Diabetes mellitus is a devastating disease and over 6% of the population is affected worldwide. The success achieved over the last few years with islet transplantation suggest that diabetes can be cured by the replenishment of deficient β cells. These observations are proof of concept and have intensified interest in treating diabetes or other diseases not only by cell transplantation but also by stem cells. Work with ES cells has not yet produced cells with the phenotype of true β cells, but there has been recent progress in directing ES cells to the endoderm. Bone marrow-derived stem cells could initiate pancreatic regeneration. Pancreatic stem/progenitor cells have been identified, and the formation of new β cells from duct, acinar and liver cells is an active area of investigation. Some agents including glucagon-like peptide-1/exendin-4 can stimulate the regeneration of β cells in vivo. Overexpression of embryonic transcription factors in stem cells could efficiently induce their differentiation into insulin-expressing cells. New technology, known as protein transduction technology, facilitates the differentiation of stem cells into insulin-producing cells. Recent progress in the search for new sources of β cells has opened up several possibilities for the development of new treatments for diabetes.

View full abstract

Selective arterial calcium stimulation and hepatic venous sampling (ASVS) for insulin secretion is used as a diagnostic procedure in patients with insulinomas or adult nesidioblastosis. In some of those patients, severe hypoglycemia requiring urgent glucose administration occurs during the procedure. Such glucose administration, however, may affect the results and damage the validity of the test. We report two cases of hyperinsulinemic hypoglycemia, in which ASVS tests were successfully performed under hyperinsulinemic euglycemic glucose clamps. A 40-year-old male with nesidioblastosis developed continual severe hypoglycemia several years after a Billroth II-Braun gastrectomy, and continuous glucose infusion could not be stopped even during ASVS tests. A 9-year-old girl with an insulinoma that showed atypical hypovascularity on imaging examinations had ASVS tests under a glucose clamp for safety. Hyperinsulinemic (≈100 μU/ml) euglycemic (≈90 mg/dl) clamps were achieved by an artificial endocrine pancreas. The insulin analogue lispro was utilized for clamps and endogenous insulin was measured with an assay that does not cross-react with the analogue. Diagnostically significant responses (more than twofold) of insulin secretion were observed under hyperinsulinemic clamps in both cases. The use of the hyperinsulinemic glucose clamp technique during the ASVS test should be considered for maintaining the safety of some hypoglycemic patients.

View full abstract

A variety of thyroid disorders develop following external radiation to head and neck cancers. Hypothyroidism is the most common clinical consequence of the radiotherapy and lifelong thyroid hormone replacement is required in many cases. Patients who received both hemithyroidectomy and the external radiation to the neck are at especially high risk for permanent hypothyroidism. Here we report an unusual case with radiation-induced hypothyroidism who had undergone hemithyroidectomy for adenomatous goiter 8 years before the radiotherapy for nasopharyngeal cancer and subclinical hyperthyroidism due to Graves' disease developed during thyroxine replacement therapy. Thus subclinical hyperthyroidism due to Graves' disease can develop in patients with radiation-induced hypothyroidism even if they have undergone hemithyroidectomy for thyroid nodules. Therefore careful and periodic evaluation of thyroid function is required even on adequate thyroxine replacement therapy.

View full abstract

The relation between the incidence of methimazole (methylmercaptoimidazole; MMI)-induced agranulocytosis and initial MMI dose was evaluated in a group of 514 patients with Graves' disease who were treated between 1995 and 2005. One hundred and forty-six (28.40%) patients had received an initial dose of 30 mg MMI and 277 (53.89%) patients had been treated with 15 mg MMI. Nine patients (1.75%) developed agranulocytosis due to MMI treatment. Six (4.11%) of 146 patients who received an initial dose of 30 mg MMI, two (4.54%) of 44 patients given an initial dose of 20 mg MMI, and one (0.36%) of 277 patients given an initial dose of 15 mg MMI developed agranulocytosis. There was a statistically significant difference in agranulocytosis incidence between patients receiving an initial dose of 30 mg MMI and those who received an initial dose of 15 mg. Although 8 (4.10%) of 195 patients in the high-dose group (20 mg or higher) developed agranulocytosis, only 1 (0.31%) of 319 patients in the low-dose group (15 mg or lower) did. In conclusion, the incidence of agranulocytosis with low-dose MMI therapy was ten times lower than that of the high-dose regimen.

