Dipeptidyl peptidase-4 inhibitor linagliptin attenuates neointima formation after vascular injury.

BACKGROUND: Recently, glucagon-like peptide-1 (GLP-1)-based therapy, including dipeptidyl peptidase-4 (DPP-4) inhibitors and GLP-1 receptor agonists, has emerged as one of the most popular anti-diabetic therapies. Furthermore, GLP-1-based therapy has attracted increased attention not only for its glucose-lowering ability, but also for its potential as a tissue-protective therapy. In this study, we investigated the vascular-protective effect of the DPP-4 inhibitor, linagliptin, using vascular smooth muscle cells (VSMCs). METHODS: Six-week-old male C57BL/6 mice were divided into control (n =19) and linagliptin (3 mg/kg/day, n =20) treated groups. Endothelial denudation injuries were induced in the femoral artery at 8 weeks of age, followed by evaluation of neointima formation at 12 weeks. To evaluate cell proliferation of rat aortic smooth muscle cells, a bromodeoxyuridine (BrdU) incorporation assay was performed. RESULTS: Linagliptin treatment reduced vascular injury-induced neointima formation, compared with controls (p <0.05). In these non-diabetic mice, the body weight and blood glucose levels did not change after treatment with linagliptin. Linagliptin caused an approximately 1.5-fold increase in serum active GLP-1 concentration, compared with controls. In addition, the vascular injury-induced increase in the oxidative stress marker, urinary 8-OHdG, was attenuated by linagliptin treatment, though this attenuation was not statistically significant (p =0.064). Moreover, linagliptin did not change the serum stromal cell-derived factor-1α (SDF-1α) or the serum platelet-derived growth factor (PDGF) concentration. However, linagliptin significantly reduced in vitro VSMC proliferation. CONCLUSION: Linagliptin attenuates neointima formation after vascular injury and VSMC proliferation beyond the glucose-lowering effect.

Prevalence and clinical characteristics of primary aldosteronism in Japanese patients with type 2 diabetes mellitus and hypertension.

The prevalence of primary aldosteronism (PA) is around 3-15% in patients with hypertension. Hypertension is a frequent complication of type 2 diabetes mellitus (DM) because of the close etiological relationship between these two diseases. However, the possibility of PA in patients with DM and hypertension is often overlooked and the prevalence of PA in patients with DM and hypertension in Japan is unknown. We enrolled 124 hospitalized patients with both DM and hypertension. PA was diagnosed according to the modified criteria for Japanese patients. We examined the prevalence of PA and compared clinical characteristics between patients with and without PA. In another analysis of 43 patients with a confirmed diagnosis of PA, we compared the characteristics of patients with and without DM. Overall, 14/124 patients with DM and hypertension (11.3%) were diagnosed with PA. Multivariate logistic regression showed that the duration of DM was significantly shorter in the PA group. Fisher's direct probability test revealed that history of hypertension before the diagnosis of DM was a significant factor in patients with PA. Treatment with an angiotensin II receptor blocker (ARB) did not affect the diagnosis of PA in these patients. Among 43 patients with PA, those with DM were significantly older and the delay to the diagnosis of PA was significantly longer compared with patients without DM. In conclusion, almost 10% of patients with DM and hypertension actually have PA. More extensive screening for PA is recommended in patients with DM and hypertension, regardless of the use of ARBs.

Proposed diagnostic criteria for subclinical Cushing's syndrome associated with adrenal incidentaloma.

Subclinical Cushing's syndrome (SCS) associated with adrenal incidentaloma is usually characterized by autonomous cortisol secretion without overt symptoms of Cushing's syndrome (CS). Although the diagnostic criteria for SCS differ among countries, the 1 mg dexamethasone suppression test (DST) is essential to confirm the presence and the extent of cortisol overproduction. Since 1995, SCS has been diagnosed in Japan based on serum cortisol levels ≥3 µg/dL (measured by radioimmunoassay [RIA]) after a 1 mg DST. However, the increasing use of enzyme immunoassays (EIA) instead of RIA has hindered the diagnosis of SCS because of the differing sensitivities of commercially available assays, particularly for serum cortisol levels of around 3 µg/dL. One way to overcome this problem is to lower the cortisol threshold level after a 1 mg DST. In the present study, we examined the clinical applicability of lowering the cortisol threshold to 1.8 µg/dL, similar to the American Endocrine Society's guidelines for CS, by reanalyzing 119 patients with adrenal incidentaloma. Our findings indicate that serum cortisol levels ≥1.8 µg/dL after 1 mg DST are useful to confirm the diagnosis of SCS if both of the following criteria are met: (1) basal ACTH level <10 pg/mL (or poor plasma ACTH response to corticotrophin-releasing hormone) and (2) serum cortisol ≥5 µg/dL at 21:00 to 23:00 h. If only one of (1) and (2) are met, we recommend that other clinical features are considered in the diagnosis of SCS, including serum dehydroepiandrosterone sulfate levels, urine free cortisol levels, adrenal scintigraphy, and clinical manifestation.

Acute inflammatory syndrome and intrahepatic cholestasis caused by an interleukin-6-producing pheochromocytoma with pregnancy.

We herein describe the case of a 30-year-old woman who experienced high fever during the puerperal period and was diagnosed with pheochromocytoma. Acute inflammatory syndrome, as indicated by the elevated serum levels of interleukin-6 (IL-6), and cholestatic liver dysfunction were observed. Since this condition resolved before the operation, it was probably caused by massive central necrosis within the tumor. The IL-6 production from the tumor cells was confirmed by immunohistochemistry. When a case of pheochromocytoma accompanied with acute inflammatory syndrome is encountered, the possibility that the tumor itself might produce some cytokines should be considered, even in the presence of massive necrosis within the tumor.

