Fetal origins of type 2 DM

There is an increasing body of evidence to suggest the type 2 diabetes originates in early life. Babies who were small at birth have been shown to have increased risk of type 2 diabetes in later life. These associations have been found in various populations across the globe and seem to depend on reduced fetal growth rather than prematurity. It is hypothesized that the fetus adapts its structure and physiology in response to an adverse environment in utero, which predisposes to chronic disease in later life. Animal studies indeed convincingly show that undernutrition during gestation alters glucose homeostasis and induces diabetes. Underlying mechanisms include programming of the HPA axis, insulin signalling pathways and islet development. Emerging evidence from both animal and human studies suggest that epigenetic regulation of gene expression plays a crucial role in the developmental origins of type 2 diabetes.

Famine and feast

Throughout history, famine and feast have occurred around the globe. Currently, being overweight is a bigger health threat around the world than hunger and undernutrition. Over 1 billion people in the world are overweight, while 815 million people suffer from undernutrition. Since type 2 diabetes is one of the most important health problems related to obesity, it is not surprising that type 2 diabetes is now becoming a worldwide epidemic. In the year 2000, there were 171 million people with diabetes and it is predicted that these numbers will have doubled by the year 2030.

Thirfty genotype hypothesis

One of the first hypotheses explaining the current diabetes epidemic is the The thrifty gene hypothesis [1][2]. In prehistoric times of hunting and gathering, people who possessed genes that promoted efficient deposition of body fat in times of food abundance (‘feast’) had a better chance of surviving in times of poor food availability (‘famine’). The selective survival of these ‘thrifty genes’ is suggested to have led to the expansion of obesity and diabetes in our present situation of abundance. The drawbacks of this theory are that the responsible genes remain largely elusive and that a purely genetic mechanism cannot explain the dramatic increase in type 2 diabetes that has occurred within the last couple of generations.

Thrifty phenotype hypothesis

The discovery of a strong link between small size at birth and an increased risk of type 2 diabetes in a population of men and women born in Hertfordshire [3], England, led to the ‘thrifty phenotype’ hypothesis as an alternative explanation for the rapid increase of type 2 diabetes worldwide[4]. The ‘thrifty phenotype’ hypothesis postulates that type 2 diabetes results from undernutrition during fetal life. The fetus is suggested to adapt its structure and physiology in response to poor nutritional circumstances, resulting in a diminished capacity to produce insulin and also results in insulin resistance. These properties may offer a survival benefit in a postnatal environment of scarcity, but predispose to the development of glucose intolerance and type 2 diabetes in a postnatal environment of abundance. The ‘thrifty phenotype’ or ‘fetal origins of disease’ concept can help explain why type 2 diabetes is spreading so rapidly, especially in developing countries. Our diet is changing rapidly from a low calorie/low fat diet to a high calorie/high fat diet. Fetal nutrition, however, remains limited due to intergenerational constraints on placental growth. The apparent contradiction between undernutrition during fetal life followed by overnutrition in adult life may lead to type 2 diabetes in later life. This contrast is most prominent in developing countries like India, which are currently undergoing the transition from chronic malnutrition to adequate nutrition. In fact, it is expected that by the year 2030, India will have the most inhabitants with diabetes worldwide. There is a very strong body of evidence to support the developmental origins of diabetes hypothesis - and the link between small size at birth and later type 2 diabetes has been confirmed in many populations across the globe [5].

Animal experiments

Various animal models have been used to study the effects of the intra-uterine environment on glucose metabolism in later life [6][7]. Mild as well as severe maternal caloric restriction during pregnancy in the rat has been demonstrated to lead to low birth weight, beta-cell dysfunction and glucose intolerance in later life. Treatment with leptin during the first two weeks of life completely reverses the detrimental effects of such severe maternal caloric restriction . Uterine artery ligation leads to growth restriction in utero, reduced pancreatic beta-cell mass, glucose intolerance and insulin resistance in later life. Low protein diets during pregnancy also induce diabetes in the offspring [6]. Additionally, treatment with the synthetic glucocorticoid, dexamethasone, during pregnancy has been shown to lead to a reduced birth weight, along with long-term hypertension, hyperglycaemia and hyperactivity of the hypothalamic-pituitary-adrenal axis. The phenotypic outcomes of the different models have thus been strikingly similar in terms of long-term consequences for glucose and insulin metabolism.