View full abstract

The influence of hypothyroidism on haemostasis is an active research area. Not only bleeding tendency but also hypercoagulable states have been reported in hypothyroid patients. Decreased and increased fibrinolytic activity in hypothyroid patients has been shown in several studies. Thrombin activatable fibrinolysis inhibitor (TAFI) is an inhibitor of fibrinolysis, which has been recently isolated from human plasma. The aim of our study was to determine plasma TAFI antigen levels in overt and subclinical hypothyroidism, and to investigate the effect of levothyroxine treatment on TAFI levels. The study was performed in age- and sex- matched 30 overt hypothyroid, 30 subclinical hypothyroid patients, and 30 healthy controls. Blood samples were obtained from patients with overt and subclinical hypothyroidism before levothyroxine replacement, and one month after achieving a euthyroid state with levothyroxine. TAFI antigen levels were measured using Enzyme-Linked ImmunoSorbent Assay kits (Affinity Biologicals; Ontario, Canada). In baseline evaluation both the overt and subclinical hypothyroid groups had higher TAFI antigen levels than control group (p<0.05). High levels of TAFI antigen were correlated with the degree of thyroid failure. After achieving euthyroid state with levothyroxine replacement, TAFI antigen levels decreased significantly in patients with overt and subclinical hypothyroidism (p<0.05). Our data suggest that there are elevated plasma levels of TAFI antigen both in overt and subclinical hypothyroidism, which may be associated with hypofibrinolysis and elevated risk of thrombosis. Normalization of thyroid state by levothyroxine replacement seems to be effective in lowering of TAFI antigen levels in hypothyroidism.

View full abstract

Colestimide is a new anion-exchange resin used to lower serum cholesterol in Japan. Because of its excellent compliance, colestimide can replace cholestyramine. To clarify the effect of colestimide on glycemic controls, colestimide (3 g/day) or pravastatin (10 mg) was given orally to patients with type 2 diabetes treated with oral hypoglycemic agents or insulin who had low-density lipoprotein (LDL) cholesterol levels exceeding 3.6 mmol/l. In the colestimide groups, fasting plasma glucose concentrations had decreased significantly from 8.5 ± 1.4 to 7.7 ± 1.5 mmol/l at 3 months (P<0.05), as had glycated hemoglobin (HbA_1c) from 7.7 ± 0.7% to 6.8 ± 0.5%, for an 8% reduction (P<0.01). Fasting plasma glucose and HbA_1c did not change in the pravastatin group. Total cholesterol and LDL-cholesterol decreased significantly (P<0.01) with either medication, with similar reduction rates for both drugs. Doses of oral hypoglycemic agents and insulin did not change during the study, and body weight remained stable. Considering that patients with type 2 diabetes often have hyperlipidemia, colestimide therapy may have a clinically useful dual action in such patients.

View full abstract

We report here the case of a 34-year-old female with puerperal alactogenesis. Her menstrual cycle was regular and breast development normal. She had delivered a healthy boy but could not breast-feed after parturition. Endocrinological studies disclosed that the cause was a prolactin (PRL) deficiency. In addition, she showed accompanying impaired ACTH secretion that was believed to be triggered by encephalitis, although her plasma levels of GH, TSH, LH and FSH remained intact. Pituitary MRI showed no specific findings and anti-pituitary antibody tests were negative. Interestingly, both her mother and grandmother also reported puerperal alactogenesis. The sequences of all five exons of the PRL gene, including promoter region and transcription initiation point, were surveyed in order to examine for certain genetic disorders, but no mutations were identified. Although it cannot be definitively concluded that this PRL deficiency was not a genomic DNA disorder, in our case at least, her PRL gene was normal and, therefore, was not directly responsible for the patient's impaired PRL secretion. This evidence suggests that familial puerperal alactogenesis and PRL deficiency can be induced by other causes such as via disorders of unknown transcription factors or molecules that contribute to translation of PRL gene.