Efficacy of dipeptidyl peptidase-4 inhibitor linagliptin in patients with type 2 diabetes undergoing hemodialysis.

BACKGROUND: Incretin therapy is feasible in patients with type 2 diabetes mellitus undergoing hemodialysis (HD). However, few studies have examined the safety and efficacy of this therapeutic approach in patients with diabetes and renal impairment. Here, we examined glycemic control and the anti-oxidative-stress effects of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin in patients with type 2 diabetes undergoing HD. METHODS: Thirty-five patients with type 2 diabetes undergoing HD (including 13 insulin-treated patients) were switched from ongoing therapy to linagliptin (5 mg, once daily). Levels of fasting blood glucose, C-peptide immunoreactivity (CPR), glycated albumin, B-type natriuretic peptide, oxidized low-density lipoprotein (oxLDL), high-sensitivity C-reactive protein, 8-hydroxy-2'-deoxyguanosine (8OHdG), body mass index, blood pressure, and other biologic characteristics (liver function, renal function, lipid profile) were determined before and 3 months after linagliptin treatment. Patients were classified into insulin-treated and non-insulin groups. RESULTS: With the exception of levels of total bilirubin, aspartate aminotransferase, and CPR, none of the patients exhibited changes in glucose metabolism after switching to linagliptin treatment. However, oxLDL levels were decreased significantly by linagliptin therapy in the non-insulin-treated group despite the absence of changes in glycemic control. CONCLUSION: Linagliptin can decrease serum levels of oxLDL in patients with type 2 diabetes undergoing HD independent of its glucose-lowering effect.

Exendin-4, a GLP-1 receptor agonist, attenuates prostate cancer growth.

Recently, pleiotropic benefits of incretin therapy beyond glycemic control have been reported. Although cancer is one of the main causes of death in diabetic patients, few reports describe the anticancer effects of incretin. Here, we examined the effect of the incretin drug exendin (Ex)-4, a GLP-1 receptor (GLP-1R) agonist, on prostate cancer. In human prostate cancer tissue obtained from patients after they had undergone radical prostatectomy, GLP-1R expression colocalized with P504S, a marker of prostate cancer. In in vitro experiments, Ex-4 significantly decreased the proliferation of the prostate cancer cell lines LNCap, PC3, and DU145, but not that of ALVA-41. This antiproliferative effect depended on GLP-1R expression. In accordance with the abundant expression of GLP-1R in LNCap cells, a GLP-1R antagonist or GLP-1R knockdown with small interfering RNA abolished the inhibitory effect of Ex-4 on cell proliferation. Although Ex-4 had no effect on either androgen receptor activation or apoptosis, it decreased extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) phosphorylation in LNCap cells. Importantly, Ex-4 attenuated in vivo prostate cancer growth induced by transplantation of LNCap cells into athymic mice and significantly reduced the tumor expression of P504S, Ki67, and phosphorylated ERK-MAPK. These data suggest that Ex-4 attenuates prostate cancer growth through the inhibition of ERK-MAPK activation.

The efficacy of incretin therapy in patients with type 2 diabetes undergoing hemodialysis.

BACKGROUND: Although incretin therapy is clinically available in patients with type 2 diabetes undergoing hemodialysis, no study has yet examined whether incretin therapy is capable of maintaining glycemic control in this group of patients when switched from insulin therapy. In this study, we examined the efficacy of incretin therapy in patients with insulin-treated type 2 diabetes undergoing hemodialysis. METHODS: Ten type 2 diabetic patients undergoing hemodialysis received daily 0.3 mg liraglutide, 50 mg vildagliptin, and 6.25 mg alogliptin switched from insulin therapy on both the day of hemodialysis and the non-hemodialysis day. Blood glucose level was monitored by continuous glucose monitoring. After blood glucose control by insulin, patients were treated with three types of incretin therapy in a randomized crossover manner, with continuous glucose monitoring performed for each treatment. RESULTS: During treatment with incretin therapies, severe hyperglycemia and ketosis were not observed in any patients. Maximum blood glucose and mean blood glucose on the day of hemodialysis were significantly lower after treatment with liraglutide compared with treatment with alogliptin (p < 0.05), but not with vildagliptin. The standard deviation value, a marker of glucose fluctuation, on the non-hemodialysis day was significantly lower after treatment with liraglutide compared with treatment with insulin and alogliptin (p < 0.05), but not with vildagliptin. Furthermore, the duration of hyperglycemia was significantly shorter after treatment with liraglutide on both the hemodialysis and non-hemodialysis days compared with treatment with alogliptin (p < 0.05), but not with vildagliptin. CONCLUSIONS: The data presented here suggest that patients with type 2 diabetes undergoing hemodialysis and insulin therapy could be treated with incretin therapy in some cases.

Severe hypocalcemia complicated by postsurgical hypoparathyroidism and hungry bone syndrome in a patient with primary hyperparathyroidism, Graves' disease, and acromegaly.

We herein report a case of severe postsurgical hypocalcemia associated with primary hyperparathyroidism (pHPT), Graves' disease (GD) and acromegaly (AC). A 54-year-old woman was referred to our clinic for treatment of pHPT and GD. She also had active AC and was clinically diagnosed as multiple endocrine neoplasm type 1 because of pHPT and AC. Two enlarged parathyroid glands were detected by preoperative examinations. We performed total parathyroidectomy and thyroidectomy. After the operation, she showed severe hypocalcemia induced by postsurgical hypoparathyroidism and hungry bone syndrome. This is a rare case of postsurgical severe hypocalcemia associated with pHPT, GD and AC.