Toward an Expanded Toward an Expanded View of Diabetes View of Diabetes

Prevention:Prevention:Native People Had It Native People Had It

Right All AlongRight All Along

Ann Bullock, MDAnn Bullock, MDIHS Division of Diabetes IHS Division of Diabetes

Treatment and PreventionTreatment and Prevention

Our model of Diabetes has Our model of Diabetes has been too small…been too small…

We’ve thought it was only about:We’ve thought it was only about: Genes we inheritGenes we inherit Our lifestyle choices (diet & exercise)Our lifestyle choices (diet & exercise)

But it’s now clear that these alone do But it’s now clear that these alone do notnot explain all of diabetes risk explain all of diabetes risk

It’s also becoming clear that the roots It’s also becoming clear that the roots of diabetes overlap with the roots of of diabetes overlap with the roots of other chronic problems: heart disease, other chronic problems: heart disease, depression, substance abuse, domestic depression, substance abuse, domestic violence, learning problems, etc.violence, learning problems, etc.

Childhood Trauma Predicts Childhood Trauma Predicts Adult HealthAdult Health

Children born in Helsinki, Finland between 1934-44Children born in Helsinki, Finland between 1934-44 320 were evacuated abroad during WW II—320 were evacuated abroad during WW II—

separated from their parentsseparated from their parents Average age at evacuation: 4.8 years oldAverage age at evacuation: 4.8 years old Average duration of evacuation: 1.7 yearsAverage duration of evacuation: 1.7 years

60 years later, compared with children not 60 years later, compared with children not evacuated, evacuees were much more likely to have:evacuated, evacuees were much more likely to have: Heart disease (OR 2.0) and hypertensionHeart disease (OR 2.0) and hypertension Type 2 Diabetes (OR 1.4)Type 2 Diabetes (OR 1.4) Depressive symptoms (OR 1.7)Depressive symptoms (OR 1.7)

““This study is among the first to show that early life This study is among the first to show that early life trauma predicts higher prevalence of cardiovascular trauma predicts higher prevalence of cardiovascular disease and type 2 diabetes in late adulthood...”disease and type 2 diabetes in late adulthood...” Ann MedAnn Med. 2009;41(1):66-72, . 2009;41(1):66-72, Am J EpidemiolAm J Epidemiol. 2007;166(10):1126-33, . 2007;166(10):1126-33, Am J Hum BiolAm J Hum Biol

2008;20(3):345-512008;20(3):345-51

For diabetes risk, it matters For diabetes risk, it matters what’s happened…what’s happened…

To us as adultsTo us as adults Diet and exercise choicesDiet and exercise choices

Food of poor nutritional quality: another Food of poor nutritional quality: another stimulus to overeatstimulus to overeat

Stress and traumaStress and trauma To us as childrenTo us as children

Nutrition and StressNutrition and Stress To us in the wombTo us in the womb

Nutrition and stressNutrition and stress To our parentsTo our parents

Nutrition and stressNutrition and stress To our grandparentsTo our grandparents

Nutrition and stress Nutrition and stress Eur J Human Genetics Eur J Human Genetics 2007;15:784-790 2007;15:784-790

and 2002;10:682-688and 2002;10:682-688 ““It is through epigenetic marks It is through epigenetic marks

that environmental factors like that environmental factors like diet, stress and prenatal nutrition diet, stress and prenatal nutrition can make an imprint on genes that can make an imprint on genes that is passed from one generation to is passed from one generation to the next.”the next.” TimeTime 1/18/10, p. 50 1/18/10, p. 50

“…confronting the origins of disparities in physical and mental health early in life may produce greater effects than attempting to modify health-related behaviors or improve access to health care in adulthood.”

Shonkoff, Boyce, McEwen JAMA 2009;301(21):2252-2259

““Adverse pre- and postnatal Adverse pre- and postnatal experiences can have a profound effect experiences can have a profound effect

on the course of health and on the course of health and development over a lifetime. … development over a lifetime. …

biological events that occur during biological events that occur during fetal and postnatal life predispose the fetal and postnatal life predispose the child to an elevated risk of subsequent child to an elevated risk of subsequent

problems in physical and mental problems in physical and mental health.”health.”

