Diabetes in Young Diabetes in Young WomenWomen
Francine R. Kaufman, M.D.Francine R. Kaufman, M.D.
Professor of PediatricsProfessor of Pediatrics
The Keck School of Medicine of USCThe Keck School of Medicine of USC
Head, Center for Diabetes and Head, Center for Diabetes and EndocrinologyEndocrinology
Childrens Hospital Los AngelesChildrens Hospital Los Angeles
Life Goes on ….Life Goes on ….
Diabetes does not have to stop youDiabetes does not have to stop you That can only happen if you face your That can only happen if you face your
diabetesdiabetes 24/7 24/7 Just do itJust do it
If people react negatively If people react negatively They are uninformed – you need to educate themThey are uninformed – you need to educate them If they cannot be enlightened – you don’t need If they cannot be enlightened – you don’t need
themthem Make it a positive – or at least a neutralMake it a positive – or at least a neutral
Points of DiscussionPoints of Discussion
Practical Strategies for Managing Practical Strategies for Managing DiabetesDiabetes
Leaving Home – Taking RisksLeaving Home – Taking Risks Colleges Life and Employment Colleges Life and Employment Dating - MarriageDating - Marriage PregnancyPregnancy Avoiding ComplicationsAvoiding Complications
Question
What are the Targets?
Glycemic TargetsGlycemic TargetsGlucose values are plasma Glucose values are plasma
(mg/mL)(mg/mL)AgeAge Pre-Meal Pre-Meal
BGBGHS/Night HS/Night
BGBGHbA1cHbA1c
Toddler Toddler
(0-5 yrs)(0-5 yrs)100-180100-180 110-200110-200 ≥≥7.5 & 7.5 &
≤8.5%≤8.5%
School-School-ageage
(6-11 yrs)(6-11 yrs)
90-18090-180 100-180100-180 <8%<8%
AdolescenAdolescentt
(12-19 (12-19 yrs)yrs)
90-13090-130 90-15090-150 <7.5%<7.5%
Adults Adults <7%<7%
HbA1c Statistics for CHLA 2003 HbA1c Statistics for CHLA 2003 Type 1: Diabetes > 1 year, Type 1: Diabetes > 1 year,
followed > 1 yearfollowed > 1 yearEnrolled in Long-term study – Enrolled in Long-term study –
total n 1800total n 1800nn Average ± SDAverage ± SD
All patientsAll patients 11811181 8.2 ± 1.68.2 ± 1.6
MalesMales 579579 8.2 ± 1.68.2 ± 1.6
FemalesFemales 602602 8.2 ± 1.68.2 ± 1.6
< 5 < 5 5151 7.8 ± 1.37.8 ± 1.3
5-10 5-10 355355 7.9 ± 1.3 7.9 ± 1.3
11-16 11-16 489489 8.4 ± 1.88.4 ± 1.8
17-1917-19
>20>20157157
1271278.3 ± 1.58.3 ± 1.5
7.4 7.4 ++ 1.3 1.3
Question
Strategies for Diabetes Management?
Managing DiabetesManaging Diabetes
In DCCT, intensively treated adolescents In DCCT, intensively treated adolescents (13-17 yrs of age) manifested a greater (13-17 yrs of age) manifested a greater absolute rate of severe hypoglycemia and absolute rate of severe hypoglycemia and higher mean HbA1higher mean HbA1cc levels. levels.
Why?Why? Adolescents are faced with rapid physiological Adolescents are faced with rapid physiological
and psychological modifications with the onset and psychological modifications with the onset of puberty which may destabilize glycemic of puberty which may destabilize glycemic control.control.
DCCT Results: Comparison of DCCT Results: Comparison of Adults Versus AdolescentsAdults Versus Adolescents
Adults Adolescents
Intensive Therapy Intensive Therapy
Glycemia Mean BG (mg/dL) 155 ± 30 171 ± 31 HbA1c (%) 7.12 ± 0.03 8.06 ± 0.03 Change in HbA1c 1.7 ± 0.1 1.7 ± 0.2Risk Reduction Retinopathy 63% 61% Microalbuminuria 54% 35%Hypoglycemia Episodes/100 pt-yrs 61.2 85.7 Relative Risk 3.3 2.8
Insulin managementInsulin management
Fixed dose regimens: Fixed dose regimens: requires scheduled meals and snacks and is not requires scheduled meals and snacks and is not
flexible enough for most lifestylesflexible enough for most lifestyles Basal: bolus regimens:Basal: bolus regimens:
Long-acting relatively peak free analogue with Long-acting relatively peak free analogue with pre-food injection of rapid acting analogue pre-food injection of rapid acting analogue useful only if child is willing to take frequent useful only if child is willing to take frequent injectionsinjections
Insulin pumps being increasingly used in all Insulin pumps being increasingly used in all age groups but child must be willing to wear age groups but child must be willing to wear the devicethe device
Relationship Between Relationship Between Number of Blood Glucose Number of Blood Glucose Determinations and A1CDeterminations and A1C
0
1
2
3
4
5
6
7
8
>10/day 8-10/day 6-8/day 4-6/day <4/day
<5%
5%-6%
6%-7%
7%-8%
>8%
Number of Blood Glucose Levels per DayNumber of Blood Glucose Levels per Day
A1C (%)A1C (%)
Question
Does Good Diabetes Control Interfere with My Life?
