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Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department of Diabetes and Endocrinology, Saint- Louis Hospital, INSERM UMRS 872, team 8, Paris, France

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Page 1: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Foetal programming of the cardiovascular risk: Effect of maternal diabetes

12th meeting of the MGSD, Casablanca, Morocco, 2011

Jean-François Gautier,

Department of Diabetes and Endocrinology, Saint-Louis Hospital,

INSERM UMRS 872, team 8,

Paris, France

Page 2: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

What is fœtal programming ?

• DefinitionAlteration of intrauterine environment that predisposes to the development of disorders and diseases later in life

• First evidencesCaloric restriction during pregnancy has been associated with a higher metabolic and cardiovascular risk at adult age

(review in Hales Diabetologia 2003)

Page 3: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Outline

• Epidemiological evidences of maternal transmission of diabetes

• Metabolic defects associated with foetal exposure to maternal diabetes

• Potential mechanisms: what did we learn from animal studies?

• Multi organ defects as a consequences of maternal diabetes in human offspring

• Late consequences

Page 4: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Maternal influence in the development of T2D

Reference Population Ratio mother/father

with T2D

Alcolado J.C.et al.1992

Mitchell B.D.et al.1993

Thomas F.et al.1994

Lin R.S.et al. 1994

Young C.A.et al.1995

Viswanathan M.et al.1995

McCarthy M.et al.1996

Klein B.E.K.et al.1996

Riley M.D.et al.1996

Karter A.J.et al.1999

Meigs J.B.et al.2000

Bo S.et al.2000

Bjornholt J.V.et al.2000

UK

Mexican/Caucasian Americans

France

Taiwan

Europeans/ Caraïbes

Indians

Indians

Wisconsin,USA

Tasmania

California

Framingham

Italy

Norway

2.1

NS

2.1

2.6

2.1/ 1.9

NS

NS

2.0

2.7

1.2

NS

4.0

1.5Review in Alcolado 2002

Page 5: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

• 2527 offspring from 1303 Caucasian families • All offspring and parents were formally tested for

diabetes• The risk of developing diabetes was similar among

offspring of diabetic mothers and of diabetic fathers • However, offspring of mothers who had diabetes before

the age of 50 years had a marked increased risk for developing : Impaired glucose tolerance OR 9.0 (4.2-19.7) Type 2 diabetes OR 9.7 (4.3-22)

→ Possible role of foetal environment ?

The Framingham Offspring Study

Meigs Diabetes 2000

Page 6: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

In Utero Exposure to Hyperglycemia Increases Risk of Diabetes in Pima Indians

0

10

20

30

40

50

No DM DM

Maternal Status During Pregnancy

Prevalence of T2DM among 20-24 year olds%

with

T2D

M

Pettitt Diabetes 1988

Page 7: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Is there a threshold of blood glucose level during pregnancy ?

Franks Diabetes 2006

Page 8: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

What are the mechanisms that explain the higher risk for type 2 diabetes in offspring of diabetic mothers in Pima Indians?

Body composition ?

Insulin action ?

Insulin secretion ?

Page 9: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

400

800

1200

1600

DM No DM

AIR

(pm

ol/l)

Reduced acute insulin response in adult NGT offspring of diabetic women

P = 0.018

0

5

10

15

20

DM No DMM

720 (m

mol

/kg

MB

S. m

in) P = 0.6

Maternal DM status during pregnancy

Gautier J.F. Diabetes, 2001

Insulin secretion Insulin action

Page 10: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Conclusion

Intra uterine exposure to maternal diabetes in Pima Indians :

• Increases the risk for type 2 diabetes in offspring

• Is associated with a decreased acute insulin response to IV glucose in adult offspring with normal glucose tolerance

• Does not worsen insulin resistance and body fat accumulation usually observed in Pima Indians

“In utero diabetes” acquired defect in insulin secretion

Page 11: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

The effects of intrauterine exposure to diabetes may be confounded by genetic

factors :

Women who develop diabetes at earlier age might carry more diabetes-susceptibility genes than those who develop diabetes later and therefore might transmit greater genetic susceptibility to their offspring

