Low fertility and the risk of type 2 diabetes in women
Advanced Access publication on October
Low fertility and the risk of type 2 diabetes in women
Clara C. Elbers 0 1 2
N. Charlotte Onland-Moret 1 2
Marinus J.C. Eijkemans 2
Cisca Wijmenga 3
Diederick E. Grobbee 2
Yvonne T. van der Schouw 2
0 Department of Genetics, School of Medicine, University of Pennsylvania , Philadelphia, PA , USA
1 Complex Genetics Section, Department of Medical Genetics-DBG, University Medical Center Utrecht , Utrecht , The Netherlands
2 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht , STR 6.131, PO Box 85500, 3508 GA Utrecht , The Netherlands
3 Department of Genetics, University Medical Center Groningen, University of Groningen , Groningen , The Netherlands
background: Fertility problems are frequently followed by early menopause, and early menopause has been associated with increased risk of type 2 diabetes (T2D). Thus far, it is unknown whether low fertility is independently associated with future T2D risk. methods: We assessed the association between measures of low fertility and T2D in the Prospect-European Prospective Investigation into Cancer and Nutrition (EPIC) cohort of 17 357 Dutch women, aged 49 - 70 years at baseline using Cox proportional hazards models, adjusted for various confounders. To investigate whether BMI and waist circumference influence the observed associations, analyses were additionally adjusted for these variables. results: At baseline, 332 women had T2D. During a mean follow-up of 9.1 + 3.6 years, 535 T2D cases occurred. Out of 15 707 Prospect-EPIC women who wanted to get pregnant, 1940 consulted a physician for fertility problems and 700 remained childless. No relation was found between consulting a physician for fertility problems or nulliparity and T2D risk. Of all women who wanted to get pregnant, 3946 (25.1%) had one or more miscarriages, with an average of 1.4 (+0.9) miscarriages and a maximum of 10 miscarriages. Women who had one or more miscarriage showed the same risk for T2D as women who had no miscarriage. Also, none of the other measures of low fertility were associated with increased risk for T2D. conclusions: Generally, measures of low fertility were not independently associated with a risk of T2D in a cohort of 17 357 Dutch women.
type 2 diabetes / low fertility / infertility / miscarriages / irregular menstrual cycle
Introduction
Compared with all other populations with a modern lifestyle, the
age-adjusted prevalence of type 2 diabetes (T2D) in populations of
European ancestry is relatively low (King et al., 1998; Uitewaal et al.,
2004; Nolan et al., 2011); in the USA, for populations of European,
African, Hispanic and Pima Indian descent, the prevalence of T2D in
both sexes is 7.6, 13, 17 and 50%, respectively (King et al., 1998). It
has been proposed that these differences in T2D susceptibility
between European and non-European populations are the genetic
and evolutionary consequences of geographical differences in the
history of food consumption (Diamond, 2003; Corbett et al., 2009).
The ‘thrifty genotype theory’ hypothesized that the T2D phenotype
gives a survival advantage during periods of famine but is maladaptive
in societies with high food abundance (Neel, 1962). Historical data
show that, starting from about 1600, European societies became
capable of efficiently avoiding famine, by redistributing any
overabundance of grain to areas of food scarcity (Rotberg et al., 1985).
Diamond suggested that as a result, Europeans should have undergone
an epidemic in T2D starting several centuries before the present as a
result of the new reliability of sufficient food supplies, and eliminated
the most T2D-prone genotypes by processes of natural selection
(Diamond, 2003).
Natural selection works through differences in reproductive success
rather than simple differential survival. As fertility is a driving force
behind evolution, infertility could be one of the underlying mechanisms
through which T2D genotype is selected against, especially as T2D is a
late-onset disease and therefore not directly acting on survival.
Therefore, we hypothesize that reduced fertility could be one of the
underlying causes of the decreased T2D genotype frequencies in
Europeans. However, it is unknown whether T2D is associated with
reproductive problems earlier in life, although there is indirect
evidence suggesting that patients with T2D experience reproductive
problems before disease onset. Fertility problems are frequently followed
by early menopause (Kok et al., 2003), and early menopause has been
associated with premenopausal diagnosis of T2D (Dorman et al.,
2001). Obesity, the most important risk factor for T2D, is associated
with reduced fertility. Previously, a U-shaped association between BMI
and relative risk of ovarian infertility was observed in the Nurses’
Health Study II, with increased risk for ovarian infertility for women
with a BMI ,20 and .24 kg/m2 (Rich-Edwards et al., 2002).
Thus far, it is unknown (...truncated)