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Context Insulin resistance (IR) is associated with polycystic ovaries and hyperandrogenism, but underpinning mechanisms are poorly understood and therapeutic options are limited. Objective To characterize hyperandrogenemia and ovarian pathology in primary severe IR (SIR), using IR of defined molecular etiology to interrogate disease mechanism. To extend evaluation of gonadotropin-releasing hormone (GnRH) analogue therapy in SIR. Methods Retrospective case note review in 2 SIR national referral centers. Female patients with SIR with documented serum total testosterone (TT) concentration. Results Among 185 patients with lipodystrophy, 65 with primary insulin signaling disorders, and 29 with idiopathic SIR, serum TT ranged from undetectable to 1562 ng/dL (54.2 nmol/L; median 40.3 ng/dL [1.40 nmol/L]; n = 279) and free testosterone (FT) from undetectable to 18.0 ng/dL (0.625 nmol/L; median 0.705 ng/dL [0.0244 nmol/L]; n = 233). Higher TT but not FT in the insulin signaling subgroup was attributable to higher serum sex hormone–binding globulin (SHBG) concentration. Insulin correlated positively with SHBG in the insulin signaling subgroup, but negatively in lipodystrophy. In 8/9 patients with available ovarian tissue, histology was consistent with polycystic ovary syndrome (PCOS). In 6/6 patients treated with GnRH analogue therapy, gonadotropin suppression improved hyperandrogenic symptoms and reduced serum TT irrespective of SIR etiology. Conclusion SIR causes severe hyperandrogenemia and PCOS-like ovarian changes whether due to proximal insulin signaling or adipose development defects. A distinct relationship between IR and FT between the groups is mediated by SHBG. GnRH analogues are beneficial in a range of SIR subphenotypes.

ContextPatients with lipodystrophy have dyslipidemia and insulin resistance. Leptin treatment with metreleptin in lipodystrophy decreases insulin resistance and lowers triglycerides without changing high-density lipoprotein. Detailed measurement of lipoprotein particles with nuclear magnetic resonance (NMR) spectroscopy can offer insights into cardiovascular disease (CVD) risk and lipid metabolism beyond a standard lipid panel. We hypothesized that patients with lipodystrophy would have a more atherogenic lipid profile than controls at baseline, which would be ameliorated with metreleptin treatment.ObjectiveTo characterize the lipoprotein profile in patients with lipodystrophy compared with controls and to evaluate effects of metreleptin treatment.Design, Setting, Patients, and InterventionPatients with lipodystrophy (N = 17) were studied before and after metreleptin for 2 weeks and 6 months and compared with 51 insulin-sensitive sex-matched controls.Main Outcome MeasuresLipoprotein profiles were measured by NMR with the LP4 deconvolution algorithm, which reports triglyceride-rich lipoprotein particles (TRLPs), high-density lipoprotein particles (HDLPs), and low-density lipoprotein particles (LDLPs).ResultsPatients with lipodystrophy had elevated large TRLPs and smaller HDLPs and LDLPs compared with controls. Five patients with lipodystrophy had chylomicrons, compared with zero controls. Metreleptin decreased the size and concentration of TRLPs, eliminated chylomicrons in all but one patient, decreased LDLPs, and increased LDLP size. Metreleptin treatment did not have major effects on HDLPs.ConclusionsPatients with lipodystrophy had an atherogenic lipoprotein profile at baseline consistent with elevated CVD risk, which improved after metreleptin treatment. The presence of fasting chylomicrons in a subset of patients with lipodystrophy suggests saturation of chylomicron clearance by lipoprotein lipase.

Background: Black mothers in the United States have shorter breastfeeding (BF) durations and less exclusive breastfeeding (EBF) than others. The factors underlying these disparities require investigation. Methods: Using longitudinal data from a CDC-sponsored birth cohort in Cincinnati, Ohio, we analyzed the factors mediating racial disparity in BF outcomes. Study mothers were enrolled in prenatal clinics associated with two large birth hospitals. Analysis was restricted to racial groups with sufficient numbers in the cohort, non-Hispanic Black (n = 92) and White (n = 113) mothers, followed to at least 6 months postpartum. Results: Black mothers were 25 times more likely to reside in socioeconomically deprived neighborhoods and 20 times more likely to have an annual household income

Lipodystrophies (LD) are defined by deficient adipose tissue, causing low leptin and metabolic disease including severe insulin resistance and hypertriglyceridemia. Recombinant leptin (metreleptin, ML) treatment in LD improves insulin resistance and lowers triglycerides without changing HDL. Detailed measurement of lipoprotein particles using NMR spectroscopy can offer insights into cardiovascular disease (CVD) risk and lipid metabolism beyond a standard lipid panel and has never been performed in LD. We hypothesized that patients with LD would have a more atherogenic lipid profile than controls at baseline, which would be ameliorated with ML treatment secondary to improvements in insulin sensitivity. Patients with LD (N=17) were enrolled in a study evaluating short- and long-term effects of ML on metabolic disease and compared to 51 insulin sensitive (SI