View full abstract

Angiogenesis is a process of new blood vessel development from pre-existing vasculature. It is a crucial process in normal physiology, as well as in several pathological conditions. The vascular endothelial growth factor (VEGF) represents a family of specific endothelial cell mitogens, involved in normal angiogenesis and in tumour development. The aim of the present study was to estimate the influence of L-thyroxine (L-T₄) administration on poor-platelet plasma (P-PP) VEGF concentrations in patients with induced short-term hypothyroidism, monitored for differentiated thyroid carcinoma. In the present study, P-PP concentrations of VEGF, thyroglobulin, thyrotropin and free thyroid hormones were investigated in a population of 24 hypothyroid patients, who were withdrawn from L-T₄ treatment for 5 weeks and studied before and after 2 months of L-T₄ therapy. Only healthy female patients with no evidence of metastasis in whole body scintigraphy were included in the study. They were then compared with 20 healthy control subjects, matched for age, sex and body mass index (BMI). The patients had significantly lower plasma VEGF concentrations before treatment with L-T₄ than after administration of that hormone. There was no significant difference in plasma VEGF levels, either between the patients treated with L-T₄, and the controls, or between the patients untreated with L-T₄, and the controls. Even short-time changes in thyrometabolic profile exert an important influence on P-PP VEGF concentrations, even if there is no thyroid tissue.

View full abstract

Subclinical hypothyroidism (SCH) is a prevalent condition among adult population, however it is frequently overlooked. Thyroid functions affect metabolic syndrome (MetS) parameters including HDL cholesterol, triglycerides, blood pressure and plasma glucose. On the other hand, the relation between MetS and thyroid dysfunction is not clearly identified yet. The aim of the present study was to investigate the prevalence of SCH among MetS patients and to identify its relation with MetS parameters. Two hundred and twenty MetS patients (MetS group; 167 female, 53 male, mean age: 48.5 ± 11.3) and 190 patients without MetS (Control group; 142 female, 48 male, mean age: 46.3 ± 11.9) attending consecutively to Internal Medicine outpatient clinics were included in this study. Groups were compared in terms of SCH prevalence. SCH was defined as a condition with high thyrotrophin and normal free thyroxine levels. SCH was found in 36 (16.4%) cases in the MetS group and in 11 (5.8%) cases in the control group (p = 0.001). Only female gender was associated with the presence of SCH. About one sixth of MetS patients had SCH. This finding indicates a need for investigating the presence of SCH during the management of MetS patients.

View full abstract

APS, a tyrosine kinase adaptor protein with pleckstrin homology and Src homology 2 domains, is rapidly and strongly tyrosine-phosphorylated by insulin receptor kinase upon insulin stimulation. We have previously shown that APS knockout mice have increased insulin sensitivity, and that this enhancement is possibly due to increased insulin-response on adipose tissues. However, the function of APS in insulin signaling has so far been controversial. Here, we report that APS enhanced ligand-dependent multi-ubiquitination of the insulin receptor (IR) in CHO cells overexpressing the IR. APS-mediated ubiquitination of the IR induced enhancement of the IR internalization, but did not affect the IR degradation. This finding shows one of the pleiotropic functions of APS in insulin signaling.

