Discordance in the reduction rate between glycated albumin and glycated hemoglobin levels in type 2 diabetes patients receiving SGLT2 inhibitors.

AIMS: Although the difference in HbA1c reduction between sodium-glucose cotransporter 2 (SGLT2) inhibitors and other oral glucose-lowering agents is relatively small, SGLT2 inhibitors exhibit beneficial cardiorenal protection. This study was based on the hypothesis that changes of HbA1c in patients treated with SGLT2 inhibitors may not accurately reflect an improved glycemic profile. METHODS: Two studies were conducted: 1) a retrospective cohort study of 3039 patients administered with either an SGLT2 or a dipeptidyl peptidase-4 (DPP4) inhibitor for 12 months comparing the changes in glycated albumin (GA) and HbA1c levels and 2) a pilot study of 10 patients whose glycemic dynamics were evaluated using flash glucose monitoring at baseline and 2 months after treatment with an SGLT2 inhibitor. RESULTS: SGLT2 inhibitors reduced GA more markedly than HbA1c in both studies. DPP4 inhibitors decreased both GA and HbA1c to a comparable degree. The mean glucose levels and glycemic standard deviation were significantly reduced after treatment with an SGLT2 inhibitor, in concordance with GA decline, although the lowering of HbA1c was marginal. CONCLUSIONS: Changes in HbA1c levels underestimated the glucose-lowering effect and the diminished glycemic fluctuation induced by SGLT2 inhibitors. Thus, the distinct biomarker roles of GA and HbA1c should be reevaluated.

Hemodialysis-Related Glycemic Disarray Proven by Continuous Glucose Monitoring; Glycemic Markers and Hypoglycemia.

OBJECTIVE: There is a high risk of asymptomatic hypoglycemia associated with hemodialysis (HD) using glucose-free dialysate; therefore, the inclusion of glucose in the dialysate is believed to prevent intradialytic hypoglycemia. However, the exact glycemic fluctuation profiles and frequency of asymptomatic hypoglycemia using dialysates containing >100 mg/dL glucose have not been determined. RESEARCH DESIGN AND METHODS: We evaluated the glycemic profiles of 98 patients, 68 of whom were men, with type 2 diabetes undergoing HD (HbA1c 6.4 ± 1.2%; glycated albumin 20.8 ± 6.8%) with a dialysate containing 100, 125, or 150 mg/dL glucose using continuous glucose monitoring. RESULTS: Sensor glucose level (SGL) showed a sustained decrease during HD, irrespective of the dialysate glucose concentration, and reached a nadir that was lower than the dialysate glucose concentration in 49 participants (50%). Twenty-one participants (21%) presented with HD-related hypoglycemia, defined by an SGL <70 mg/dL during HD and/or between the end of HD and their next meal. All these hypoglycemic episodes were asymptomatic. Measures of glycemic variability calculated using the SGL data (SD, coefficient of variation, and range of SGL) were higher and time below range (<70 mg/dL) was lower in participants who experienced HD-related hypoglycemia than in those who did not, whereas time in range between 70 and 180 mg/dL, time above range (>180 mg/dL), HbA1c, and glycated albumin of the two groups were similar. CONCLUSIONS: Despite the use of dialysate containing 100-150 mg/dL glucose, patients with diabetes undergoing HD experienced HD-related hypoglycemia unawareness frequently. SGL may fall well below the dialysate glucose concentration toward the end of HD.

Identification and quantification of plasma free salusin-ß, an endogenous parasympathomimetic peptide.

Salusin-ß is an endogenous parasympathomimetic proatherosclerotic peptide. Salusin-ß was initially predicted from bioinformatic analyses and later immunologically detected in human biofluids. However, elucidation of salusin-ß bioactivity has faced enormous challenges because of its unique physicochemical characteristics that cause it to strongly adhere to laboratory apparatus materials. In the strictest sense, the discovery of bioactive peptides is not complete until their exact native sequences have been confirmed in the peripheral circulation. In this study, we determined the plasma molecular form and levels of free salusin-ß to determine its pathophysiological significance. Ultra-high-yield enrichment and preseparation of non-tryptic human plasma was followed by LC-MS/MS, and full-length salusin-ß and seven different endogenous fragment sequences were identified. We established a new ELISA that specifically detects plasma free salusin-ß without cross-reacting with any of its identified endogenous fragments. Free salusin-ß levels exhibited a profound early morning nadir and rapidly decreased in response to parasympathetic nervous augmentation. Our technical advance in plasma native peptide analysis successfully identified a hard-to-detect bioactive peptide, salusin-ß, together with its formerly unrecognized fragments, and further suggests that conventional immunological measurements of target peptides may not be fully representative.