Page 12: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

1.5

2

2.5

3

20 40 60 80

Log

AIR

(

U/m

l)

Age of Diabetes Onset of the Mother (years)

P=0.03; r=0.23

Relationship Between Insulin Secretion and Parental Age of Diabetes Onset

DMO > 49y

DMO < 35y

0

500

1000

1500

50 100 150 200 250 300

Plasma Glucose (mg/dl)In

sulin

Sec

retio

n R

ate

(pm

ol/m

in)

P =0.02

Gautier J.F. Diabetes, 2001

Adjusted for age, sex, % body fat, and insulin action

Page 13: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Conclusion

Offspring of mothers with early onset diabetes have lower insulin secretion rates with no aggravation of insulin resistance

Inherited factors Insulin secretion

Page 14: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

How to solve the problem ? To determine the role of intrauterine exposure per se

• To compare the prevalence of diabetes in Pima nuclear families in which at least 1 sibling was born before and after the mother was diagnosed with T2D

• To study the effect of intrauterine exposure to type 1 diabetes (to circumvent the confounding effect of genetic factors related to T2D)

Page 15: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

58 siblings from 19 families

• In 15 of the sibships :

diabetes more frequent after mother ’s diagnosis of diabetes

• In 4 of the sibships :

diabetes occured only before mother ’s diagnosis of diabetes

Odds ratio : 3.7 (CI: 1.3-11.3) ; p = 0.024

Dabelea D, Diabetes, 2000, 49: 2208-11

Page 16: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Dabelea D, 2000

Page 17: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Inclusion Criteria

We proposed to adult offspring of confirmed type 1 diabetic patients attending our department to participate in the study if :

• They were non diabetic• They were born after the diagnosis of parental

diabetes• They had no family history of type 2 diabetes (first-

degree relative)• They had no type 1 diabetes-associated

autoantibodies (ICA, anti-GAD, anti-IA2)

Page 18: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

INVESTIGATIONS

• Measurement of body composition by dual-energy X ray absorptiometry (DEXA)

• 75g Oral Glucose Tolerance Test: Glucose tolerance status (WHO 1985 criteria) Early insulin secretion (I30 – I0 / G30 – G0)

• Insulin action: Euglycemic Hyperinsulinemic Clamp at 80 mU/m2/min

• Insulin secretion: Graded glucose infusion (5 x 40 min steps) at 2, 4, 8, 12 et 16 mg/kg/min with measurement of glucose and C-peptide Calculation of Insulin Secretion Rate by C-peptide deconvolution analysis

Page 19: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Oral Glucose Tolerance

• Offspring of Type 1 diabetic mothers (n = 15) Impaired glucose tolerance: 33% (5/15)Normal glucose tolerance: 67% (10/15)

• Offspring of Type 1 diabetic fathers (n = 16)All had normal glucose tolerance (100%)

Page 20: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Insulin action N=10 N=5Early insulin secretion

Sobngwi E. Lancet 2003

0

5

10

15

20

25

Off father NGT Off mother IGT Off mother(I

30

-I0

)/(G

30

-G0

)

p = 0.037

p = 0.035

Insulin action and secretion in offspring of T1DM mothers

02468

10121416

NGT offspring of type 1 father

NGT offspring of type 1 mother

IGT offspring of type 1 mother

Ad

jus

ted

M-v

alu

ein

mg

.min

-1.k

g-1

of

fat-

fre

e m

as

s

Page 21: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

y = -0,0123x2 + 0,7632x - 2,1253

y = -0,0065x2 + 0,6974x - 1,2287

y = 0,8497x - 2,0582

0

2

4

6

8

10

12

14

16

18

0 5 10 15 20 25

Plasma glucose (mmol.l-1)

Insu

lin s

ecre

tio

n r

ate

(pm

ol.l

-1m

in-1

)

Controls (all NGT)

NGT subjects

IGT subjects

ISR

Sobngwi Lancet 2003

Page 22: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Summary

This study suggests that in utero exposure to a type 1 diabetic environment :

