Prevalence of GORD (gastro-oesophageal reflux disease) in Type 2 diabetes and a comparison of clinical profiles between diabetic patients with and without GORD.

AIMS: To examine the incidence of gastro-oesophageal reflux disease (GORD) and its associated factors in patients with Type 2 diabetes mellitus (Type 2 DM). METHODS: In 859 Type 2 DM outpatients, we conducted a QUEST inquiry and considered those showing a QUEST score of 4 or higher as having GORD. We surveyed clinical variables (physical findings, gender, age, duration of disease, glycated haemoglobin (HbA(1c)), type of oral glucose-lowering agent, presence or absence of insulin therapy, complications, and presence or absence of agents that may be associated with GORD [Ca channel blocker (CCB) anti-platelet agents]) to investigate their association with the onset of GORD. RESULTS: We analysed 813 subjects, of whom 56.6% were male. The mean age was 63.7 +/- 11.3 years and HbA(1c) 7.2 +/- 1.2%. The incidence of GORD was 29.0% (n = 221). GORD was positively correlated with body weight, body mass index (BMI) and HbA(1c). It was negatively correlated with age, serum creatinine and proportion of patients treated with pioglitazone or CCB. In addition, GORD was more common in females. The incidence of GORD was significantly higher in younger patients. CONCLUSIONS: Previous studies have suggested a relationship of GORD with pioglitazone/CCB. However, the results of this study do not support this; these agents may not induce GORD.

Iodinating activity of thyroid tissue in toxic diffuse goiter.

Thyroid tissue obtained from 12 patients with Graves' disease and treated with thionamide drugs for 3-7 mo before subtotal thyroidectomy, from 12 patients with Graves' disease, similarly treated, and given 50 mug of triiodothyronine (T3) for 10 days before surgery, and from 12 euthyroid patients with solitary cold nodules was investigated to compare in vitro iodination of thyroglobulin in toxic diffuse goiter and in normal thyroid tissue. The supernates of the homogenates (105,000g) were subjected to sucrose density gradient centrifugation (5--28%) to separate the thyroglobulin fraction. The precipitates were treated with 1% digitonin and centrifuged to collect the supernate (particulate fraction). When thyroglobulin and particulate fractions obtained from the same patient were incubated with 125I-, iodide, glucose, and glucose oxidase, the amount of iodine bound to thyroglobulin was several times greater in toxic diffuse goiter than in normal thyroid tissue; administration of T3 did not affect iodination in toxic diffuse goiter. When the thyroglobulin fraction from each patient was incubated with a standardized quantity of peroxidase instead of the individual particulate fraction, the amount of iodine bound to thyroglobulin was the same among the three groups of patients. Finally, when bovine serum albumin was substituted for thyroglobulin from each of the patients, iodination of bovine serum albumin was several times greater with the particulate fraction obtained from toxic diffuse goiter tissue than with that obtained from normal tissue. The guaiacol-oxidizing activity oty. These results suggest that in vitro iodination of thyroglobulin is increased in toxic diffuse goiter even when patients are made euthyroid by treatment with thionamide drugs as well as when they are given additional T3 for 10 days before operation. The increase in iodination of thyroglobulin appears to be due to an increase in peroxidase activity in the particulate fraction.

Inhibition of the accumulation of lipid droplets in macrophage J774 by bafilomycin B1 and destruxin E.

Two microbial metabolites, bafilomycin B1 and destruxin E, have been found to inhibit significantly the oxidized low density lipoprotein (LDL)-induced accumulation of lipid droplets at 3 nM and 0.5 microM, respectively, in macrophage J774. The incorporation of [14C]oleate into cholesteryl esters in the cells incubated with oxidized LDL was inhibited to the same extent by the two compounds. Both compounds had no effect on the cell surface binding at 4 degrees C and the internalization of oxidized 125I-LDL as well as on the activity of acyl-CoA:cholesterol acyltransferase. However, when incubated with these compounds at 37 degrees C, receptors for oxidized LDL were partially trapped within the cell. In accordance with receptor accumulation, ATP-dependent acidification of endosomes and lysosomes was significantly inhibited by 50 nM bafilomycin B1 and 1 microM destruxin E, respectively. From these results it was concluded that the inhibition of ATP-dependent acidification of endosomes and lysosomes by bafilomycin B1 and destruxin E resulted in the reduction of oxidized LDL-induced synthesis of cholesteryl ester and thereby caused a reduced accumulation of lipid droplets in macrophage J774.

