Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).

Background: Infants of diabetic mothers have been characterized by macrosomia due to hyperinsulinism. A relation has been observed between circulating levels of leptin and the intrauterine growth pattern. Methods: We studied the leptin and insulin concentrations in the cord blood of 29 newborn infants of mothers with type 1 diabetes (iT1DM), 70 newborn infants of mothers with gestational diabetes and 105 newborn infants of nondiabetic mothers. Results: There were significant differences (p < 0.001) between the 3 groups with the highest leptin levels 24.9 µg/l (range 1.7–94.1) in infants of mothers with iT1DM and the second-highest levels 14.0 µg/l (range 2.6–74.9) in infants of mothers with gestational diabetes (iGDM), whereas the control infants had the lowest leptin levels 10.0 µg/l (range 0.10–45.9). Girls had higher leptin concentrations than boys among the iT1DM and control infants. The insulin concentrations were 18.1 mU/l (range 1.9–123.3), 6.1 mU/l (range 1.1–51.4) and 3.6 mU/l (range 0.5–21.5) in the 3 groups (p < 0.001), respectively. A significant correlation was observed between leptin and insulin concentrations in iGDM and control infants (r = 0.51; p < 0.001 and r = 0.25; p < 0.05). Both absolute and relative birth weights correlated with leptin levels in all 3 groups (r = 0.60, p = 0.01 and r = 0.51, p = 0.05 in iT1DM; r = 0.51 and 0.56, p < 0.001 in iGDM and r = 0.42 and 0.59, p < 0.001 in control infants). Conclusion: Our results confirm the relation between leptin concentrations and birth weight. They also suggest that leptin may be involved in the increased accumulation of adipose tissue characteristic of infants of diabetic mothers.

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