To determine the effect of thyroid hormone excess on insulin secretion, metabolism and action in humans, we examined intravenous glucose tolerance, glucose-induced insulin secretion, insulin clearance, monocyte insulin receptor binding, and the dose-response characteristics for the effects of insulin on glucose production, uptake, oxidation, and nonoxidative disposal in 10 normal volunteers for 14 days before and after oral administration of triiodothyronine (T3) in doses that increased plasma T3 to levels observed in spontaneous thyrotoxicosis (P less than 0.001). After T3 postabsorptive plasma glucose (P less than 0.05) and insulin (P less than 0.05) both increased; intravenous glucose tolerance was unaffected, but plasma insulin responses were increased (P less than 0.01); basal glucose production, uptake, and oxidation all increased (all P less than 0.05), whereas nonoxidative glucose disposal was unaffected (P = NS); monocyte insulin receptor binding increased (P less than 0.01) due to increased receptor affinity (P less than 0.05); and receptor number was not significantly altered (P = NS). Insulin clearance was increased. Insulin-induced suppression of glucose production was impaired (Km 22 +/- 3 vs. 37 +/- 7 microU/ml, P less than 0.02); maximal insulin-induced glucose uptake (10.7 +/- 0.6 vs. 13.0 +/- 0.9 mg X kg-1 X min-1, P less than 0.001) and oxidation (3.41 +/- 0.30 vs. 5.34 +/- 0.59 mg X kg-1 X min-1, P less than 0.001) were increased without a significant change in Km. However, submaximal rates of nonoxidative glucose disposal and glucose uptake were inappropriately low for the increased insulin receptor binding.(ABSTRACT TRUNCATED AT 250 WORDS)

We assessed glucose counterregulation during intensive insulin therapy in 20 patients with insulin-dependent diabetes mellitus (IDDM) by injecting therapeutic doses of regular insulin subcutaneously after overnight maintenance of euglycemia. As compared with nondiabetic controls matched for age and weight, 17 of the patients had more severe and more prolonged hypoglycemia (nadir, 42 +/- 2 in patients vs. 60 +/- 2 mg per deciliter in controls P less than 0.01; duration, 6.2 +/- 0.4 vs 2.1 +/- 0.6 hours, P less than 0.01). Most patients had decreased responses of several counterregulatory hormones. Marked rebound hyperglycemia (approximately equal to 300 mg per deciliter) ultimately developed in 11 patients. The only features distinguishing patients with rebound hyperglycemia from those without it were plasma free insulin concentrations during recovery from hypoglycemia (those with vs. those without, 7 +/- 1 vs. 22 +/- 2 microU per milliliter, P less than 0.01) and insulin-antibody binding (5 +/- 1 vs. 30 +/- 5 per cent, P less than 0.01). Rates of plasma glucose recovery from hypoglycemia were inversely correlated with plasma free insulin concentrations (r = -0.84, P less than 0.01); the latter in turn were directly correlated with insulin-antibody binding (r = 0.94, P less than 0.01). We conclude that many patients with IDDM have impaired glucose counterregulation due to multiple defects in counterregulatory-hormone secretion. This is associated with increased insulin-antibody binding, which prolongs the half-life of insulin. In such patients, intensive insulin therapy may be hazardous.

We reviewed 10 cases of pleomorphic lobular (ductal lobular) carcinoma in situ (PL/DLCIS) of the breast and compared them with 14 cases of pleomorphic lobular carcinoma in situ (PLCIS) found in association with invasive pleomorphic lobular carcinoma. The histologic features; immunohistochemical staining for estrogen receptors (ERs), p53, Ki67, E-cadherin, and gross cystic disease fluid protein-15 (GCDFP-15); and results of fluorescence in situ hybridization for HER-2/neu gene amplification were evaluated in all 24 cases. Histologically, PL/DLCIS cells were similar to those of PLCIS with invasion in that they were discohesive and medium to large in size with moderate to marked nuclear pleomorphism, small to prominent nucleoli, and moderate to abundant eosinophilic or vacuolated cytoplasm. In both groups, central necrosis was present in a small number of cases, and classic LCIS coexisted with the in situ lesion in less than half of the cases; in situ carcinomas were positive for ERs in 23 (100%) of 23 cases, p53 in 6 (25%) of 24 cases, and GCDFP-15 in 14 (74%) of 19 cases. The percentage of Ki67-positive tumor nuclei indicated moderate to high (more than 20%) proliferative activity in 8 (47%) of 17 cases. Immunostaining for E-cadherin was negative in all 24 cases. HER-2/neu gene amplification was observed in 1 (4%) of 23 cases. In cases with associated invasion, PLCIS had cytologic features and immunostaining patterns similar to those of the invasive pleomorphic component. Seven of the 10 patients who had PL/DLCIS without invasion underwent lumpectomy or simple mastectomy. Six of these patients had no evidence of disease in follow-up periods ranging from 4 to 32 months; the seventh patient developed recurrent disease 12 months after undergoing lumpectomy. We conclude that the cytologic features and biomarker expression profile of PL/DLCIS are similar to those of PLCIS with invasion but somewhat different from those of classic LCIS and ductal carcinoma in situ. Long-term follow-up studies are needed to further define the natural history of PL/DLCIS and its optimal management.

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