Published papers

Background and aims: To investigate the association between the frequency of intermittent-scanning continuous glucose monitoring (isCGM) and diurnal variation of time in range (TIR), time above range (TAR), and time below range (TBR), we performed a post hoc analysis of the ISCHIA study, a multicenter, prospective, open-label, randomized crossover study of patients with type 1 diabetes mellitus. Method: Data of 93 people who completed the ISCHIA study were used. We calculated scan frequency, TAR, TIR, and TBR of four approximately 6-h intervals: 6:00–11:59 (morning), 12:00–17:59 (afternoon), 18:00–23:59 (evening), and 0:00–5:59 (night). The correlation between scan frequency and diurnal variation of CGM metrics was analyzed using nonparametric Spearman correlation analysis. Results: More frequent scanning was associated with higher TIR in the afternoon (rho = 0.343, P < 0.001), evening (rho = 0.243, P = 0.019), and night (rho = 0.218, P = 0.036); furthermore, it was associated with lower TAR in the afternoon (rho = -0.275, P = 0.008) and TBR in the evening (rho = -0.235, P = 0.024). Concern about the effect of blood glucose fluctuation on social communication affected the number of scans during the day. Concerns about loneliness and hypoglycemia when alone also influenced the number of nighttime scans. Conclusion: Scan frequency is influenced by psychological factors. Afternoon scans were associated with the highest increase in TIR and decrease in TAR. Evening scans were linked to a reduction in TBR.

Perirenal fat (PRF), an ectopic fat depot lying adjacent to kidneys, is a risk factor for cardiometabolic and renal dysfunctions in patients with obesity and type 2 diabetes. We aimed to investigate the involvement of PRF in the pathophysiology and treatment of primary aldosteronism (PA). To this end, we measured PRF volume by abdominal CT and evaluated the relationships among PRF volume, cardiometabolic and renin-angiotensin-aldosterone system (RAAS) parameters, and therapeutic response to mineralocorticoid receptor antagonist (MRA) treatment in well-phenotyped PA patients. In addition, we evaluated the effects of MRA treatment on inflammation and fibrosis, potential downstream targets of MR signaling, by analyzing PRF obtained from obese (db/db) mice. PRF volume (PRF%) and visceral fat volume (VFV) were associated with various cardiometabolic and renal risk markers and RAAS parameters, such as body mass index, creatinine, triglyceride, high-density lipoprotein cholesterol, uric acid, fasting glucose, C-reactive protein, 24-h urine aldosterone, and 24-h urine normetanephrine (all P < 0.05). PRF%, but not VFV, positively correlated with changes in systolic and diastolic blood pressure and initial estimated glomerular filtration rate (eGFR) fall following MRA treatment after adjusting for confounders (all P < 0.05). In addition, MRA treatment decreased PRF expression of markers of macrophage infiltration and fibrosis in db/db mice (all P < 0.05). In conclusion, our results suggest that PRF accumulation is involved in the mechanisms linking MR activation to cardiometabolic and renal dysfunctions in PA patients. Moreover, PRF could be not only a prognostic factor but also a new therapeutic target for MRA-resistant hypertension.

Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (IH) during sleep, is increasingly recognized as a driver of metabolic dysfunction. However, its impact on circadian metabolic regulation remains poorly understood. Here, we investigated how chronic IH reshapes 24-hour hepatic and systemic metabolic programs in a mouse model mimicking OSA-associated chronic hypoxia. Through integrated circadian transcriptomic, metabolomic, and physiological 24-hour profiling, we show that 4 weeks of rest phase–restricted IH reprograms hepatic and systemic metabolism in a time-specific manner. This reorganization involves the coordinated circadian regulation of glucose, lipid, and redox pathways, with a shift away from oxidative metabolism toward oxygen-sparing processes such as gluconeogenesis, glycogen turnover, and lipid mobilization. These changes align with the hypoxic phase exposure and coincide with reshaped hepatic metabolite oscillations and systemic autonomic rhythms, supporting a functional adaptation to intermittent oxygen availability. Mechanistically, we identify the cAMP-CREB1 pathway as a driver of circadian transcriptional remodeling in the liver and a central integrator of IH-dependent adrenergic stress. Our findings establish chronic IH as a potent metabolic zeitgeber that rewires hepatic transcriptional and metabolic programs, revealing a circadian dimension to the metabolic consequences of sleep-disordered breathing.

