Efficacy of combined treatments in NIDDM patients with secondary failure to sulphonylureas. Is it predictable?

The treatment of NIDDM patients with secondary failure to sulphonylurea is a common problem. We performed a crossover study in 50 NIDDM patients with secondary failure to glibenclamide by comparing the addition to sulphonylurea of either a low-dose bedtime NPH insulin or a t.i.d. oral metformin and by analyzing treatment efficacy in relation to patient and disease characteristics. Both combined therapies clearly improved glycaemic control. HbA1 c were similarly reduced by the addition of either bedtime NPH insulin (7.6+/-0.34 vs 8.7+/-0.35, p<0.01) or metformin (7.6+/-0.22 vs 8.6+/-0.31, p<0.01). Also fasting plasma glucose (FPG) and post-prandial plasma glucose (PPPG) significantly decreased (p<0.01) with both treatments. Bed-time NPH insulin was more effective on FPG reduction than metformin (-36+/-2% vs -25+/-2%, p<0.01); in contrast, metformin addition was more effective on PPPG reduction than bedtime NPH insulin addition (-30+/-2% vs 20+/-3%, p<0.01). Serum cholesterol was marginally but significantly decreased after metformin (5.49+/-0.19 vs 5.91 +/-0.18 mM, p<0.05) but not after NPH insulin. Body weight increase was significantly greater after insulin addition than after metformin (1.47+/-0.25 Kg vs 0.64+/-0.17 p=0.02). All patients preferred the addition of metformin rather than NPH insulin. None of the measured clinical and metabolic variables (before treatment FPG and PPPG, HbA1 c, post-glucagon C-peptide levels, insulin sensitivity, patient age, BMI and diabetes duration) significantly correlated to the efficacy of the two combined treatments studied. In conclusion, in NIDDM patients with secondary failure to sulphonylureas the addition of either low-dose bedtime NPH insulin or t.i.d. metformin is similarly effective in improving glycaemic control. Metformin is better accepted by patients and provides a modest advantage in terms of body weight and cholesterol levels. The most common clinical and metabolic variables are not useful for predicting the efficacy of these two combined treatments.

Increased aggressiveness of thyroid cancer in patients with Graves' disease.

To evaluate whether coexistence of Graves' disease affects the prognosis of thyroid cancer we examined the clinical and pathological characteristics of 22 differentiated thyroid carcinomas concomitant with hyperthyroidism; 13 were associated with Graves' disease, and 9 with autonomous thyroid nodules. Carcinomas were identified in a consecutive series of 359 hyperthyroid patients (132 with Graves' disease and 227 with autonomous thyroid nodules) who underwent surgery during a 6-yr period. One hundred and thirty-seven thyroid carcinomas were found in the 582 euthyroid patients operated on in the same period. In Graves' patients, carcinomas were more often multifocal (46.1% vs. 0%), locally invasive (61.5% vs. 11.1%), and metastatic to lymph nodes (61.5% vs. 11.1%) or to distant sites (23.0% vs. 0%) than in patients with autonomous thyroid nodules. In addition, carcinomas concomitant with Graves' disease were larger (3.3 +/- 1.8 vs. 1.0 +/- 0.7 cm) than the ones associated with autonomous thyroid nodules and showed a high recurrence rate. In euthyroid patients, aggressiveness of thyroid cancer was intermediate. Serum TSH levels were suppressed in all hyperthyroid patients with thyroid cancer. However, circulating thyroid-stimulating antibodies were present in 12 of 13 cancer patients with Graves' disease, but were absent in patients with autonomous thyroid nodules. Our study suggests, therefore, that TSAb may play a role in determining the high aggressiveness of thyroid cancer in Graves' disease patients and indicates that a vigorous treatment should be pursued in this subgroup of patients.

Prevention and treatment of endemic iodine-deficiency goiter by iodination of a municipal water supply.

A recently described method for the prevention and treatment of endemic iodine deficiency and goiter, introduction of iodine into a public water supply, was tested in Troina, a town of about 13,000 inhabitants in northeast Sicily. There, before initiation of the program, a goiter endemic of moderate severity was present, as evidenced by goiter prevalence of 55% in school children. Iodine deficiency in nongoitrous adults was indicated by daily urinary iodine excretion of 40.7 +/- 2.6 micrograms (mean +/- SE) and 24-h thyroid radioiodine uptake of 50.8 +/- 2.4%. Iodination of the water supply was initiated in November 1979 using a stream-splitting device that diverts a controlled fraction of the total water flow to a canister containing iodine crystals, where the water becomes saturated with iodine (approximately 300 mg/liter) before returning to the main stream. Except for a 15-month interruption during which governmental authorization of the program was being reconfirmed, treatment of the water has continued to the present time, initially at a level of 81 +/- 25 micrograms/liter (mean +/- SD) and since resumption at a level of 46.5 +/- 5 micrograms/liter. Iodination of the water was followed by a prompt and marked reduction in goiter prevalence, and by improvement in biochemical indices of iodine deficiency. By April 1983, overall goiter frequency in school children had declined to 6.1%, and large goiters (WHO Grade 2) had virtually disappeared. By January 1984, daily urinary iodine excretion had increased to 85.6 +/- 6.5 (SEM) micrograms and radioiodine uptake had decreased to 40.7 +/- 4.7%. Serum thyroid-related hormone concentrations were as follows (pretreatment vs. November-December 1983): T4, 5.8 +/- 0.3 vs. 8.4 +/- 0.3 microgram/dl; T3, 1.6 +/- 0.05 vs. 1.2 +/- 0.06 ng/ml; TSH, 3.7 +/- 0.2 vs. 2.2 +/- 0.1 microU/ml; all changes being statistically significant. By late 1983, serum T4, T3, and TSH values in Troina were almost identical to those in Catania, a community in which iodine deficiency is not present (goiter prevalence in school children, 2.2%). In contrast, in Troina serum T4 concentrations were significantly higher and serum TSH concentrations were significantly lower than those in Maniaci, a iodine-deficient town near Troina, in which the water was not iodinated. Iodinated water was well tolerated by the population of Troina, and no adverse effects of water iodination, including any increase in the frequency of hyperthyroidism, was observed. At present prices, the cost of the water iodination program in Troina would be approximately 4 cents (U.S.) per person per year.(ABSTRACT TRUNCATED AT 400 WORDS)