Metabolic Control and Metabolic Control and Quality of LifeQuality of Life
The study involved 20 centres in 17 The study involved 20 centres in 17 countries in Europe, Japan and North countries in Europe, Japan and North America.America.
Adolescents aged 10-18 yrs at each Adolescents aged 10-18 yrs at each study centre were invited to participate.study centre were invited to participate.
2,101 adolescents were enrolled.2,101 adolescents were enrolled. Samples and information from 79% of Samples and information from 79% of
all patients registered at the centres all patients registered at the centres were obtained.were obtained.
Daily insulin regimen
1 injection
2 injections
3 injections
4 or more injections
Premixed insulin, n (%)
Insulin dose (U/kg/day)
Boys(n=1085)
8
472
295
307
445 (41)
0.94 ± 0.32
Girls(n=1016)
10
380
287
339
407 (40)
1.01 ± 0.32
Results as means ± SD# Adjusted for center, age and duration of diabetes.
P-value
<0.05
0.66
<0.0001#
Patient characteristics on insulin management
Worries about diabetes in adolescents by age, gender and HbA1C
Score
Wo
rrie
s a
bo
ut
dia
be
tes
1211
15
20
25
30
1413 1615 18
F 10.9%
F 6.8%
M 10.9%
M 6.8%
17
HbA1 C
Years
Age
Metabolic Control and Quality of Life
Key messagesKey messages
First large international study evaluating the First large international study evaluating the relationship between metabolic control and QOL in relationship between metabolic control and QOL in 2,101 adolescents with diabetes2,101 adolescents with diabetes
Lower HbALower HbA1c1c associated with better QOL of associated with better QOL of adolescents and lesser perceived family burden adolescents and lesser perceived family burden
Question
Leaving Home?
Taking Risks
Adolescent IssuesAdolescent Issues
Desire for peer acceptanceDesire for peer acceptance Rebellion against authorityRebellion against authority Expectations of increasing Expectations of increasing
responsibilities outside of homeresponsibilities outside of home
Taking RisksTaking Risks
AlcoholAlcohol DrugsDrugs DrivingDriving Hiding diabetes – impacts on it allHiding diabetes – impacts on it all
Question
College Life
College LifeCollege Life
Fun Fun FoodFood FriendsFriends FraternityFraternity FocusFocus
Keeping in TouchKeeping in Touch
Stay with health care provider who Stay with health care provider who knows you versus changing at knows you versus changing at college or before you gocollege or before you go
Email programEmail program Less frequent visitsLess frequent visits Stressors and stress reductionStressors and stress reduction
Question
Dating and Marriage
DatingDating
When to tell about diabetesWhen to tell about diabetes What to tellWhat to tell Where to find informationWhere to find information How do you handle different How do you handle different
responsesresponses
MARRIAGEMARRIAGE
Question
Pregnancy
Prevalence of Diabetes in Prevalence of Diabetes in PregnancyPregnancy
in the United States of in the United States of AmericaAmericaMore than 135,000 GDM + 200,000 More than 135,000 GDM + 200,000
T2DM + T2DM + 6,000 T1DM pregnancies annually6,000 T1DM pregnancies annuallyDiabetes
8%
Non-diabetes92%
American Diabetes Association. Diabetes Care. 1998;21(Suppl. 2).