Circadian misalignment of the feeding behavior and the terrestrial cycle is associated with obesity and metabolic perturbations. However, it remains unclear whether the quantity and timing of dietary salt intake influence temporal sodium handling and blood pressure regulation. Here, we demonstrate that the colonic mineralocorticoid receptor (MR) and peripheral clock affect the daily sodium absorption and blood pressure variations. Genes related to sodium handling display diurnal rhythms in synchrony with the daily rhythms of aldosterone and the colonic circadian clock. Cistromic analysis substantiated the overlap of occupancy between the MR and brain and muscle ARNT-like 1 (BMAL1). Diurnal oscillation of aldosterone and peripheral clocks, as well as blood pressure, was robustly driven by nighttime feeding of a low-salt diet but markedly disrupted by daytime feeding of a high-salt diet in nocturnal mice. These findings delineate the colonic temporal sensing of dietary sodium abundance and highlight the transcriptional mechanisms of daily salt handling and blood pressure variations.

To date, no systematic review has examined whether adrenalectomy (ADX) or mineralocorticoid receptor antagonist (MRA) treatment is more effective in patients with unilateral primary aldosteronism (uPA). Comparing clinical and biochemical data before and after treatment, we performed a systematic review to determine whether either ADX or MRA treatment is superior to the other in patients with uPA. Article search was performed using the PubMed, Cochrane Library, and ICHUSHI electronic databases. A comparative analysis was performed when at least 3 articles were available in each outcome. The collected data were used to calculate the effect measures represented as mean difference (MD) or odds ratio (OR). Our search strategy identified 526 abstracts, of which 7 research papers were finally included in the analysis. ADX for uPA patients significantly reduced the incidence of cerebro-cardiovascular disease (OR 0.63 [95% confidence interval 0.46, 0.85]), lowered the systolic BP (-8.78 mmHg [-11.61, -5.95]), and increased the serum potassium levels (0.43 mmol/L [0.35, 0.51]) compared to MRAs. In conclusion, ADX is more effective than MRA treatment in patients with uPA, but with higher risk of increased serum potassium levels. Graphical abstract: ADX adrenalectomy, MRAs mineralocorticoid receptor antagonists, PA primary aldosteronism, SBP systolic blood pressure.

Hypertension frequently requires combination therapy to attain efficient control to prevent cardiovascular diseases effectively. This study was conducted to determine which add-on treatment is better, namely calcium channel blockers or diuretics, in improving vascular damage. In 70 nondiabetic chronic kidney disease stage 1/2 patients who had been already treated with angiotensin II type 1 receptor blocker valsartan for at least 12 months, amlodipine or hydrochlorothiazide was added to their existing medication. Pulse wave velocity (PWV), intima-media thickness (IMT) of the carotid arteries, urinary albumin excretion (UAE), and 24-hour ambulatory blood pressure (BP) were determined before and 12 months after the start of add-on treatments. Add-on amlodipine and add-on hydrochlorothiazide significantly and similarly decreased 24-hour ambulatory BP by 18 and 19 mm Hg, respectively, PWV by 206 and 184 cm/s, respectively, and UAE, but did not change the IMT. The decreases in BP significantly contributed to the decreases in PWV and UAE and suggested that the decrease in serum cholesterol level brought about by add-on amlodipine also contributed to the decrease in UAE. These results suggest that 12 months of add-on treatment with either amlodipine or hydrochlorothiazide could have beneficial effects in nondiabetic chronic kidney disease stage 1/2 patients already being treated with valsartan.