Chlorpropamide-induced hyponatremia: incidence and risk factors.

The incidence and risk factors of chlorpropamide-induced hyponatremia were assessed in diabetic outpatients. In 176 chlorpropamide-treated patients, 11 (6.3%) exhibited hyponatremia (serum sodium less than or equal to 129 meq/L) during the mean follow-up period of 7.4 yr. In contrast, only one (0.6%) developed hyponatremia in 162 tolbutamide- or glibenclamide-treated patients (P less than 0.005). Moreover, administration to elderly patients and combination with thiazide diuretics were regarded as significantly potent risk factors for the development of hyponatremia in patients receiving chlorpropamide.

Epidermal growth factor stimulates growth hormone secretion from superfused rat adenohypophyseal fragments.

Epidermal growth factor (EGF) stimulated GH secretion from superfused rat adenohypophyseal fragments in a dose-related manner (8-50 ng/ml). Secretion of PRL or TSH was not affected by EGF at concentrations up to 50 ng/ml. These results indicate that EGF may be a specific secretagogue for GH in rats.

Changes in serum triiodothyronine, thyroxine, and thyrotropin during treatment with thyroxine in severe primary hypothyroidism.

Studies were performed on 40 patients with severe primary hypothyroidism, during treatment with varying doses of T4. Therapy was initiated with 50 mug/day and was continued for at least 2 months. Subsequent repeated increases of 25 mug/day were continued for at least 2 months until the serum TSH level was less than 10 muU/ml. Measurements of serum T4 and T3, RT3U, and serum TSH were carried out at monthly intervals. TRH tests were performed after TSH levels of less than 10 muU/ml had been attained and the dose of T4 had been maintained for at least 2 months. In most of the samples obtained during treatment with various doses of T4 (50-175 mug/day), serum T4 concentrations were within the normal range, even when patients were receiving only 50 mug/day of T4; however, approximately 60% of the samples had subnormal T3 concentrations. Fifty per cent of the samples had elevated TSH concentrations despite normal T4 levels, while only 7% of the samples with normal T3, as well as T4, levels had slightly elevated TSH concentrations. Similar relationships were observed between serum TSH and free T4 indices and free T3 indices. Among patients with serum TSH levels of less than 10 muU/ml, none showed subnormal T4 concentrations, while subnormal T3 concentrations were found in some of them. Hyper-response to TRH was noted in patients with subnormal T3 levels, and normal responses were observed in patients with normal T3 and T4 concentrations. These data indicate that, during the treatment of hypothyroidism with T4, 1) normal basal TSH correlates better with normal serum T4 and T3 than with normal T4 alone, 2) the response of TSH to TRH is supranormal in patients with subnormal T3 levels, in spite of normal basal TSH and T4, and 3) the calculated maintenance dose of T4, which is associated with a normal TRH response, is 2.08 mug/day/kg of body weight.

Endocrine and immunohistochemical studies on thyrotropin (TSH)-secreting pituitary adenomas: responses of TSH, alpha-subunit, and growth hormone to hypothalamic releasing hormones and their distribution in adenoma cells.

Endocrine and immunohistochemical studies were performed in two cases of TSH-secreting pituitary adenomas. The patients had elevated serum TSH and alpha-subunit concentrations despite high serum thyroid hormone levels. In addition, one patient (no. 1) had elevated serum GH levels with clinical evidence of acromegaly. GH-releasing hormone infusion increased serum levels of TSH, alpha-subunit and GH in the two patients. TRH injection increased serum TSH levels in both patients and, concomitantly, serum alpha-subunit and GH levels in patient 1. Basal TSH levels and their responses to TRH changed reciprocally to changes in serum thyroid hormone levels, although TRH-induced GH release did not. The administration of GnRH also increased serum TSH, alpha-subunit, and GH levels in patient 1. In accordance with these in vivo results, pituitary adenoma cells in culture obtained from patient 1 responded to GH-releasing hormone, TRH, or GnRH to secrete TSH, alpha-subunit, and GH. Incubation of cells with dexamethasone resulted in inhibition of TSH and stimulation of GH secretion without a significant change in alpha-subunit secretion. On the basis of light microscopic and electron microscopic double gold immunohistochemistry, the tumor from patient 1 was a bimorphous adenoma composed of two separate cell types: cells with TSH beta-subunit (TSH beta) and alpha-subunit, and those with GH and alpha-subunit. The remainder consisted mainly of cells with TSH beta and alpha-subunit. The coproduction of the unusual combination of two hormones such as GH and alpha-subunit in a single-type of adenoma cell and the coexistence of thyrotrophs and somatotrophs in one pituitary adenoma along with the aberrant responses of TSH beta, alpha-subunit, and GH to multiple hypothalamic hormones suggest the dedifferentiation of pituitary cells to multipotential progenitor cells by neoplastic transformation.

