A case of malignant insulinoma: successful control of glycemic fluctuation by replacing octreotide injections with octreotide LAR injections.

A 73-year-old woman with malignant insulinoma was treated with 100 µg/day octreotide for unresected insulinoma and liver metastases. The daily administration of the drug induced hyperglycemia after dinner in addition to existing fasting hypoglycemia possibly because this drug suppressed both insulin and glucagon secretion and its blood concentration was unstable. After replacing a daily injection of octreotide with a monthly injection of octreotide long-acting repeatable (LAR), blood glucose levels stabilized within the normal range. The findings of the present study showed that octreotide LAR could be useful for the long-term treatment of unresectable insulinomas.

Fulminant type 1 diabetes mellitus with anti-programmed cell death-1 therapy.

Anti-programmed cell death-1 (PD-1) antibodies are regarded as a risk factor for insulin-dependent diabetes mellitus as a side-effect. While a small number of cases have been reported, evidence remains limited. This is the first report of an Asian patient developing insulin-dependent diabetes during anti-PD-1 therapy. A 55-year-old euglycemic woman receiving nivolumab for malignant melanoma showed abrupt onset of ketonuria, and elevated levels of plasma glucose (580 mg/dL) and hemoglobin A1c (7.0%). Over the next 2 weeks, serum C-peptide levels fell below the limit of detection. Islet autoantibodies were negative, and the patient showed a human leukocyte antigen haplotype associated with type 1 diabetes. Anti-PD-1 therapy can cause rapid onset of insulin-dependent diabetes, possibly because of inappropriate activation of T cells. Human leukocyte antigen haplotypes might be related to the onset of this disease. Physicians should be aware of this serious adverse event and carry out routine blood glucose testing during anti-PD-1 therapy.

A 13-week toxicity study of bismuth in rats by intratracheal intermittent administration.

Although bismuth is widely used as a lead substitute in the industrial field, the toxicity of bismuth by inhalation is little known. We performed a 13-wk intratracheal intermittent bismuth dose toxicity study. Bismuth was administered at dose levels of 0, 0.8, 4, 20 mg/kg to male Crj:CD(SD)IGS rats (SPF) by intratracheal intermittent administration once a week for thirteen weeks to investigate its potential toxic effects; especially for specific adverse effects and changes related to pre-neoplastic lesions. Our results showed foreign body inflammation in the lungs, which was caused by intratracheal administration of bismuth, and physical changes related to pulmonary lesions; however, there were no serious changes in other organs. We concluded that dose-dependent, but not specific adverse effects, were attributable to bismuth inhalation in the rat.

Oral toxicity of bismuth in rat: single and 28-day repeated administration studies.

The consumption and production of bismuth are increasing, however there is very little information about the direct toxic effect of bismuth. The present study aimed to characterize the potential toxic effects of bismuth through oral administration and observation for fourteen days following single dose of 0 and 2,000 mg/kg (acute oral toxicity study), and repeated oral administration for twenty-eight days at dose levels of 0, 40, 200, and 1,000 mg/kg daily (28-d repeated oral dose toxicity study) to male and female Crj:CD (SD) IGS rats (SPF). We found no deaths and no abnormalities in clinical signs, body weights, and necropsy findings for any of the animals in the acute oral toxicity study and no changes attributable to bismuth in either males or females in the dose group up to 1,000 mg/kg of the 28-d repeated-dose toxicity study. Therefore, we determined that the lethal dose with a 50% mortality rate (LD50) is greater than 2,000 mg/kg and the no-observed-adverse-effect level (NOAEL) of bismuth is 1,000 mg/kg in both sexes. We conclude that the adverse toxic effects of bismuth as a simple metal substance are low compared to lead toxicity under the conditions tested in our studies.

Efficacy of ezetimibe as monotherapy or combination therapy in hypercholesterolemic patients with and without diabetes.