• Is associated with impaired glucose tolerance in 1/3 adult offspring in the study population

• Is associated with a defective insulin secretory response (kinetics and magnitude) to oral and intravenous glucose

• Is not associated with altered insulin sensitivity

• Is not associated with fat mass accumulation

Page 23: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Prevalence of impaired glucose tolerance in offspring of diabetic mothers

198 offspring of mothers with T1D or gestational diabetes

Range of yr T1D Gestational diabetes

1 - 9 yr 10.8%

( 14 / 129 )

13%

( 9 / 69 )

1 - 4 yr 9.4%

( 10 / 106 )

11.1%

( 6 / 54 )

5 - 9 yr 17.4%

(4 / 23 )

20.0%

( 3 / 15 )

Plagemann Diabetologia 1997

Page 24: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Early insulin secretion in adult offspring of mothers with young-onset of T2D

Singh Diabetologia 2006

M M M MPP P P

Page 25: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Outline

• Epidemiological evidences of maternal transmission of diabetes

• Metabolic defects associated with foetal exposure to maternal diabetes

• Potential mechanisms: what did we learn from animal studies?

• Multi organ defects as a consequences of maternal diabetes in human offspring

• Late consequences

Page 26: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

What are the cellular and molecular mechanisms ?

• Oxidative stress due to hyperglycaemia (apoptosis, disturbed organogenesis)

• Foetal hyperinsulinism (abnormal hypothalamic development)

• Altered angiognenesis• Exposure to glucocorticoid excess• Epigenetic modifications (imprinted genes or

not) Reduced organ massMulti organ defect

Page 27: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

1st generation Mild diabetes Severe diabetes6.5 and 9.8 mmol/l glycaemia > 20 mmol/l

2nd generationFoetus Mild Hyperglyc. Severe Hyperglyc.

Hypersinsulinaemia HypoinsulinaemiaMacrosomia Microsomia

Adult Decreased -cell Increased -cellresponse response

Insulin resistancePregnant Gestational diabetes Gestational diabetes

Animal studies

Aerts 1997 ; Holemans 1991 ; Gauguier 1990 ; Bihoreau 1986 …..

Page 28: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Goto Kakizaki (GK) rats

• Rodent model of non obese type 2 diabetes• Produced by selective breeding of individuals with mild glucose

intolerance from a non diabetic Wistar rat colony (Portha 1991)• Foetuses have a reduced beta cell mass (Serradas 1998) • Adults display :

Mild hyperglycaemia, glucose intolerance Impaired glucose-induced insulin secretion Decreased beta cell mass Hepatic glucose overproduction Moderate peripheral insulin resistant (muscle and adipose) tissues

(Portha 1991 , Bisbis 1993 . Movassat 1995)

Page 29: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

R. Gill-Randall et al Diabetologia (2004) 47:1354–1359

Adult offspring from Wistar gametes reared in hyperglycaemic GK mothers were significantly more hyperglycaemic at adulthood than offspring from Wistar gametes transferred back into euglycaemic Wistar mothers

At 6 months

Page 30: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Diabetes 53:752–761, 2004

Control CAM Hyperglycaemic glucose-injected CAM

Endothelial cell Proliferation

Page 31: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department
Page 32: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

L’exposition in utero au diabète maternel chez le rat entraîne une réduction du capital néphronique

Page 33: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Outline

• Epidemiological evidences of maternal transmission of diabetes

• Metabolic defects associated with foetal exposure to maternal diabetes

• Potential mechanisms: what did we learn from animal studies?

