[Insulin-derived amyloidosis (insulin ball) and skin-related complications of insulin therapy].

Skin-related complications of insulin therapy have long been a problem as a factor interfering with insulin therapy. Among the traditional skin-related complications, lipoatrophy and insulin allergy have decreased markedly with the development of insulin preparations, but lipohypertrophy is still common in insulin-treated patients. Recently, there have been more reports of a skin-related complication called insulin-derived amyloidosis or insulin ball. Insulin-derived amyloidosis is a condition in which injected insulin becomes amyloid protein and is deposited at the injection site. Insulin-derived amyloidosis causes poor glycemic control and increased insulin dose requirements, which are caused by decreased insulin absorption. Lipohypertrophy also decreases insulin absorption, but insulin-derived amyloidosis causes a more significant decrease in insulin absorption and has a greater clinical impact. Therefore, it is important to make a differential diagnosis between insulin-derived amyloidosis and lipohypertrophy, but sometimes it is difficult to distinguish the two and imaging studies are required. The diagnosis of insulin-derived amyloidosis is often difficult in the general practice, and its pathogenesis and prevalence have not been fully clarified. Recently, it has been reported that insulin-derived amyloidosis can be toxic, suggesting an association with minocycline use. The treatment of insulin-derived amyloidosis and lipohypertrophy is to avoid the site of amyloidosis or lipohypertrophy and inject insulin, but the dose of insulin injection should be reduced. Prevention of both insulin-derived amyloidosis and lipohypertrophy is important, and for this purpose, observations of the insulin injection site and instruction on appropriate insulin injection techniques are necessary, and multidisciplinary cooperation is extremely important.

Multiple Endocrine Neoplasia Type 1 with Functional Parathyroid Cysts.

A 51-year-old woman was admitted because of hypercalcemia. Neck ultrasonography and computed tomography revealed the presence of parathyroid cysts on both sides. After primary hyperparathyroidism was diagnosed by technetium-99m-methoxyisobutylisonitrile scintigraphy, the patient was successfully treated with total parathyroidectomy and autotransplantation. She also had a non-functioning pancreatic neuroendocrine tumor, prolactinoma, and adrenal tumors with subclinical Cushing's syndrome. Given these clinical features and her family history, multiple endocrine neoplasia type 1 (MEN1) was suspected, and germline DNA sequencing revealed a missense mutation (c.1013T>C, [corrected] p.Leu338Pro) in exon 7 of MEN1. This case demonstrates the phenotypic and genetic diversity of MEN1.

A case of nonislet cell tumor hypoglycemia associated with malignant mesothelioma requiring a multifaceted approach for optimal glycemic control.

Nonislet tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome characterized by refractory hypoglycemia, which often requires multifaceted therapy. We reported a case of a patient with pleural malignant mesothelioma and developed NICTH, for which chemotherapy, glucocorticoids, and nutrition were given to achieve optimal glycemic control.

Insulin-derived amyloidosis without a palpable mass at the insulin injection site: A report of two cases.

To date, almost all case reports of insulin-derived amyloidosis described the presence of a subcutaneous mass that was observable on physical examination. This report presents two cases of insulin-derived amyloidosis without palpable masses at insulin injection sites. In both cases, blood glucose concentrations improved, and the insulin dose could be reduced by an average of 45% after changing the insulin injection sites. The insulin absorption at the site was reduced to at most 40% of that at a normal site in one case. Magnetic resonance imaging and ultrasonography were useful to screen and differentiate insulin-derived amyloidosis without a palpable mass. This report showed that insulin-derived amyloidosis without a palpable mass can be present at the insulin injection site, and has similar clinical effects to insulin-derived amyloidosis with palpable masses.

Toxicity of insulin-derived amyloidosis: a case report.

BACKGROUND: Insulin-derived amyloidosis is a skin-related complication of insulin therapy that interferes with insulin therapy. Although toxicities of in vitro-formed insulin amyloid fibrils have been well studied, the toxicity of insulin-derived amyloidosis remains to be clarified. CASE PRESENTATION: A 58-year-old man with type 2 diabetes mellitus underwent a lower limb amputation due to diabetic gangrene. Several antibiotics including minocycline were administered for infection and sepsis. A hard mass at the insulin injection sites in the lower abdomen was discovered by chance four months later. Although no abnormal findings in the surface skin of the mass were observed, necrotic tissue was seen around the mass when a biopsy was performed. Histological and toxicity studies were performed for this patient and four other patients with abdominal masses at insulin injection sites. Histological and immunohistochemical studies showed that the masses had typical characteristics of amyloid deposits in all cases, whereas necrotic findings were seen adjacent to the amyloid deposit only in the case presented. Toxicity studies indicated that the amyloid tissue from the present case had significant cell toxicity compared to the control skin tissue or the amyloid tissues from the other four cases. CONCLUSIONS: This report showed that toxic insulin-derived amyloidosis can occur. In addition, this report suggested that toxic insulin-derived amyloidosis may cause necrosis in the surrounding tissue. Although the toxic amyloid deposit of insulin-derived amyloidosis was found in only one patient, no structural differences between toxic and non-toxic deposits were seen on histological and immunohistochemical studies.

