Pregnancy-induced changes in ß-cell function: what are the key players?

Maternal metabolic adaptations during pregnancy ensure appropriate nutrient supply to the developing fetus. This is facilitated by reductions in maternal peripheral insulin sensitivity, which enables glucose to be available in the maternal circulation for transfer to the fetus for growth. To balance this process and avoid excessive hyperglycaemia and glucose intolerance in the mother during pregnancy, maternal pancreatic ß-cells undergo remarkable changes in their function including increasing their proliferation and glucose-stimulated insulin secretion. In this review we examine how placental and maternal hormones work cooperatively to activate several signalling pathways, transcription factors and epigenetic regulators to drive adaptations in ß-cell function during pregnancy. We also explore how adverse maternal environmental conditions, including malnutrition, obesity, circadian rhythm disruption and environmental pollutants, may impact the endocrine and molecular mechanisms controlling ß-cell adaptations during pregnancy. The available data from human and experimental animal studies highlight the need to better understand how maternal ß-cells integrate the various environmental, metabolic and endocrine cues and thereby determine appropriate ß-cell adaptation during gestation. In doing so, these studies may identify targetable pathways that could be used to prevent not only the development of pregnancy complications like gestational diabetes that impact maternal and fetal wellbeing, but also more generally the pathogenesis of other metabolic conditions like type 2 diabetes.

Maternal melatonin treatment rescues endocrine, inflammatory, and transcriptional deregulation in the adult rat female offspring from gestational chronodisruption.

Introduction: Gestational chronodisruption impact maternal circadian rhythms, inhibiting the nocturnal increase of melatonin, a critical hormone that contributes to maternal changes adaptation, entrains circadian rhythms, and prepares the fetus for birth and successful health in adulthood. In rats, we know that gestational chronodisruption by maternal chronic photoperiod shifting (CPS) impaired maternal melatonin levels and resulted in long-term metabolic and cardiovascular effects in adult male offspring. Here, we investigated the consequences of CPS on mother and adult female offspring and explored the effects of melatonin maternal supplementation. Also, we tested whether maternal melatonin administration during gestational chronodisruption rescues maternal circadian rhythms, pregnancy outcomes, and transcriptional functions in adult female offspring. Methods: Female rats raised and maintained in photoperiod 12:12 light: dark were mated and separated into three groups: (a) Control photoperiod 12:12 (LD); (b) CPS photoperiod; and (c) CPS+Mel mothers supplemented with melatonin in the drinking water throughout gestation. In the mother, we evaluated maternal circadian rhythms by telemetry and pregnancy outcomes, in the long-term, we study adult female offspring by evaluating endocrine and inflammatory markers and the mRNA expression of functional genes involved in adrenal, cardiac, and renal function. Results: In the mothers, CPS disrupted circadian rhythms of locomotor activity, body temperature, and heart rate and increased gestational length by almost 12-h and birth weight by 12%, all of which were rescued by maternal melatonin administration. In the female offspring, we found blunted day/night differences in circulating levels of melatonin and corticosterone, abnormal patterns of pro-inflammatory cytokines Interleukin-1a (IL1a), Interleukin-6 (IL6), and Interleukin-10 (IL10); and differential expression in 18 out of 24 adrenal, cardiac, and renal mRNAs evaluated. Conclusion: Maternal melatonin contributed to maintaining the maternal circadian rhythms in mothers exposed to CPS, and the re-establishing the expression of 60% of the altered mRNAs to control levels in the female offspring. Although we did not analyze the effects on kidney, adrenal, and heart physiology, our results reinforce the idea that altered maternal circadian rhythms, resulting from exposure to light at night, should be a mechanism involved in the programming of Non-Communicable Diseases.