““A Science-Based Framework for Early Childhood A Science-Based Framework for Early Childhood Policy: Using Evidence to Improve Outcomes in Policy: Using Evidence to Improve Outcomes in Learning, Behavior, and Health for Vulnerable Learning, Behavior, and Health for Vulnerable

Children”, Center on the Developing Child at Harvard Children”, Center on the Developing Child at Harvard University, August 2007, p.6 University, August 2007, p.6

http://www.developingchild.harvard.eduhttp://www.developingchild.harvard.edu

International International Diabetes Diabetes

FederationFederationConference on Type 2 Diabetes

Etiologies 2002 2002

1.1. GeneticsGenetics

2.2. Fetal OriginsFetal Origins

3.3. LifestyleLifestyle

4.4. StressStress

1. Genetics1. Genetics Genes Genes InheritedInherited

It does matter what genes we inheritIt does matter what genes we inherit But But only 15% of genes in cells “turned on” at any only 15% of genes in cells “turned on” at any

given time given time

Genes Genes ExpressedExpressed ““Epigenetics”: the “on/off switches” Epigenetics”: the “on/off switches”

for genesfor genes reaction to the environmentreaction to the environment not always reversible if at key developmental stage of lifenot always reversible if at key developmental stage of life we know the body’s “on/off switches”: DNA methylation, we know the body’s “on/off switches”: DNA methylation,

histone acetylation, histone acetylation, microRNAmicroRNA

JAMA 294(17):2221-4, 2005 and NEJM 359:61-73, 2008

NEJM 359:61-73, 2008

EpigeneticsEpigenetics No longer “nature vs. nurture”—nurture No longer “nature vs. nurture”—nurture affectsaffects

naturenature Rat pups raised by nurturing mothersRat pups raised by nurturing mothers

Gene which affects stress hormone receptors “turned on”Gene which affects stress hormone receptors “turned on” Grow up to be stress resilientGrow up to be stress resilient

Rat pups raised by neglectful mothersRat pups raised by neglectful mothers Gene which affects stress hormone receptors “turned off”Gene which affects stress hormone receptors “turned off” Grow up to be very stress reactiveGrow up to be very stress reactive

Same process has now been shown in humans Same process has now been shown in humans Nature Neuroscience Nature Neuroscience

2009;2009;12:342-34812:342-348 “…“…there is no change in gene sequence; the changes are only there is no change in gene sequence; the changes are only

in…gene expression. Hence, these kinds of effects are called in…gene expression. Hence, these kinds of effects are called epigeneticepigenetic. Epigenetic mechanisms can provide a potential . Epigenetic mechanisms can provide a potential pathway by which early experience can have lasting effects pathway by which early experience can have lasting effects on behavior.”on behavior.” JAMA 2005;JAMA 2005;294(17):2221-4294(17):2221-4

2. Fetal Origins Alcohol/DrugsAlcohol/Drugs NutritionNutrition SmokingSmoking Maternal DiabetesMaternal Diabetes Toxic/Infectious Toxic/Infectious ExposuresExposures Maternal Low Birth Maternal Low Birth Weight Weight Maternal Stress/Mental Maternal Stress/Mental HealthHealth

Mother’s own ChildhoodMother’s own Childhood Current/Prenatal Current/Prenatal

Low Birth Weight (SGA) Low Birth Weight (SGA) and Pretermand Preterm

Babies can be either/both SGA and Babies can be either/both SGA and PretermPreterm they they bothboth are strongly associated with that are strongly associated with that

baby’s later risk for chronic diseasebaby’s later risk for chronic disease DiabetesDiabetes 2009;58:523-526 2009;58:523-526

Maternal stressful life events during 1Maternal stressful life events during 1stst trimester ↑ risk of preterm birth (OR 2.4) trimester ↑ risk of preterm birth (OR 2.4) and SGAand SGA

Am J Obstet GynecolAm J Obstet Gynecol 2010;203:34.e1-8 2010;203:34.e1-8

Prenatal Depression Effects Prenatal Depression Effects on the Fetus and Newbornon the Fetus and Newborn