GlucoGlucosese
Insulin
MotherFetusP
lace
nta
FetalHyperglycemia
FetalHyperinsulinemia
Stimulates fetal
pancreas
Data At CHLAData At CHLA225 Teens at Risk225 Teens at Risk
5-6 pregnancies / year5-6 pregnancies / year >50% interrupted or SAB>50% interrupted or SAB 2-3 Live Births / year2-3 Live Births / year 1/3 Require Prolonged Hospitalization1/3 Require Prolonged Hospitalization Last 3 years – no anomaliesLast 3 years – no anomalies
Overall increased rate of anomalies 6-12% Overall increased rate of anomalies 6-12% compared to 2-3% - a 2-5 fold increasecompared to 2-3% - a 2-5 fold increase
But this can be modified by pre-But this can be modified by pre-conception planning and meticulous conception planning and meticulous diabetes controldiabetes control
Question
How To Avoid Complications
DCCT Results: Comparison of DCCT Results: Comparison of Adults Versus AdolescentsAdults Versus Adolescents
Adults Adolescents
Intensive Therapy Intensive Therapy
Glycemia Mean BG (mg/dL) 155 ± 30 171 ± 31 HbA1c (%) 7.12 ± 0.03 8.06 ± 0.03 Change in HbA1c 1.7 ± 0.1 1.7 ± 0.2Risk Reduction Retinopathy 63% 61% Microalbuminuria 54% 35%Hypoglycemia Episodes/100 pt-yrs 61.2 85.7 Relative Risk 3.3 2.8
1
3
5
7
9
11
13
15
6 7 8 9 10 11 12
DR
Neph
Sev NPDR
Neurop
Microalb
RE
LA
TIV
E R
ISK
HbA1c
Relative Risk of Progression of Relative Risk of Progression of Diabetic Complications by Mean HbA1cDiabetic Complications by Mean HbA1c
Based on DCCT DataBased on DCCT Data
*Not statistically significant due to small number of events.†Showed statistical significance in subsequent epidemiologic analysis.DCCT Research Group. N Engl J Med. 1993;329:977-986; Ohkubo Y, et al. Diabetes Res Clin Pract. 1995;28:103-117; UKPDS 33: Lancet. 1998;352: 837-853; Stratton IM, et al. Brit Med J. 2000;321:405-412.
Intensive Therapy for Intensive Therapy for Diabetes:Diabetes:
Reduction in Incidence of Reduction in Incidence of ComplicationsComplications
T1DM T1DM DCCTDCCT
T2DMT2DMKumamotKumamot
ooT2DMT2DMUKPDSUKPDS
A1CA1C 9% 9% 7% 7% 9% 9% 7% 7% 8% 8% 7% 7%
RetinopathRetinopathyy
63%63% 69%69% 17%17%––21%21%
NephropatNephropathyhy
54%54% 70%70% 24%24%––33%33%
NeuropathNeuropathyy
60%60% 58%58% ––
CardiovascCardiovascular ular disease disease
41%* 41%* 52*52* 16%*16%*
T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus.
Recommendations For Recommendations For Treatment Of RetinopathyTreatment Of Retinopathy
Annual screening should be done Annual screening should be done when the child is ≥ 10 years old and when the child is ≥ 10 years old and has diabetes for 3-5 yearshas diabetes for 3-5 years
Questions:Questions: Is this early enough for a child with Is this early enough for a child with
poorly controlled diabetes for longer poorly controlled diabetes for longer than 3-5 years?than 3-5 years?
Recommendations For Recommendations For Microalbuminuria TestingMicroalbuminuria Testing
Annual screening for urinary albumin Annual screening for urinary albumin should begin when should begin when Child is ≥ 10 yrs oldChild is ≥ 10 yrs old DM of 5 years durationDM of 5 years duration
If urine albumin: creat ratio on spot If urine albumin: creat ratio on spot urine is abnormal (30-299 mg/gm urine is abnormal (30-299 mg/gm creatinine)creatinine) Confirm with 2 additional urine specimensConfirm with 2 additional urine specimens Obtain up: down urine specimen to rule Obtain up: down urine specimen to rule
out orthostatic proteinuriaout orthostatic proteinuria
Recommendations For Recommendations For Microalbuminuria TreatmentMicroalbuminuria Treatment ACE Inhibitors may reverse ACE Inhibitors may reverse
microalbuminuria or delay rate of microalbuminuria or delay rate of progression to macro-albuminuriaprogression to macro-albuminuria
Treat BP aggressivelyTreat BP aggressively
Questions:Questions: Should these children all be referred to a Should these children all be referred to a
nephrologist for evaluation and treatment?nephrologist for evaluation and treatment? Should children with poorly controlled DM be Should children with poorly controlled DM be
evaluated sooner?evaluated sooner? Should children with HTN be evaluated sooner?Should children with HTN be evaluated sooner?
