
Travis, DM in Children, MPCP29, 1987
11
Modes of Discovery
  • Incidental hyperglycemia
  • Incidentally discovered diabetes
  • routine sports PE
  • relative with diabetes
  • The polys, No DKA
  • Diabetic ketoacidosis

12
Symptoms and Signs
13
ADA Guidelines for Diabetes
  • 1. Symptoms casual glucose gt200
  • 2. Fasting plasma glucose gt125
  • 3. Glucose in OGTT _at_ 2 hr gt200
  • OGTT not recommend for routine clinical practice
  • in absence of metabolic decompensation, must be
    repeated on a different day
  • Normal fasting lt100, 2 hr lt140

14
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

15
Initial Phases of Management
  • Diagnosis
  • Metabolic control
  • Patient and family education
  • techniques
  • physiology
  • diet
  • Family support

16
Diabetic Emergencies
  • Diabetic Ketoacidosis (DKA)
  • recurrent DKA
  • Severe Hypoglycemia
  • Hyperosmolar Non-ketotic Coma (HNC)

17
What Kills Diabetics in DKA?
  • Cerebral edema (brain swelling)
  • Hyperkalemia
  • Hypokalemia
  • Dehydration

18
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

19
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

20
The Core Compromise of Diabetes
21
What Kills Diabetics?
  • Acute
  • DKA
  • brain swelling
  • metabolic
  • others
  • Hypoglycemia
  • Chronic Complications
  • macrovascular
  • heart
  • lower extremities
  • microvascular
  • retinopathy
  • nephropathy
  • neuropathy

22
Historical Control Concepts
  • Keep them sweet
  • a bit of glucose in the urine
  • Very limited technology for monitoring
  • Most pediatricians (still) dont have to deal
    with complications

http//jchemed.chem.wisc.edu/JCESoft/CCA/CCA5/MAIN
/1ORGANIC/ORG18/TRAM18/B/1001311/PICTURE.HTM?3
23
Measurement of Glucose
  • Direct
  • Methods
  • meters
  • future sensors
  • Data analysis
  • average
  • variability
  • extremes

24
Measuring GlucoseMeters 2005
www.diabeteshealth.com
25
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26
GlucoseData Analysis
27
GlucoseData Analysis
28
Burmeister DTT 212, 2000
29
Measurement of Glucose
  • Indirect
  • Glycated proteins
  • glycated hemoglobin
  • total glycated hemoglobin
  • hemoglobin A1c (HbA1c)
  • glycated albumin
  • glycated LDL
  • other glycated proteins

30
Hemoglobin A1c
http//www.cem.msu.edu/cem252/sp97/ch18/ch18s20.G
IF
31
Hemoglobin A1c
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parebsandhga1c.gif
32
DCCT
DCCT NEJM, 329977,1993
33
Glucose Control
DCCT NEJM, 329977,1993
34
Glucose ControlGlycosylated Hemoglobin
DCCT NEJM, 329977,1993
35
RetinopathyPrimary Prevention
DCCT NEJM, 329977,1993
36
AlbuminuriaPrimary Prevention
gt300 mg/24hr
gt40 mg/24hr
DCCT NEJM, 329977,1993
37
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38
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.

39
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)

40
Other Factors Associated with Complications
  • Hypertension
  • Lipids
  • Smoking
  • Age
  • Sex
  • Ethnicity
  • SES

41
Risk Modifiers
  • Direct treatment
  • laser treatment of retinopathy
  • kidney transplant
  • CVS

42
Risks of Tight Control
  • Hypoglycemia
  • relationship to age
  • permanent damage
  • performance impairment
  • detection
  • often missed, frequently at night

43
Symptoms of Hypoglycemia
  • Neurogenic
  • adrenergic
  • anxiety
  • tremor
  • palpitations
  • increased HR
  • cholinergic
  • sweating
  • hunger
  • paraesthesias
  • Neuroglycopenic
  • changes in mentation
  • coma
  • rarely focal
  • seizures
  • death

44
Driving While Low
Cox, Diabetes, 42239, 1993
45
Seizures Are Bad (Duh!)
  • 16 children, 7 years, 9 had seizures
  • lower perceptual, motor, memory, attention
  • Rovet, J Peds, 134503, 1999
  • 55 children, 2.6 years, 8 had seizures
  • decreased memory skills
  • Kaufman, J Diab Compli, 1331, 1999

46
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

47
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)

48
Current Practice
  • As low as possible without (significant)
    hypoglycemia
  • Limited by technology
  • Limited by family time
  • Limited by professional time

49
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

50
Insulin Action(hours)
51
Insulin Action Curves
52
Insulin Action Curves
53
New Age Two Shots
54
Three Shots
55
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

56
Pump Example
57
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

58
The Next Steps
  • Type 1 Diabetes TrialNet (NIH)
  • 14 center clinical research group to conduct
    trials to prevent, delay, reverse Type 1 diabetes

59
Selection of Test PopulationsNew Onset vs At Risk
  • New onset diabetics
  • Easy to find
  • Further along in the disease process
  • May limit efficacy
  • Allows for a more intense intervention
  • At risk for diabetes
  • Very difficult to find
  • Earlier in the disease process
  • May enhance efficacy
  • Limits intensity of intervention
  • Screening methods
  • General population

60
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

61
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

62
Carbon vs Silicon
  • Transplants
  • source of material
  • rejection
  • autoimmune
  • Mechanical
  • Lag associated with glucose sensor and insulin
    action
  • FDA approval

63
Diabetes Summer Camps2009
  • Teen Cruise Camp
  • Camp Sequoia Lake
  • Camp De los Ninos
  • www.diabetessociety.org/
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