Distinct biomarker roles for HbA1c and glycated albumin in patients with type 2 diabetes on hemodialysis.

AIMS: HbA1c and glycated albumin (GA) are used to monitor glycemia, but their accuracy to represent glycemic profiles in hemodialysis remains controversial. METHODS: Continuous glucose monitoring in 97 patients with type 2 diabetes (41 on hemodialysis [HD] and 56 without nephropathy) was analyzed to evaluate whether HbA1c and/or GA serve as appropriate glycemic profile markers. RESULTS: The average glucose significantly correlated with HbA1c in both HD group and group without nephropathy (r=0.59, P<0.0001; r=0.40, P<0.005). The slopes of linear regression lines were statistically indistinguishable (F=0.30, P=0.744), while the y-intercepts were significantly different (F=57.86, P<0.0001). GA showed strong correlation with the glycemic standard deviation (r=0.68, P<0.0001), and with the average glucose (r=0.42, P<0.001). Least square analysis revealed that only HbA1c, but not GA, was significantly associated with the average glucose (F=10.20, P<0.0005; F=0.38, P=0.5427), while only GA was significantly associated with the glycemic variability in HD group. CONCLUSIONS: In HD participants, HbA1c correlates with the average glucose more than GA, but underestimates it, and a correction formula of HbA1c can be developed as an appreciable marker. GA value itself reflects the average glucose, but less accurately than HbA1c, while it could serve as an indicator for hyperglycemia/hypoglycemia excursion.

Levels of albuminuria and risk of developing macroalbuminuria in type 2 diabetes: historical cohort study.

Although increased urinary albumin excretion may increase the risk of adverse renal outcomes in patients with diabetes, it remains unclear whether microalbuminuria is associated with a higher incidence of macroalbuminuria in the absence of non-diabetic kidney events that frequently develop during the long-term course of type 2 diabetes. This historical cohort study included patients with type 2 diabetes, spot urine albumin:creatinine ratio (ACR) <300 mg/gCr and normal serum creatinine concentrations treated between August 1988 and April 2015. Patients with any evidence suggesting non-diabetic kidney diseases at baseline were excluded. Over a median follow-up of 50 months, 70 of the 1760 included patients developed macroalbuminuria. Twenty-one of these patients were diagnosed with non-diabetic renal events. The five-year cumulative incidence of macroalbuminuria in patients with ACRs of 0-7.5 mg/gCr, 7.5-30 mg/gCr, 30-150 mg/gCr, and 150-300 mg/gCr were 0%, 0.53%, 3.5%, and 36.0%, respectively, with significant differences between each pair of ACR categories. In type 2 diabetes, higher urinary ACR, even within a level of normoalbuminuria, was associated with a greater incidence of macroalbuminuria when non-diabetic renal events were excluded. These results conflict with findings suggesting that microalbuminuria is a poor indicator for the progression of diabetic nephropathy.

A very rare case of primary meningococcal arthritis in an adult male.

We report here a very rare case of primary meningococcal arthritis of the knee joint without clinical features associated with meningococcemia, meningitis, or meningococcal complications. The patient suffered from diabetes mellitus and had experienced two episodes of joint trauma. Intravenous infusion of ampicillin/sulbactam for 18 consecutive days was successful.

Physiological fluctuations of human plasma total salusin-ß, an endogenous parasympathomimetic/proatherosclerotic peptide.

Salusin-ß is an endogenous bioactive peptide that systemically exerts acute parasympathomimetic hemodynamic actions and locally induces atherogenesis. Due to its unique physicochemical characteristics to immediately adhere to all types of plastic and glassware, its plasma concentrations have only been successfully determined very recently. Using a total of 50 healthy adults (median age 28 years, range 24-57 years), we evaluated whether circulating salusin-ß levels are affected by the autonomic nervous functions. Plasma total salusin-ß levels obtained during daytime ambulatory monitoring of heart rate variability showed strong negative correlations with variables reflecting parasympathetic nervous activity, high frequency amplitude (HF; r=-0.27, p=0.0018) and the square root of the mean squared differences of successive normal-to-normal intervals (RMSSD; r=-0.19, p=0.0292), but did not with low frequency amplitude (LF) or LF/HF, variables influenced by sympathetic nervous activity. Because early morning nadir in the diurnal variation of plasma total salusin-ß levels appeared to follow the nighttime parasympathetic nervous activity peak as quantified by HF and RMSSD, we determined whether parasympathetic stimulation reduces plasma salusin-ß levels. Both Valsalva maneuver (p<0.05) and urination (p<0.05) significantly reduced plasma total salusin-ß levels. Despite the fact that salusin-ß is the sole endogenous parasympathomimetic peptide identified to date, the current results argue against the contention that physiological parasympathetic augmentation is the consequences of upregulated circulating salusin-ß. Rather, circulating salusin-ß levels are suppressed following physiological parasympathetic stimulation and appear to constitute a negative feedback relationship with the parasympathetic nervous system.