In vitro studies on nobiletin isolated from citrus plants and the bioactive metabolites, inhibitory action against gelatinase enzymatic activity and the molecular mechanisms in human retinal Müller cell line.

Diabetic retinopathy (DR) is the most common cause of vision loss in patients with diabetes mellitus. Despite the presence of effective therapy, DR is still a significant health burden. A recent research suggests that matrix metalloproteinases (MMPs) could be promising targets, which exert multiple actions on early- and late-stage pathogenesis of DR. Among the MMP family, gelatinases (MMP-2 and MMP-9) act as potent proinflammatory, proangiogenic, and pro-apoptotic factors. Therefore, the pharmacological inhibitory effect of gelatinases on retinal MMP-producing cells may be useful in the treatment or prevention of DR. Nobiletin isolated from citrus plants is a multi-functional polymethoxylated flavone, which exerts biological effects including inhibitory action against MMP activity in several cancer cells. In the present study, we demonstrated that nobiletin isolated from citrus plants attenuated MMP-9 enzymatic activity through the suppression of transcription for MMP-9 gene expression and augmentation of TIMP-1 production in retinal Müller cells. Nobiletin regulated MMP-9 gene expression and TIMP-1 by inhibiting the PI3K/Akt signaling pathway. In addition, we observed the augmentation of inhibitory action against MMP-9 enzymatic activity by 4'-demethylated nobiletin, which is a major metabolite of nobiletin. We believe that the enhancement of inhibitory action against MMP-9 enzymatic activity by 4'-demethylated nobiletin is through the dual inhibition on Erk1/2 and Akt phosphorylation. The structure-activity relationship analysis revealed that, for the enhancement of inhibitory action against MMP-9 enzymatic activity, demethylation at position 4' in B-ring was a key structural modification in Müller cells, which are an important source of MMPs found in vitreous fluid and retinal tissues in retinal proliferative diseases. These results suggested that nobiletin, derived from a natural source, may serve as a novel MMP inhibitor with minimal side effects, and lead compound for the design of more efficacious drugs.

Insulin-derived amyloidosis and poor glycemic control: a case series.

OBJECTIVES: Insulin-derived amyloidosis is a rare skin-related complication of insulin therapy. The purpose of this study was to show the effects of insulin-derived amyloidosis on blood glucose levels, insulin dose requirements, and insulin absorption. METHODS: Seven patients were found to have insulin-derived amyloidosis at the Tokyo Medical University Ibaraki Medical Center. The clinical characteristics and insulin therapy of the 7 patients were investigated. Insulin absorption was studied by comparing the serum insulin levels after insulin injections into insulin-derived amyloidosis sites versus injections into normal sites in 4 patients. RESULTS: When the insulin-derived amyloidosis was discovered, the mean hemoglobin A1c level was 9.3%, and the mean daily insulin dose was 57 units. After changing the injection sites to avoid the insulin-derived amyloidosis, the blood glucose concentrations improved, and the mean daily insulin dose could be reduced to 27 units (P = .035; 53% reduction). The insulin absorption at insulin-derived amyloidosis sites was 34% of that at normal sites (P = .030). CONCLUSIONS: Insulin-derived amyloidosis caused poor glycemic control and increased insulin dose requirements because of impairments in insulin absorption.

Successful treatment of postsurgical hypoparathyroidism by intramuscular injection of vitamin D3 in a patient associated with malabsorption syndrome due to multiple abdominal surgeries.

A 56-year-old patient with postsurgical hypothyroidism and hypoparathyroidism associated with gastrointestinal malabsorption syndrome was prescribed with L: -thyroxine and 1alpha(OH)D(3) at a massive daily dosage of 600 and 39 mug, respectively. Although the patient became nearly euthyroid, she had been hypocalcemic, requiring frequent intravenous injection of calcium gluconate to prevent tetany. Because the serum level of 1,25(OH)(2)D hardly increased after an oral intake of 21 microg 1alpha(OH)D(3), vitamin D(3) was administered intramuscularly. After stoss therapy (600,000 IU), the patient has been receiving 300,000 IU vitamin D(3) at intervals of 2-4 months so that she remained slightly hypocalcemic (7-8 mg/dl). At 1.5 years later, serum levels of 25(OH)D and 1,25(OH)(2)D were maintained at about 60 ng/ml and 30-50 pg/ml, respectively, and renal function was maintained well. These data suggest that intramuscular injection of 300,000 IU vitamin D(3) at an interval of a few months to maintain a slightly increased serum level of 25(OH)D and a slightly decreased serum level of calcium is a safe and cost-effective treatment in such a parathyroid hormone-deficient hypoparathyroid patient with malabsorption syndrome.