Effects of fasting, refeeding, and fasting with T3 administration on Na-K,ATPase in rat skeletal muscle.

It is known that Na-K,adenosine triphosphatase (ATPase) in cell membranes represents an important consumer of cellular energy, eg, adenosine triphosphate (ATP), and that the concentration and activity of this enzyme change in a dose-dependent manner with serum thyroid hormone levels. To examine the hypothesis that low triiodothyronine (T3) syndrome represents a cellular adaptation in generalized severe illnesses that saves tissue energy expenditure, we measured the muscle Na-K,ATPase concentration and its activity in rats that led to low T3 syndrome induced by fasting. The Na-K,ATPase concentration was measured by 3H-ouabain binding to soleus muscle, and its activity was measured by 42K uptake in the contralateral soleus muscle. The effects of refeeding or T3 administration on Na-K,ATPase in soleus muscle in fasted rats were also examined. Na-K,ATPase concentration and activity were both increased in hyperthyroid rats and decreased in hypothyroid rats. In the fasting state, they were decreased to as low as the levels seen in hypothyroidism. Furthermore, with fasting + refeeding or fasting + T3 administration, Na-K,ATPase in soleus muscle returned to the normal level. These results suggest that tissue energy expenditure, as assessed by Na-K,ATPase, in skeletal muscles of fasted rats with low T3 syndrome is actually decreased to levels seen in hypothyroidism, due at least partly to the decrease in serum T3 concentrations, and that there exist some adaptation mechanisms in the peripheral tissues for the accommodation of energy metabolism in the body through decreased thyroxine (T4) to T3 conversion.

Characteristics of cranial nerve palsies in diabetic patients.

The incidence of palsy in the third, sixth and seventh cranial nerves was studied with regard to central nervous system involvement in diabetic patients. Among 1961 diabetic patients, 19 (0.97%) demonstrated cranial nerve palsies. Nine out of these 19 patients showed facial palsy; 6 palsy of the oculomotor nerve; 2 palsy of the abducent nerve; and 3 both oculomotor and abducent nerve palsies. In contrast, only 5 out of 3841 non-diabetic patients (0.13%) had any cranial nerve palsies; all 5 were cases of facial palsy. The incidence of cranial palsies in diabetic patients was significantly higher than that in non-diabetic patients (P less than 0.01). Concerning age, sex, the state of glycemic control, diabetic complications and method of treatment, there were no differences disclosed in the diabetic patients with cranial nerve palsy. The incidences of diabetic complications were compared between the patients with facial palsy and those with ophthalmoplegia. Only one out of 9 patients with facial palsy (11%) had diabetic complications, whereas 7 out of 10 patients with ophthalmoplegia (70%) demonstrated diabetic complications and the difference was significant. Thus ophthalmoplegia appears to be more closely related to diabetic metabolism while facial palsy is less strongly correlated with diabetes.

Hyperproinsulinemia in Japan.

Four families with hyperproinsulinemia found in Japan were described. The details of the first case, who was investigated by Kanazawa et al., were reported and the similarity of the first case to the following cases was shown. Arginine 65 of the proinsulin molecule might be a hot spot of the insulin gene. A possible abnormality of insulin release in affected individuals was disclosed by investigation of the family members of the first case.

Serum gliclazide concentration in diabetic patients. Relationship between gliclazide dose and serum concentration.

