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We previously reported a syndrome of severe hyperinsulinemia and early-onset hypertension in three patients with dominant-negative mutations in the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR)-gamma. We now report the results of further detailed pathophysiological evaluation of these subjects, the identification of affected prepubertal children within one of the original families, and the effects of thiazolidinedione therapy in two subjects. These studies 1) definitively demonstrate the presence of severe peripheral and hepatic insulin resistance in the affected subjects; 2) describe a stereotyped pattern of partial lipodystrophy associated with all the features of the metabolic syndrome and nonalcoholic steatohepatitis; 3) document abnormalities in the in vivo function of remaining adipose tissue, including the inability of subcutaneous abdominal adipose tissue to trap and store free fatty acids postprandially and the presence of very low circulating levels of adiponectin; 4) document the presence of severe hyperinsulinemia in prepubertal carriers of the proline-467-leucine (P467L) PPAR-gamma mutation; 5) provide the first direct evidence of cellular resistance to PPAR-gamma agonists in mononuclear cells derived from the patients; and 6) report on the metabolic response to thiazolidinedione therapy in two affected subjects. Although the condition is rare, the study of humans with dominant-negative mutations in PPAR-gamma can provide important insight into the roles of this nuclear receptor in human metabolism. [ABSTRACT FROM AUTHOR]

Women with pre-existing diabetes (T1DM/T2DM) face increased risk in pregnancy. Optimising glycaemic control, folic acid use and smoking cessation are all advised to improve outcomes. Maintaining these goals can be difficult. We retrospectively analysed data from sites across our Atlantic DIP network from 2015-17 and compared outcomes to data 2010-14 to see if prior improvements were maintained. Data was collected on pre-pregnancy care (PPC), glycaemic targets and neonatal outcomes. In total 98 women attended; 76 (78%)/22 (22%) with T1DM and T2DM respectively. Booking maternal BMI reduced but a fall in PPC attendance lead to lower folic acid use, greater teratogenic medication use and static smoking rates. Trimester 1 HbA1C was suboptimal in T1DM but patients subsequently reached target. HbA1C improved throughout pregnancy for T2DM and was at target (Table 1). Between the two time periods outcomes were unchanged for miscarriage, shoulder dystocia, NICU admission, macrosomia, LGA, SGA and birth weight. We recorded no stillbirths or congenital malformations. Improvements occurred in prematurity (<003C34w) and neonatal hypoglycaemia. It is reassuring to record maintenance/improvement in neonatal outcomes but ongoing education on the importance of PPC and novel ways to reach patients are required. Disclosure: C. Newman: Speaker's Bureau; Self; Sanofi. L. Carmody: None. A.M. Egan: None. L.A. Owens: None. F. Dunne: None. [ABSTRACT FROM AUTHOR]

pGCD59 is an emerging biomarker for diabetes and GDM. In 1,000 women undergoing 2-step GDM screening, pGCD59 at weeks 24-28 classified GDM subjects with high sensitivity and specificity and was associated with the risk of large for gestational age (LGA) babies. GDM early in pregnancy is a public health challenge because it increases the risk of adverse outcomes. To assess pGCD59 as a predictor of early GDM and abnormal outcomes, levels of pGCD59 were measured in 807 samples from women undergoing a 1-step OGTT (75gr-2hr; WHO 2013 criteria) at <20 weeks gestation in the DALI study, a European trial of women at high risk of GDM. Results: Among 807 samples, 481 subjects had normal glucose tolerance throughout the pregnancy (Controls) and 205 met WHO 2013 criteria for GDM at <20 weeks (Cases). Age, race/ethnicity, and BMI were similar among Cases and Controls. pGCD59 accurately predicted the diagnosis of GDM in early pregnancy (AUCROC = 0.9). The risk of LGA (>90thpercentile) was positively associated with pGCD59 (p = 0.04) in Cases but not in Controls. Cases who delivered LGA newborns had higher median levels of pGCD59 than those who delivered non-LGA newborns (pGCD59 (SPU): Case-LGA: 4.4[1.5], Case-non-LGA 3.8[1.2]; p = 0.03). In contrast, median levels of pGCD59 were similar in Controls who delivered LGA or non-LGA newborns. The risk of congenital malformations or neonatal hypoglycemia was also associated with higher maternal levels of pGCD59: i) mothers who delivered babies with malformations had 60% higher mean pGCD59, ii) the odds ratio of a malformation was 3.4 (95% CI: 1.1, 10.1) in the 4th as compared with the 1st quartile of pGCD59, and iii) one unit increase in pGCD59 was associated with a 70% higher odds ratio of neonatal hypoglycemia. HbA1c failed to predict GDM or abnormal neonatal outcomes. Conclusion: Our results indicate that pGCD59 is a simple and accurate biomarker for early detection of GDM and for risk assessment of its potentially serious complications. Disclosure: J. Halperin: Stock/Shareholder; Self; Mellitus, LLC. D. Ma: None. M.A. Luque-Fernandez: None. D. Bogdanet: None. G. Desoye: None. F.P. Dunne: None. Funding: National Institutes of Health (R01DK101442 to J.H.); European Union (242187) [ABSTRACT FROM AUTHOR]

The article focuses on a randomized, controlled study of a rapid-acting insulin analog in pregnant women with Type 1 diabetes where the development of insulin antibodies (AB) was assessed. It has been found that levels of AB were similar between insulin aspart (IAsp) and human insulin (HI) groups. There is also a lack of clear evidence of transfer of IAsp across the placenta.