View full abstract

Obesity is a growing problem and is associated with numerous medical conditions. In several genes coding for molecules involved in the regulation of body weight (fat mass) and thermogenesis, polymorphisms have been reported which possibly modify human obesity risk. The aim of this study was to determine the incidence of the following polymorphisms in the following genes in 262 obese (BMI≥30) and 138 control (BMI≤25) subjects: leptin receptor (LEPR)-Gln223Arg, B₃-adrenergic receptor (B₃-AR)-Trp64Arg, serotonin transporter (5-HTT)-a 44-base pair insertion/deletion functional polymorphism in the 5-HTTLPR and insulin receptor substrate-1 (IRS-1)-Gly972Arg. Our hypothesis was that these polymorphisms would occur more frequently in the obese population. The polymorphisms were determined by polymerase chain reaction (PCR) and restriction genotyping in study population. In our results, no strong associations were observed between BMI status and these polymorphisms. Weak, though significant, association coefficients obtained with HTT and LEPR loci indicate that the genotype numbers at these loci may depend on BMI status to some extent.

View full abstract

In some patients with insulinoma, surgery is not possible due to either difficulties in detecting the tumor or advanced age. These patients need medical treatment for hypoglycemia. We report a case of benign insulinoma using the long-acting octreotide formulation, octreotide long-acting repeatable (octreotide LAR), as a medical therapy. A 67-year-old woman was referred to our hospital for examinations of hypoglycemia. A blood sample taken during a hypoglycemic episode revealed low plasma glucose concentration, hyperinsulinemia and a high C-peptide level. An abdominal CT scan demonstrated a hypervascular tumor in the body of pancreas. She was diagnosed with insulinoma. As the patient refused surgical resection of the pancreas tumor, we started to use the somatostatin analogue, octreotide, for treatment of hypoglycemia. After the treatment her plasma glucose levels were elevated and serum immunoreactive insulin (IRI) levels were decreased. For long-term treatment, we changed the treatment from daily subcutaneous injection of octreotide to monthly intramuscular administration of octreotide LAR. This treatment was also effective and hypoglycemic attacks disappeared. Both plasma glucose levels and serum IRI levels were improved. Our case demonstrated that octreotide LAR was useful for long-term medical treatment of insulinoma.

View full abstract

We investigated the effect of arginine vasopressin (AVP) on inorganic phosphate (Pi) transport in A-10 rat aortic vascular smooth muscle cells (VSMCs). AVP time- and dose-dependently stimulated Na-dependent Pi transport in A-10 cells. This stimulatory effect of AVP on Pi transport was markedly suppressed by V1 receptor antagonist. A protein kinase C (PKC) inhibitor calphostin C partially suppressed the stimulatory effect of AVP. The selective inhibitors of c-Jun-NH₂-terminal mitogen-activated protein (MAP) kinase (Jun kinase) attenuated AVP-induced Pi transport, but Erk kinase or p38 MAP kinase inhibitors did not. Wortmannin, a phosphatidylinositol (PI) 3-kinase inhibitor, suppressed AVP-induced Pi transport. Rapamycin, a selective inhibitor of S₆ kinase, reduced this effect of AVP, while Akt kinase inhibitor did not. The combination of inhibitors for PKC, Jun kinase and PI 3-kinase completely suppressed the AVP-enhanced Pi transport. Furthermore, AVP rescued the VSMC from high phosphate-induced cell death and enhanced mineralization of these cells. In summary, these results suggest that AVP stimulates both Na-dependent Pi transport and mineralization in VSMCs. The mechanism is mediated by the activation of multiple signaling pathways including PKC, PI 3-kinase, S₆ kinase and Jun kinase.