• Multi organ defects as a consequences of maternal diabetes in human offspring

• Late consequences

Page 34: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

11,511,7

0

2

4

6

8

10

12

14

16

PDT1 MDT1

%

Insulin sensitivity

Fat mass (DXA)

p = 0.44

p = 0.75

glucose utilisation(mg/kg fat free mass /min)

(±sd)

N=29 N=29

N=29 N=29

Page 35: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Early insulin secretion in response to OGTT

7,8

11,3

0

2

4

6

8

10

12

14

16

18

20In

dex

in

suli

no

gén

iqu

e (m

UI/

mm

ol)

Off T1D F OFF T1D M

p = 0.06

(médiane)

Page 36: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Plasma glucose (mmol/l)

Insu

lin

se

cre

tio

n r

ate

(p

mo

l/kg

pe

r m

in)

Offspring of father

Offspring of mother

Male

Female

Group Gender

5 10 15 20 25

0

2

4

6

8

10

12

14

16

18

20

Insulin secretion in response to IV glucose

Significant interaction between group and offspring gender was found for the slope of ISR ( p= 0.03)

Page 37: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Pancreatic exocrine dysfunction

Off of DT1 Fathers(n=29)

Off of T1D Mothers(n=29) p

Stool weight, moy (sd) , g/24h 124 (56) 112 (66) 0.57

Faecal fat output, moy (sd) , g/24h 4.9 (2.7) 3.7 (2.3) 0.13

Chymotrypsin activity, moy (sd), U/g 22.8 (13.0) 14.5 (7.2) 0.016

Elastase concentration, moy (sd) µg/g 451 (100) 487 (30) 0.12

Page 38: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

GFR changes

Relative changes: +8(13), p= 0.019 Relative changes: +19(17), p= 0.002

Inter-group changes p= 0.009

GF

R (

mL

/min

)

Basal Stimulated

50

75

100

125

150

Offspring of mothers

GF

R (

mL

/min

)50

75

100

125

150

Basal Stimulated

Offspring of fathers

Diabetes 2010

Page 39: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Outline

• Epidemiological evidences of maternal transmission of diabetes

• Metabolic defects associated with foetal exposure to maternal diabetes

• Potential mechanisms: what did we learn from animal studies?

• Multi organ defects as a consequences of maternal diabetes in human offspring

• Late consequences

Page 40: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department
Page 41: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department
Page 42: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department
Page 43: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

In Utero Exposure to Maternal Type 1 DiabetesRisk of Diabetes

0

10

20

30

40

50

No DM DM

Maternal Status During Pregnancy

Prevalence of prediabetes among 22 year olds%

with

T2D

M

Clausen Diabetes Care 2008

9 % (14/160)3 % (4/128)

Page 44: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Nelson 1998

Page 45: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Conclusions (1)• Intrauterine exposure to maternal diabetes is associated

in adult offspring with multi organ dysfunction: an insulin secretion dysfunction (female offspring) a defect of the exocrine pancreas a decrease in renal functional reserve

• Late consequences of exposure in utero to maternal type 1 diabetes are IGT, type 2 diabetes, high blood pressure, microalbuminuria, metabolic syndrome and possibly CVD

• This need to be confirmed in larger longitudinal studies with adequate control groups

Page 46: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Conclusions (2)

• Underlying mechanisms need to be unraveled : epigenetic studies capillary density studies …..

• Intensive glucose control maintained throughout pregnancy may contribute to a decrease in the prevalence of T2D and renal dysfunction in later life

Page 47: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Pathophysiologic vicious circle model for development of type 2 diabetes

Diabetes

Diabetes during

pregnancy

IGT

Cell dysfunction

Insulin resistance

Genetic Factors

Environmentalfactors

Parents

Offspring

CV disease Renal dysfunction

Genetic Factors

Environmentalfactors

Page 48: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department
Page 49: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Contact

Dr LS Fetita• Tel : 01 42 49 48 57 / 96 96

• Cell : 06 14 52 64 53

• Fax : 01 42 49 41 78

• E-mail : [email protected]

Page 50: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

PROJET

Page 51: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

ETUDE EPIDEMIOLOGIQUE• Objectif :

montrer une augmentation de la prévalence du diabète de type 2 chez les descendants adultes de mères ayant un diabète de type 1 comparativement aux descendants de pères diabétiques de type 1

• Nombre de sujets nécessaire:Hypothèse : prévalence à 4 ans du diabète de type 2

respectivement 10.8% vs 1% 110 par groupe de descendants âgés de plus de 30 ans

• Méthodes :Questionnaire aux parents DT1 : Descendants diabétiques et non diabétiques (T1 et