Mothers with depressive symptomsMothers with depressive symptoms ↑↑stress hormone (cortisol), ↓serotonin/dopamine stress hormone (cortisol), ↓serotonin/dopamine

levelslevels More likely to deliver prematurely and have low birth More likely to deliver prematurely and have low birth

weight babiesweight babies Newborns of mothers with depressive symptoms:Newborns of mothers with depressive symptoms:

↑ ↑ cortisol and ↓serotonin/dopamine levels (like mom)cortisol and ↓serotonin/dopamine levels (like mom) ↓ “↓ “neurobehavioral profiles”neurobehavioral profiles”

Infant Behavior & DevelopmentInfant Behavior & Development 2004;27:216-229 2004;27:216-229

Preterm delivery risk increases with depression Preterm delivery risk increases with depression severityseverity 44% of 791 pregnant patients had depressive 44% of 791 pregnant patients had depressive

symptoms, half of them severesymptoms, half of them severe

Human ReproductionHuman Reproduction 2009;24(1):146-153 2009;24(1):146-153

Prenatal Effects on Stress Prenatal Effects on Stress Hormones PersistHormones Persist

Girls born to mothers who had Girls born to mothers who had significant anxiety during pregnancy, significant anxiety during pregnancy, themselves had increased stress themselves had increased stress hormones—as hormones—as adolescentsadolescents

And this was associated with depressive And this was associated with depressive symptoms in these adolescents symptoms in these adolescents

NeuropsychopharmacologyNeuropsychopharmacology 33:536-545, 200833:536-545, 2008

Copyright ©2005 American Physiological Society

Mcmillen IC, et al. Physiol. Rev. 85: 571-633 2005;doi:10.1152/physrev.00053.2003

FIG. 7. The physiological mechanisms underlying the programming of the separate and combined elements of the metabolic syndrome

Risk of Type 2 DiabetesRisk of Type 2 Diabetes Fetuses of obese mothers develop insulin Fetuses of obese mothers develop insulin

resistance resistance in uteroin utero “…“…maternal obesity creates a significant risk for maternal obesity creates a significant risk for

the next generations with metabolic compromise the next generations with metabolic compromise already apparent at birth.” already apparent at birth.” Diabetes CareDiabetes Care 2009;32:1076-1080 2009;32:1076-1080

Inverse relationship between birth weight Inverse relationship between birth weight and risk of diabetesand risk of diabetes

JAMA JAMA 2008;300:2886-28972008;300:2886-2897

Rapid weight gain in the first 3 months of life Rapid weight gain in the first 3 months of life is associated with several determinants of is associated with several determinants of CVD and type 2 diabetes by early adulthoodCVD and type 2 diabetes by early adulthood

JAMAJAMA 2009;301(21)2234- 2009;301(21)2234-22422242

““Fetal Programming of Fetal Programming of Type 2 Diabetes”Type 2 Diabetes”

“…“…intrauterine environment may modify gene intrauterine environment may modify gene expression permanently. …They might also be expression permanently. …They might also be inherited transgenerationally, affecting the inherited transgenerationally, affecting the health of future generations. …During health of future generations. …During intrauterine life, there are waves of epigenomic intrauterine life, there are waves of epigenomic modification, intimately associated with growth modification, intimately associated with growth and development, and opportunities galore for and development, and opportunities galore for environmental factors to influence these environmental factors to influence these processes. A fetus thus programmed travels a processes. A fetus thus programmed travels a path of limited options.”path of limited options.”

Diabetes CareDiabetes Care 30(10): 2754-5, 2007 30(10): 2754-5, 2007

Stress of RacismStress of Racism

“The lifelong accumulated experiences of racial discrimination by African American women constitute an independent risk factor for preterm delivery.” Odds ratio of 2.6 Independent of maternal sociodemographic,

biomedical, and behavioral characteristics.