View full abstract

Insulinoma is the most common cause of fasting hypoglycemia resulting from autonomous insulin hypersecretion. A 59-year-old woman who had previously had an insulinoma and had undergone a partial pancreatectomy was admitted to our hospital because of recurrence of hypoglycemia after 27 years. She had two unusual endocrinological features: 1) the serum insulin response to intravenous secretin injection was not impaired, and 2) the serum C-peptide levels and ratios of serum C-peptide to insulin were relatively low. Two pancreatic tumors were readily detectable by computed tomography (CT) and magnetic resonance imaging (MRI). The selective arterial calcium injection (SACI) test showed a hyperinsulinemic response by calcium administration to the gastroduodenal artery. A partial pancreatectomy was done and her hypoglycemia disappeared. Histology revealed that the tumors were composed of monotonous, small round cells that were positive for both insulin and cathepsin B. As previous in vitro studies have shown that C-peptide can be metabolized within human insulinoma cells by proteolytic cleavage by cathepsin B, our patient's low serum C-peptide levels might have been caused by degradation of C-peptide by cathepsin B. According to the data from the literature, the molar ratio of serum C-peptide to insulin is generally decreased in patients with insulinoma than normal subjects. This case highlights the need for careful interpretation of C-peptide levels and the intravenous secretin injection test in the diagnosis of insulinoma.

View full abstract

The rodent prostate has a complex structure, consisting of a ventral prostate (VP), lateral prostate (LP), dorsal prostate (DP) and anterior prostate (AP), and most studies so far have focused on the VP. Androgen-responsive prostatic secretory proteins, such as prostatein and kallikreins, are mainly produced in the VP, but others are abundant in the LP and DP, though little is known about differences of androgen regulation among the different lobes. Here, the mRNA expression levels of some representative androgen-responsive genes, including those encoding prostatic secreted proteins, were quantitatively determined in each of the prostatic lobes of intact rats and castrated rats treated with testosterone alone or plus flutamide. The results show that the transcriptional regulation of prostatic secretory proteins differs greatly among lobes, generally being more tightly regulated in the VP. A number of growth factor mRNAs were differentially expressed in separate lobes and were regulated by testosterone in a lobe-specific manner. Lobe-specific regulation by androgen was also found for other genes, including the DAD-1 and calreticulin genes. Thus, hormone-dependent transcriptional regulation of prostate genes differs among lobes, and there is also interlobar diversity of basal mRNA expression levels.

View full abstract

In TSH-secreting pituitary adenomas (TSHoma), octreotide (OCT) therapy reduces tumor size and TSH secretion in some cases but not in others. As OCT acts through various types of somatostatin receptors (SSTRs), the different responses of TSHoma to OCT might be explained by the differences of SSTR expression. We therefore studied the expression of subtype-specific SSTR mRNA transcripts in tumor tissues by RT-PCR. Type 2 (SSTR2) mRNA transcripts were detected in all 8 tumors but those of SSTR3 and SSTR5 were demonstrated only in 5 of them. Serum TSH levels were decreased by OCT administration test in all patients but OCT therapy was effective in two patients out of three. SSTR5 mRNA was detected in two tumors from the responder, but not in one tumor that was resistant to OCT. These observations suggest that the temporal decrease of TSH by OCT may be mediated by SSTR2, and that the long term response to OCT therapy may be related with the expression of SSTR5. Therefore, the expression of SSTR5 in TSHoma may be a useful marker for predicting the outcome of the therapy, but further studies with larger numbers of patients are necessary.

View full abstract

We studied the cross-sectional relationship between GA and HbA1c in 142 type 2 diabetic patients who had an HbA1c level <7.5% for at least one year without fluctuation by more than 0.5%. We also followed the changes of GA and HbA1c in 18 type 2 diabetic patients for 16 weeks as they progressed from untreated severe hyperglycemia (HbA1c≥9.0%) to good glycemic control (HbA1c≤6.5%) by intensive insulin treatment. The annual mean levels of GA and HbA1c in the stably controlled patients showed a weak, but significant, correlation (r = 0.23, p<0.001) in the 142 diabetic patients. However, the GA/HbA1c ratio ranged widely from 2.0 to 4.0 showing a normal distribution (2.9 ± 0.34, M ± SE), although patients with conditions affecting albumin turnover or RBC lifespan were excluded from the study. The GA/HbA1c ratio was significantly higher when patients were in hyperglycemic than when glycemic control was good (3.5 ± 0.15 vs. 2.9 ± 0.07, M ± SE, p<0.01). GA decreased more rapidly than HbA1c during intensive insulin therapy, but the percent reduction of HbA1c eventually corresponded with that of GA by 16 weeks after the start of treatment. These results demonstrate that, although unknown influences on GA or HbA1c may exist, GA may be a useful marker for monitoring short-term variations of glycemic control during treatment of diabetic patients.