Dutch famine

Summary of the Dutch famine results
Summary of the Dutch famine results
In line with evidence from experimental animal studies and studies of size at birth, the Dutch famine birth cohort study showed for the first time in humans that glucose tolerance was impaired after exposure to famine during gestation [8][9][10][11]. Interestingly, the effects of famine exposure on glucose tolerance were also found among those with normal birthweight, suggesting that the effects of prenatal nutrition are independent of the effects of fetal growth.

Gene–environment interactions

The fetal origins hypothesis proposes that type 2 diabetes originates through adaptations made by the fetus in response to an adverse intrauterine environment. This environment changes gene expression and leads to physiological or morphologic phenotypes associated with disease. On this basis, one would predict that genes associated with glucose/insulin metabolism will have different effects in people who had different fetal environments.There is indeed evidence that the effects of undernutrition interact with the effects of the Pro12Ala polymorphism of the PPAR-g2 gene (peroxisome proliferator activated receptor-g2), which is involved in adipocyte differentiation, regulating glucose, and lipid homeostasis. People exposed to famine in midgestation more often had type 2 diabetes when they were carriers of the mutant Ala allele [10]. This is thought to be due to a combined deficit in insulin secretion, caused by a famine-induced maldevelopment of the beta cell in combination with carriership of the Ala allele and suggests that the early environment can affect gene expression. Epigenetic processes such as methylation are likely to underlie this phenomenon.

Transgenerational transmission

More than 30 years ago Dorner suggested that susceptibility to diabetes could be acquired through transmission in utero from the mother to the child [2]. Finding a greater diabetes prevalence among adults born to mothers with diabetes rather than fathers with diabetes, he proposed the possibility of an epigenetic mode of diabetes transmission by the mother. It was postulated that the influence of maternal diabetes could extend beyond the first generation based on the finding of an increased diabetes prevalence among descendants of diabetic great grandmothers through the maternal than through the paternal line. Since Dorners initial postulation of the developmental origins of diabetes a large body of evidence has emerged to support this notion, though the transgenerational study of humans has been limited and complicated by obvious limitations of study design (which are retrospective and based on historical data with usually limited information on the paternal side) and lack of sufficiently detailed data. But the animal experiments suggest clear transgenerational effects on type 2 diabetes, and the underlying epigenetic mechanisms are being discovered [6].

References

  1. ^ Dorner G, et al. On possible genetic and epigenetic modes of diabetes transmission. Endokrinologie 1975: 66: 225-227

  2. ^ Dorner G et al. Evidence for decreasing prevalence of diabetes mellits in childhood apparently produced by prevention of hyperinsulinsim in the fetus and newborn. Experimental and CLinical Endocrinology and Diabetes 1984: 84:134-142.

  3. ^ Hales CN, Barker DJP. Type 2 diabetes: the thrifty phenotype hypothesis. Diabetologia 1992: 35: 595-601

  4. ^ Barker DJ. The origins of the developmental origins theory. Journal of INternal Medicine 2007: 261: 412-417.

  5. ^ Whincup P EARLY READ consortium. Birth weight and risk of type 2 diabetes. JAMA 2008: 300 (24) 2886-2897.

  6. ^ Ozanne SE and Hales CN. Early programming of glucose-insulin metabolism. Trends Endocrinol Metab 2002, 13: 368-373.

  7. ^ Holemans et al. Lifetime consequences of abnormal fetal pancreatic development. J Physiology 2003: 547:11-20.

  8. ^ Ravelli AC et al. Glucose tolerance in adults after prenatal exposure to famine. Lancet 2001;357:473.

  9. ^ SR de Rooij et al. Impaired insulin secretion after prenatal exposure to the Dutch famine. Diabetes Care 2006 29(8):1897-901

  10. ^ SR de Rooij et al. The effects of the Pro12Ala polymorphism of the Peroxisome Proliferator-Activated Receptor-2 gene on glucose/insulin metabolism interact with prenatal exposure to famine. Diabetes Care 2006. 29(5): 1052-1057

  11. ^ SR de Rooij et al. Glucose tolerance at age 58 and the decline of glucose tolerance in comparison with age 50 in people prenatally exposed to the Dutch famine. Diabetologia 2006: 49(4): 637-643.

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