Am J Public Health. 94:2132–2138, 2004

3. Lifestyle3. LifestyleOvereating as an Overeating as an AdaptiveAdaptive

ResponseResponse Food Insecurity:Food Insecurity: Prevalence of overweight in women ↑’s as food Prevalence of overweight in women ↑’s as food

insecurity ↑insecurity ↑ Journal of Nutrition. Journal of Nutrition. 2001;131:1738-17452001;131:1738-1745

Pregnancy: food insecurity assoc with pregravid Pregnancy: food insecurity assoc with pregravid obesity, ↑ gest wt gain, and gest diabetesobesity, ↑ gest wt gain, and gest diabetes

J Am Diet Assoc J Am Diet Assoc 2010;110:692-7012010;110:692-701

42% of households below poverty level are food 42% of households below poverty level are food insecure, 21% of households w/childreninsecure, 21% of households w/children

NEJMNEJM 2010;363:6-9 2010;363:6-9

Carbohydrates affect brain serotonin levelsCarbohydrates affect brain serotonin levels Obes Res 1995 Suppl 4:477S-480SObes Res 1995 Suppl 4:477S-480S

““Comfort Foods” ↓ HPA axis stress responseComfort Foods” ↓ HPA axis stress response Proc Natl Acad SciProc Natl Acad Sci 2003;100:11696- 2003;100:11696-

1170111701

4.4. StressStress

Chronic exposure to Intimate Chronic exposure to Intimate Partner Violence almost doubles (OR Partner Violence almost doubles (OR 1.8) risk of obesity at age 5 years.1.8) risk of obesity at age 5 years.

Arch Pediatr Adolesc Arch Pediatr Adolesc MedMed 2010;164:540-546 2010;164:540-546

““As the twig is bent, so the As the twig is bent, so the tree inclines”tree inclines”

Adverse Childhood Experiences (ACE) Adverse Childhood Experiences (ACE) StudyStudy--Overall Exposure: 86%--Overall Exposure: 86% (among 7 (among 7 tribes)tribes)

Non-Native Non-Native NativeNativePhysical Abuse-M 30% Physical Abuse-M 30%

40%40%Physical Abuse-F 27 42Physical Abuse-F 27 42Sexual Abuse-M 16 24Sexual Abuse-M 16 24Sexual Abuse-F 25 31Sexual Abuse-F 25 31Emotional Abuse 11 30Emotional Abuse 11 30Household ETOH 27 65Household ETOH 27 65Four or More ACEs 6 33Four or More ACEs 6 33

Am J Prev Med 2003;25:238-244Am J Prev Med 2003;25:238-244

ACE Score ≥4ACE Score ≥4 4-12 x risk for alcoholism, drug 4-12 x risk for alcoholism, drug

abuse, depression and suicide attemptabuse, depression and suicide attempt 2-4 x risk for smoking, teen 2-4 x risk for smoking, teen

pregnancy, STDs, multiple sexual pregnancy, STDs, multiple sexual partnerspartners

1.4-1.6 x risk for severe obesity1.4-1.6 x risk for severe obesity Strong graded relationship at Strong graded relationship at all all

levels of ACEs for almost all levels of ACEs for almost all outcomes, including heart diseaseoutcomes, including heart disease

Am J Prev Med Am J Prev Med 1998;14:245-258 and 1998;14:245-258 and Circulation Circulation 2004;110:1761-17662004;110:1761-1766

Reducing Prenatal Reducing Prenatal and Early Life Risk and Early Life Risk

Factors for Factors for DiabetesDiabetes

Cultural/Group SupportCultural/Group Support Pima Pride/ActionPima Pride/Action

-DPP pilot study-DPP pilot studyPeople randomized to “Action” groupPeople randomized to “Action” group

-Structured diet/exercise meetings-Structured diet/exercise meetingsPeople randomized to “Pride” control People randomized to “Pride” control

groupgroup-Unstructured activities -Unstructured activities

emphasizingemphasizingPima culture and historyPima culture and history

““Pima Pride” group showed more Pima Pride” group showed more positive outcomes on every biological positive outcomes on every biological parameter measuredparameter measured

Narayan Narayan et al, Diabet Med 1998;15:66-72et al, Diabet Med 1998;15:66-72

Parenting is KeyParenting is Key

2-3x ↑ risk for anxiety and disruptive 2-3x ↑ risk for anxiety and disruptive behavior disorders and major behavior disorders and major depression in children of depressed depression in children of depressed parentsparents

Treating the mothers’ depression Treating the mothers’ depression reduces symptoms in reduces symptoms in bothboth mothers mothers and childrenand children