BP RecommendationsBP Recommendations
Repeat with child sitting and relaxed Repeat with child sitting and relaxed on 2 more occasionson 2 more occasions
HTN defined as BP≥ 95% for age, HTN defined as BP≥ 95% for age, sex and height measured on at least sex and height measured on at least 3 separate days3 separate days
High normal BP is ≥ 90% but < 95%High normal BP is ≥ 90% but < 95% Rule out non-diabetes causesRule out non-diabetes causes
BP: When to TreatBP: When to Treat
High normal BPHigh normal BP Diet (limit salt) and exercise for 3-6 monthsDiet (limit salt) and exercise for 3-6 months If still high normal, treat with ACE inhibitorIf still high normal, treat with ACE inhibitor Consider adding ARBs if 90% on maximal Consider adding ARBs if 90% on maximal
dosesdoses Hypertension (confirmed)Hypertension (confirmed)
Treat with ACEI to achieve BP< 90%Treat with ACEI to achieve BP< 90%
Questions Remaining:Questions Remaining:At what age to treat?At what age to treat?At what level to treat?At what level to treat?
Children with diabetes have increased Children with diabetes have increased
muscle thickness & stiffnessmuscle thickness & stiffness Carotid artery intima media thickness is Carotid artery intima media thickness is
significantly increased in youth with significantly increased in youth with diabetes compared to controls matched diabetes compared to controls matched for age and genderfor age and gender
-correlated with LDL-C levels-correlated with LDL-C levels Brachial artery reactivity is decreased in Brachial artery reactivity is decreased in
children with diabetes compared to children with diabetes compared to matched controlsmatched controls
Radial artery tonometry Radial artery tonometry → → stiffer vessels stiffer vessels in children with diabetes compared to in children with diabetes compared to BMI, age, sex matched controlsBMI, age, sex matched controls
Cardiovascular Disease Risk Cardiovascular Disease Risk Factors in Adolescents with Type Factors in Adolescents with Type
1 Diabetes Mellitus1 Diabetes Mellitus
M.V. Karantza, S. Bababeygy, M.V. Karantza, S. Bababeygy,
H.N. Hodis, H.N. Hodis,
W.J. Mack, C.-R. Liu, C.-H. Liu, W.J. Mack, C.-R. Liu, C.-H. Liu,
and F.R. Kaufmanand F.R. Kaufman
Division of Endocrinology, Diabetes, and Metabolism, Division of Endocrinology, Diabetes, and Metabolism, Childrens Hospital Los AngelesChildrens Hospital Los Angeles
Supported by ADA Clinical Research AwardSupported by ADA Clinical Research Award
1-01-CR-061-01-CR-06
Background Background Atherosclerosis is a Major Cause of Morbidity and Atherosclerosis is a Major Cause of Morbidity and
Mortality in Patients with T1DMMortality in Patients with T1DM
May be initiated earlyMay be initiated early
Accelerated by traditional CVD factorsAccelerated by traditional CVD factors Hig blood pressure, dyslipidemia, cigarette Hig blood pressure, dyslipidemia, cigarette
smoking, obesity smoking, obesity
Inflammatory and prothrombotic factors Inflammatory and prothrombotic factors
Background Background Previous InvestigationsPrevious Investigations
Atherosclerosis assessed by IMT measurement Atherosclerosis assessed by IMT measurement 142 subjects with T1DM 142 subjects with T1DM Mean age 16.0 Mean age 16.0 ± 2.6 yr, mean T1DM duration 6.6 ± 7.9 yr± 2.6 yr, mean T1DM duration 6.6 ± 7.9 yr 87 matched healthy subjects87 matched healthy subjects
Results:Results: Adolescents with T1DM had increased Adolescents with T1DM had increased
atherosclerosis compared to controlsatherosclerosis compared to controls Risk factors for increased IMT included Risk factors for increased IMT included
diabetic complications, and HDL and LDL/HDL diabetic complications, and HDL and LDL/HDL ratioratio
Krantz JS, Krantz JS, et alet al, J Pediatr 2004;145: 452-457, J Pediatr 2004;145: 452-457
.5.5
5.6
.65
.7.7
5IM
T m
m
6 8 10 12 14
HbA1c (%)
P<0.05, r=0.34
IMT vs HbA1c
.4.5
.6.7
.8
No Tobacco Exposure
Tobacco Exposure
IMT and Tobacco Exposure in Males with T1DMIM
T m
m
P=0.02
0.575 ± .0480.624 ± .042
IMT vs Lipids in T1DMIMT vs Lipids in T1DM
In males, IMT is significantlyIn males, IMT is significantlyassociated with associated with Total Cholesterol (r=0.32, p<0.05)Total Cholesterol (r=0.32, p<0.05) Apolipoprotein B (r=0.41, p<0.05)Apolipoprotein B (r=0.41, p<0.05)
In females, IMT is negatively correlatedIn females, IMT is negatively correlatedwith with HDL (r=HDL (r=--0.30, p<0.050.30, p<0.05))
