Denosumab is Effective for Controlling Serum Calcium Levels in Patients with Humoral Hypercalcemia of Malignancy Syndrome: A Case Report on Parathyroid Hormone-related Protein-producing Cholangiocarcinoma.

Hypercalcemia resulting in the elevation of serum parathyroid hormone-related protein (PTHrP) and suppression of serum PTH was observed in a patient with advanced cholangiocarcinoma (CCC) and multiple lymph node metastases. We confirmed humoral hypercalcemia of malignancy based on PTHrP-producing CCC. Chemotherapy with gemcitabine and cisplatin could not control the patient's serum PTHrP levels and the patient was affected with bisphosphonate-refractory hypercalcemia. We administered a single dose of denosumab, an anti-receptor activator of nuclear factor-kappaB ligand monoclonal antibody, and the patient's serum calcium levels remained close to the normal range for approximately 3 weeks without additional treatment.

Beneficial Effects of Vildagliptin on Metabolic Parameters in Patients with Type 2 Diabetes.

Blood pressure and lipid profile are important determinants of cardiovascular risk in patients with type 2 diabetes mellitus (T2DM). To identify the pleiotropic effects of vildagliptin other than blood glucose lowering effect, a retrospective study was conducted in 128 patients with T2DM treated with vildagliptin 50 mg twice daily. The patients were separated into two groups: patients who were initiated with vildagliptin as monotherapy or add-on therapy (add-on group, n = 66) and patients who were switched from sitagliptin 100 mg once daily to vildagliptin (switching group, n = 62). Hemoglobin A1c (HbA1c), body mass index (BMI), systolic/diastolic blood pressure, lipid profiles, and uric acid (UA) at 3, 6, and 12 months of vildagliptin therapy were compared with those at baseline in each group. At baseline, there were no significant differences in HbA1c, BMI, blood pressures, lipid profiles, and UA levels between the two groups. After vildagliptin initiation, HbA1c decreased significantly but BMI and blood pressure did not change in both groups. Only in the add-on group, total cholesterol and low density lipoprotein cholesterol decreased significantly from baseline to 3, 6, and 12 months. On the other hand, triglyceride and high-density lipoprotein cholesterol did not change in both groups. Serum UA levels decreased only in the switching group from baseline to 3, 6, and 12 months. These results indicate that vildagliptin add-on treatment may have beneficial effects on lipid profiles, and switching from sitagliptin to vildagliptin reduces UA in patients with T2DM; these are important findings linked to the beneficial effects of vildagliptin on lipid and UA metabolisms in the treatment of T2DM.

The relation between CA 19-9 level and early-phase insulin secretion in normoglycemic and prediabetic subjects.

BACKGROUND: Carbohydrate antigen (CA) 19-9 is used as a clinical tumor marker of pancreatic cancer; recent studies report that CA 19-9 is also associated with changes in blood glucose levels. The aim of the present study was to investigate the relationship between serum CA 19-9 levels and early-phase insulin secretion in nondiabetic individuals. METHODS: We enrolled 269 normoglycemic participants and 172 prediabetic participants who had undergone the 75-g oral glucose tolerance test during their annual health examination. Insulin secretion was estimated using the disposition index (DI) [(Δinsulin(0-30 min)/Δglucose(0-30 min) × (1/HOMA-IR)], which is an adjusted measure of relationship between ß-cell sensitivity and insulin sensitivity. RESULTS: Serum CA 19-9 level was significantly higher in the prediabetic participants than in the normoglycemic participants. Simple linear regression analysis showed a negative correlation between CA 19-9 levels and DI for all participants and prediabetic participants (r = -0.126, p = 0.009, and r = -0.189, p = 0.002, respectively). However, in the normoglycemic participants, CA 19-9 levels did not correlate with DI. For all participants, and prediabetic subjects, multivariate linear regression analysis revealed that serum CA 19-9 levels were one of the independent predictors of DI (adjusted ß = -0.098, p = 0.025, and adjusted ß = -0.177, p = 0.004, respectively). CONCLUSIONS: Serum CA 19-9 levels significantly correlate with early-phase insulin secretion in the prediabetic individuals. Our results indicate that CA 19-9 may be involved in the endocrine function of pancreas.

