Association between serum ALT levels and incidence of new-onset diabetes in general population of Japanese: a longitudinal observational study (ISSA-CKD).

OBJECTIVE: We aimed to clarify the relationship between serum alanine transaminase (ALT) levels and incidence of new-onset diabetes in a Japanese general population. SETTING: Population-based retrospective cohort study using annual health check-up data for residents of Iki City, Nagasaki Prefecture, Japan. PARTICIPANTS: A total of 5330 Japanese individuals (≥30 years old) without diabetes at baseline were analysed. PRIMARY AND SECONDARY OUTCOME MEASURES: Serum ALT levels were determined using an enzymatic method and were classified into gender-specific quartile groups as follows: group 1 (3-16 U/L in men and 3-13 U/L in women), group 2 (17-21 U/L in men and 14-16 U/L in women), group 3 (22-29 U/L in men and 17-22 U/L in women) and group 4 (30-428 U/L in men and 23-268 U/L in women). The study outcome was the incidence of diabetes (fasting glucose ≥7.0 mmol/L, non-fasting glucose ≥11.1 mmol/L, glycated haemoglobin ≥6.5% or use of glucose-lowering therapies). RESULTS: After an average follow-up period of 5.0 years, 279 individuals developed diabetes. The incidence rate of diabetes increased with elevation of serum ALT levels (0.7% per 100 person-years in group 1, 0.9% in group 2, 0.9% in group 3 and 1.7% in group 4) (p<0.001 for trend). This association was significant after adjustment for other risk factors including age, sex, obesity, hypertension, dyslipidaemia, smoking, current daily alcohol intake and regular exercise (p<0.001 for trend). Comparable associations were observed between men and women (p=0.459 for interaction). CONCLUSION: Serum ALT levels were associated with future development of diabetes in the general Japanese population.

Clinical evaluations of pituitary apoplexy in incidental nonfunctional pituitary adenomas.

Pituitary apoplexy is an uncommon syndrome that often results in spontaneous hemorrhage or infarction of pituitary tumors or glands. We previously reported pituitary apoplexy occurred most frequently in nonfunctional pituitary adenomas among all types of pituitary incidentalomas. In the present study, we aimed to investigate the characteristics of pituitary apoplexy in patients with incidental nonfunctional pituitary adenomas. 65 patients with pituitary incidentaloma were enrolled. All patients underwent clinical/endocrinological/pathological investigations. As a result, 33 patients were diagnosed with nonfunctional pituitary adenomas. Of these, 12.1% of patients had pituitary apoplexy. There was no difference in tumor diameter, age, or sex between the apoplexy and the non-apoplexy groups. However, the liver enzymes aspartate transaminase and alanine aminotransferase were significantly higher, and plasma sodium and chloride levels were significantly lower in the apoplexy group than in the non-apoplexy group (each P < .05). In addition, low-density lipoprotein-cholesterol was significantly higher in the apoplexy group than in the non-apoplexy group (P < .05). Besides, thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, and prolactin deficiencies were significantly more frequent in the apoplexy group than in the non-apoplexy group (each P < .05), and growth hormone and adrenocorticotropic hormone deficiencies were more frequent in the apoplexy group than in the non-apoplexy group (P = .09 and.08, respectively). Furthermore, tumor diameter was not associated with pituitary apoplexy, whereas thyroid-stimulating hormone, luteinizing hormone, and follicle-stimulating hormone deficiencies were significantly associated with the apoplexy group (each P < .05). Hence, the present study indicated that pituitary apoplexy could not be related to tumor diameter. Moreover, hormonal deficiencies, hepatic dysfunction, hyponatremia or hypochloremia, and dyslipidemia might be indicators of pituitary apoplexy. There could be the possibility the treatment for dyslipidemia prevents pituitary apoplexy.

Clinical investigation of a unique type of hypothalamic adrenal insufficiency.

