The effects of maternal fructose intake on offspring health remain largely unknown, despite the marked increase in consumption of sweetened beverages that has paralleled the obesity epidemic. The present study investigated the impact of maternal fructose intake on placental, fetal, and neonatal development. Female Wistar rats were time-mated and allocated to receive either water [control (CONT)] or fructose solution designed to provide 20% of caloric intake from fructose (FR). FR was administered from d 1 of pregnancy until postnatal day (P) 10. All dams had ad libitum access to standard laboratory chow and water. Dams and offspring were killed at embryonic day (E) 21 and P10. FR dams demonstrated increased total caloric intake and maternal hyperinsulinemia at E21 as well as increased maternal plasma fructose levels at E21 and P10. FR intake did not alter maternal blood glucose, β-hydroxybutyrate (BHB), or electrolyte levels at either time point. Fetal weights at E21 were unchanged, although placental weights were reduced in FR female but not FR male fetuses. Plasma leptin, fructose, and blood glucose levels were increased and BHB levels decreased in FR female but not male fetuses. Plasma insulin levels were not different between CONT and FR groups. Male and female FR neonates had higher plasma fructose levels and were hypoinsulinemic but euglycemic at P10 compared with CONT. Blood BHB levels were increased in FR male neonates but not females at P10. P10 plasma leptin levels were not different between groups. Stomach content leptin levels were increased in all FR offspring at P10, but no differences in stomach content insulin or fructose levels were observed. This study reports for the first time that maternal FR intake resulted in sex-specific changes in offspring development, whereby females appear more vulnerable to metabolic compromise during neonatal life. Independent follow-up studies are essential to investigate the long-term consequences of maternal FR consumption on offspring health.

Disordered neovascularization and impaired wound healing are important contributors to diabetic vascular complications. We recently showed that high-density lipoproteins (HDLs) enhance ischemia-mediated neovascularization, and mounting evidence suggests HDL have antidiabetic properties. We therefore hypothesized that HDL rescue diabetes-impaired neovascularization. Streptozotocin-induced diabetic mice had reduced blood flow recovery and neovessel formation in a hindlimb ischemia model compared with nondiabetic mice. Reconstituted HDL (rHDL) infusions in diabetic mice restored blood flow recovery and capillary density to nondiabetic levels. Topical rHDL application rescued diabetes-impaired wound closure, wound angiogenesis, and capillary density. In vitro, rHDL increased key mediators involved in hypoxia-inducible factor-1α (HIF-1α) stabilization, including the phosphoinositide 3-kinase/Akt pathway, Siah1, and Siah2, and suppressed the prolyl hydroxylases (PHD) 2 and PHD3. rHDL rescued high glucose–induced impairment of tubulogenesis and vascular endothelial growth factor (VEGF) A protein production, a finding associated with enhanced phosphorylation of proangiogenic mediators VEGF receptor 2 and endothelial nitric oxide synthase. Siah1/2 small interfering RNA knockdown confirmed the importance of HIF-1α stability in mediating rHDL action. Lentiviral short hairpin RNA knockdown of scavenger receptor class B type I (SR-BI) in vitro and SR-BI−/− diabetic mice in vivo attenuated rHDL rescue of diabetes-impaired angiogenesis, indicating a key role for SR-BI. These findings provide a greater understanding of the vascular biological effects of HDL, with potential therapeutic implications for diabetic vascular complications.

The consumption of artificially sweetened processed foods, particularly high in fructose or high fructose corn syrup, has increased significantly in the past few decades. As such, interest into the long term outcomes of consuming high levels of fructose has increased significantly, particularly when the exposure is early in life. Epidemiological and experimental evidence has linked fructose consumption to the metabolic syndrome and associated comorbidities—implicating fructose as a potential factor in the obesity epidemic. Yet, despite the widespread consumption of fructose-containing foods and beverages and the rising incidence of maternal obesity, little attention has been paid to the possible adverse effects of maternal fructose consumption on the developing fetus and long term effects on offspring. In this paper we review studies investigating the effects of fructose intake on metabolic outcomes in both mother and offspring using human and experimental studies.

Impaired angiogenesis in ischemic tissue is a hallmark of diabetes. Thioredoxin-interacting protein (TXNIP) is an exquisitely glucose-sensitive gene that is overexpressed in diabetes. As TXNIP modulates the activity of the key angiogenic cytokine vascular endothelial growth factor (VEGF), we hypothesized that hyperglycemia-induced dysregulation of TXNIP may play a role in the pathogenesis of impaired angiogenesis in diabetes. In the current study, we report that high glucose–mediated overexpression of TXNIP induces a widespread impairment in endothelial cell (EC) function and survival by reducing VEGF production and sensitivity to VEGF action, findings that are rescued by silencing TXNIP with small interfering RNA. High glucose–induced EC dysfunction was recapitulated in normal glucose conditions by overexpressing either TXNIP or a TXNIP C247S mutant unable to bind thioredoxin, suggesting that TXNIP effects are largely independent of thioredoxin activity. In streptozotocin-induced diabetic mice, TXNIP knockdown to nondiabetic levels rescued diabetes-related impairment of angiogenesis, arteriogenesis, blood flow, and functional recovery in an ischemic hindlimb. These findings were associated with in vivo restoration of VEGF production to nondiabetic levels. These data implicate a critical role for TXNIP in diabetes-related impairment of ischemia-mediated angiogenesis and identify TXNIP as a potential therapeutic target for the vascular complications of diabetes.