DiabetesTypes 1 and 2

Darrell M Wilson, MD

dwilson@stanford.edu

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/