Effect of a sulfonylurea (gliclazide) treatment on insulin sensitivity and glucose-mediated glucose disposal in patients with non-insulin-dependent diabetes mellitus (NIDDM).

Five male non-obese newly diagnosed NIDDM and 5 age-, sex- and body mass index (BMI) matched healthy controls without a family history of diabetes were submitted to a frequently sampled intravenous (i.v.) glucose tolerance test modified by exogenous insulin administration for estimation of insulin sensitivity (SI) and glucose-mediated glucose disposal (SG) with Bergman's minimal model computer analysis of glucose kinetics. The tests were repeated after 3 months treatment with a second generation sulfonylurea, gliclazide, in the diabetics subjects. SI and SG were markedly reduced before gliclazide therapy in the diabetics in comparison to the paired controls. After gliclazide, despite significantly lower (almost normal) plasma glucose, normalization of glycosylated hemoglobin and increased fasting insulin levels, there was a slight but significant increase in SI while SG showed a further reduction, the improvement in glucose control being also associated to the significant increased first and 2nd phase insulin release for the first 20 min after glucose infusion.

A model for the effect of estrogen antagonists on cooperative estradiol binding.

Partial agonists such as estriol and estrone have been reported to diminish or even eliminate the upward convexity of the Scatchard plot of the binding of labeled estradiol to estrogen receptor. This has been interpreted as agonist interference with the receptor dimerization induced by estradiol. In order to investigate how a partial agonist or antagonist might interfere with dimerization we have developed a theoretical mass-action law model, where soluble receptors can dimerize and bind to two different ligands. Special attention was devoted to manifestations of positive cooperativity to determine whether they could be modified by competition with a second ligand. This was done using a computer program that evaluated a large set of combinations of affinity constants in an effort to explore all possible situations. The model could reproduce the effect of a second ligand on the cooperative binding of estradiol to the estrogen receptor but only if the second ligand was anticooperative, which is not the case of estriol, estrone and tamoxifen. Furthermore, even when the Scatchard plot was linear, the model still required dimerization of the receptor in most of the cases, showing that the addition of an antagonist may eliminate the upward curvature of the Scatchard without truly eliminating dimerization or cooperativity. We conclude that the effect of a second ligand on the binding of labeled estradiol to estrogen receptor is not necessarily due to interference with dimerization and/or cooperativity. The inability of this model to fully explain the published data for estriol, estrone, clomiphene, and tamoxifen suggests that a more complex mechanism is involved.

Short- and long-term gliclazide effects on pancreatic islet cell function and hepatic insulin extraction in non-insulin-dependent diabetes mellitus.

Nine non-obese males with non-insulin-dependent diabetes mellitus (NIDDM) were evaluated before and after 3 and 12 months (6 patients) treatment with the second generation hypoglycemic sulfonylurea: gliclazide. They underwent an oral glucose tolerance test, intravenous glucose and arginine tests measuring plasma insulin and C-peptide responses. Pre-hepatic insulin production and insulin delivery to peripheral tissues were calculated by deconvolution techniques and hepatic extraction of insulin estimated. An improvement was observed in the beta-cell function of the patients on gliclazide treatment: reduction of fasting plasma glucose associated with a progressive increase in C-peptide level but insulin levels decreased at 12 months, suggesting an increase in hepatic insulin extraction at this time. In the same way, while plasma glucose values after oral and i.v. glucose were greatly reduced at 3 and 12 months treatment, insulin did not change but C-peptide levels increased significantly at 12 month treatment. While the prehepatic insulin secretion rate increased progressively on gliclazide during all glucose challenges, the fractional hepatic insulin extraction fell after 3 and increased at 12 month treatment, with opposite changes in insulin delivered to peripheral tissues. Thus the insulinogenic effect of gliclazide could be masked during long-term administration by a concomitant effect of gliclazide which increases hepatic extraction of insulin. The maintenance of the responsiveness to the non-glucose secretagogue, arginine, as evaluated by the C-peptide levels, before and after correction of hyperglycemia, suggested improvement of beta-cell sensitivity to glucose after sulfonylurea treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of Y-chromosome-specific DNA probes to evaluate an XX male.

1. The function of a Y human chromosomal DNA sequence was evaluated. The Y-5 probe was isolated from a flow-sorted chromosome library and detects Y-specific sequences. 2. The Y-5 probe and other Y-specific probes were used to analyze an XX male patient without ambiguous genitalia. 3. DNA sequences from the short arm of the chromosome Y that were detected with pDP1007 and pDP105 in the patient's genome explain the testis differentiation observed in this case. 4. Failure of the patient's DNA to hybridize to the Y-5 probe shows that the primitive gonads can differentiate into testes even in the absence of this chromosome region. In contrast, a gene controlling spermatogenesis may exist in this region because the patient is azoospermic.

Use of y-chromosome-specific DNA probes to evaluate an XX male

The function of a Y human chromosomal DNA sequence was evaluated. The Y-5 probe was isolated from a flow-sorted chromosome library and detects Y-specific sequences. The Y-5 probe and other T-specific probes were used to analyze an XX male patient without ambiguous genitalia. DNA sequences from the short arm of the chromosome Y that were detected with pDP1007 and DP105 in the patient's genome explain the testis differentation observed in this case. Failure of the patient's DNA to hybridize to the Y-5 probe shows that the primitive gonads can differentiate into testes even in the absence of this chromosome region. In contrast, a gene controlling spermatogenesis may exist in this region because the patient azoospermic

Non-metric cranial variants in Brazilian skulls.

The incidence of 27 non-metric cranial variants is studied in a sample of 124 skulls from Brazil. The unilateral and bilateral frequencies of the variants are determined. The Brazilian population sample was compared with 28 population samples from different parts of the world.