Kosuke Mukai

Glycated albumin is set lower in relation to plasma glucose levels in patients with Cushing's syndrome

BACKGROUND Glycated albumin (GA) is an indicator of glycemic control, which has some specific characters in comparison with HbA1c. Since glucocorticoids (GC) promote protein catabolism including serum albumin, GC excess state would influence GA levels. We therefore investigated GA levels in patients with Cushings syndrome. METHODS We studied 16 patients with Cushings syndrome (8 patients had diabetes mellitus and the remaining 8 patients were non-diabetic). Thirty-two patients with type 2 diabetes mellitus and 32 non-diabetic subjects matched for age, sex and BMI were used as controls. RESULTS In the patients with Cushings syndrome, GA was significantly correlated with HbA1c, but the regression line shifted downwards as compared with the controls. The GA/HbA1c ratio in the patients with Cushings syndrome was also significantly lower than the controls. HbA1c in the non-diabetic patients with Cushings syndrome was not different from the non-diabetic controls, whereas GA was significantly lower. In 7 patients with Cushings syndrome who performed self-monitoring of blood glucose, the measured HbA1c was matched with HbA1c estimated from mean blood glucose, whereas the measured GA was significantly lower than the estimated GA. CONCLUSIONS We clarified that GA is set lower in relation to plasma glucose levels in patients with Cushings syndrome.

Glycated Albumin, Rather than Hba1c, Reflects Diabetic Retinopathy in Patients with Type 2 Diabetes Mellitus

Background: It has recently been shown that glycated albumin (GA) has some different aspects from HbA1c as an indicator of chronic glycemic control, besides it reflects shorter periods of glycemia. In this study, we investigated whether both indices of chronic glycemia are differently influenced by diabetic duration and diabetic vascular complications. Methods: The present study included 63 patients with type 2 diabetes mellitus (40 men, 23 women) in whom HbA1c and GA were simultaneously measured every other month during a year. Annual mean levels of HbA1c, GA, and the GA/HbA1c ratio were determined, and the associations of these values with diabetes duration, diabetic retinopathy, and diabetic nephropathy were analyzed. Results: Annual mean levels of the GA/HbA1c ratio were significantly correlated with diabetes duration, whereas those of HbA1c and GA were not associated with it. Annual mean levels of GA and the GA/HbA1c ratio were significantly higher in the patients with diabetic retinopathy than in those without it, whereas those of HbA1c were not different between both groups. Annual mean levels of HbA1c, GA and the GA/HbA1c ratio were not different between the patients with diabetic nephropathy and those without it. By multivariate regression analysis, GA as well as diabetic duration were explanatory variables for diabetic retinopathy. Conclusion: These results indicate that GA, rather than HbA1c, reflects diabetic retinopathy in patients with type 2 diabetes mellitus.

Metformin decreases glycated albumin to glycated haemoglobin ratio in patients with newly diagnosed type 2 diabetes

Background To know whether metformin improves postprandial hyperglycaemia, we examined the effect of metformin on the glycated albumin (GA) to glycated haemoglobin (HbA1c) ratio (GA/HbA1c ratio) in patients with newly diagnosed type 2 diabetes. Methods Metformin and lifestyle interventions were initiated in 18 patients with newly diagnosed type 2 diabetes. Metformin was titrated to 1500 mg/day or maximum-tolerated dose. HbA1c and GA were measured every four weeks up to 24 weeks. Results HbA1c decreased significantly from 9.0 ± 2.1% at baseline to 6.5 ± 0.9% at week 24, and GA decreased significantly from 24.3 ± 8.2% to 16.2 ± 3.1%. The GA/HbA1c ratio decreased significantly from 2.66 ± 0.37 at baseline to 2.47 ± 0.29 at week 24 (P < 0.01), despite that the GA/HbA1c ratio reached a plateau value at week 16. The change in the GA/HbA1c ratio during 24 weeks (ΔGA/HbA1c ratio) was significantly correlated with both baseline HbA1c and GA. Moreover, the ΔGA/HbA1c ratio was significantly correlated with the change in GA during 24 weeks but not with the change in HbA1c. Conclusions Metformin decreased the GA/HbA1c ratio in patients with newly diagnosed type 2 diabetes. This suggests that metformin improves postprandial hyperglycaemia in patients with newly diagnosed type 2 diabetes.