T2)Aux descendants non diabétiques : HGPO, Ac, HLA

Page 52: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

ETUDE PHYSIOLOGIQUE

Evaluer si l’exposition au diabète in utero est associée à :

• Une altération globale de la fonction pancréatique

• Des anomalies rénales

Page 53: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Explorations de la fonction endocrine       Sécrétions d’insuline et de glucagon : en réponse

au glucose et à l’arginine

Action de l’insuline : clamp euglycémique hyperinsulinique et

Exploration de la fonction exocrine du pancréas

Dosage des graisses totales, de l’élastase et de l’activité chymotrypsique fécales

ETUDE PHYSIOLOGIQUE

Page 54: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Exploration de la fonction rénale• Dosage de l’excrétion urinaire d’albumine au

repos et à l’effort• Holter tensionnel des 24h • Réserve fonctionnelle rénale:

Débit de filtration glomérulaire isotopique en réponse à une perfusion d’acides aminés

Composition corporelle (DEXA)

ETUDE PHYSIOLOGIQUE

Page 55: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Mécanismes

1. Défaut d’angiogénèse pendant la vie fœtale

Atteinte multiviscérale ?

2. Phénomène d’empreinte maternelle ?

Page 56: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Diabète in utero et anomalies rénales( Nelson R.G. et al. Diabetes 1998)

Population : 503 Indiens Pimas diabétiques de type 2- 207 descendants de mères non diabétiques- 246 descendants de mères diabétiques postérieurement à la grossesse- 50 descendants de mères diabétiques pendant la grossesse

Prévalence de l’élévation de l’excrétion urinaire de l’albumine- Descendants de mères non diabétiques 40 %- Descendants de mères diabétiques postérieurement à la grossesse 43 % - Descendants de mères diabétiques 58 %

Odd Ratio d’une excrétion urinaire d’albumine élevée 3.8 (95% CI 1.7-8.4) chez les descendants de mères diabétiques par rapport aux descendants de mères diabétiques postérieurement à la grossesse(ajustement pour l’âge, le sexe, la durée du diabète, HbA1C et la pression artérielle)

Page 57: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

• Trait familial :Obésité, insulino-sensibilité, et insulino-sécrétionLillioja 1987, Knowler 1991, Janssen 1994, Sakul 1997

• Analyses de Ségrégation :Un gène majeur influence l ’âge de survenue du diabète Hanson R et al, Am J Hum Genet, 1995, 57 : 160-170

Porte-t-il sur la composition corporelle, l’action de l’insuline ou la sécrétion de l’insuline ?

Diabète de type 2

Page 58: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

0

100

200

300

0 2 3 4 6 80

200

400

600

0 2 3 4 6 8

Pla

sma

Glu

cose

(m

g/dl

)

Pla

sma

Insu

lin

(mU

/l)

GINF (mg.kg-1.min-1) GINF (mg.kg-1.min-1)

DMO > 49 y

DMO < 35 y

Study 2: Changes in Plasma Glucose and Insulin Concentrations During the Stepped Glucose Infusion Test

Page 59: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Prévalence du diabète de type 2 chez les indiens Pimas âgés de 20 à 24 ans :

• ~ 45 % lorsque la mère était diabétique pendant la grossesse

• ~ 9 % lorsque la mère a développé un diabète postérieurement à la grossesse

Pettitt DJ et al, Diabetes, 1988, 37 : 622-628

Effet du Diabète Pendant la Grossesse sur la Prévalence du Diabète de Type 2 dans la

Descendance

Page 60: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

But de l’Etude

Evaluer les mécanismes possibles responsables de l’augmentation du risque de diabète de type 2 chez les descendants de mère diabétique pendant la grossesse

Composition corporelle ?Action de l’insuline ?

Sécrétion de l’insuline ?

