Maternal Diabetes and Fetal Programming Toward Neurological Diseases: Beyond Neural Tube Defects

Abstract

The purpose of this review was to search for experimental or clinical evidence on the effect of hyperglycemia in fetal programming to neurological diseases, excluding evident neural tube defects. The lack of timely diagnosis and the inadequate control of diabetes during pregnancy have been related with postnatal obesity, low intellectual and verbal coefficients, language and motor deficits, attention deficit with hyperactivity, problems in psychosocial development, and an increased predisposition to autism and schizophrenia. It has been proposed that several childhood or adulthood diseases have their origin during fetal development through a phenomenon called fetal programming. However, not all the relationships between the outcomes mentioned above and diabetes during gestation are clear, well-studied, or have been related to fetal programming. To understand this relationship, it is imperative to understand how developmental processes take place in health, in order to understand how the functional cytoarchitecture of the central nervous system takes place; to identify changes prompted by hyperglycemia, and to correlate them with the above postnatal impaired functions. Although changes in the establishment of patterns during central nervous system fetal development are related to a wide variety of neurological pathologies, the mechanism by which several maternal conditions promote fetal alterations that contribute to impaired neural development with postnatal consequences are not clear. Animal models have been extremely useful in studying the effect of maternal pathologies on embryo and fetal development, since obtaining central nervous system tissue in humans with normal appearance during fetal development is an important limitation. This review explores the state of the art on this topic, to help establish the way forward in the study of fetal programming under hyperglycemia and its impact on neurological and psychiatric disorders.

Keywords: diabetes; fetal programming; neurological disorders; pregnancy; psychiatric disease.

Figure 1

Possible outcomes related to intrauterine hyperglycemia.

Figure 2

Altered energy and food intake balance in diabetic dams offspring. In normal conditions (gray lines and arrows), leptin activates POMC/CART neurons (pro-opiomelanocortin/cocaine- and amphetamine-regulated transcript) and inhibits NPY/AgRP neurons (neuropeptide Y/agouti-related protein) promoting satiety and a balance between food intake and energy expenditure. In diabetic offspring (black lines and arrows), a decrease in the activation of POMC/CART neurons takes place due to leptin resistance, which reduces melanocortin release at the PVN (paraventricular nuclei), promoting an increase in food intake leading to obesity and diabetes. 3V, third ventricle.

Figure 3

Schematic proposal of the effect of maternal diabetes on embryo and offsprings cerebellum. Sagittal views of the embryonic neural tube and adult cerebellum in control (top) and diabetic (bottom). r1 indicates the rhombomere (rb) from which the cerebellum (Cb) rise. The scheme shows that embryos from diabetic animals present a smaller r1 and that this may reduce the size of the Cb, and the number of Purkinje and granular cells in the adult. Telen, telencephalon; Dienc, diencephalon; Mes, mesencephalon; Met, Metencephalon; Mye, Myelencephalon; WM, white matter.