Add-on treatment with mitiglinide improves residual postprandial hyperglycemia in type 2 diabetic patients receiving the combination therapy with insulin glargine and sitagliptin.

The combination of a dipeptidyl peptidase-4 (DPP-4) inhibitor and a long-acting insulin analogue is widely used in clinical practice. However, some patients fail to achieve lower postprandial hyperglycemia. Mitiglinide, a short-acting insulinotropic sulfonylurea receptor ligand, is effective for postprandial hyperglycemia. Recently, it has been reported that the combination therapy of mitiglinide with a DPP-4 inhibitor could improve glycemic control. However, the efficacy of those under long-acting insulin analogue therapy remains to be investigated. Thus, we conducted a prospective single-center study of eight Japanese patients with type 2 diabetes mellitus receiving mitiglinide added to the combination therapy of sitagliptin and insulin glargine, and evaluated its efficacy and safety by continuous glucose monitoring (CGM). Participants' (four men and four women) mean age was 70.3 ± 10.6 years. Their mean body mass index, HbA1c level, and urinary C-peptide level were 22.0 ± 2.8 kg/m(2), 9.2 ± 1.2%, and 50.0 ± 31.4 µg/day, respectively. CGM showed that as compared with the combination of only sitagliptin and insulin glargine, mitiglinide in combination with sitagliptin and insulin glargine significantly reduced glycemic fluctuation indices, total area for the range of 24-h glycemic fluctuations (p = 0.04), mean amplitude of glycemic excursions (p = 0.03), and the proportion of time in hyperglycemia (p = 0.02) without significant difference in the proportion of time in hypoglycemia (p = 0.18). Hence, we have demonstrated the efficacy and safety of the add-on treatment with mitiglinide in type 2 diabetic patients, receiving the combination therapy of sitagliptin and insulin glargine.

Desmopressin orally disintegrating tablet in Japanese patients with central diabetes insipidus: a retrospective study of switching from intranasal desmopressin.

Central diabetes insipidus (CDI) is a rare disease characterized by polyuria and polydipsia. Patients with CDI have been successfully treated with desmopressin administered either by intranasal instillation or oral tablets. Recently, a desmopressin orally disintegrating tablet (ODT) was approved as the first oral desmopressin tablet for CDI treatment in Japan. We conducted a retrospective single-center study of 15 Japanese CDI patients treated with desmopressin ODT therapy, which aimed to evaluate the efficacy and safety of switching to desmopressin ODT and to analyze the clinical factors that affect the desmopressin ODT dose in Japanese patients. The daily mean dose of desmopressin ODT was 104 ± 46.30 µg and the mean ratio of oral to nasal desmopressin dose was 17.0 ± 7.6, both of which are considerably smaller than those of previous dose-titration study. Moreover, the nasal spray group needed significantly smaller ratios of nasal to oral desmopressin than the nasal drop group (11.7 ± 6.5 vs 21.0 ± 5.5, p = 0.02). The ratio of oral to nasal desmopressin dose had a significant inverse correlation with the required nasal desmopressin dose. Multiple regression analysis demonstrated the ratios of nasal to oral desmopressin dose depended on intranasal formulations. In conclusion, desmopressin ODT was safe and effective in the treatment of Japanese adult CDI patients. When switching to ODT, we should care about the possibility that patients require smaller ODT doses than what was initially expected based on previously published data and also nasal formulations in terms of their differences of expected switching ratio.

Angiogenic and vasoprotective effects of adrenomedullin on prevention of cognitive decline after chronic cerebral hypoperfusion in mice.

BACKGROUND AND PURPOSE: Although subcortical vascular dementia, the major subtype of vascular dementia, is caused by a disruption in white matter integrity after cerebrovascular insufficiency, no therapy has been discovered that will restore cerebral perfusion or functional cerebral vessels. Because adrenomedullin (AM) has been shown to be angiogenic and vasoprotective, the purpose of the study was to investigate whether AM may be used as a putative treatment for subcortical vascular dementia. METHODS: A model of subcortical vascular dementia was reproduced in mice by placing microcoils bilaterally on the common carotid arteries. Using mice overexpressing circulating AM, we assessed the effect of AM on cerebral perfusion, cerebral angioarchitecture, oxidative stress, white matter change, cognitive function, and brain levels of cAMP, vascular endothelial growth factor, and basic fibroblast growth factor. RESULTS: After bilateral common carotid artery stenosis, mice overexpressing circulating AM showed significantly faster cerebral perfusion recovery due to substantial growth of the capillaries, the circle of Willis, and the leptomeningeal anastomoses and reduced oxidative damage in vascular endothelial cells compared with wild-type mice. Vascular changes were preceded by upregulation of cAMP, vascular endothelial growth factor, and basic fibroblast growth factor. White matter damage and working memory deficits induced by bilateral common carotid artery stenosis were subsequently restored in mice overexpressing circulating AM. CONCLUSIONS: These data indicate that AM promotes arteriogenesis and angiogenesis, inhibits oxidative stress, preserves white matter integrity, and prevents cognitive decline after chronic cerebral hypoperfusion. Thus, AM may serve as a strategy to tackle subcortical vascular dementia.