The Continuum Of Vascular Damage in T1DMThe Continuum Of Vascular Damage in T1DM Conventional CVD risk factors result in increased IMT and Conventional CVD risk factors result in increased IMT and
probably cause the initial endothelial dysfunction in our probably cause the initial endothelial dysfunction in our cohort of youth with T1DMcohort of youth with T1DM
The subsequent loss of normal endothelial homeostatic The subsequent loss of normal endothelial homeostatic properties leading to a proinflammatory, proadhesive, and properties leading to a proinflammatory, proadhesive, and procoagulant endothelial surface is not yet present in our procoagulant endothelial surface is not yet present in our cohortcohort
Early treatment of modifiable risk factors could avert the Early treatment of modifiable risk factors could avert the chronic inflammatory process which, if unabated, will result chronic inflammatory process which, if unabated, will result in the advanced atherosclerotic plaque formationin the advanced atherosclerotic plaque formation
Recommendations For Lipid Recommendations For Lipid ManagementManagement
When to testWhen to test Pre-pubertal children >2 years old should havePre-pubertal children >2 years old should have
Fasting lipids at diagnosis if there is positive FH Fasting lipids at diagnosis if there is positive FH of increased lipids or early cv event (<50 males, of increased lipids or early cv event (<50 males, < 60 females)< 60 females)
If initial LDL-c < 100 mg/dl, repeat every 5 If initial LDL-c < 100 mg/dl, repeat every 5 yearsyears
If initial LDL-c > 100 mg/dl, begin therapeutic If initial LDL-c > 100 mg/dl, begin therapeutic lifestyle change (TLC) lifestyle change (TLC)
Fasting lipids at puberty or at age 12 yrs if FH Fasting lipids at puberty or at age 12 yrs if FH normalnormal
Pubertal children or > 12 years old should have Pubertal children or > 12 years old should have fasting lipid profile done at time of diagnosis after fasting lipid profile done at time of diagnosis after BG control establishedBG control established
Recommendations For Lipid Recommendations For Lipid ManagementManagement
LDL-c > 100 mg/dlLDL-c > 100 mg/dl Step 2 diet (< 7% saturated fat, < 200 mg/d chol)Step 2 diet (< 7% saturated fat, < 200 mg/d chol) Exercise 60 minutes dailyExercise 60 minutes daily Intensify efforts to normalize BGIntensify efforts to normalize BG Repeat 3-6 monthsRepeat 3-6 months
LDL-c >130 mg/dl & ≤ 160 mg/dl after 3-6 LDL-c >130 mg/dl & ≤ 160 mg/dl after 3-6 mosmos Consider treatmentConsider treatment
LDL-c > 160 mg/dl after 3-6 monthsLDL-c > 160 mg/dl after 3-6 months TreatTreat
Pittsburgh Epidemiology Pittsburgh Epidemiology of Diabetes of Diabetes
Complications StudyComplications Study
10 year follow up of patients with Type 10 year follow up of patients with Type 1 diabetes diagnosed before age 171 diabetes diagnosed before age 17
Showed that increased LDL is an Showed that increased LDL is an independent factor of microvascular independent factor of microvascular disease, macrovascular disease, and disease, macrovascular disease, and mortalitymortality
LDL 100-129 RR 5.3LDL 100-129 RR 5.3LDL 130-159 RR 5.6LDL 130-159 RR 5.6LDL >160 RR 12.1 (p<0.01 in LDL >160 RR 12.1 (p<0.01 in
all)all)
Unanswered QuestionsUnanswered Questions
At what age should we begin At what age should we begin medication to decrease lipids?medication to decrease lipids?
Should we wait until glycemic Should we wait until glycemic control is achieved before initiation control is achieved before initiation of lipid lowering medicationsof lipid lowering medications
At what level of LDL-c should we At what level of LDL-c should we treat?treat?
Should we be monitoring hsCRP?Should we be monitoring hsCRP? What drugs should we use?What drugs should we use?
Life Goes on ….Life Goes on ….
Diabetes does not have to stop youDiabetes does not have to stop you That can only happen if you face your That can only happen if you face your
diabetesdiabetes 24/7 24/7 Just do itJust do it
If people react negatively If people react negatively They are uninformed – you need to educate themThey are uninformed – you need to educate them If they cannot be enlightened – you don’t need If they cannot be enlightened – you don’t need
themthem Make it a positive – or at least a neutralMake it a positive – or at least a neutral
