Diabetic pregnancy as a novel risk factor for cardiac dysfunction in the offspring—the heart as a target for fetal programming in rats

Abstract

Aims/hypothesis The impact of diabetic pregnancy has been investigated extensively regarding offspring metabolism; however, little is known about the influence on the heart. We aimed to characterise the effects of a diabetic pregnancy on male adult offspring cardiac health after feeding a high-fat diet in an established transgenic rat model. Methods We applied our rat model for maternal type 2 diabetes characterised by maternal insulin resistance with hyperglycaemia and hyperinsulinaemia. Diabetes was induced preconceptionally via doxycycline-induced knock down of the insulin receptor in transgenic rats. Male wild-type offspring of diabetic and normoglycaemic pregnancies were raised by foster mothers, followed up into adulthood and subgroups were challenged by a high-fat diet. Cardiac phenotype was assessed by innovative speckle tracking echocardiography, circulating factors, immunohistochemistry and gene expression in the heart. Results When feeding normal chow, we did not observe differences in cardiac function, gene expression and plasma brain natriuretic peptide between adult diabetic or normoglycaemic offspring. Interestingly, when being fed a high-fat diet, adult offspring of diabetic pregnancy demonstrated decreased global longitudinal (−14.82 ± 0.59 vs −16.60 ± 0.48%) and circumferential strain (−23.40 ± 0.57 vs −26.74 ± 0.34%), increased relative wall thickness (0.53 ± 0.06 vs 0.37 ± 0.02), altered cardiac gene expression, enlarged cardiomyocytes (106.60 ± 4.14 vs 87.94 ± 1.67 μm), an accumulation of immune cells in the heart (10.27 ± 0.30 vs 6.48 ± 0.48 per fov) and higher plasma brain natriuretic peptide levels (0.50 ± 0.12 vs 0.12 ± 0.03 ng/ml) compared with normoglycaemic offspring on a high-fat diet. Blood pressure, urinary albumin, blood glucose and body weight were unaltered between groups on a high-fat diet. Conclusions/interpretation Diabetic pregnancy in rats induces cardiac dysfunction, left ventricular hypertrophy and altered proinflammatory status in adult offspring only after a high-fat diet. A diabetic pregnancy itself was not sufficient to impair myocardial function and gene expression in male offspring later in life. This suggests that a postnatal high-fat diet is important for the development of cardiac dysfunction in rat offspring after diabetic pregnancy. Our data provide evidence that a diabetic pregnancy is a novel cardiac risk factor that becomes relevant when other challenges, such as a high-fat diet, are present. Graphical abstract

Evaluation of Fetal Cardiac Geometry and Contractility in Gestational Diabetes Mellitus by Two-Dimensional Speckle-Tracking Technology

“…Studies suggest that diabetes-related cardiac function changes persist in the neonatal period [ 19 , 33 ], but generally normalize over time [ 49 , 50 ]. However, Schütte et al demonstrated that male adult offspring from type 2 diabetic rats develop cardiac dysfunction only after a hyper-fat diet [ 51 ]. It is generally thought that fetal programming is mediated by epigenetic changes in the expression of specific genes, and various patterns of DNA methylation have indeed been incriminated in ‘malprogramming’ diabetes-exposed fetuses [ 52 ].…”

Research Progress of Maternal Metabolism on Cardiac Development and Function in Offspring

“…For example, one study found that before dietary challenges, echocardiography showed no significant alterations comparing the diabetic adult group and the control group. However, after 28 weeks of a high-fat diet, the diabetic group exhibited cardiomyocyte hypertrophy, increased inflammation reaction, and cardiovascular risks, while the control group showed no such changes [65]. Offspring exposed to intrauterine hyperglycemia also showed a diminished tolerance to myocardial ischemia.…”

Long-term outcomes and potential mechanisms of offspring exposed to intrauterine hyperglycemia

“…Diabetic offspring was also shown to have a higher blood pressure ( 71 ), a greater vasoconstriction under electrical stimulation ( 72 ), an impaired vascular nitric oxid (NO)–ROS signaling ( 148 ), and endothelial dysfunction ( 73 ) in adulthood. HFD after birth induced cardiomyocyte hypertrophy, pro-inflammation status, and cardiac trauma in O-GDM ( 143 ). Ischemia-induced cardiac infarction size was bigger in O-GDM.…”

“…Thus, the blastocyst development was impaired, the embryo implantation was inhibited, and the growth and development of the fetus during middle and late gestational periods were delayed ( 140 ). Systematic pro-inflammatory cytokines or local immune cells acted on islets ( 27 , 141 ), liver ( 35 ), peripheral adiposity ( 142 ), heart ( 75 , 143 , 144 ), kidney ( 80 ), brain ( 145 , 146 ), reproductive tract ( 140 ), lung ( 130 ), and microbiota ( 133 ), resulting in damage to organ function.…”

“…• Inflammation inhibited embryo implantation and growth of fetus (140). • Inflammation acts on islets (27,141), liver (35), adiposity (142), heart (75,143,144), kidney (80), brain (101,145,146), reproductive system (110,116,140), lung (130).…”