A case of cortisol producing adrenal adenoma without phenotype of Cushing's syndrome due to impaired 11beta-hydroxysteroid dehydrogenase 1 activity.

This report concerns a case of cortisol-producing adrenocortical adenoma without the phenotype of Cushing's syndrome. A left adrenal tumor was incidentally detected in this patient. A diagnosis of adrenal Cushing's syndrome was based on the results of endocrinological and radiological examinations, although she showed none of the physical signs of Cushing's syndrome, glucose intolerance, hypertension or dyslipidermia. After a successful laparoscopic left adrenalectomy, the pathological diagnosis was adrenocortical adenoma. Slow tapering of glucocorticoids was needed to prevent adrenal insufficiency after surgery, and the plasma ACTH level remained high even though the serum cortisol level had reached the upper limit of the normal range. Further examination showed a urinary THF + allo-THF/THE ratio of 0.63, which was lower than that of control (0.90 +/- 0.13, mean +/- SD). Serum cortisol/cortisone ratios after the cortisone acetate administration were also decreased, and the serum half-life of cortisol was shorter than the normal range which has been reported. These findings indicated a partial defect in 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) activity, which converts cortisone to cortisol. Our case suggests that a change in 11beta-HSD1 activity results in inter-individual differences in glucocorticoid efficacy.

Antithyroid drugs inhibit thyroid hormone receptor-mediated transcription.

CONTEXT: Methimazole (MMI) and propylthiouracil (PTU) are widely used as antithyroid drugs (ATDs) for the treatment of Graves' disease. Both MMI and PTU reduce thyroid hormone levels by several mechanisms, including inhibition of thyroid hormone synthesis and secretion. In addition, PTU decreases 5'-deiodination of T(4) in peripheral tissues. ATDs may also interfere with T(3) binding to nuclear thyroid hormone receptors (TRs). However, the effect of ATDs on the transcriptional activities of T(3) mediated by TRs has not been studied. OBJECTIVE: The present study was undertaken to determine whether ATDs have an effect on the gene transcription regulated by T(3) and TRs in vitro. METHODS: Transient gene expression experiments and GH secretion assays were performed. To elucidate possible mechanisms of the antagonistic action of ATDs, the interaction between TR and nuclear cofactors was examined. RESULTS: In the transient gene expression experiments, both MMI and PTU significantly suppressed transcriptional activities mediated by the TR and T(3) in a dose-dependent manner. In mammalian two-hybrid assays, both drugs recruited one of the nuclear corepressors, nuclear receptor corepressor, to the TR in the absence of T(3). In addition, PTU dissociated nuclear coactivators, such as steroid receptor coactivator-1 and glucocorticoid receptor interacting protein-1, from the TR in the presence of T(3). Finally, MMI decreased the GH release that was stimulated by T(3). CONCLUSIONS: ATDs inhibit T(3) action by recruitment of transcriptional corepressors and/or dissociation of coactivators. This is the first report to show that ATDs can modulate T(3) action at the transcriptional level.

Expression of the adrenomedullin gene in adipose tissue.

Adrenomedullin (AM) is a potent vasodilating peptide originally isolated from human pheochromocytoma cells. This report concerns the expression and secretion of AM from adipose tissue. Northern blot analysis demonstrated marked expression of AM mRNA in mouse adipose tissue. Expression levels in adipose tissues were 2.5-3.2 times higher than in the kidney. AM mRNA level in mature adipocytes was 7.3 times higher than in the stroma-vascular fraction of adipose tissue. In mature adipocyte culture, time-dependent increase of AM peptide concentration in the culture medium was detected. AM expression was also detected in human subcutaneous adipose tissue. Adipose AM expression significantly increased in obesity mouse model, high-fat diet fed mice and ob/ob mice. These results suggest that adipose tissue, especially mature adipocytes, is major source of AM in the body, and that adipocyte-derived AM plays a pathophysiological role in obesity.