Impact of serum triglyceride and high density lipoprotein cholesterol levels on early-phase insulin secretion in normoglycemic and prediabetic subjects.

BACKGROUND: Increased triglycerides (TGs) and decreased high density lipoprotein cholesterol (HDL-C) levels are established as diabetic risks for nondiabetic subjects. The aim of this study was to investigate the relationship among TG, HDL-C, TG/HDL-C ratio, and early-phase insulin secretion in normoglycemic and prediabetic subjects. METHODS: We evaluated 663 Japanese subjects who underwent the 75-g oral glucose tolerance test. On the basis of these results, the subjects were divided into four groups: those with normal glucose tolerance (NGT; n=341), isolated impaired fasting glucose (i-IFG; n=211), isolated impaired glucose tolerance (i-IGT; n=71), and combined IFG and IGT (IFG+IGT; n=40). Insulin secretion was estimated by the insulinogenic index (IGI) (Δinsulin/Δglucose [30 to 0 minutes]) and disposition index (DI) (IGI/homeostasis model assessment of insulin resistance). RESULTS: In prediabetic subjects (i-IFG, i-IGT, and IFG+IGT), linear regression analyses revealed that IGI and DI were positively correlated with HDL-C levels. Moreover, in subjects with i-IGT and (IFG+IGT), but not with i-IFG, the indices of insulin secretion were negatively correlated with the log-transformed TG and TG/HDL-C ratio. In both the subjects with i-IGT, multivariate linear regression analyses revealed that DI was positively correlated with HDL-C and negatively with log-transformed TG and TG/HDL-C ratio. On the other hand, in subjects with NGT, there was no association between insulin secretion and lipid profiles. CONCLUSION: These results revealed that serum TG and HDL-C levels have different impacts on early-phase insulin secretion on the basis of their glucose tolerance status.

Correlation between mean platelet volume and blood glucose levels after oral glucose loading in normoglycemic and prediabetic Japanese subjects.

AIMS/INTRODUCTION: Mean platelet volume (MPV) reflects platelet activity, and high MPV is associated with thrombogenic activation and increased cardiovascular disease risk. Although a positive correlation between MPV and fasting plasma glucose (FPG) levels has been reported, the correlation between MPV and postprandial glucose levels remains unclear. The purpose of the present study was to evaluate the correlation between MPV and postprandial glucose levels in prediabetic and normoglycemic participants. MATERIALS AND METHODS: We evaluated 1,080 Japanese participants who underwent the 75-g oral glucose tolerance test (OGTT). Based on these results, the participants were divided into three groups: normal glucose tolerance group (NGT; n = 582), impaired fasting glucose group (IFG; n = 205) and impaired glucose tolerance group (IGT; n = 252). The relationship between MPV, FPG, and postchallenge glucose levels after 1 h (1 h-PG) and 2 h (2 h-PG) were analyzed. RESULTS: Bivariate correlation analyses showed a significant positive correlation between MPV and both FPG and 1 h-PG levels in the NGT group, as well as between MPV and 2 h-PG, total cholesterol, and low-density lipoprotein cholesterol in the IGT group. In contrast, no significant correlation was observed between MPV and postchallenge glucose levels in the IFG group. Multiple correlation analyses showed that FPG levels significantly correlated with MPV in the NGT and IGT groups. In addition, 1 h-PG and 2 h-PG levels correlated with MPV in the NTG and IGT groups, respectively. CONCLUSIONS: These results suggest a possible mechanism by which subjects with postprandial hyperglycemia might be at increased cardiovascular risk.

Serum triglyceride levels correlated with the rate of change in insulin secretion over two years in prediabetic subjects.