Page 61: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Masse grasse et action de l’insuline

Diabète Pendant la Grossesse de la Mère

0

5

10

15

20

Oui NonM72

0 (m

mol

/kg

MB

S. m

in) P = 0,6

15.5 14.9

0

10

20

30

40

Oui Non

Mas

se G

rass

e (%

)

34 33

P = 0,8

Page 62: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Diabète Pendant la Grossesse de la Mère

400

800

1200

1600

Oui Non

Insu

lino

-séc

réti

on(p

mol

/l)

Phase Précoce de l’Insulino-sécrétion

*

Moyenne Géométrique(IC 95%)P = 0,018

740

1255

Ajustée pour l’âge, le sexe, la masse grasse et l’action de l’insulineGautier J.F., Diabetes, 2001

Page 63: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Résumé

Cette étude suggère que le diabète in utero chez les indiens Pimas :

• Entraîne une diminution de la phase précoce de l’insulino-sécrétion en réponse au glucose chez les descendants adultes ayant une tolérance au glucose normale

• N’aggrave pas l’insulino-résistance habituellement observée dans cette population

• Ne contribue pas à une accumulation de masse grasse supplémentaire

Le « diabète in utero » déficit acquis de l’insulino-sécrétion

Page 64: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Solution 2

Evaluer les effets du diabète in-utero sur les facteurs métaboliques prédisposant au diabète de type 2 chez les descendants de patients présentant un diabète de type 1

Composition corporelle ?Action de l’insuline ?

Sécrétion de l’insuline ?

Page 65: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Méthodes

Descendants majeurs de patients diabétiques de type 1 suivis à l’hôpital Saint-Louis :

• Nés après le diagnostic du diabète chez leur parent• Non diabétiques • Sans stigmates d’autoimmunité du diabète de type 1

(ICA, anti-GAD, anti-IA2) • Sans antécédents familiaux connus de diabète de type 2

Descendants de mères Descendants de pères (groupe contrôle)

Page 66: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Méthode (2)

• Composition corporelle: DEXA• HGPO: Tolérance au glucose (critère OMS)• Action de l’insuline:

Clamp hyperinsulinémique euglycémique 80 mU/m2/min

• Sécrétion de l’insuline: Perfusion de glucose par palier de 40 min 2, 4, 8, 12 et 16 mg/kg/min

Page 67: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Sujets

31 sujets répondaient aux critères d ’inclusion :Mère diabétique avant la grossesse

n = 15Père diabétique avant la naissance du

descendant

n = 16

Page 68: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Characteristics of volunteers

  Offspring of diabetic mother

(Subjects)

Offspring of diabetic father

(Controls)

Mean difference [95% CI]

N 15 16

M:F (n) 6:9 6:10  

Age (yr)¤ 23.9 5.9 22.7 4.1 -1.2 [-4.8 ; 2.6]

Birth weight (g)¤ 3306 400 3322 319 16 [-302 ; 333]

SBP (mmHg)¤ 118 13 119 9 2 [-6 ; 9]

DBP (mmHg)¤ 65 8 70 14 6 [-3 ; 14]

Serum creatinine (mol.l-1)¤ 82 10 79 10 -3 [-11 ; 4]

BMI (kg.m-²)¤ 22.5 3.6 23.1 5.6 0.7 [-2.8 ; 4.1]

Percent body fat (%)¤ M F

 13.9 5.127.0 5.9

  12.4 6.1

31.0 12.2

  -1.5 [-9.3 ;

6.3] 4.0 [-6.2 ;

14.3] ¤ Mean SD

Page 69: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

  NGT Controls NGT Subjects IGT Subjects

N 16 10 5

G0 4.6 0.5 4.5 0.7 5.0 0.4

G30 6.6 1.5 7.0 1.3 7.3 2.2

G120 5.3 1.2 6.0 1.0 8.6 0.7

I0 4.7 2.4 5.6 5.1 3.8 2.1

I30 37.8 19.4 42.4 27.6 25.4 16.2

I120 25.5 16.6 34.4 23.2 33.3 19.4

OGTT

Page 70: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

MLM

0

2

4

6

8

10

12

14

16

NGT offspring oftype 1 father

NGT offspring oftype 1 mother

IGT offspring oftype 1 mother

Ad

just

ed M

-val

ue

in

mg

.min

-1.k

g-1

of

fat-

free

mas

s

Page 71: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Early Insulin Secretion