Circulating levels of human salusin-ß, a potent hemodynamic and atherogenesis regulator.

Using bioinformatics analysis, we previously identified salusin-ß, an endogenous bioactive peptide with diverse physiological activities. Salusin-ß is abundantly expressed in the neuroendocrine system and in systemic endocrine cells/macrophages. Salusin-ß acutely regulates hemodynamics and chronically induces atherosclerosis, but its unique physicochemical characteristics to tightly adhere to all types of plastic and glassware have prevented elucidation of its precise pathophysiological role. To quantitate plasma total salusin-ß concentrations, we produced rabbit and chicken polyclonal antibodies against the C- and N-terminal end sequences, circumvented its sticky nature, and successfully established a sandwich enzyme-linked immunosorbent assay (ELISA). Salusin-ß was abundantly present in the plasma of healthy volunteers, ranging from 1.9 to 6.6 nmol/L. Reverse phase-high performance liquid chromatography analysis showed that a single immunoreactive salusin-ß peak coincided with synthetic authentic salusin-ß. Plasma salusin-ß concentrations were unaffected by postural changes and by potent vasopressin release stimuli, such as hypertonic saline infusion or smoking. However, salusin-ß concentrations showed significant circadian variation; concentrations were high during the daytime and reached the lowest concentrations in the early morning. Plasma salusin-ß levels in subjects with diabetes mellitus, coronary artery disease, and cerebrovascular disease showed distinctly higher levels than healthy controls. Patients with panhypopituitarism combined with complete central diabetes insipidus also showed significantly higher plasma salusin-ß levels. Therefore, the ELISA system developed in this study will be useful for evaluating circulating total salusin-ß levels and for confirming the presence of authentic salusin-ß in human plasma. The obtained results suggest a limited contribution of the neuroendocrine system to peripheral total salusin-ß concentrations and a role for plasma total salusin-ß concentrations as an indicator of systemic vascular diseases.

New indices for predicting glycaemic variability.

Blood glucose variability is known to be associated with increased risk of long-term complications. Reliable indices for predicting hyperglycaemic and hypoglycaemic fluctuations are therefore needed. Glycaemic standard deviation (SD) obtained by continuous glucose monitoring correlates closely with nine previously described glycaemic variability formulas. Here, new indices predictive of glycaemic variability were developed, which can be calculated from laboratory measures based on a single blood draw. The indices included the glycated albumin (GA) to HbA1c ratio (GA/A1c ratio) and the fasting C-peptide immunoreactivity (FCPR) to fasting plasma glucose (FPG) ratio (FCPR index). Predictive values of these indices were assessed in 100 adults with diabetes. GA/A1c ratio and FCPR index showed close associations with glycaemic SD in addition to the nine existing glucose variability formulas. Subjects with a GA/A1c ratio ≥ 2.8 and FCPR index <3.0 showed the greatest SD and longest durations of hypoglycaemia, while those with a GA/A1c ratio <2.8 and FCPR index ≥ 3.0 had smaller SDs and little sign of hypoglycaemia. In adults with diabetes, a high GA/A1c ratio and low FCPR index value reflect higher glycaemic excursions, irrespective of diabetes type. Simultaneous measurements of GA, HbA1c, FPG and FCPR may help to identify a group of patients who warrant closer monitoring in relation to glycaemic variability and hypoglycaemia.

A woman with salt-wasting congenital adrenal hyperplasia presenting with a mucinous ovarian cystadenoma during pregnancy.

Women with congenital adrenal hyperplasia (CAH) caused by steroid 21-hydroxylase deficiency show reduced fertility, especially with the salt-wasting form. A 27-year-old pregnant woman with this disease underwent laparotomy and oophorectomy to remove a multilocular ovarian tumor at 14 weeks of pregnancy. This proved to be a mucinous cystadenoma. Toward the third trimester, she presented with marked elevations of 17α-hydroxyprogesterone and plasma renin activity. Careful management of endocrine and body fluid homeostasis allowed her to give birth to a healthy female infant with normal external genitalia. This case illustrates endocrinological parameters during pregnancy in a woman with classical salt-wasting CAH.