BACKGROUND/AIMS: Increased triglyceride (TG) and decreased high-density lipoprotein cholesterol (HDL-C) levels are considered risk factors for diabetes among prediabetic subjects. In this study, we retrospectively investigated the relationship between lipid profiles and the rate of change in early-phase insulin secretion in prediabetic subjects. METHODS: To evaluate insulin secretion, 50 prediabetic subjects underwent a 75-gram oral glucose tolerance test at the beginning of the study (baseline), and they were reexamined after a 2-year interval. The results were expressed as insulinogenic index (IGI) and disposition index (DI). RESULTS: The lipid profiles and indices of insulin secretion had not significantly changed over 2 years. However, Pearson's correlation analyses indicated that the rate of change in IGI and DI was negatively correlated with log-transformed baseline TG level, but not with baseline HDL-C level. Multiple linear regression analysis confirmed that the rate of change in IGI and DI was negatively correlated with the log-transformed baseline TG level (ß = -0.38, p = 0.006, and ß = -0.39, p = 0.006, respectively). CONCLUSIONS: Baseline TG level of prediabetic subjects appeared to be associated with rate of change in IGI and DI over a 2-year period, indicating that TG levels among prediabetic subjects should be carefully monitored.

Correlation between serum lipids and 1-hour postload plasma glucose levels in normoglycemic individuals.

BACKGROUND: One-hour plasma glucose (1-h PG) level of ≥ 155 mg/dL during an oral glucose tolerance test (OGTT) predicts the development of type 2 diabetes mellitus among individuals with normal glucose tolerance (NGT). In addition, high triglyceride (TG) and low high-density lipoprotein-cholesterol (HDL-C) levels are risks factors for development of diabetes mellitus in the future. OBJECTIVE: To examine the association between 1-h PG levels and serum lipid profiles in individuals with NGT. METHODS: We enrolled 736 individuals with NGT who underwent a 75-g OGTT. They were divided into 2 groups, those with 1-h PG levels < 155 mg/dL (n = 543) and those with 1-h PG levels ≥ 155 mg/dL (n = 193). Multivariate linear regression analyses were performed to assess correlations between 1-h PG levels and lipid profiles. RESULTS: The multiple linear regression analyses showed that 1-h PG levels negatively correlated with HDL-C in individuals with NGT who had 1-h PG levels ≥ 155 mg/dL as well as those with 1-h PG levels < 155 mg/dL (ß = -0.137, P = .001 and ß = -0.214, P = .003, respectively). In addition, 1-h PG levels positively correlated with log-transformed TG/HDL-C ratio in both groups (ß = 0.098, P = .032 and ß = 0.152, P = .035, respectively). Moreover, even after adjusting for confounding parameters, TG was higher and HDL-C was lower in individuals with NGT who had 1-h PG levels ≥ 155 mg/dL compared with those who had 1-h PG levels < 155 mg/dL. CONCLUSION: HDL-C levels and TG/HDL-C ratios closely correlate with 1-h PG levels in individuals with NGT.

Diagnostic challenge of pheochromocytoma in a patient receiving levodopa for Parkinson's disease.

OBJECTIVE: The diagnosis of pheochromocytoma in patients receiving levodopa is challenging because the standard diagnostic biochemical tests may be confounded by dopaminergic therapy. We aim to showcase our experience with the diagnosis of pheochromocytoma in a patient with a known case of Parkinson's disease who was receiving levodopa. METHODS: We present the case of an elderly male who was diagnosed as having pheochromocytoma while receiving dopaminergic therapy for Parkinson's disease. RESULTS: A 75-year-old man presented with vague abdominal symptoms. Computed tomography revealed a 3.5 x 3.2 cm right adrenal mass with a well-defined margin. As revealed by magnetic resonance imaging, the mass was hypointense on T1-weighted and hyperintense on T2-weighted images. Biochemical tests revealed elevated levels of urinary dopamine, which was considered to be caused by levodopa therapy. However, concurrent elevation in urinary adrenaline and his metanephrine and vanillylmandelic acid levels suggested an underlying case of pheochromocytoma. An 123I-metaiodobenzylguanidine (123I-MIBG) scintigraphy scan performed under levodopa therapy showed positive tracer uptake in the right adrenal gland. Histopathology of the adrenalectomy specimen confirmed the diagnosis of pheochromocytoma. CONCLUSION: Our experience with the present case indicates that although the standard diagnostic biochemical tests for pheochromocytoma may be confounded by dopaminergic therapy, 123I-MIBG scintigraphy has diagnostic value for confirming pheochromocytoma even in patients receiving dopaminergic therapy.

