Significant morbidity and mortality among patients with diabetes mellitus result largely from a greatly increased incidence of microvascular complications. Proliferative diabetic retinopathy (PDR) and end stage renal disease (ESRD) are two of the most common and severe microvascular complications of diabetes. A high concordance exists in the development of PDR and ESRD in diabetic patients, as well as strong familial aggregation of these complications, suggesting a common underlying genetic mechanism. However, the precise gene(s) and genetic variant(s) involved remain largely unknown. Erythropoietin (EPO) is a potent angiogenic factor observed in the diabetic human and mouse eye. By a combination of case-control association and functional studies, we demonstrate that the T allele of SNP rs1617640 in the promoter of the EPO gene is significantly associated with PDR and ESRD in three European-American cohorts [Utah: P ‫؍‬ 1.91 ؋ 10 ؊3 ; Genetics of Kidneys in Diabetes (GoKinD) Study: P ‫؍‬ 2.66 ؋ 10 ؊8 ; and Boston: P ‫؍‬ 2.1 ؋ 10 ؊2 ]. The EPO concentration in human vitreous body was 7.5-fold higher in normal subjects with the TT risk genotype than in those with the GG genotype. Computational analysis suggests that the risk allele (T) of rs1617640 creates a matrix match with the EVI1/MEL1 or AP1 binding site, accounting for an observed 25-fold enhancement of luciferase reporter expression as compared with the G allele. These results suggest that rs1617640 in the EPO promoter is significantly associated with PDR and ESRD. This study identifies a disease risk-associated gene and potential pathway mediating severe diabetic microvascular complications. diabetic microvascular complication ͉ end stage renal disease ͉ proliferative diabetic retinopathy ͉ SNP ͉ association

We report intrauterine growth restriction (IUGR) increases vascular stiffening in both male and female rats through increased collagen content and altered elastin structure more than a high-fat diet (HFD) alone. Our study shows the importance of stiffness supporting the hypothesis that there are physiologic differences and potential windows for early intervention targeting vascular remodeling mechanisms.

Intrauterine growth restriction (IUGR) and maternal consumption of a high‐saturated‐fat diet (HFD) increase the risk of hypercholesterolemia, a leading cause of morbidity and mortality. Many pregnant women eat a HFD, thus exposing the fetus to a HFD in utero. The cumulative effect of in utero exposure to IUGR and a HFD on offspring cholesterol levels remains unknown. Furthermore, little is known about the mechanism through which IUGR and maternal HFD consumption increase cholesterol. We hypothesize that IUGR combined with a maternal HFD would increase offspring serum and hepatic cholesterol accumulation via alteration in levels of key proteins involved in cholesterol metabolism. To test our hypothesis we used a rat model of surgically induced IUGR and fed the dams a regular diet or a HFD. HFD‐fed dams consumed the same kilocalories as regular diet‐fed dams, with no difference between surgical intervention groups. In the offspring, IUGR combined with a maternal HFD increased hepatic cholesterol levels, low‐density lipoprotein (LDL) receptor protein levels, and Ldlr activity in female rat offspring at birth and both sexes at postnatal day 14 relative to non‐IUGR offspring both from regular diet‐ and HFD‐fed dams. These findings suggest that IUGR combined with a maternal HFD increases hepatic cholesterol accumulation via increased LDL cholesterol uptake into the liver with resulting persistent increases in hepatic cholesterol accumulation.

Background: Intrauterine growth restriction (IUGR) increases the risk of adult-onset hypercholesterolemia. High-fat diet (HFD) consumption potentiates IUGR-induced increased cholesterol. Cholesterol is converted to bile acids by Cyp7a1 in preparation for excretion. We hypothesized that IUGR rats fed a HFD will have increased cholesterol, decreased Cyp7a1 protein levels, and decreased bile acids compared to control rats fed a HFD. Methods: At day 21, IUGR and control pups were placed on one of three diets: a regular chow or one of two HFDs containing 1% or 2% cholesterol. Cholesterol levels and hepatic Cyp7a1 protein levels were quantified a postnatal week 28. results: Both HFDs increased serum cholesterol levels in control rats, and HFD fed IUGR rats had further increased serum cholesterol up to 35-fold. Both HFDs increased hepatic cholesterol levels, and IUGR further increased hepatic cholesterol levels up to fivefold. IUGR decreased hepatic Cyp7a1 protein up to 75%, and hepatic bile acids up to 54%. conclusion: IUGR increased cholesterol and bile acids and decreased Cyp7a1 protein in rats fed a HFD without changing food intake. These findings suggest that IUGR increases the vulnerability of HFD fed rats to hypercholesterolemia via decreased cholesterol conversion to bile acids. i ntrauterine growth restriction (IUGR) predisposes to adultonset hypercholesterolemia (1,2). Epidemiologic studies demonstrate that late-gestation exposure to famine makes individuals more susceptible to hypercholesterolemia only when combined with postnatal consumption of a high-fat diet (HFD) (3). These results suggest that the postnatal nutritional environment impacts cholesterol metabolism differently in IUGR individuals compared their normally grown peers. A better understanding of the mechanism through which IUGR combined with a postnatal HFD impacts cholesterol metabolism would provide a foundation to pursue further research into preventing hypercholesterolemia in IUGR individuals.While the effects of HFD consumption in individuals born IUGR are not well understood, the detrimental effects of HFD consumption in the general population has been extensively documented. HFD consumption often leads to hypercholesterolemia and eventually cardiovascular disease (4). Higher cholesterol levels increase the risk of cardiovascular disease in a continuous, graded fashion (5,6). IUGR may potentiate hypercholesterolemia in individuals that consume a HFD and thus increase morbidity and mortality in this population. The impact of IUGR on cholesterol levels in humans is more evident in the recent decades due to the changing Western diet (7). Average daily fat and cholesterol intake in the United States is ~23-33 g of saturated fat and up to 400 mg cholesterol, both well above the recommended daily intake of ~16 g or no more than 7% of caloric intake for saturated fat and 200 mg cholesterol (7).The liver is the primary organ for regulating both serum and hepatic cholesterol levels. Cholesterol homeostasis is regulated by a series of hepatic genes...