Thatcher's Thoughts Diabetes & Maternal Age

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Index for entries posted 09/15/00:

1. Birth weight and risk of type 2 diabetes 
2. Obesity gene
3. Maternal age and risk of type 1 diabetes

Birth weight and risk of type 2 diabetes
Title:The fetal and childhood growth of persons who develop type 2 diabetes
Author: T. Forsen, et al.
Address: Helsinki, Finland
Source: Annals of Internal Medicine 133: 176-182 (August) 2000
Summary:Because type 2 diabetes is linked to low birthweight followed by obesity in adulthood, researchers speculated that those who develop the disease might have a particular pattern of growth from birth through childhood. Thus, they examined the relation of type 2 diabetes to size at birth and childhood growth. Researchers identified 471 men and women born in Helsinki between 1924 and 1933, and still lived in Finland in 1971, who developed type 2 diabetes. The cumulative incidence of type 2 diabetes was 7.9% in men and 5.4% in women. The incidence increased with decreasing birthweight, birth length, ponderal index, and placental weight. The odds ratio for type 2 diabetes was 1.38 for each 1 kg decrease in birthweight. The mean weights and heights of the children at 7 years of age who later developed type 2 diabetes were about average. Thereafter, their growth in weight and height was accelerated until 15 years of age. Children of both sexes whose mothers had a high body mass index in pregnancy had more rapid growth during childhood and an increased incidence of type 2 diabetes. Researchers concluded that their findings are consistent with the hypothesis that type 2 diabetes is programmed in utero in association with low rates of fetal growth. 
Comment: The relationship between low birthweight and insulin resistance is clearly established. There has been less information on birthweight and diabetes. There also seems to be an association between low birthweight and premature adrenarche (pubic hair development). One hypothesis is that stress related to growth restriction results in a premature activation of the adrenal axis. This same effect could contribute to the development of PCOS. A potential outcome of the additional possible effect is the development of PCOS, possibly a non-genetic cause of PCOS. To the contrary, large babies are sometimes associated with gestational diabetes, also a known risk factor for later development of type 2 diabetes. 

Obesity gene
Title:Independent confirmation of a major focus for obesity on chromosome 10
Author: A. Hinney, et al.
Address:Marburg, France
Source:The Journal of Clinical Endocrinology & Metabolism 85:2962-2965 (August) 2000
Summary: Linkage of obesity to chromosome 10p12 with a maximal multipoint LOD score of 4.85 was reported upon use of an affected sib-pair approach including nuclear families in which the adult index case had a BMI greater than or equal to 40kg/m2 and at least one further sibling had a BMI greater than or equal to 27 kg/m2. In an effort to reproduce this linkage finding, researchers genotyped 11 markers spanning approximately 23 cm from 10p13 to 10q11 in a total of 386 individuals stemming from 93 nuclear families with two or more young obese offspring with a BMI greater than or equal to the 90th age percentile. The highest multipoint maximum likelihood binomial LOD score using the extreme concordant sib-pair approach in which one sib had a BMI greater than or equal to the 95th percentile, and other sibs a BMI less than or equal to the 90th percentile was 2.32. Six markers yielded nominal p-values less than 0.05, the highest two point MLB-LOD score of 2.45 was obtained for the marker TCF8. Transmission disequilibrium tests for the most frequent parental allele yielded no nominal p-value less than 0.05. The linkage results confirm the presence of a major susceptibility locus for obesity in a region near the centromere on chromosome 10. 
Comment: Once the (a) gene is found, can it be fixed? 

Maternal age and risk of type 1 diabetes
Title:Influence of maternal age at delivery and birth order on risk of type 1 diabetes in childhood: prospective population based family study
Author: P. Bingley, et al. 
Address: Bristol, England
Source:British Medical Journal 321: 420-424 (August) 2000
Summary: In a prospective population based family study, researchers studied the impact of parental age at delivery and birth order on subsequent risk of childhood diabetes. Subjects were 1375 families in which one child or more had diabetes. Of 3221 offspring, 1431 had diabetes and 1790 remained non-diabetic at a median age of 16.1 years. It was discovered that maternal age at delivery was strongly related to the risk of type 1 diabetes in the offspring. The risk increased by 25% for each five year increase of maternal age, so that maternal age at delivery of greater than or equal to 45 years was associated with a relative risk of 3.11 when compared with a maternal age of less than 20 years. Paternal age was also associated with a 9% increase for each five year increase in paternal age. However, the relative risk of diabetes, adjusted for parental age at delivery and sex of offspring, decreased with increasing birth order. The overall effect was a 15% risk reduction per child born. Researchers speculated that the increase in maternal age at delivery in the United Kingdom over the past two decades could partly account for the rise in incidence of childhood diabetes over this period.
Comment: A curious association, but a mechanism is still lacking. 

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