[Familial aggregation and HLA typing of pedigrees in insulin-dependent diabetes mellitus].

In 280 patients with IDDM, the positive family history of diabetes was 26.8% of IDDM probands. The prevalence of diabetes in relatives was 68% in first degree relatives, 28% in second degree relatives, and 4% in third degree relatives. HLA typing of 87 members in 13 pedigrees with IDDM was performed. These data support the hypothesis that IDDM is a multigenic hereditary disorder.

[Investigation of the form of onset in 139 cases of insulin-dependent diabetes mellitus].

A retrospective study of 139 cases of IDDM patients (male 54 cases, female 85 cases) were investigated. Average age 31.74 +/- 12.20 yr. One third of all patients had virus infection before the onset of IDDM and the infection in upper respiratory system and intestine occupied most of the cases (85%). In two cases, the onset of the disease was induced after BCG vaccination. There is no relationship between virus infection and the occurrence of DKA as primary form of onset. The average age in the group of positive virus infection is significantly younger than in the group of negative virus infection (P < 0.02). About one fourth of all cases had positive family history of diabetes which is much higher than the similar reports in Western countries.

Activation of alpha 2-adrenergic receptors decreases Ca2+ influx to inhibit insulin secretion in a hamster beta-cell line: an action mediated by a guanosine triphosphate-binding protein.

Activation of the sympathetic nervous system inhibits insulin secretion. We tested the hypothesis that activation of alpha 2-adrenergic receptors on the beta-cell by epinephrine or clonidine attenuates insulin release by an effect on the voltage-dependent Ca2+ channel (VDCC) and examined the role of G-proteins in this signal transduction pathway. Using a cultured SV40-transformed hamster beta-cell line (HIT cells) as a model system, we determined the effect of alpha 2-adrenergic agonists on insulin secretion, 86Rb+ efflux (a marker for K+ channel flux), and the free cytosolic Ca2+ level [( Ca2+]i) monitored in fura-2-loaded cells. In a dose-dependent manner, epinephrine and clonidine (10(-8)-10(-5)M) attenuated the increase in [Ca2+]i and insulin secretion induced by either K+ depolarization or stimulation of the VDCC with the agonist Bay K 8644. Epinephrine failed to affect the rise in [Ca2+]i induced by carbamylcholine, an agent that mobilizes intracellular Ca2+. Epinephrine also did not changes 86Rb+ efflux from HIT cells. The inhibitory effects of epinephrine were prevented by the alpha 2-adrenergic antagonist idazoxan, but were unaffected by the alpha 1-adrenergic antagonist phenoxybenzamine. Pretreatment of HIT cells with pertussis toxin (0.1 micrograms/ml) overnight abolished the inhibitory effects of epinephrine and clonidine on both [Ca2+]i and insulin secretion. These data suggest that one mechanism by which alpha 2-adrenergic agonists inhibit insulin secretion is by inhibiting Ca2+ influx through VDCC, an action that is mediated through a pertussis toxin-sensitive G-protein.

Sulfonylurea signal transduction.

In the pancreatic beta cells the proximal step in sulfonylurea signal transduction is the binding of these clinically important drugs to high-affinity receptors in the beta cell membrane. Using HIT cells as a model system, we have established an extremely close correlation between the affinity of binding of glyburide and its analog, iodoglyburide, and the activation of various steps in stimulus-secretion coupling--inhibition of 86Rb+ efflux, increase in [Ca2+]i resulting from gating of voltage-gated calcium channels by cell depolarization, and the exocytosis of insulin. Two different L-type channel cDNAs have been identified in an HIT cell library, one neuroendocrine in type and one more cardiac-like. A HIT cell membrane protein of Mr 140,000, which we believe to be the high-affinity sulfonylurea receptor, can be covalently linked to 5(125)-iodo-2-hydroxyglyburide by ultraviolet irradiation. The receptor has been solubilized and retains binding activity and the same rank order of displacement of the 5(125)-iodo-2-hydroxyglyburide as observed with the native receptor. The Mr 140,000 protein has been partially purified and the amino acid sequences of three proteolytic fragments have been used to design oligonucleotides to screen HIT cell cDNA libraries. Since the binding constant of glyburide or iodoglyburide is closely correlated with the ability of these compounds to inhibit the ATP-sensitive K+ channel, increase [Ca2+]i, and elicit insulin secretion, we have identified the Mr 140,000 protein as the sulfonylurea receptor. Expression of the cloned cDNA should allow us to test this hypothesis directly.

Somatostatin inhibits insulin secretion by a G-protein-mediated decrease in Ca2+ entry through voltage-dependent Ca2+ channels in the beta cell.

