Lifetime consequences of abnormal fetal pancreatic development

Abstract

There is ample evidence that an adverse intrauterine environment has harmful consequences for health in later life. Maternal diabetes and experimentally induced hyperglycaemia result in asymmetric overgrowth, which is associated with an increased insulin secretion and hyperplasia of the insulin-producing B-cells in the fetuses. In adult life, a reduced insulin secretion is found. In contrast, intrauterine growth restriction is associated with low insulin secretion and a delayed development of the insulin-producing B-cells. These perinatal alterations may induce a deficient adaptation of the endocrine pancreas and insulin resistance in later life. Intrauterine growth restriction in human pregnancy is mainly due to a reduced uteroplacental blood flow or to maternal undernutrition or malnutrition. However, intrauterine growth restriction can be present in severe diabetes complicated by vasculopathy and nephropathy. In animal models, intrauterine growth retardation can be obtained through pharmacological (streptozotocin), dietary (semi-starvation, low protein diet) or surgical (intrauterine artery ligation) manipulation of the maternal animal. The endocrine pancreas and more specifically the insulin-producing B-cells play an important role in the adaptation to an adverse intrauterine milieu and the consequences in later life. The long-term consequences of an unfavourable intrauterine environment are of major importance worldwide. Concerted efforts are needed to explore how these long-term effects can be prevented. This review will consist of two parts. In the first part, we discuss the long-term consequences in relation to the development of the fetal endocrine pancreas and fetal growth in the human; in the second part, we focus on animal models with disturbed fetal and pancreatic development and the consequences for later life.

Mother to child transmission of diabetes mellitus: does gestational diabetes program Type 2 diabetes in the next generation?

“…We infer that a woman whose mother has T2D M in later life is more likely to have been exposed to GDM as a fetus. There is evidence to suggest that pancreatic β‐cell mass is largely fixed by the end of fetal life and is compromised by a hyperglycaemic intrauterine environment [9], leading to reduced β‐cell reserve in later life. This will predispose daughters to develop GDM during their own pregnancies, which will then establish conditions for transmission of the same defect to a third generation.…”

Sex differences in transgenerational alterations of growth and metabolism in progeny (F2) of female offspring (F1) of rats fed a low protein diet during pregnancy and lactation

“…However, difficulties with socio‐economic confounds and the inability to include precise contemporaneous controls in epidemiological studies demonstrate the need for carefully controlled animal investigations to address the association between maternal nutrient intake and subsequent health of the offspring. There are five main protocols that have been used for the evaluation of developmental programming of metabolism: (1) exposure of the mother to an isocaloric low protein diet (Stewart et al 1975; Ozanne et al 1996; Reusens & Remacle, 2001 a ); (2) global nutrient restriction (Garofano et al 1997, 1998 a ); (3) experimentally induced maternal diabetes (Holemans et al 1997; Holemans et al 2003); (4) restriction of uterine blood flow (Simmons et al 2001); and (5) over‐exposure of the fetus to glucocorticoids (Nyirenda et al 2001). Several studies have demonstrated altered glucose and insulin metabolism in the offspring of protein restricted rats and other rodents (Dahri et al 1991; Petry et al 2000; Kind et al 2003).…”

Ultrasound diagnosis of diabetic fetopathy

“…Постоянная гипергликемия у женщины в период бе-ременности является причиной реактивной гипертрофии ПЖ и гиперплазии β-клеток у ее плода -развивается ги-перинсулинемия [33], являющаяся характерной особен-ностью ДФ [16,34]. Иммуногистохимические исследова-ния показали гиперплазию островковой ткани ПЖ плода с увеличением как инсулин-позитивных, так и инсулин-негативных клеток.…”

“…Увеличение ядерной зоны β-клеток не исправляется инсулинотерапией. При плохо контроли-руемом СД матери (гликемия >16,7 ммоль/л) происходит дегрануляция большинства β-клеток с набуханием мито-хондрий [34]. Однако длительная декомпенсация СД у ма-тери во время первых двух триместров беременности мо-жет, наоборот, привести к истощению β-клеток плода, к гипоинсулинемии и впоследствии к развитию синдрома задержки роста плода (СЗРП) [16].…”

“…Однако длительная декомпенсация СД у ма-тери во время первых двух триместров беременности мо-жет, наоборот, привести к истощению β-клеток плода, к гипоинсулинемии и впоследствии к развитию синдрома задержки роста плода (СЗРП) [16]. Количество инсулин-продуцирующих β-клеток и общий объем эндокринной ткани ПЖ при гипотрофии плода снижены [34].…”