Hypothalamic adrenal insufficiency (AI) is a rare but distinct type of AI. The leading cause of hypothalamic AI is a secondary side-effect of exogenous steroid intake, particularly in large amounts and/or long-term periods. The next cause would be the effect of the tumor in the hypothalamic lesions. We show here 9 cases of hypothalamic AI without any disorder on imagings and a history of steroid administration. All patients had general fatigue; 7 patients (77.8%) had a history of hypoglycemia; 5 patients (55.6%) had a history of hypotension. None of the patients had hyponatremia, hyperkalemia, or eosinophilia. Their morning plasma adrenocorticotropic hormone (ACTH) value was low at 8.5 ± 4.2 pg/mL, and serum cortisol value was low at 4.5 ± 1.3 µg/dL. All patients demonstrated normal responses during the corticotropin-releasing hormone loading (CRH) test but inadequate responses during the insulin tolerance test (ITT). After hydrocortisone replacement therapy, their morning plasma ACTH and serum cortisol values were significantly recovered (P < .05). Moreover, more than half of the patients were fine after discontinuing hydrocortisone replacement therapy. These results indicate that this unique type of hypothalamic AI has a curable clinical course making hydrocortisone replacement therapy a novel therapeutic option.

Association between pulse pressure and progression of chronic kidney disease.

The aim of this study was to investigate the association between pulse pressure (PP) and chronic kidney disease (CKD) progression among the general population in Japan. We conducted a population-based cohort study of the residents of Iki Island, Nagasaki, Japan, from 2008 to 2018. We identified 1042 participants who had CKD (estimated glomerular filtration rate(eGFR) < 60 mL/min/1.73 m2 or the presence of proteinuria) at baseline. Cox's proportional hazard model was used to evaluate the association between PP and progression of CKD. During a 4.66-year mean follow-up, there were 241 cases of CKD progression (incident rate: 49.8 per 1000 person-years). A significant increase existed in CKD progression per 10 mmHg of PP elevation, even when adjusted for confounding factors [adjusted hazard ratio 1.17 (1.06-1.29) p < 0.001]. Similar results were obtained even after dividing PP into quartiles [Q2: 1.14 (0.74-1.76), Q3: 1.35 (0.88-2.06), Q4: 1.87 (1.23-2.83) p = 0.003 for trend]. This trend did not change significantly irrespective of baseline systolic or diastolic blood pressures. PP remained a potential predictive marker, especially for eGFR decline. In conclusion, we found a significant association between PP and CKD progression. PP might be a potential predictive marker for CKD progression.

Effect of denosumab, a human monoclonal antibody of receptor activator of nuclear factor kappa-B ligand (RANKL), upon glycemic and metabolic parameters: Effect of denosumab on glycemic parameters.

Osteoporosis is a complication of type 2 diabetes mellitus (T2DM). Blockade of receptor activator of nuclear factor kappa-B ligand (RANKL) improves osteoporosis, but might also improve glucose tolerance through reduction of hepatic insulin resistance. However, the effect of denosumab (a human monoclonal antibody of RANKL) upon glycemic and metabolic parameters is controversial. We revealed the effect of denosumab upon glycemic and metabolic parameters for 52 weeks. We evaluated 20 individuals diagnosed with both osteoporosis (male and female: postmenopausal) and T2DM. We measured glycemic and metabolic parameters before and 26/52 weeks after administration of denosumab (60 mg per 26 weeks) without changing any other medication each patient was taking. All patients completed the study without complications and the T-score (lumbar spine and femoral neck) improved significantly from baseline to 52 weeks after denosumab administration (P < .001, .001, respectively). None of the glycemic parameters changed significantly from baseline to 26 weeks after denosumab administration, but levels of glycated hemoglobin and homeostasis model assessment of insulin resistance improved significantly from baseline to 52 weeks after administration (P = .019, .008, respectively). The levels of liver enzymes did not change significantly from baseline to 26 weeks after denosumab administration, but levels of aspartate transaminase and alanine aminotransferase improved significantly from baseline to 52 weeks after administration (P = .014, .004, respectively). None of the markers of lipid metabolism and body mass index changed significantly from baseline to 26/52 weeks after denosumab administration. These data demonstrated that denosumab is useful for T2DM patients with osteoporosis for glycemic control via improvement of insulin resistance. Also, the effect of denosumab might be due to improvement of hepatic function.

Clinical investigation of pituitary incidentalomas: A two-center study.