We tested the hypothesis that somatostatin (SRIF) inhibits insulin secretion from an SV40 transformed hamster beta cell line (HIT cells) by an effect on the voltage-dependent Ca2+ channels and examined whether G-proteins were involved in the process. Ca2+ currents were recorded by the whole cell patch-clamp method, the free cytosolic calcium, [Ca2+]i, was monitored in HIT cells by fura-2, and cAMP and insulin secretion were measured by radioimmunoassay. SRIF decreased Ca2+ currents, [Ca2+]i, and basal insulin secretion in a dose-dependent manner over the range of 10(-12)-10(-7)M. The increase in [Ca2+]i and insulin secretion induced by either depolarization with K+ (15 mM) or by the Ca2+ channel agonist, Bay K 8644 (1 microM) was attenuated by SRIF in a dose-dependent manner over the same range of 10(-12)-10(-7) M. the half-maximal inhibitory concentrations (IC50) for SRIF inhibition of insulin secretion were 8.6 X 10(-12) M and 8.3 X 10(-11) M for K+ and Bay K 8644-stimulated secretion and 1 X 10(-10) M and 2.9 X 10(-10) M for the SRIF inhibition of the K+ and Bay K 8644-induced rise in [Ca2+]i, respectively. SRIF also attenuated the rise in [Ca2+]i induced by the cAMP-elevating agent, isobutylmethylxanthine (1 mM) in the presence of glucose. Bay K 8644, K+ and SRIF had no significant effects on cAMP levels and SRIF had no effects on adenylyl cyclase activity at concentrations lower than 1 microM. SRIF (100 nM) did not change K+ efflux (measured by 86Rb+) through ATP-sensitive K+ channels in HIT cells. SRIF (up to 1 microM) had no significant effect on membrane potential measured by bisoxonol fluorescence. Pretreatment of the HIT cells with pertussis toxin (0.1 microgram/ml) overnight abolished the effects of SRIF on Ca2+ currents, [Ca2+]i and insulin secretion implying a G-protein dependence in SRIF's actions. Thus, one mechanism by which SRIF decreases insulin secretion is by inhibiting Ca2+ influx through voltage-dependent Ca2+ channels, an action mediated through a pertussis toxin-sensitive G-protein.

[Effect of rifampin on the metabolism of glucocorticoids in Addison's disease].

To investigate the effect of rifampicin on the metabolism of hydrocortisone, we measured serum sodium level and blood glucose concentration before lunch in a patient with Addison's disease when treated with hydrocortisone 30 mg/day alone and together with rifampicin 450 mg/day for more than two weeks. We also studied the area under the plasma cortisol curve (AUC), half-life (T 1/2) and clearance rate (CLs) of hydrocortisone after both oral ingestion and intravenous injection of 20 mg hydrocortisone. The results showed that rifampicin increased the metabolism of cortisol by shortening of its T 1/2, increasing its CLs and decreasing its AUC. It decreases the blood sodium level and glucose concentration and makes the patient liable to have hypoglycemic symptoms before lunch. We conclude that the increase of metabolism of cortisol after simultaneous taking of rifampicin may induce adrenal crisis in Addison's disease.

[Clinical study of fifty cases of Klinefelter's syndrome].

The authors report the clinical manifestations of 50 cases of Klinefelter's Syndrome proven by chromosome studies. The number of cases with the genotype of 47 XXY, 46 XY/47 XXY, 46 XX/47 XXY and 48 XXXY were 42, 6, 1 and 1 respectively. The chief complaint of 68% of the patients was maldevelopment of sex and that of 26% was gynecomastia. One fourth of the patients was born when their mothers' age already exceeded 35. About 1/5 had low intelligence. Secondary sexual characteristics were absent in all the patients. About 2/5 had gynecomastia. The average testicular volume was 4.0-1.3 ml, but no sperm was found in their semen. Their serum testosterone concentration decreased to 5.4 +/- 5.3 mM/L, but the serum TeBG, FSH and LH levels were significantly increased to 66.8 +/- 22.0 nM/L, 24.7 +/- 7.1 IU/L and 12.3 +/- 7.3 IU/L.

[Effect of testosterone preparations on the function of the hypothalamic pituitary axis in Klinefelter's syndrome].

This article prospectively observed the suppressive effects of the testosterone preparations on the elevated gonadotropin levels in Klinefelter's syndrome (KS). After sublingual administration of methyl testosterone 5 mg Bid, the serum T levels increased 97 and 126 ng/ml respectively in 6 normal men and 9 patients of KS and the serum FSH and LH levels did not changed significantly. After intramuscular injection of testosterone propionate 25 mg 3/week testovirone 100 mg 1/10 days and testosterone enanthate 200 mg/20 days, the serum T levels increased significantly both in 6 normal mon and 17 patients with KS. It took about 1 month for the LH levels to decrease to normal range and 3-6 months for the FSH levels to become normal. Our result indicates that it is necessary to treat the KS patients for long period to normalize the increased hypothalamic pituitary function.