Ezetimibe selectively inhibits dietary and biliary cholesterol absorption and reduces serum cholesterol levels when administered alone (monotherapy) and along with common lipid-regulating agents (combination therapy). To evaluate the effect of ezetimibe therapy on the lipid profile, glucose metabolism, and levels of cholesterol absorption and synthesis markers, we administered 10 mg ezetimibe to 50 hypercholesterolemic patients with or without diabetes. The serum levels of low-density lipoprotein cholesterol and total cholesterol were significantly reduced at 4 and 12 weeks of ezetimibe therapy in diabetic patients of both the monotherapy and combination-therapy groups and in nondiabetic patients of the combination-therapy group. The serum levels of the cholesterol absorption markers were significantly reduced, while those of the cholesterol synthesis markers were significantly increased at 12 weeks of ezetimibe therapy. No significant differences were noted in the values of the parameters of glucose metabolism in all patients. We also investigated the clinical characteristics of patients who exhibited a good response to ezetimibe (ezetimibe responders); however, multivariate regression analysis did not reveal a correlation between ezetimibe efficacy and patient characteristics such as gender, age, BMI, diabetic condition, method of ezetimibe administration, and the initial absolute values of cholesterol absorption/synthesis markers levels. In conclusion, ezetimibe therapy significantly improved the lipid profile without disturbing glucose metabolism. We were unable to identify the specific characteristics of ezetimibe responders among our subjects. However, we may interpret this result as suggesting that ezetimibe can be used in any population to lower low-density lipoprotein cholesterol levels.

Autoimmune diabetes in HIV-infected patients on highly active antiretroviral therapy.

CONTEXT: Various autoimmune diseases, especially autoimmune thyroid disease, are known to occur in HIV-infected patients on highly active antiretroviral therapy (HAART). However, no reports have described the development of autoimmune diabetes during HAART. OBJECTIVE: Our objective was to investigate the clinical course of the development of autoantibodies and diabetes during HAART. PATIENTS AND METHODS: Based on their high antiislet autoantibody titers and requirement for insulin therapy, we diagnosed three HIV-infected patients with autoimmune diabetes. To clarify the relationship between the development of an autoimmune reaction against pancreatic beta-cells and recovery of CD4+ T lymphocyte (CD4) counts, we retrospectively assayed stored samples of the patients' plasma for antiglutamic acid decarboxylase antibody (GAD-Ab). RESULTS: No GAD-Ab was detected in the plasma samples of any of the three patients prior to HAART, and their CD4 counts were below 20 cells/microl at their nadir. The GAD-Ab tests became positive from 6 to 38 months after the start of HAART, and their conversion to positive followed a dramatic increase in the patients' CD4 count. Two patients developed diabetes after testing positive for GAD-Ab. Although one patient had mild diabetes prior to testing positive for GAD-Ab, the rapid worsening of glycemic control and introduction of insulin therapy almost coincided with the detection of GAD-Ab. The high magnitude of the CD4 increase during HAART and the timing of the detection of autoantibody were similar to the magnitude and timing reported in HAART-associated autoimmune thyroid disease. CONCLUSIONS: Autoimmune diabetes develops in some HIV-infected patients after immune restoration during HAART.

Genotoxicity studies of heavy metals: lead, bismuth, indium, silver and antimony.

OBJECTIVES: Many kinds of heavy metals are used in industry; thus, it is important for us to clarify their toxicity. For example, lead, which is a component of solder, is notorious for its neurotoxicity, and substitute materials have been sought for many years. Therefore, we examined the genotoxicity of lead and also those of metallic bismuth, indium, silver and antimony which are possible substitutes for lead in solder. METHODS: Bacterial reverse mutation tests and chromosomal aberration tests in cultured mammalian cells were performed according to standard procedures. RESULTS: Antimony showed genotoxicity in both tests, and bismuth also showed positive results in the chromosomal aberration test. In contrast, lead, indium, and silver were considered to be inactive by the criteria of the present study. CONCLUSIONS: Although further studies are needed because of the difficulty of genotoxicity evaluation using an in vitro system, sufficient precautions should be made when antimony and bismuth are used.

Oral toxicity of indium in rats: single and 28-day repeated administration studies.

Indium is widely used in the electronics industry to make semiconductors, liquid-crystal panels, and plasma display panels, and its production is increasing. However, it is necessary to handle it more cautiously than before, because the pulmonary toxicity of inhaled indium has been identified. The present study aimed to characterize the potential toxic effects of indium through oral administration and observation for fourteen days following a single dose of 0 or 2,000 mg/kg (acute oral toxicity study), and repeated oral administration for 28 days at dose levels of 0, 40, 200, or 1,000 mg/kg daily (28-day repeated oral dose toxicity study) to male and female Crj:CD (SD) IGS rats (SPF). No deaths and no abnormalities in clinical signs, body weights, and necropsy findings were observed for any of the animals in the acute oral toxicity study. Furthermore, no changes related to indium were also observed in the dose groups up to 1,000 mg/kg of the 28-day repeated oral dose toxicity study. From the results described above, the lethal dose 50% (LD(50)) of indium is greater than 2,000 mg/kg under these study conditions, and the no-observed-adverse-effect-level (NOAEL) is considered to be 1,000 mg/kg for males and females under these conditions.