Recent advances in imaging technology resulted in an increase in pituitary incidentalomas (PIs) detection. PIs were reported to be present in 1.6% persons with magnetic resonance imaging of the brain. Whereas, there were few studies about PIs with detailed investigation. We aimed to investigate the clinical and endocrinological characteristics of PIs. We evaluated 65 patients diagnosed with PIs who underwent detailed clinical and endocrinological evaluations. Of the 65 patients, 33 (50.8%) had non-functional pituitary adenomas (NFPAs), 11 (16.9%) had Rathke's cleft cysts (RCCs), 7 (10.8%) had functional pituitary adenomas (FPAs), 6 (9.2%) had benign extra-pituitary tumors (BEPTs), and 8 (12.3%) had malignant tumors (MTs). Compared with patients with NFPAs, those with MTs were significantly younger and had a significantly lower body mass index, lower prevalence of hypertension, and lower prevalence of dyslipidemia. Patients with MTs had significantly higher prevalence of central diabetes insipidus than those with NFPAs. In addition, patients with NFPAs had significantly higher prevalence of pituitary apoplexy than those with FPAs, BEPTs, and MTs. In conclusion, our study demonstrated clinical and endocrinological characteristics of PIs. Highly detailed clinical and endocrinological investigations should be performed for PIs. In addition, MTs should be considered in the differential diagnosis for young and lean patients with central diabetes insipidus.

Differences in the actions of adrenaline and noradrenaline with regard to glucose intolerance in patients with pheochromocytoma.

Glucose intolerance is often observed in patients with pheochromocytoma. However, it remains controversial issue that glucose intolerance on pheochromocytoma is caused by impaired insulin secretion and/or by increased insulin resistance. We aimed to reveal the mechanism of glucose intolerance on pheochromocytoma with regard to the type and amount of catecholamines released. We evaluated 12 individuals diagnosed with pheochromocytoma and who underwent surgery to remove it. We examined glycemic parameters before and after surgery and investigated the association between the change of parameters of insulin secretion (homeostasis model assessment of ß-cell function (HOMA-ß)), insulin resistance (homeostasis model assessment of insulin resistance (HOMA-IR)) and that of urinary levels of metanephrine/normetanephrine before and after surgery. Overall, fasting plasma glucose, glycated hemoglobin (HbA1c), HOMA-ß, and HOMA-IR were improved significantly after surgery. Regression analysis showed that the improvement in HOMA-ß from before to after surgery was significantly positively associated with an improvement in urinary levels of metanephrine from before to after surgery and showed a significantly negative association with improvement in urinary levels of normetanephrine from before to after surgery. The improvement in HOMA-IR from before to after surgery was significantly positively associated with an improvement in urinary levels of normetanephrine from before to after surgery. Our results showed that pheochromocytoma extirpation improved glycemic parameters. Furthermore, the different effects elicited by excess amounts of adrenaline and noradrenaline on glucose intolerance were demonstrated.

Dietary inflammatory index and risk of upper aerodigestive tract cancer in Japanese adults.

BACKGROUND: The inflammatory potential of diet that has been shown to be associated with cancer risk. We examined the association between dietary inflammatory potential as measured by the dietary inflammatory index (DII®) and risk of upper aerodigestive tract cancers in a Japanese case-control study. RESULTS: A positive association was observed between increasing DII scores and overall upper aerodigestive tract cancers, and across anatomic subsites. For upper aerodigestive tract cancers, the ORQ4vsQ1 = 1.73 (95% CI: 1.37-2.20); head and neck cancer, the ORQ4vsQ1 was 1.92 (95% CI: 1.42-2.59); and for esophageal cancer, the ORQ4vsQ1 was1.71 (95% CI: 1.54-1.90). Risks for hypopharyngeal and nasopharyngeal cancers were greatly elevated: (ORQ4vsQ1 = 4.05 (95% CI: 1.24-13.25) for hypopharyngeal cancer and ORQ4vsQ1 = 4.99 (95% CI: 1.14-21.79) for nasopharyngeal cancer. CONCLUSION: A more pro-inflammatory diet was associated with an elevated risk of upper aerodigestive tract cancers after accounting for important confounders. All anatomic subsites, except larynx, showed the consistently elevated risk with increasing DII score. Those subsites with known etiological associations with persistent infection showed the largest elevation in risk. These results warrant further evaluation in future studies. MATERIALS AND METHODS: This is a case-control study of 1,028 cases and 3,081 age- and sex-matched non-cancer controls recruited at Aichi Cancer Center. DII scores were computed based on estimates of macro- and micro-nutrients from a self-administered food frequency questionnaire. Scores were further categorized into quartiles (based on the distribution in controls). Conditional logistic regression models were fit to estimate odds ratio (OR) and 95% confidence intervals (CIs) adjusted for smoking, ethanol consumption, alcohol flushing, number of teeth, and occupation group.