JAMA. JAMA. 2006;295:1389-13982006;295:1389-1398

Maternal warmth buffers the effects of Maternal warmth buffers the effects of low early-life SES on pro-inflammatory low early-life SES on pro-inflammatory signaling in adulthood. signaling in adulthood. Molecular Molecular Psychiatry Psychiatry 2010;doi:10.1038/mp.2010.532010;doi:10.1038/mp.2010.53

Stimulation in Early Stimulation in Early Childhood: Has Effects Childhood: Has Effects

Years LaterYears Later Psychosocial stimulation (weekly play sessions Psychosocial stimulation (weekly play sessions

with mother and child over 2 years) given to with mother and child over 2 years) given to growth retarded children age 9-24 months growth retarded children age 9-24 months resulted in less anxiety, depression, attention resulted in less anxiety, depression, attention problems and higher self-esteem problems and higher self-esteem 16 years after 16 years after the intervention.the intervention.

Intervention aimed to improve the mother-child Intervention aimed to improve the mother-child relationship: listening and talking to children, relationship: listening and talking to children, allowing them to experience success/praise, allowing them to experience success/praise, reducing punishmentreducing punishment

BMJ 2006;BMJ 2006; doi:10.1136/bmj.38897.55208.2Fdoi:10.1136/bmj.38897.55208.2F

Prenatal/Early Prenatal/Early Life Home Life Home

VisitingVisitingOne of the key evidence-based One of the key evidence-based

interventions proven to improve interventions proven to improve the life trajectories of low income the life trajectories of low income

women and childrenwomen and children

28““There is a magic There is a magic window duringwindow during pregnancy…it’s a pregnancy…it’s a time when the time when the desire to be a good desire to be a good mother and raise a mother and raise a healthy, happy child healthy, happy child creates motivation creates motivation to overcome to overcome incredible obstacles incredible obstacles including poverty, including poverty, instability or abuse instability or abuse with the help of a with the help of a well-trained nurse.”well-trained nurse.”

David Olds, PhD, David Olds, PhD, Founder, Nurse-Family Founder, Nurse-Family PartnershipPartnership

29

Nurse-Family Partnership Nurse-Family Partnership is…is…

An evidence-based, nurse home visiting An evidence-based, nurse home visiting program program

Transforming lives of vulnerable first-time Transforming lives of vulnerable first-time mothers living in povertymothers living in poverty

Improving prenatal care, quality of Improving prenatal care, quality of parenting and life prospects for mothers parenting and life prospects for mothers by partnering them with a registered by partnering them with a registered nursenurse..

Nurse-Family Partnership

Nurse-Family Partnership

31Nurse-Family Partnership

32Nurse-Family Partnership

Nurse-Family Partnership home visiting intervention: Monetary Benefits

Nurse-Family Partnership home visiting intervention: Monetary Benefits

Used with permission from the Prevention Research Center for the Promotion of Human Development/2005 data

Fayette Fayette County, PA County, PA

Number of families servedNumber of families served 280280Benefit minus cost per Benefit minus cost per familyfamily

$37,367$37,367

Per dollar return on Per dollar return on investmentinvestment

$3.59$3.59

Total economic benefit for Total economic benefit for Fayette CountyFayette County

$10,462,70$10,462,7077

State of State of PAPA

Estimated number of NFP Estimated number of NFP programs statewideprograms statewide

2525

Estimated number of Estimated number of families served statewidefamilies served statewide

23002300

Total potential economic Total potential economic benefit statewidebenefit statewide

$119,574, $119,574, 400400

What then must we do?What then must we do?Parenting, Nutrition, Parenting, Nutrition,

Stress/TraumaStress/Trauma Alleviate food insecurity/provide good nutritionAlleviate food insecurity/provide good nutrition Advocate for home visiting interventionsAdvocate for home visiting interventions Teach parenting and coping skillsTeach parenting and coping skills Screen for/treat depression and substance abuseScreen for/treat depression and substance abuse Intervene in adverse childhood experiencesIntervene in adverse childhood experiences Advocate for economic justiceAdvocate for economic justice Strengthen traditional values , worldviews and Strengthen traditional values , worldviews and

practices practices Especially to care for pregnant women, children and Especially to care for pregnant women, children and

young parentsyoung parents Take the “long view”—good things that happen now Take the “long view”—good things that happen now

may take several generations to show their full benefitmay take several generations to show their full benefit Change Change ourselvesourselves

““Dance with Desire to Dance with Desire to Make the World Well”Make the World Well”

Early Life Experience and the Brain

Developing brain is remarkably shapeable and adaptable “The brain’s exquisite sensitivity to experience in early childhood allows traumatic experiences during infancy and childhood to impact all future emotional, behavioral, cognitive, social, and physiologic functioning.”

