MON-611 Biux2x2

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.