Dietary deprivation Adult-onset DM §Dietary deprivation IUGR l first described by James Lucas [1794]: advocated “temperance in diet, a diminution in.

Dietary deprivation Dietary deprivation Adult-onset DMAdult-onset DM

Dietary deprivation IUGR first described by James Lucas [1794]: advocated “temperance in

diet, a diminution in the usual quantity and a change in the quality of food” to allow for sub-optimal growth in cases of past CPD.

Also noted in situations of starvation during wartime:

• Leningrad siege [1942] & Netherlands [winter 1944-45]

LBW Syndrome X [Metabolic syndrome]• NIDDM, hypertension & hyperlipidaemia

• Animal experimental models

– low protein isocalorific diet causes: » reduced pancreatic beta cell mass -> reduced insulin secretion

» insulin target cells programmed to insulin resistance

J. Petrik et al: Endocrinology 1999, 140:4861-4873

DJP. Barker et al: Diabetologia 1993, 36:62-67

Lumey LH. Pediatric Perinat Epidemiol. 1992 Apr; 6(2): 240-253

RISK FOR ADULT-ONSET DISEASE [GDM] BY BIRTH WEIGHT““The Laurel and Hardy association”The Laurel and Hardy association”

0.00

1.00

2.00

3.00

Od

ds

ratio

<2000 2000-2500 2500-4000 4000-4500 >4500

Birth-weight

P < 0.05

C. Savona-Ventura & M. Chircop: Acta Diab 2003, 40:101-104

.

Gestational diabetes predisposes to Macrosomia

Association has long been identified Mechanism postulated over 50 years

ago by J. Pederson.

Increasing severity makes situation worse suggesting excessive intrauterine nutritional effect

INTRAUTERINE NUTRITION PREDISPOSES TO MACROSOMIAINTRAUTERINE NUTRITION PREDISPOSES TO MACROSOMIAThe Brocktorff Family – Nurture factorsThe Brocktorff Family – Nurture factors

0

5

10

15

20

25

% t

ota

l in

fan

t p

op

.

Norm

al G

T

mild

GDM

mod

erat

e G

DM

seve

re G

DM

pre-

DM

P << 0.05

P << 0.05

0

2

4

6

8

10

12

% t

ota

l in

fan

t p

op

.

BMI <30 BMI =>30

P << 0.05

C. Savona-Ventura et al.: Int J Gynecol Obstet, 2003, 82:217-218C. Savona-Ventura, M. Gatt: Int J Diabetes Metabolism, 2006, 14(2):p.88-91

..

0

10

20

30

40

50

60

70

80

90

%

Lower NGT Upper NGT borderline GT Mild-Sev GDM

GESTATIONAL STATUS

LNGTUNGT

IGTDM

Metabolic status of Maltese women 8 years postpartum.

GDM IS A RISK DETERMINANT FOR GDM IS A RISK DETERMINANT FOR ADULT-ONSET DISEASEADULT-ONSET DISEASE

Wizard’s Crystal BallWizard’s Crystal Ball

AG. Schranz, C. Savona-Ventura: Exper Clin Endocrinol Diab, 2002, 110:219-222…

Family history statistically linked only to MATERNAL & SIBLINGS

No statistical link to PATERNAL history

Consanguinity did not appear to contribute to an increased risk

C. Savona-Ventura, AG. Schranz, M. Chircop: Malta Med J, 2003, 15(2):25-27

G. Katona et al, 1983: WHO.NCD/OND/DIAB/83.2

FAMILY HISTORY RELATIONSHIPSFAMILY HISTORY RELATIONSHIPSThe Brocktorff Family – Nature factorsThe Brocktorff Family – Nature factors

0.0

1.0

2.0

3.0

4.0

5.0

6.0

Od

ds

Ris

k R

ati

o

M aternal Paternal Sibling

Follow-up

Non-Pregnant

P<<0.05

P<<0.05

P >0.05

-

Aetiology - Thrifty phenotypeMaternal

thrifty fugal restricted diet during pregnancy

IUGR causing FetalNeuro-endocrine changes with

reduced pancreatic beta-cell mass? Genetic

Predisposition

Thrifty Phenotype with tendency to Insulin Resistance

Availability of high fat and refined carbohydrate foods & Obesity

Gestational DM in pregnancy?

Hyperinsulinaemia causing •Fetal Pancreatic changes• Hypothalamic changes

• DNA changes due to oxidative stress Macrosomia

.-

Type 2 DM in later life

...

…

The Maltese ArchipelagoThe Maltese Archipelago

Total Area: 316 km2

Population [1940]: 270755 agricultural land restriction Long historical dependence on

food imports from Sicily

After declaration of War on Allies by Italy on 11th June 1940, the Islands became isolated and dependant on food stores through convoys via Gibraltar and Alexandria.

Islands heavily bombed; Food shortage lasted until August 1942.

0

500

1000

1500

2000

1940 1941 1942 1943 1944

An

nu

al N

um

ber

of

Air

Rai

d A

lert

s

0.0

1.0

2.0

3.0

4.0

5.0

6.0

Ave

rag

e n

um

ber

of

Air

Rai

d

aler

ts p

er d

ay

June 1940 – August 1942Period of ~900 days Total of 2537 alerts of air attacks

average: 2.8 alerts per day

Underground shelters

Queuing for water

Queuing for bread

Queuing for vegetables

6.0

7.2

4.7

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

1937-39 1940-42 1943-45

death rate from diabetes per 10000 population

42.245.3

65.3 65.4

41.6

23.0

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

1937-39 1940-42 1943-45

infant death rate from congenital debility per 1000 births

maternal mortality from hypertension per 100000 births

Increase in infant deaths from congenital debilitycongenital debility [dysmaturity] and in maternal deaths from hypertensive diseasehypertensive disease noted both situations associated with Intra-uterine growth retardation.Infant mortality also higher for infectious disease; all other causes of maternal deaths registered lower rates during the war years.

Aetiology - Aetiology - Thrifty Diet phenotypeThrifty Diet phenotype

1st Generation

Women pregnant during the Second World War period

Restricted perinatal nutrition causing placental insufficiency

2nd Generation

Low birth weight infants with a Thrifty Diet Phenotype

3rd Generation

Infants with increased predisposition to a higher birth weight

Maternal thrifty frugal restricted diet during

pregnancy

Placental insufficiency from hypertensive disease

Post-War availability of high fat and refined

carbohydrate foods Obesity & Type 2 DM

METHODOLOGYMETHODOLOGY

The study looked at birth weight data of infants born at St. Luke's

Hospital during August 1967 – July 1968 to mothers themselves born

during the War period [1940-43] and to those born before [1937-39]

and after the siege [1944-45]. During the period under study Total of 1554 births.

After excluding for absent age & birth weight data, macerated stillbirths,

twins and premature deliveries; and identifying women born during the

1937-1945 Total of 724 births

1937-39 167 mothers

1940-42 243 mothers

1943-45 314 mothers

Statistical analyses: t-test comparing the differences between the means.

Statistical significance identified as a p value <0.05

RESULTSRESULTS

3.383.49

3.35

2.5

3

3.5

4

4.5

1937-39 1940-42 1943-45

Bir

th w

eig

ht

mea

n +

/- 1

sd

P=0.027 P=0.0005

Maltese women born during the period of the Second World War were more likely to

have infants of 3.3-4.2% higher birth weights than women from before and after the conflict.

Every man is some months elder than he bethinks him; for we live, move, have a being and are subject to the actions of the elements and the malice of disease in that other World, the truest Microcosm, the Womb of our Mother.

Sir Thomas Brown: “Religio Medici” 1642