Quantitative assessment of pituitary resistance to thyroid hormone from plots of the logarithm of thyrotropin versus serum free thyroxine index.

Previous studies have shown that, in patients with primary alterations in thyroid hormone secretion, the level of the natural logarithm of serum TSH (lnTSH) is negatively related to the level of free T4. Because such patients can generally be assumed to exhibit normal tissue responsivity to thyroid hormone, we were interested in determining whether the lnTSH/free T4 index (FTI) relationship in patients with established thyroid hormone resistance (THR) exhibit a lower slope than patients with normal tissue sensitivity to thyroid hormone. We have therefore analyzed the relationship between the lnTSH and the FTI in members of three families with documented THR. In these patients, a given dose of T4 was maintained for a 1- to 2-month period, to achieve hormonal equilibration. Two of the families, though not related, exhibited the same mutation, E460K. The third was identified as A317T. As anticipated, the slope of the lnTSH/FTI ratio was significantly lower in the patients with THR than in T4-treated patients who were presumed to have normal sensitivity to thyroid hormone. The slope of the lnTSH/FTI relationship seemed to be characteristic of the specific mutation involved in the three genotypes (wild-type and two mutations) examined. Further, the in vivo slope of the lnTSH/FTI relationship seemed to be linearly related to the T3 association constant of the in vitro translated receptor. These findings support the potential usefulness of measuring the slope of lnTSH, as a function of the FTI, in quantitating pituitary THR.

Stimulation of insulin secretion by fructose ingested with protein in people with untreated type 2 diabetes.

OBJECTIVE: Ingested protein provides substrate for gluconeogenesis and strongly stimulates insulin and glucagon secretion, but it has little effect on the glucose concentration in people with type 2 diabetes. Ingested fructose also is a substrate for gluconeogenesis, modestly stimulates insulin and glucagon secretion, and has little effect on the plasma glucose. Therefore we were interested in determining if ingestion of fructose along with protein would result in an additive, greater than additive, or less than additive effect on circulating insulin, glucagon, and glucose concentrations. RESEARCH DESIGN AND METHODS: Seven male subjects with untreated type 2 diabetes were fasted overnight and then were given either 25 g fructose, 25 g protein, 25 g fructose plus 25 g protein, or water only at 0800. Subjects also ingested 50 g glucose on two separate occasions. Plasma glucose, insulin, C-peptide, glucagon, alpha-amino nitrogen, urea nitrogen, nonesterified fatty acids, and triglyceride concentrations were determined over the subsequent 5 h. RESULTS: The glucose concentration was only modestly increased and the area responses were similar when protein, fructose, or the combination was ingested. Thus, the glucose response to the combination was less than additive. The insulin area response to protein was 2.5-fold greater than to fructose, and the response to the two nutrients was additive and quantitatively similar to the response to 50 g glucose. The glucagon area response was less than additive, i.e., there was an interaction between the protein and fructose that resulted in a smaller than expected response. CONCLUSIONS: When protein and fructose were ingested together, the insulin response was similar to that following ingestion of 50 g glucose. It also was as expected based on the response to the individual nutrients. In contrast, the glucose and glucagon responses were significantly less than expected. These data may be useful in dietary planning for subjects with type 2 diabetes.

Isoform-specific 3,5,3'-triiodothyronine receptor binding capacity and messenger ribonucleic acid content in rat adenohypophysis: effect of thyroidal state and comparison with extrapituitary tissues.

Although the role of the three functional thyroid hormone receptor isoforms (TR beta 1, TR beta 2, and TR alpha 1) remains unclear, studies by Hodin and Lazar et al. have suggested that restriction of TR beta 2 messenger RNA (mRNA) to rat pituitary could reflect a specific regulatory role in the pituitary. Supporting their hypothesis was a significant fall in pituitary TR beta 2 mRNA after T3 administration. These observations prompted us to assess the effect of thyroidal state on the level of TR beta 2 protein, as inferred by immunoprecipitation of TR beta 2 nuclear binding activity. In contrast to the behavior of the mRNA, we noted surprising stability in the levels of total nuclear TR binding capacity and TR isoform distribution in the transition from hypo- to hyperthyroid states. Calculations based on these and previous data from this laboratory (7) show that the average cellular content of TR beta 2 mRNA in pituitary is 0.6 molecules, whereas the content of TR beta 2 mRNA molecules in extrapituitary tissues is less than 0.007 molecule/cell. A high TR beta 2 protein/mRNA ratio in extrapituitary tissues thus could reflect a rapid turnover of TR beta 2 mRNA compared to TR beta 2 protein. This would explain the widespread distribution of TR beta 2 protein and the scarcity of mRNA in extrapituitary tissues.