A Novel Missense Mutation of the MEN1 Gene in a Patient with Multiple Endocrine Neoplasia Type 1 with Glucagonoma and Obesity.

A 35-year-old obese diabetic man presented with recurrent primary hyperparathyroidism during a three-year outpatient follow-up. He was clinically diagnosed with multiple endocrine neoplasia type 1 (MEN1) due to the presence of a pituitary adenoma and multiple glucagonomas. The glucagonomas may have affected his glycemic control. However, he did not demonstrate weight loss, suggesting that the patient's obesity could have obscured the early diagnosis of a glucagonoma. Genetic testing revealed a novel missense mutation at codon 561 in exon 10, resulting in an amino acid substitution from methionine to arginine (M561R) in the MEN1 gene. This mutation appeared to be responsible for the MEN1 pathogenicity.

Diffuse thyroid enlargement following metastasis of lung adenocarcinoma.

A 55-year-old man presented with a rapidly enlarging thyroid. He had been diagnosed with lung adenocarcinoma nine months earlier. Computed tomography (CT) and ultrasound (US) detected reticular cord-like structures, but no nodules, in the thyroid. A fine-needle aspiration biopsy (FNAB) of the thyroid revealed thyroglobulin-negative adenocarcinoma cells, thus establishing the diagnosis of diffuse thyroid metastases of lung cancer. Moreover, the fluid demonstrated milky chyliform effusion. This case suggests that the presence of reticular cord-like structures on US and CT may be a key imaging finding for the clinical diagnosis of diffuse thyroid metastases and that chyliform effusion may contribute to rapid goiter formation.

Pseudohypoparathyroidism type II in a woman with a history of thyroid surgery.

We herein describe the case of a woman with pseudohypoparathyroidism (PHP) type II. She had a history of subtotal thyroidectomy against Graves' disease without levothyroxine supplementation and presented with stiffness, numbness and muscle cramps. Her surgical history suggested the possibility of secondary hypoparathyroidism; however, the serum intact parathyroid hormone level and results of a Ellsworth-Howard test led to the diagnosis of PHP type II. In the present case, making the differential diagnosis was challenging because two distinct disorders, such as PHP and secondary hypoparathyroidism, may exist simultaneously. This case demonstrates the need to consider the possibility of PHP type II in patients exhibiting hypocalcemia.

Prolonged disturbance of consciousness caused by severe hypophosphatemia: a report of two cases.

We herein describe two patients with a prolonged disturbance of consciousness due to severe hypophosphatemia. Case one presented with pneumococcal infection and acute exacerbation of chronic obstructive pulmonary disease and asthma. Case two presented with diabetic foot infections and diabetic ketoacidosis. Both patients responded to initial therapy for their primary diseases, but consciousness became worse in both cases. Their test results for impaired consciousness revealed severe hypophosphatemia; therefore, phosphate replacement therapy was administered, thus resulting in complete alertness. These cases demonstrate that we should consider the possibility of hypophosphatemia in critically ill patients with an altered consciousness.

Evaluation of the effects of exenatide administration in patients with type 2 diabetes with worsened glycemic control caused by glucocorticoid therapy.

Glucocorticoid-induced hyperglycemia is common in patients with or without known diabetes mellitus. Exenatide, a glucagon-like peptide-1 receptor agonist, improves glycemic control without causing weight gain or hypoglycemia and is currently widely used in patients with type 2 diabetes mellitus. We herein report four cases of patients with type 2 diabetes with worsened glycemic control due to glucocorticoids who were successfully treated with exenatide administration.

Liraglutide administration in type 2 diabetic patients who either received no previous treatment or were treated with an oral hypoglycemic agent showed greater efficacy than that in patients switching from insulin.