Serum levels of gliclazide were determined by radioimmunoassay in seven healthy controls and in 18 diabetic in-patients receiving single oral dosing and consecutive dosing over 5 days. Following a single oral dose of 40 mg in the seven controls and eight diabetic patients, and 120 mg in ten diabetic patients, the serum levels of gliclazide peaked on average at 2 h, followed by a slow decline, the t1/2 being 16.5 h in the volunteers, 12.3 h in the diabetic patients receiving 40 mg, and 10.5 h in those receiving 120 mg. During consecutive administration, the serum levels both at fasting and at the peak reached a plateau in 2 days and no further accumulations were observed. The steady-state peak levels of gliclazide in the diabetic patients revealed a strongly positive correlation with the dose per m2 body surface area (r = 0.78, P less than 0.001), and their steady-state fasting levels correlated positively but weakly with the dose per m2 body surface area (r = 0.48, P less than 0.05). Thus, measuring either the fasting or the peak concentration of gliclazide will be useful for monitoring drug concentration in the serum. Pharmacokinetics of gliclazide will contribute to the elucidation of the relationship of serum level and clinical effectiveness in diabetic subjects.

Peroxidatic degradation and ether link cleavage of thyroxine in a particulate fraction of human thyroid.

The present study was undertaken to investigate degradation of thyroxine (T4) mediated by thyroid peroxidase in man. A particulate fraction (1,000-100,000 x g) of normal human thyroid tissue was prepared and used as crude enzyme. 125I-T4 and unlabeled T4 were incubated with the particulate fraction in buffer containing glucose and glucose oxidase for generation of H2O2. After incubation, iodoamino acids were extracted with ethanol and the products of T4 degradation were analyzed by thin layer chromatography. In this system, T4 was degraded in time-, temperature- and pH-dependent manners, but not in the absence of the H2O2-generating system. The rate of degradation was related to concentration of the particulate fraction. The reaction was inhibited by methimazole, propylthiouracil and catalase. When [3',5'-125I] T4 was used as a tracer, major labeled products of T4 degradation were inorganic iodide and ethanol-unextracted fraction and no detectable labeled 3,5,3'-triiodothyronine (T3) or 3,3',5'-triiodothyronine (rT3) was generated. From a kinetic study by adding various doses of unlabeled T4, the apparent Km value for T4 was 30 microM and the Vmax value was 230 pmol/mg protein/min. When [3,5-125I] T4 was incubated with enzyme preparation, one third of degraded T4 was recovered as diiodotyrosine (DIT) and half of 125I-DIT was degraded in parallel incubation. No formation of radiolabeled DIT was observed in incubation with Na- 125I done in tandem. These findings suggest that thyroid hormones can be metabolized by peroxidase in human thyroid by pathways that include cleavage of ether linkage.

Big insulin-like growth factor II-producing hepatocellular carcinoma associated with hypoglycemia.

A 76-year-old female with a hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) was hospitalized because of fasting hypoglycemia. Her sera contained a low concentration of immunoreactive insulin and insulin-like growth factor (IGF)-I, while the IGF-II level was normal. However, most of the IGF-II consisted of the high molecular weight form (big IGF-II). The tumor tissue contained fetal type of IGF-II mRNA (6.0 kb). Furthermore, we found that one of the four patients examined with HCV-related HCC had big IGF-II in serum. This indicates that non-islet cell tumor hypoglycemia (NICTH) in HCV-related HCC might be accompanied by production of big IGF-II by the tumor.

[A pedigree with maternally transmitted diabetes mellitus, deafness and cardiomyopathy].

A pedigree with maternally transmitted diabetes mellitus, deafness, and cardiomyopathy is described. A A-->G mutation at nucleotide pair 3243 in mitochondrial gene was detected by Apa I digestion of PCR amplified genomic DNA from 3 brothers and their mother. The proband, suffering from CHF, showed unique fine granular pattern of hyperechogenic cardiomyopathy as his brother and their mother did. Although he is recently treated with insulin, he was initially NIDDM treated by sulfonylurea. His urinary CPR excretion decreased gradually to as low as less than 10 micrograms/day in these 3 years. The insulin response to oral glucose was decreased in all other family members with the mutation. It is suggested that the defective insulin secretion exists in this family with the mutation and the progressive decrease in insulin secretion might resulted in IDDM in the proband.