0

5

10

15

20

25

NGT Controls NGT Subjects IGT Subjects

Ea

rly

in

su

lin

se

cre

tio

n

[(I3

0-I

0)/

G3

0-G

0]

p = 0.037

p = 0.035

Page 72: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

EVOLUTION DE LA GLYCEMIE AU COURS DE LA PERFUSION DE GLUCOSE PAR PALIER

mg.kg-1.min-11612842

Gly

cem

ie (

mm

ol/

l) m

oy+

/-S

D

30

25

20

15

10

5

0

Desc. de

Pere

Mere

Page 73: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

C-Peptide

0

0.5

1

1.5

2

2.5

3

3.5

4

0 5 10 15 20 25

Plasma glucose (mmol.l-1)

Pla

sm

a C

-pe

pti

de

(p

mo

l.l-1

)

Controls (all NGT)

NGT subjects

IGT subjects

**

*

*

¤

¤¤

Page 74: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Résumé

Cette étude suggère que le diabète de type 1 in utero :

• Est associé à une intolérance au glucose chez plus de 30 % des descendants majeurs

• Entraîne une diminution de l’insulino-sécrétion en réponse au glucose oral et intraveineux

• N’entraîne pas une insulino-résistance • Ne contribue pas à une accumulation de masse

grasse

Page 75: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Conclusion

Le diabète de type 1 in utero:• Entraîne un déficit acquis de l’insulino-sécrétion

en réponse au glucose chez les descendants adultes

• Confère aux descendants adultes une fréquence élevée d’intolérance au glucose

Augmente le risque de développer un diabète de type 2 ?Mécanismes ?

Page 76: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Maternal Diabetes Onset <35 yr >49 yrN (M/F) 4/4 7/8Age (y) 322 321BMI (kg/m2) 313 362Body Fat (%) 313 342Glucose (mg/dl) Fasting 2-h

97413111

8921229

M130 (mg/kg MBS.min) 3.31.2 3.00.4

Study 2: Characteristics of the Subjects

Page 77: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Study 2: Relationship Between Insulin Secretion Rates and Plasma Glucose Levels

0

500

1000

1500

50 100 150 200 250 300

Plasma Glucose (mg/dl)

Insu

lin

Sec

reti

on R

ate

(pm

ol/m

in) DMO > 49 y

DMO < 35 y

P =0.02 Average ISR 65080

43986 P=0.007

Gautier J.F., Diabetes, 2001

Page 78: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

PP

0

5

10

15

20

25

30

35

PP0 PP30 PP120

IGT Subjects

NGT Subjects

NGT Controls

overall p = 0.016

overall p = 0.025 overall p = 0.010

Page 79: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Résumé

Cette étude suggère que le diabète in utero chez les indiens Pimas :

• Entraîne une diminution de la phase précoce de l’insulino-sécrétion en réponse au glucose chez les descendants adultes ayant une tolérance au glucose normale

• N’aggrave pas l’insulino-résistance habituellement observée dans cette population

• Ne contribue pas à une accumulation de masse grasse supplémentaire

Le « diabète in utero » déficit acquis de l’insulino-sécrétion

Page 80: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Prévalence de l’intolérance au glucose chez les descendants de mères diabétiques

Tranche d’âge N IGT

< 5 ans 168 1.2%

5 – 9 ans 111 5.4%

10 – 16 ans 88 19.3% (p<0.005)

Groupe contrôle (10-16ans)

80 2.5%

Silverman Diabetes Care 1995

367 descendants de mères DT1 ou ayant présenté un diabète gestationnel

Page 81: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department
Page 82: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Increased hepatic glucose output

Metabolic Defects in Type 2 Diabetes

Haffner Diabetes Care 1999

Peripheral insulin resistance

in muscle and fat

Decreased pancreatic insulin secretion

Page 83: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Physiopathologie du diabète de type 2

Etudes des descendants de parents diabétiques

Facteurs environnementaux

Facteurs génétiques

Page 84: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Diabète de type 2

• Obésité• Diminution de l’action de l’insuline• Altération de la sécrétion de l’insuline