The more from East-Asian, the better: risk prediction of colorectal cancer risk by GWAS-identified SNPs among Japanese.

BACKGROUND: Little is known about the difference of genetic predisposition for CRC between ethnicities; however, many genetic traits common to colorectal cancer have been identified. This study investigated whether more SNPs identified in GWAS in East Asian population could improve the risk prediction of Japanese and explored possible application of genetic risk groups as an instrument of the risk communication. METHODS: 558 Patients histologically verified colorectal cancer and 1116 first-visit outpatients were included for derivation study, and 547 cases and 547 controls were for replication study. Among each population, we evaluated prediction models for the risk of CRC that combined the genetic risk group based on SNPs from GWASs in European-population and a similarly developed model adding SNPs from GWASs in East Asian-population. We examined whether adding East Asian-specific SNPs would improve the discrimination. RESULTS: Six SNPs (rs6983267, rs4779584, rs4444235, rs9929218, rs10936599, rs16969681) from 23 SNPs by European-based GWAS and five SNPs (rs704017, rs11196172, rs10774214, rs647161, rs2423279) among ten SNPs by Asian-based GWAS were selected in CRC risk prediction model. Compared with a 6-SNP-based model, an 11-SNP model including Asian GWAS-SNPs showed improved discrimination capacity in Receiver operator characteristic analysis. A model with 11 SNPs resulted in statistically significant improvement in both derivation (P = 0.0039) and replication studies (P = 0.0018) compared with six SNP model. We estimated cumulative risk of CRC by using genetic risk group based on 11 SNPs and found that the cumulative risk at age 80 is approximately 13% in the high-risk group while 6% in the low-risk group. CONCLUSION: We constructed a more efficient CRC risk prediction model with 11 SNPs including newly identified East Asian-based GWAS SNPs (rs704017, rs11196172, rs10774214, rs647161, rs2423279). Risk grouping based on 11 SNPs depicted lifetime difference of CRC risk. This might be useful for effective individualized prevention for East Asian.

Hypertrophy and loss of podocytes in diabetic nephropathy.

OBJECTIVE: The loss of podocytes has been reported to have a role in the onset and progression of diabetic nephropathy (DN). Although structural changes such as podocyte hypertrophy are considered to be associated with podocyte loss, the relationship has not been thoroughly investigated using human DN renal tissues. METHODS: The subjects were 17 patients with DN diagnosed histopathologically by renal biopsy. Immunostaining was performed with antibodies for Wilm's tumor 1 (WT1) and synaptopodin (SPD), which are markers of podocytes, to determine the number of podocytes and assess podocyte hypertrophy. RESULTS: The number of podocytes was decreased in DN patients compared with the controls. An inverse correlation was observed between the number of podocytes and both the urinary protein excretion and the extent of mesangial expansion. Podocyte hypertrophy was also more marked in DN patients compared with controls. CONCLUSION: Based on these results, podocyte loss and hypertrophy were suggested to be involved in the development and progression of human DN.

Expression of alpha-actinin-4 in human diabetic nephropathy.

BACKGROUND: Alpha-actinin-4 is an actin filament crosslinking protein that interacts with intercellular adhesion molecules. Recent animal studies suggested that alpha-actinin-4 is an essential component of the glomerular filtration barrier. However, little is known about its expression in human diabetic nephropathy (DN). METHODS: Renal biopsy tissues were obtained from 17 patients with DN. We determined the mRNA and protein expression levels of alpha-actinin-4 by in situ hybridization and immunohistochemistry. The histopathological severity of DN was classified into two groups: mild and moderate mesangial expansion groups. We also measured urinary protein excretion and creatinine clearance. RESULTS: Podocytes were positively stained for alpha-actinin-4 mRNA and protein. In the glomeruli, the percentage of cells positive for alpha-actinin-4 mRNA was significantly lower in moderate mesangial expansion group than in mild mesangial expansion group and control. The percentage of immunohistochemically positive area for alpha-actinin-4 protein in moderate mesangial expansion group was significantly lower than in mild mesangial expansion group and control. The percentage of cells positive for alpha-actinin-4 mRNA and area positive for the protein correlated inversely with severity of proteinuria. CONCLUSION: Our results suggest that low expression levels of alpha-actinin-4 mRNA and protein are linked to the progression of glomerulopathy and proteinuria in human DN.