Child Adolesc Psychiatr Clin N Am 1998;7(1):33-51

Early life risk factors combine and take their toll on the brain

Family Structure Parental employment Father’s absence Teen parenthood

Human Capital Maternal education Maternal verbal ability

Mental Health Maternal depression Stressful life events

“…associated with lower IQ scores as early as age 2-4 years and more behavior problems by age 3.”

Fuligni and Brooks-Gunn from Promoting Health: Intervention

Strategies from Social and Behavioral Research, 2000

Brain Development

From Neurons to Neighborhoods: the Science of Early Child Development. National Academy of Sciences, 2000, p. 188

National Academy of Sciences, 2000, p. 199

““It is important to It is important to understand that the story understand that the story is not about birth weight is not about birth weight

but about fetal but about fetal programming, and that programming, and that

intergenerational intergenerational prevention of type 2 prevention of type 2 diabetes (primordial diabetes (primordial

prevention) will need to prevention) will need to target maternal nutrition target maternal nutrition

and metabolism.”and metabolism.”““Fetal Programming of Diabetes: Still So Much Fetal Programming of Diabetes: Still So Much

to Learn!”to Learn!”Diabetes CareDiabetes Care 2010;33:1146-1148 2010;33:1146-1148

Early Life Risk Factors for Early Life Risk Factors for Obesity at Age 7 yearsObesity at Age 7 years

1.1. Parental obesityParental obesity2.2. Birth weightBirth weight3.3. Weight gain in 1Weight gain in 1stst year of life year of life (“catch-up (“catch-up

growth”, “adiposity rebound”)growth”, “adiposity rebound”)4.4. >8 hrs/week TV watching at age 3 yrs>8 hrs/week TV watching at age 3 yrs5.5. Short sleep duration at age 3 yrsShort sleep duration at age 3 yrs6.6. NotNot : calories eaten, junk food, breastfeeding : calories eaten, junk food, breastfeeding

Reilly, Reilly, et alet al. 2005. . 2005. BMJBMJ, , doi:10.1136/bmj.38470.670903.E0doi:10.1136/bmj.38470.670903.E0

Maternal depression during pregnancy is risk factor Maternal depression during pregnancy is risk factor for childhood obesity. “…disparities in childhood for childhood obesity. “…disparities in childhood obesity may be determined by factors that operate at obesity may be determined by factors that operate at the earliest stages of life.”the earliest stages of life.”

PediatricsPediatrics 2010;125:686-695 2010;125:686-695

Adverse Childhood Adverse Childhood Experiences and Adult Risk Experiences and Adult Risk

Factors for DiseaseFactors for Disease Dunedin, New Zealand: 32 yr longitudinal study of Dunedin, New Zealand: 32 yr longitudinal study of

birth cohortbirth cohort Adverse childhood experiences in first decade of life:Adverse childhood experiences in first decade of life:

Low SESLow SES MaltreatmentMaltreatment Social IsolationSocial Isolation

Controlled for birth weight, family history, childhood Controlled for birth weight, family history, childhood BMI, adult health behaviorsBMI, adult health behaviors

Attributable to adverse childhood experiences:Attributable to adverse childhood experiences: 31.6% of depression31.6% of depression 13% of elevated inflammation13% of elevated inflammation 32.2% of cases with clustering of metabolic risk markers32.2% of cases with clustering of metabolic risk markers

As severity of each ACE ↑’d, greater # of health As severity of each ACE ↑’d, greater # of health risks in a dose-response fashionrisks in a dose-response fashion

Arch Pediatr Adolesc MedArch Pediatr Adolesc Med 2009;163(12):1135-11432009;163(12):1135-1143