1. Dietary deprivation  Adult-onset DM §Dietary deprivation  IUGR l 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. l 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

2. RISK FOR ADULT-ONSET DISEASE [GDM] BY BIRTH WEIGHT “The Laurel and Hardy association” P < 0.05 C. Savona-Ventura & M. Chircop: Acta Diab 2003, 40:101-104.

3. §Gestational diabetes predisposes to Macrosomia l Association has long been identified l Mechanism postulated over 50 years ago by J. Pederson. §Increasing severity makes situation worse suggesting excessive intrauterine nutritional effect INTRAUTERINE NUTRITION PREDISPOSES TO MACROSOMIA The Brocktorff Family – Nurture factors P << 0.05 C. Savona-Ventura et al.: Int J Gynecol Obstet, 2003, 82:217-218 C. Savona-Ventura, M. Gatt: Int J Diabetes Metabolism, 2006, 14(2):p.88-91..

4. Metabolic status of Maltese women 8 years postpartum. GDM IS A RISK DETERMINANT FOR ADULT-ONSET DISEASE Wizard’s Crystal Ball AG. Schranz, C. Savona-Ventura: Exper Clin Endocrinol Diab, 2002, 110:219-222 …

5. §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 RELATIONSHIPS The Brocktorff Family – Nature factors P<<0.05 P >0.05 -

6. Aetiology - Thrifty phenotype Maternal thrifty fugal restricted diet during pregnancy IUGR causing Fetal Neuro-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... …

7. The Maltese Archipelago §Total Area: 316 km 2 §Population [1940]: 270755 §agricultural land restriction §Long historical dependence on food imports from Sicily §After declaration of War on Allies by Italy on 11 th 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.

8.  June 1940 – August 1942  Period of ~900 days  Total of 2537 alerts of air attacks  average: 2.8 alerts per day

9. Underground shelters Queuing for water Queuing for bread Queuing for vegetables

11. congenital debility hypertensive disease  Increase in infant deaths from congenital debility [dysmaturity] and in maternal deaths from hypertensive 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.

12. Aetiology - Thrifty Diet phenotype 1 st Generation Women pregnant during the Second World War period Restricted perinatal nutrition causing placental insufficiency 2 nd Generation Low birth weight infants with a Thrifty Diet Phenotype 3 rd 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

13. METHODOLOGY §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]. l During the period under study  Total of 1554 births. l 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

14. RESULTS P=0.027P=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.

15.  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