Gender differences in the relationship between serum uric acid and mean platelet volume in a Japanese general population.

Mean platelet volume (MPV) can reflect platelet activity. Furthermore, high MPV is associated with thrombogenic activation and increased risk of cardiovascular disease. MPV of subjects with hypertension, hyperglycemia, or hyperlipidemia is higher compared with that of normal subjects. In contrast, the relationship between MPV and uric acid (UA) is poorly understood. The present study aims to evaluate the relationship between MPV and serum UA levels in both genders. We retrospectively studied 2104 Japanese subjects (1221 males, 883 females) undergoing general health examinations. Age, gender, body mass index (BMI), blood pressure (BP), smoking habits, alcohol intake, lipid profiles, fasting plasma glucose (FPG), high-sensitivity C-reactive protein, serum UA levels and MPV were evaluated. On the basis of the serum UA levels, the subjects were categorized into the following tertiles: 1st (Q1), 2nd (Q2), and 3rd (Q3). In males, a univariate analysis revealed that age, FPG and systolic and diastolic BP were significantly associated with MPV; in addition to these parameters, in females, UA and LDL-cholesterol correlate with MPV. Furthermore, in females, a stepwise linear regression analysis showed a significant positive correlation between UA and MPV (ß=0.059, p=0.008). MPV in females increased gradually based on the serum UA tertile, despite adjusting for confounding variables (Q1, Q2, and Q3 values were 9.88 ± 0.70, 9.95 ± 0.73, and 10.00 ± 0.77 fL, respectively; p<0.039). The serum UA levels were found to be a key determinant of MPV in females.

Humoral hypercalcemia associated with gastric carcinoma secreting parathyroid hormone: a case report and review of the literature.

Hypercalcemia with concomitant elevation of serum parathyroid hormone (PTH) and PTH-related protein (PTHrP) levels was found in a patient with advanced gastric carcinoma and multiple liver metastases. The most common features are hypercalcemia associated with hypersecretion of PTHrP and physiological suppression of PTH secretion in the syndrome of humoral hypercalcemia of malignancy (HHM). Although we initially made a diagnosis of primary hyperparathyroidism concomitant with HHM due to gastric cancer, diagnostic imaging studies, such as echography, CT, sestamibi scintigraphy, and autopsy findings, did not reveal evidence of any parathyroid tumors or ectopic parathyroid glands in the mediastinum. Both primary and metastatic tumor cells showed positive staining with PTH-specific antibody as well as PTHrP-specific antibody on immunohistochemical examination. PTH concentration in the cytosolic fraction of the metastatic tumor was elevated compared to that from a control patient with no calcium metabolic disorders in vitro. These findings indicated that PTH secreted ectopically by gastric cancer cells, not by parathyroid glands, caused hypercalcemia in this patient. To our knowledge, this is the first case report of PTH-secreting gastric carcinoma cells. We report the case and a review of the previous reported PTH-secreting non-parathyroid tumors along with the mechanisms of secretion.

Correlation between mean platelet volume and fasting plasma glucose levels in prediabetic and normoglycemic individuals.