Plasma aldosterone level within the normal range is less associated with cardiovascular and cerebrovascular risk in primary aldosteronism.

Background: Previous studies showed higher risk of cardiovascular and cerebrovascular (CCV) events in primary aldosteronism compared with essential hypertension, but the patients of these studies were limited to primary aldosteronism patients with high plasma aldosterone concentration (PAC). The introduction of the aldosterone–renin ratio as the screening test for primary aldosteronism led to the recognition of primary aldosteronism patients with normal PAC (nPA). However, there is no information on the risk of primary aldosteronism including nPA. Method: In this retrospectively and cross-sectional study, the clinical features and CCV event risk of primary aldosteronism at diagnosis including nPA were investigated and compared with essential hypertension. The study included 292 consecutive primary aldosteronism patients and 498 essential hypertension outpatients. All primary aldosteronism patients were diagnosed by autonomous aldosterone secretion using confirmatory tests, and then divided into nPA (n = 130) and primary aldosteronism patients with high PAC (hPA: n = 162) using a PAC cutoff level of less than 443 pmol/l (16 ng/dl), representing the normal upper limit of PAC. Results: nPA patients were significantly older at diagnosis of primary aldosteronism and at onset of hypertension compared with hPA patients. They had milder hypokalemia and easier-to-control blood pressure. The results suggested that nPA could be considered a mild type of primary aldosteronism but not an early-stage hPA. Moreover, the risk of all CCV events in nPA was significantly lower than that in hPA (odds ratio 0.42, 95% confidence interval 0.18–0.90, P < 0.05) and not significantly higher than that in essential hypertension (odds ratio 0.95, 95% confidence interval 0.43–1.94, P = 0.899). Conclusion: This study suggests that aggressive diagnostic workout for nPA is less effective to prevent CCV events.

Nur77 gene expression levels were involved in different ACTH-secretion autonomy between Cushing’s disease and subclinical Cushing’s disease

Cushings disease (CD) and subclinical Cushings disease (subCD) are both diseases caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas. However, ACTH autonomy in subCD is weaker than in CD and there are no Cushingoid features in subCD. The differences of molecular mechanisms in ACTH autonomy between CD and subCD have not yet been reported. Therefore, we aimed to investigate the differences in molecular mechanisms of ACTH-secretion autonomy between CD and subCD. The study included 23 patients [7 CD, 6 subCD, and 10 non-functioning pituitary tumors (NFTs)] who underwent transsphenoidal surgery at the Osaka University Hospital between December 2009 and October 2013. Using quantitative real-time PCR, various ACTH-related gene expressions in tumor tissues from CD, subCD, and NFT were measured such as pro-opiomelanocortin (POMC), POMC transcription factor (Tpit, Pitx1, NeuroD1, and Nur77), POMC peptide processing enzymes (prohormone convertase: PC1/3 and PC2), and ACTH secretion-related factors (corticotropin-releasing hormone receptor 1: CRHR1 and glucocorticoid receptor α: GRα). Only Nur77 mRNA levels were significantly higher in CD than in subCD. Furthermore, we stained 6 CD and 6 subCD with anti-Nur77 antibody. All tumor samples from CD had Nur77 protein positive cells. On the other hand, Nur77 protein was expressed in only one tumor sample from subCD. This sample showed high expression of Nur77 mRNA. Nur77 is an important to regulate POMC transcription and negative-feedback by glucocorticoids. Nur77 gene expression levels might involve different autonomy of ACTH production between CD and subCD.

