A B S T R A C T lopanoic acid has been shown to block thyroxine (T4)-5'-monodeiodination in rat anterior pituitary in vitro. To test the hypothesis that the acute decrease in thyrotropin (TSH) after infusion of T4 into hypothyroid rats requires intrapituitary T4 to 3,5,3'-triiodothyronine (T3) conversion, the effect of iopanoic acid treatment on the generation of nuclear T3 from intrapituitary conversion and the response to TSH were compared in control and iopanoic acid-treated animals. 5 mg/100 g body weight iopanoic acid given 24, 16, and 1.5 h before administration of 1251-T4 reduced the quantity of pituitary nuclear 125I-T3 from local (intrapituitary) T4 to T3 conversion by 60-100%. In association with inhibition of intrapituitary T4 to T3 conversion, there was an increase in the binding of 1251-T4 to the nuclear receptor of the pituitary but the total iodothyronine content of the nuclei was still less than half of the nuclear iodothyronine in control animals. lopanoic acid did not affect the nuclear/plasma ratio of injected 131I-T3 in the same animals, but did appear to impair 131I-T3 clearance or reduce its distribution volume. Treatment with iopanoic acid did not reduce the quantity of nuclear 1251-T3 in the liver, kidney, or heart of the same animals more than expected from the changes in serum 1251-T3. In control hypothyroid animals, 800 ng/100 g body weight T4 caused a reduction in TSH to 41% of its initial value 3 h after injection. In animals pretreated with iopanoic acid, the mean TSH was not significantly decreased from the initial value by T4 injection. Iopanoic acid pretreatment did not interfere with the acute TSH response of chronically hypothyroid rats to 70 ng of T3/100 g body weight. These Received for publication 11 February 1978 and in revised form 12 March 1979. results establish that intrapituitary generation of T3 from T4 is required for the acute decrease in TSH which occurs after T4 infusion. The data also are consistent with the concept that it is the nuclear binding of the T3 generated from T4 which initiates the inhibition of TSH release.

The role of diet in type 1 diabetes development is poorly understood. Metabolites, which reflect dietary response, may help elucidate this role. We explored metabolomics and lipidomics differences between 352 cases of islet autoimmunity (IA) and controls in the TEDDY (The Environmental Determinants of Diabetes in the Young) study. We created dietary patterns reflecting pre-IA metabolite differences between groups and examined their association with IA. Secondary outcomes included IA cases positive for multiple autoantibodies (mAb+). The association of 853 plasma metabolites with outcomes was tested at seroconversion to IA, just prior to seroconversion, and during infancy. Key compounds in enriched metabolite sets were used to create dietary patterns reflecting metabolite composition, which were then tested for association with outcomes in the nested case-control subset and the full TEDDY cohort. Unsaturated phosphatidylcholines, sphingomyelins, phosphatidylethanolamines, glucosylceramides, and phospholipid ethers in infancy were inversely associated with mAb+ risk, while dicarboxylic acids were associated with an increased risk. An infancy dietary pattern representing higher levels of unsaturated phosphatidylcholines and phospholipid ethers, and lower sphingomyelins was protective for mAb+ in the nested case-control study only. Characterization of this high-risk infant metabolomics profile may help shape the future of early diagnosis or prevention efforts.

Monoclonal antibodies to intact hCG and free beta-subunit of hCG permit the recognition of different individual antigenic sites on the hCG molecule. At least seven different epitopes may be recognized on the native molecule and a further two on the free beta-subunit. These antibodies were used in a mouse Leydig cell bioassay system to compare the degree of inhibition of hCG-induced testosterone production. Two antibodies were particularly potent at inhibiting hCG action, suggesting that they bind near to the receptor-recognition site on the hCG molecular. One antibody had little effect on biological action and was presumably binding distant from the biologically active site on the hCG. Combinations of monoclonal antibodies in immunoradiometric assays were used to develop highly sensitive and specific assays to intact hCG, free beta-subunit of hCG, and beta-subunit as part of intact hCG. Using these assays it was possible to detect 0.1 ng/ml hCG in the presence of high levels of LH. In 106 serum samples from pregnant woman free beta-subunit was considerably higher in samples with low concentrations of intact hCG, suggesting that free beta-subunit is not a limiting factor in placental production of intact hCG in early pregnancy. Comparison of urinary to serum ratios of hCG and free beta-subunit using specific immunoradiometric assays showed a good correlation for intact hCG but not for free beta subunit which was present in very high concentrations in urine.

A total of 15 SNPs within complement genes and present on the ImmunoChip were analyzed in The Environmental Determinants of Diabetes in the Young (TEDDY) study. A total of 5474 subjects were followed from three months of age until islet autoimmunity (IA: n = 413) and the subsequent onset of type 1 diabetes (n = 115) for a median of 73 months (IQR 54–91). Three SNPs within ITGAM were nominally associated (p < 0.05) with IA: rs1143678 [Hazard ratio; HR 0.80; 95% CI 0.66–0.98; p = 0.032], rs1143683 [HR 0.80; 95% CI 0.65–0.98; p = 0.030] and rs4597342 [HR 1.16; 95% CI 1.01–1.32; p = 0.041]. When type 1 diabetes was the outcome, in DR3/4 subjects, there was nominal significance for two SNPs: rs17615 in CD21 [HR 1.52; 95% CI 1.05–2.20; p = 0.025] and rs4844573 in C4BPA [HR 0.63; 95% CI 0.43–0.92; p = 0.017]. Among DR4/4 subjects, rs2230199 in C3 was significantly associated [HR 3.20; 95% CI 1.75–5.85; p = 0.0002, uncorrected] a significance that withstood Bonferroni correction since it was less than 0.000833 (0.05/60) in the HLA-specific analyses. SNPs within the complement genes may contribute to IA, the first step to type 1 diabetes, with at least one SNP in C3 significantly associated with clinically diagnosed type 1 diabetes.

No abstract