View full abstract

No consensus has been reached on whether the 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, known as statins, have beneficial effects on bone health. The purpose of our study was to evaluate the effects of atorvastatin on bone metabolism by means of measuring bone turnover markers in male patients with hypercholesterolemia both at diagnosis and prospectively after 3 months of treatment. Twenty-two Japanese male patients (mean age 62.36 ± 10.1 years) with untreated hypercholesterolaemeia were selected for this study. After 3-months treatment of atorvastatin, total cholesterol and low density lipoprotein cholesterol significantly decreased as expected (p<0.001 for both parameters). Bone-specific alkaline phosphatase (BAP) did not change significantly (p = 0.444). However, serum N-terminal telopeptide of type I collagen (NTx) significantly decreased by –19.86 ± 26.4% (p = 0.020). In addition, ΔNTx during the course of this study was negatively correlated with NTx at baseline (r = –0.645, p = 0.0008). Although there was a tendency of positive correlations of ΔNTx with Δtotal cholesterol, Δtriglycerides, and Δlow density lipoprotein cholesterol, and of negative correlations of ΔNTx and ΔBAP with Δhigh density lipoprotein cholesterol, none of them reached statistical significance. Our findings suggest that atorvastatin may have potentially beneficial effects on bone metabolism in patients with hypercholesterolemia mostly by reducing bone resorption rather than by stimulating bone formation. Further studies with more patients and longer duration are warranted to evaluate its effects, if any, on prevention of osteoporosis and subsequent fractures.

View full abstract

In man, serum concentrations of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) decrease with age after the twenties. For this reason, the decline in DHEA and DHEAS concentrations may be related to the development of some chronic diseases that are prevalent in the older age population. In this study, we evaluate the benefit and safety level of DHEA administration to men as a hormone replacement therapy. Twenty-two healthy Japanese males (age 26-63; mean ± SD, 41.0 ± 10.0 yrs.) received 25 mg DHEA once a day orally in the morning for two weeks. Serum concentrations of steroid hormones and cytokines were measured before and after the DHEA administration. Glucose tolerance and insulin resistance were also assessed before and after the DHEA administration using a 75 g oral glucose tolerance test and homeostasis model assessment (HOMA-R), respectively. Serum DHEA and DHEAS levels were significantly elevated after the DHEA administration for all ages of test subjects. In subjects who were older than 41 yrs. (older group) serum androstenedione and estradiol levels were elevated after the DHEA administration. Significant negative correlations were observed between the serum DHEA concentration and the serum concentration of fasting insulin, HOMA-R, leptin, and high-sensitivity C-reactive protein for all subjects. Daily administration of 25 mg DHEA increased the serum DHEA, DHEAS, androstenedione, and estradiol levels of the subjects of the older group to the same level as that of younger subjects.

View full abstract

We have previously reported the therapeutic efficacy of mitiglinide combined with once daily insulin glargine (mitiglinide regimen) after switching from multiple daily insulin regimen of aspart insulin and glargine (intensive insulin regimen) in inpatients with type 2 diabetes mellitus in two consecutive days. In the present study, we followed up 9 of the 15 responsive patients with these novel regimens for 6 months after discharge. The data collected from these patients were compared to those of 15 randomly chosen patients who had well matched background and received intensive insulin regimen during hospitalization which was continued after discharge. The average HbA_1c level of these 9 patients with mitiglinide regimen at 6 months was 6.7 ± 0.8% and was comparable to that of the patients with intensive insulin regimen (HbA_1c = 7.0 ± 1.0%). In conclusion, mitiglinide and insulin glargine combination therapy maintained fair gylcemic control for as long as 6 months in subpopulation of Japanese patients with type 2 diabetes.

View full abstract