Serum albumin-adjusted glycated albumin is an adequate indicator of glycemic control in patients with Cushing's syndrome

OBJECTIVES We recently reported that glycated albumin (GA) in patients with Cushings syndrome is low. In the present study, we examined whether serum albumin (SA)-adjusted GA (SAaGA) is an adequate indicator of glycemic control in patients with Cushings syndrome. DESIGN AND METHODS We studied 26 patients with Cushings syndrome (13 patients without diabetes and 13 patients with diabetes). Twenty six non-diabetic subjects and 26 patients with type 2 diabetes mellitus matched for age, sex and BMI were used as the controls. SAaGA was calculated using the regression formula between SA and GA in non-diabetic patients with Cushings syndrome and non-diabetic subjects. RESULTS SA showed a significant correlation with GA in non-diabetic patients with Cushings syndrome and non-diabetic subjects. GA, but not SAaGA, in non-diabetic patients with Cushings syndrome was significantly lower than that in the non-diabetic controls. Furthermore, the GA/HbA1c ratio, but not the SAaGA/HbA1c ratio, in diabetic patients with Cushings syndrome was significantly lower than that in the diabetic controls. The measured GA in the patients with Cushings syndrome was significantly lower than the estimated GA, but there was no difference between SAaGA and the estimated GA. CONCLUSIONS The present findings suggest that SAaGA is an adequate indicator of the glycemic control in patients with Cushings syndrome.

Evaluation of Hypothalamic–Pituitary–Adrenal Axis by the GHRP2 Test: Comparison With the Insulin Tolerance Test

Abstract Context GH-releasing peptide 2 (GHRP2) stimulates the hypothalamic–pituitary–adrenal axis (HPA) through the GH secretagogue receptor (GHSR) in the hypothalamus, in which ghrelin is a natural ligand. Therefore, the GHRP2 test (GHRP2T) could be used instead of the insulin tolerance test (ITT). Objective Can the GHRP2T replace the ITT for evaluation of HPA? Design The present retrospective study analyzed the clinical features and laboratory data from 254 patients admitted for evaluation of hypopituitarism who underwent both GHRP2T and ITT. We analyzed the association between the maximum cortisol level (Fmax) during both tests. Adrenocortical insufficiency was diagnosed by ITT. The suitability of GHRP2T was examined using the receiver operating characteristic curve. Results A strong correlation was found between Fmax measured using both tests (r = 0.777, P < 0.0001). However, the sensitivity (64%) and specificity (79%) showed that the GHRP2T was not suitable for clinical use. Various factors influenced the correlation, probably through their effects on ghrelin and/or GHSR, including functional adenoma (P < 0.05) and sex (P < 0.05). No substantial correlation was found between Fmax measured using both tests in patients with prolactinoma (n = 30). The exclusion of patients with functional adenoma revealed no factors that affected the association in male patients; however, age and menstruation significantly influenced it in female patients (P < 0.05). Analysis of the data from male subjects without functional adenoma (n = 104) showed high sensitivity (95%) and specificity (85%) for the GHRP2T. Conclusion ITT can be substituted with GHRP2T for assessment of HPA in male patients free of functional adenoma.

Saline Infusion Test highly associated with the incidence of cardio- and cerebrovascular events in primary aldosteronism

Primary aldosteronism (PA) is caused by excess secretion of aldosterone and is an independent risk factor for cardio-cerebro-vascular (CCV) events. The goal of treatment of PA should include prevention of CCV events. A definitive diagnosis of PA is established by confirmatory tests [saline infusion test (SIT), furosemide upright test (FUT) and captopril challenge test (CCT)]. However, there is no information on whether the hormone levels measured by these confirmatory tests are associated with CCV events. The aim of this retrospective study was to elucidate the relationship between the results of the above confirmatory tests and prevalence of CCV disease in patients with PA. The study subjects were 292 PA patients who were assessed for past history of CCV events at the time of diagnosis of PA. CCV events were significantly higher in patients with positive than negative SIT (12.8% vs. 3.3%, p=0.04). There were no differences in the incidences of CCV events between patients with positive and negative CCT and FUT (CCT: 11.0% vs. 3.9%, p=0.13, FUT: 6.1% vs. 5.7%, p=0.93). Our results demonstrated a higher incidence of CCV disease in PA SIT-positive patients compared to those with negative test. SIT is a potentially useful test not only for the diagnosis of PA but also assessment of the risk of CCV events.