BACKGROUND: Prediabetes is an independent risk factor for cardiovascular diseases. Mean platelet volume (MPV) can reflect platelet activity, and high MPV is associated with thrombogenic activation and an increased risk of cardiovascular disease. In diabetic patients, MPV is higher when compared with normal subjects. However, the relationship between MPV and prediabetes is poorly understood. The purpose of the present study was to compare MPV in prediabetic and normoglycemic subjects, and to evaluate the relationship between MPV and fasting plasma glucose (FPG) levels in these two groups. METHODS: We retrospectively studied 1876 Japanese subjects who had undergone health checks at Iida Municipal Hospital. Age, sex, body mass index (BMI), blood pressure, medical history, smoking habits, alcohol intake, lipid profiles, FPG levels, and MPV were evaluated. Subjects were categorized into four groups according to FPG: Q1 (70 mg/dL ≤ FPG < 90 mg/dL, n = 467), Q2 (90 mg/dL ≤ FPG < 95 mg/dl, n = 457), Q3 (95 mg/dL ≤ FPG < 100 mg/dL, n = 442), and Q4 (100 mg/dL ≤ FPG < 126 mg/dL, n = 512). Q1, Q2, and Q3 were defined as normal FPG groups and Q4 was defined as prediabetic group. RESULTS: The MPV increased with the increasing FPG levels, in the following order: Q1 (9.89 ± 0.68 fl), Q2 (9.97 ± 0.69 fl), Q3 (10.02 ± 0.72 fl), and Q4 (10.12 ± 0.69 fl). After adjusting for the confounding parameters, MPV of the prediabetic group was higher than that in other groups (P < 0.001 for Q4 vs. Q1 and Q2, and P < 0.05 for Q4 vs. Q3). MPV in the high-normal glucose group (Q3) was significantly higher than in the low-normal glucose group (Q1). MPV was independently and positively associated with FPG, not only in prediabetic subjects but also in normal FPG subjects (ß = 0.020 and ß = 0.006, respectively). CONCLUSIONS: MPV in patients with prediabetes was higher than that in normal subjects, and was positively associated with FPG levels in prediabetic and normal subjects.

Cell-specific expression of NADPH-dependent cytosolic 3,5,3'-triiodo-L-thyronine-binding protein (p38CTBP).

We have previously shown that cytosolic 3,5,3'-triiodo-L-thyronine (T3)-binding protein (CTBP) possesses a high affinity for T3 binding in the presence of nicotinamide adenine dinucleotide phosphate in vitro, and that p38CTBP increases intracellular content of T3, and suppresses T3-mediated transactivity. Screening of mRNA expression in 73 different human tIssues has demonstrated that p38CTBP mRNA is expressed at high levels in brain and heart. We have examined the intracellular localization and tissue-specific distribution of this protein by using a specific antibody against human p38CTBP. Western blotting and immunoprecipitation studies have shown that the antibody recognizes human p38CTBP. Interaction of p38CTBP with the antibody did not affect the T3-binding activity of p38CTBP, and its dimer formation in vitro. Western blotting analysis has shown that p38CTBP is expressed in brain and heart predominantly, similar to the distribution of mRNA. Immunohistochemical studies have demonstrated p38CTBP in neural cells and cardiac muscle cells. p38CTBP localizes in cytoplasm rather than in nuclei in neural cells. The evidence for the presence of tIssue-specific localization of p38CTBP has indicated that p38CTBP has a tIssue-specific function, such as the regulation of T3 delivery from cytoplasm to nuclei.

Nicotinamide adenine dinucleotide phosphate-dependent cytosolic T(3) binding protein as a regulator for T(3)-mediated transactivation.

Nicotinamide adenine dinucleotide phosphate (NADPH)- dependent cytosolic T(3) binding protein (CTBP) plays a role in the regulation of nuclear transport of T(3) in vitro. However, it is not known whether CTBP regulates the T(3) action. In this study, we examined the effects of CTBP on cellular translocation of T(3) and on transcriptional activation using established CTBP-expressing CHO or GH3 cells. The expression of CTBP increased cellular and nuclear uptake of T(3) in the CTBP-expressing cells. The efflux rate was decreased by induction of CTBP. Efflux from nuclei also inhibited by induction of CTBP. Expression of CTBP suppressed the T(3)-regulated luciferase activity in GH3 cells. Suppression was observed to be related to the expression level of CTBP. T(3) induction of rat GH mRNA was lower in the cells expressing CTBP than that in CTBP-null cells. These results suggest that CTBP regulates the T(3)-induced gene expression, with which an increase in the nuclear content of the T(3) is associated. Because we observed that a part of CTBP could be transported into nuclei and that acceptor protein for CTBP is present in nuclei as previously reported, interaction of CTBP with certain proteins, including transcription factors or nuclear T(3) receptor, may contribute to the regulation.