Serum thyroglobulin levels are elevated in newborns from iodine-deficient areas.

Newborn infants have elevated serum thyroglobulin (Tg) levels and reduced iodination of Tg. To determine whether a relationship exists between serum Tg levels and the degree of Tg iodination, 699 newborn infants were studied in 3 areas of Sicily: a normal iodine-sufficient (control) area and 2 iodine-deficient areas. In the iodine-sufficient area, the mean cord serum Tg level was 25.8 ng/ml (median, 18.0; n = 183). In the iodine-deficient areas, the serum Tg levels in newborns were significantly higher, with mean levels of 43.4 ng/ml (median, 29.7; n = 304; P less than 0.01) and 60.1 ng/ml (median, 48.0; n = 212; P less than 0.005), respectively. The higher serum Tg level at birth was not entirely due to increased cord serum TSH levels, since newborns from the iodine-deficient areas with serum TSH levels at birth similar to those in infants from the control area had higher serum Tg levels. Serum Tg levels correlated with the serum T3 to T4 ratio, but not with serum TSH, T4, or T3 levels. These data suggest that iodine availability, which affects the degree of thyroid Tg iodination, partially determines serum Tg levels at birth.

Thyroglobulin release after graded endogenous thyrotropin stimulation in man: lack of correlation with thyroid hormone response.

The serum thyroglobulin (Tg), T3, and T4 responses to graded endogenous TSH stimulation were examined in 30 normal subjects for up to 96 h after TRH administration. Increasing TSH rises were elicited by TRH administration as follows: 1) 500 micrograms iv as a single bolus in 10 subjects [mean peak serum TSH, 14.3 +/- 1.8 (SE) microU/ml]; 2) 1000 micrograms infused iv in 2 h in 10 subjects (mean peak TSH, 25.5 +/- 2.6 microU/ml); 3) 40 mg orally in 10 subjects (mean peak TSH, 27.5 +/- 3.0 microU/ml, with a delayed and more prolonged rise). Nine subjects received saline and were used as controls. A significant serum T3 and T4 rise followed the TSH increase in all subjects, and the mean peak value was always reached 4 h after TRH. In contrast, a significant serum Tg increase occurred only in 3, 6, and 9 subjects after 500 micrograms, 1000 micrograms, and 40 mg TRH, respectively. In addition, the time of the Tg peak and its duration was extremely variable but it was always delayed in respect to serum T3 and T4 peaks, occurring 6 to 72 h after TRH administration. No correlation was found between serum Tg and T3 or T4 increases after TRH in any of the three groups. These studies indicate that a significant Tg release in man usually occurs only after intense and prolonged TSH stimulation of the thyroid. In addition, the Tg increase is delayed in respect to the thyroid hormone increase and it is not correlated with them.

Solitary autonomously functioning thyroid nodules and iodine deficiency.

The prevalence, characteristics, and evolution of autonomously functioning thyroid nodules (AFTN) were studied in two population groups from northeastern Sicily. One group was living in an iodine-deficient area and another was living in an iodine-sufficient area. The prevalence of AFTN was significantly higher in the iodine-deficient area (4.4% of total patients vs. 2.7%). No significant difference between the two areas was observed in sex and age distribution and size of the nodules. In addition, a higher percentage of patients with toxic nodules (1.3%) was found in the group from the iodine-deficient area. Furthermore, in a selected group of patients followed for 1-6 yr, a higher percentage of patients from the iodine-deficient area had either an increase in the size of the lesion or an increase in thyroid hormone production leading to toxicity. These data suggest that iodine deficiency is one possible factor in the development of AFTN and that iodine deficiency may also be involved in the increased frequency of toxic evolution of these lesions.

Phenformin has opposite effects on insulin and growth hormone binding to IM-9 lymphocytes.

We studied simultaneously the effect of various concentrations of phenformin on insulin and growth hormone binding to IM-9 lymphocytes, a cell type known to have receptors for both these hormones. After 24 hr preincubation with phenformin at 2 x 10(-5) M, insulin binding to IM-9 cells was increased by 80.4 +/- 10.5% over control (mean +/- SE of 10 experiments). In parallel experiments HGH binding was decreased by 43.1 +/- 2.2% (mean +/- SE). This effect of phenformin was dose-dependent for both HGH and insulin binding over the concentration range 1.5 x 10(-6) M to 5 x 10(-5) M, and was already detectable 3 hr after phenformin addition. These data indicate that phenformin has an opposite effect on insulin and growth hormone binding to IM-9 cells. Several possible mechanisms might be suggested for the decrease of HGH binding sites induced by phenformin: the simultaneous opposite effect on HGH and insulin receptors raises the possibility that some metabolic event triggered by the drug is able to induce opposite changes in the binding of these two hormones with different biological activities.