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Context There is substantial heterogeneity in insulin sensitivity, and genetics may suggest possible mechanisms by which common variants influence this trait. Objectives We aimed to evaluate an 11-variant polygenic lipodystrophy genetic risk score (GRS) for association with anthropometric, glycemic and metabolic traits in the Diabetes Prevention Program (DPP). In secondary analyses, we tested the association of the GRS with cardiovascular risk factors in the DPP. Design In 2713 DPP participants, we evaluated a validated GRS of 11 common variants associated with fasting insulin-based measures of insulin sensitivity discovered through genome-wide association studies that cluster with a metabolic profile of lipodystrophy, conferring high metabolic risk despite low body mass index (BMI). Results At baseline, a higher polygenic lipodystrophy GRS was associated with lower weight, BMI, and waist circumference measurements, but with worse insulin sensitivity index (ISI) values. Despite starting at a lower weight and BMI, a higher GRS was associated with less weight and BMI reduction at one year and less improvement in ISI after adjusting for baseline values but was not associated with diabetes incidence. A higher GRS was also associated with more atherogenic low-density lipoprotein peak-particle-density at baseline but was not associated with coronary artery calcium scores in the Diabetes Prevention Program Outcomes Study. Conclusions In the DPP, a higher polygenic lipodystrophy GRS for insulin resistance with lower BMI was associated with diminished improvement in insulin sensitivity and potential higher cardiovascular disease risk. This GRS helps characterize insulin resistance in a cohort of individuals at high risk for diabetes, independent of adiposity.

BACKGROUND: Primary aldosterone synthase deficiency (ASD) is a rare but potentially life-threatening cause of mineralocorticoid deficiency primarily due to a defect in CYP11B2, which encodes aldosterone synthase. There are two types of ASDs, both resulting in primary hypoaldosteronism, but due to differences in blockade of the terminal oxidation step, are distinguished by low 18-hydroxycorticosterone (18-OHC) in Type 1 and elevated 18-OHC in Type 2. With a wide variation in clinical severity and presentation, few cases of ASD have been reported. CLINICAL CASE: A 10-day old full term male infant born to unrelated parents of European descent presented with weight loss, poor feeding and dehydration, in the setting of hyponatremia (Na 127 mM, ref 131-145 mM) and hyperkalemia (K 8 mM, ref 3.2-6 mM). He had normal genitalia and no hyperpigmentation on exam. A cosyntropin stimulation test resulted in a cortisol of 19 μg/dL. Electrolytes transiently improved with normal saline but worsened after fluids were discontinued. Oral NaCl was initiated at a dose of 4 mEq/kg/day and titrated to 6 mEq/kg/day. Aldosterone levels while hyponatremic were inappropriately low (