• Poids corporel• Insulino-sensibilité• Insulino-sécrétion

} Anomalies prédictives

} Trait familial

Page 85: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Rôle de la mère dans la transmission du diabète de type 2

Référence Population Ratio mères/pères

atteints

Alcolado J.C.et al.1992

Mitchell B.D.et al.1993

Thomas F.et al.1994

Lin R.S.et al. 1994

Young C.A.et al.1995

Viswanathan M.et al.1995

McCarthy M.et al.1996

Klein B.E.K.et al.1996

Riley M.D.et al.1996

Karter A.J.et al.1999

Meigs J.B.et al.2000

Bo S.et al.2000

Bjornholt J.V.et al.2000

Britannique

Mexicains/Caucasiens américains

Française

Taiwanaise

Européens/Caraïbes

Indiens

Indiens

Wisconsin,USA

Tasmanie

Californie du Nord

Framingham

Italiens

Norvégienne

2.1

NS

2.1

2.6

2.1/ 1.9

NS

NS

2.0

2.7

1.2

NS

4.0

1.5

Review in Alcolado 2002

Page 86: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Anomalies génétiques : facteur de confusion des effets de l’exposition du

diabète in utero

Les femmes présentant un diabète pendant la grossesse, ont un diabète à révélation précoce et peuvent donc porter plus de gènes de susceptibilité, qu’elles peuvent transmettre à leurs descendants

Page 87: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Option 2

Descendants majeurs de patients diabétiques de type 1 :• Nés après le diagnostic du diabète chez leur parent• Non diabétiques • Sans stigmates d’autoimmunité du diabète de type 1

(ICA, anti-GAD, anti-IA2) • Sans antécédents familiaux connus de diabète de type 2

Descendants de mères Descendants de pères (groupe contrôle)

Page 88: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Conclusion

Le diabète de type 1 in utero:• Entraîne un déficit acquis de l’insulino-sécrétion

en réponse au glucose chez les descendants adultes

• Confère aux descendants adultes une fréquence élevée d’intolérance au glucose

Page 89: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Quels mécanismes cellulaires ?

1. Phénomène d’empreinte parentale ?

2. Défaut d’angiogénèse pendant la vie fœtale

Atteinte multiviscérale ?

Page 90: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

Conclusion

• Il existe un excès de transmission maternelle du diabète de type 2

• Cet excès est en partie expliqué par l’exposition au diabète in utero

• L’exposition au diabète in utero est associé à un déficit de l’insulinosécrétion chez le descendant

• Les mécanismes impliqués restent à définir

Page 91: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

The Framingham Offspring Study

Population• 2527 descendants issus de 1303 familles caucasiennes• Moyenne d’âge: 54 ans , femmes: 53%• Diabétiques: 8.6% ; intolérance au glucose: 11.4%

Diagnostic du diabète • Descendants:

Glycémie à jeun >7.8 mmol/l à 2 reprises ou HGPO Ou sous ADO

• Parents: sous ADO ou glycémie > 11.1 mmol/l

Antécédents familiaux de diabète• mère diabétique: 10.5%• père diabétique: 11.5%• 2 parents diabétiques: 1.7%• parents non diabétiques: 76.3%

Meigs Diabetes 2000

Page 92: Foetal programming of the cardiovascular risk: Effect of maternal diabetes 12th meeting of the MGSD, Casablanca, Morocco, 2011 Jean-François Gautier, Department

The Framingham Offspring Study

Population• 2527 descendants issus de 1303 familles caucasiennes• Moyenne d’âge: 54 ans , femmes: 53%• Diabétiques: 8.6% ; intolérance au glucose: 11.4%

Diagnostic du diabète • Descendants:

Glycémie à jeun >7.8 mmol/l à 2 reprises ou HGPO Ou sous ADO

• Parents: sous ADO ou glycémie > 11.1 mmol/l

Antécédents familiaux de diabète• mère diabétique: 10.5%• père diabétique: 11.5%• 2 parents diabétiques: 1.7%• parents non diabétiques: 76.3%

Meigs Diabetes 2000