Insulin is critical for lipid synthesis and inhibition of lipolysis. The dyslipidemia of type 2 diabetes (high triglycerides (TG), low HDL) is caused by selective IR with intact insulin signaling in lipogenic pathways. By contrast, knockout of all insulin signaling pathways due to insulin receptor (INSR) mutation leads to low TG and high HDL (in humans and mice), and decreased cholesterogenic gene expression, cholesterol and bile acid synthesis, PCSK9, and hepatic FFA flux (in liver INSR -/- mice). Thyroid hormone (TH) effects on lipids generally oppose those of insulin, and include increased lipolysis, FFA, and bile formation. We used patients with homozygous (-/-) and heterozygous (+/-) INSR mutations as models to understand interactions between TH and insulin action on lipids. Materials and methods: Euthyroid patients age 12-65y with proven INSR -/- (N=5) or +/- (N=2) mutation (22.2+6.5yr; 4 males) were treated with liothyronine (T3) for 2 weeks with peak target level 25-50% above upper limit of normal. Samples were obtained before and after T3 for thyroid hormones (TSH, fT4, TT4, fT3, TT3), lipids (total cholesterol, LDL, HDL, TG, number and size of lipid particles by NMR, ApoA1, ApoB), lipid regulating enzymes (CETP activity, LCAT activity and mass, PCSK9, PTPL, Lp-PLA2), lipolysis (glycerol turnover), and palmitate turnover. Results: After initiation of T3, hyperthyroid state was achieved by day 3 based on fT3 and TT3 with TSH suppression on day 4. On the standard lipid panel, TG decreased from 64.2 at baseline to 52.6mg/dl after T3 (p=.1), total cholesterol from 143±18.2 to 119.7±9.4mg/dl (p=.0009), LDL from 76.3±15.7 to 61.1±15.5mg/dl (p=.02), and HDL from 62.2±11.9 to 55.2±10.3mg/dl (p=.026). NMR analysis of lipoprotein particles showed that triglyceride-rich lipoprotein particles (TRLP) decreased from to 20±9.8 to 13±5.7 nmol/l (p=.06), LDLP from 1115±201 to 937±195 nmol/L (p=.016), large LDLP from 139±73 to 81±48 nmol/l (p=.046), size of the LDLP from 20.5±0.4 to 20.2±0.4 nm (p=.055), ApoB from 55.7±11 to 45.4±11 mg/dl (p=0.015), HDLP from 20±3 to 18.5±2 nm (p=.08), large HDLP from 3.6±1.9 to 2.8±1.8 umol/l (p=.06), size of HDLP particles from 9.5±0.6 to 9.4±0.6 nm (p=.08), and ApoA1 from 144±4 to 129±15 mg/dl (p=.02). No significant increase in FFA was seen after T3. Lipid enzymes were unchanged after T3 except for PLAC activity, which decreased from 128±30 to 111±28 nmol/min/ml (p=0.03). There was no difference in lipolysis or palmitate turnover rate after T3. In conclusion, we found that T3 had the expected effects on lipids in INSR mutation patients. No changes in key lipid enzymes were found after T3, perhaps due to small sample size. Further long-term studies are needed to determine long-term effects of TH on lipid metabolism in the setting of normal vs. impaired insulin signaling.

Background: There is an association between insulin resistance (IR) and hyperuricemia but the direction of causalityand mechanisms are unclear. In obesity and lipodystrophy, IR is “selective”, with lack of insulin signalingcausing hyperglycemia, but enhanced insulin signaling causing dyslipidemia and possibly hyperuricemia. Rare human conditions exist in which there is extreme, non-selective, IR impairing all insulin signalingpathways (e.g. mutations of the insulin receptor, INSR). We hypothesized that hyperinsulinemia withenhanced signaling through the insulin receptor causes hyperuricemia in selective IR, whereas lack ofinsulin signaling through its receptor despite hyperinsulinemia results in normal uricemia in non-selective IR. Method: Cross-sectional retrospective analysis comparing fasting insulin and serum uric acid in patients withsevere IR that was either selective (due to lipodystrophy) or non-selective (due to INSR mutation orautoantibody to the insulin receptor). Visits were chosen based on availability of serum uric acid andinsulin. If multiple visits were available, the visit with the highest insulin value was chosen. Results: We analyzed data of 68 patients with selective IR and 14 patients with non-selective IR. Fasting seruminsulin median [interquartile range] was 23.4 [14, 53] mcU/mL in selective IR vs 215 [73.7, 604] in non-selective IR, p