AIMS/INTRODUCTION: Liraglutide, a glucagon-like peptide-1 receptor agonist, is expected to provide a new treatment option for diabetes. However, the suitable timing of liraglutide administration in type 2 diabetic patients has not yet been clarified. MATERIALS AND METHODS: We reviewed type 2 diabetic patients (n = 155) who visited the Osaka Red Cross Hospital for glycemic control, with administration of liraglutide at a dose of 0.6 mg (average glycated hemoglobin [HbA1c] level, 8.7 ± 0.1%). The effect of liraglutide based on the pretreatment status was compared. We also analyzed the background factors of both a successful and failed group of patients who switched to liraglutide from insulin. RESULTS: An improvement in blood glucose levels was confirmed in 122 of 155 patients. During the 4-month observation period, the improvement in HbA1c levels was significantly greater in the group of drug-naïve/previous oral hypoglycemic agent (9.1 ± 0.2 to 7.2 ± 0.2%) than that in the group switching from insulin (8.6 ± 0.2 to 7.8 ± 0.2%). In addition, C-peptide immunoreactivity levels (fasting > 2.2 ng/mL; delta >1.6 ng/mL; urine > 70 µg/day), younger age and a smaller number of insulin units used per day were considered important when deciding on switching to liraglutide from insulin. CONCLUSIONS: Liraglutide was more effective in patients who had not been treated previously or received oral hypoglycemic agents than in patients switching from insulin. With respect to switching to liraglutide from insulin, the most important factors to be considered were C-peptide immunoreactivity levels, age, and the number of insulin units used per day.

Diabetic ketoacidosis accompanied by hypothermia: a case report.

Diabetic ketoacidosis (DKA) is an acute, life-threatening complication of diabetes mellitus and is caused by insulin insufficiency. Hypothermia is defined as a core temperature of less than 35°C and is sometimes accompanied by DKA. We report two patients with diabetes who were admitted for DKA accompanied by hypothermia.

Distal renal tubular acidosis that became exacerbated by proton pump inhibitor use.

Acid-base imbalances and electrolyte disorders induced by proton pump inhibitors (PPIs) are extremely rare. However, under certain conditions, PPIs may cause metabolic acidosis or hypokalemia, probably due to an inhibitory action on the proton pump that contributes to H(+) and K(+) homeostasis in the kidney. We herein present a case of marked hypokalemia accompanied by distal renal tubular acidosis in which a PPI appeared to contribute to the pathophysiology of metabolic acidosis.

Angiogenic roles of adrenomedullin through vascular endothelial growth factor induction.

Recently, we have reported that a vasoactive peptide adrenomedullin promotes angio/arteriogenesis and prevents cognitive decline after chronic cerebral hypoperfusion in mice. Adrenomedullin upregulated brain levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor, although the regulation mechanism needs to be determined. In this study, we showed that VEGF neutralization partially suppressed adrenomedullin-induced neovascularization and cognitive restoration in vivo. In-vitro, adrenomedullin promoted capillary tube formation of the cultured endothelium, whereas VEGF neutralization abolished these effects. Adrenomedullin was found to upregulate VEGF and basic fibroblast growth factor through the adrenomedullin receptor and the phosphatidylinositol 3-kinase pathway. These results suggest that adrenomedullin has potential as therapy for dementia through enhancement of functional vascular growth.

Circulating C-type natriuretic peptide (CNP) rescues chondrodysplastic CNP knockout mice from their impaired skeletal growth and early death.

C-type natriuretic peptide (CNP) is a potent stimulator of endochondral bone growth through a subtype of membranous guanylyl cyclase receptor, GC-B. Although its two cognate natriuretic peptides, ANP and BNP, are cardiac hormones produced from heart, CNP is thought to act as an autocrine/paracrine regulator. To elucidate whether systemic administration of CNP would be a novel medical treatment for chondrodysplasias, for which no drug therapy has yet been developed, we investigated the effect of circulating CNP by using the CNP transgenic mice with an increased circulating CNP under the control of human serum amyloid P component promoter (SAP-Nppc-Tg mice). SAP-Nppc-Tg mice developed prominent overgrowth of bones formed through endochondral ossification. In organ culture experiments, the growth of tibial explants of SAP-Nppc-Tg mice was not changed from that of their wild-type littermates, exhibiting that the stimulatory effect on endochondral bone growth observed in SAP-Nppc-Tg mice is humoral. Then we crossed chondrodysplastic CNP-depleted mice with SAP-Nppc-Tg mice. Impaired endochondral bone growth in CNP knockout mice were considerably and significantly recovered by increased circulating CNP, followed by the improvement in not only their longitudinal growth but also their body weight. In addition, the mortality of CNP knockout mice was greatly decreased by circulating CNP. Systemic administration of CNP might have therapeutic potential against not only impaired skeletal growth but also other aspects of impaired growth including impaired body weight gain in patients suffering from chondrodysplasias and might resultantly protect them from their early death.