Hiroshi Yamamoto

Type 2 diabetes (T2D) is increasingly recognized as a systemic network disorder in which impaired communication among endocrine, neural, immune, and microbial systems drives metabolic dysfunction and accelerates biological aging. Extending DeFronzo’s “Ominous Octet,” contemporary advances in immunometabolism, mitochondrial biology, circadian physiology, and incretin signaling demonstrate that metabolic homeostasis depends on the structural and functional integrity of dynamic inter-organ networks. Their progressive disruption contributes not only to classical insulin resistance and β-cell failure, but also to chronic low-grade inflammation (inflammaging), mitochondrial decay, autonomic dysregulation, and epigenetic age acceleration. Crucially, modern disease-modifying interventions—including multi-incretin receptor agonists, SGLT2 inhibitors, metabolic/bariatric surgery, and circadian-aligned lifestyle programs—produce pleiotropic benefits that extend far beyond simple glycemic control. These convergent effects suggest partial restoration of impaired metabolic networks rather than isolated correction of glucose abnormalities. In this review, we propose “Metabolic Rejuvenation” as a novel, unifying operational framework describing the systemic restoration of metabolic network integrity, physiological resilience, and biological adaptability. Mechanistically, we discuss how reactive aldehyde-driven glycative stress operates within a multifactorial cascade—together with chronic inflammation and organelle dysfunction—to drive metabolic network collapse and accelerate biological aging. Finally, we outline a multidimensional assessment framework spanning five measurable domains (Inflammatory, Energetic & Mitochondrial, Autonomic & Neuroendocrine, Clinical & Metabolic, and Digital & Behavioral) to quantify disease modification, β-cell preservation, and diabetes remission potential toward healthy metabolic longevity.

Introduction: Laparoscopic sleeve gastrectomy (LSG) for morbidly obese patients often results in remission of type 2 diabetes (T2DM), but diabetes relapses in some of those patients. The frequency of T2DM relapse in Asians and the factors involved have not been adequately investigated. Methods: The J-SMART study was conducted on 322 Japanese subjects with body mass index (BMI) ≥32 kg/m2 who underwent LSG at 10 accredited centers in Japan between 2011 and 2014. Of these, 82 T2DM subjects with diabetes in complete or partial remission at 1 year after LSG and followed postoperatively for 5 years were included in the subgroup analysis and classified into two groups: diabetes remission-maintained and diabetes relapse. Results: The mean age of all included subjects was 49.2 years, median BMI was 41.5 kg/m2, and median HbA1c was 6.7%. Compared with the diabetes remission-maintained group, the diabetes relapse group at 5 years after LSG had significantly higher preoperative HbA1c, number of antidiabetic medications, and high-density lipoprotein cholesterol level; and lower BMI and homeostasis model assessment-beta cell function (HOMA-β). As many as 83.0% of the subjects were able to achieve HbA1c <7% at 5 years after LSG, but 26.8% of the subjects had diabetes relapse. Preoperative HbA1c significantly contributed to diabetes relapse (odds ratio 1.54, p = 0.049). In addition, the diabetes relapse group tended to have lower percentage total weight loss (%TWL) at 1 year after LSG and higher percentage weight regain (%WR) from postoperative nadir weight, compared with the diabetes remission-maintained group. The hazard ratio for diabetes relapse was 3.14-fold higher in subjects with %TWL ≥20% and %WR ≥25%, and 5.46-fold higher in those with %TWL <20% and %WR ≥25%, compared with %TWL ≥20% and %WR <25%. Conclusion: While LSG provides a high remission rate for T2DM, relapse is not uncommon. Preoperative HbA1c, poor weight loss, and excess weight regain after LSG contribute to diabetes relapse, suggesting the importance of treatment strategies focusing on these factors.

The potential association between altered levels of plasma free amino acids (PFAAs) and uric acid (UA) with estimated glomerular filtration rate (eGFR) remains unknown among patients with hypertension. A total of 2804 healthy controls and 2455 hypertensive patients were included in the current analysis. eGFR was defined as reduced when it was 2. The associations between reduced eGFR and individual PFAAs and UA in the healthy control and hypertension groups were explored by logistic regression analyses adjusted for potential confounding variables. Results show that UA had a significant positive association with reduced eGFR in both healthy control and hypertension groups (P < 0.001). Among the PFAAs, citrulline, glycine and phenylalanine showed significant positive associations with reduced eGFR in both healthy control (P < 0.01 to 0.001) and hypertension (P < 0.001) groups. Moreover, alanine, asparagine and methionine achieved significant positive associations with reduced eGFR only in the hypertension group (P < 0.01 to 0.001). Conversely, serine showed significant inverse associations with reduced eGFR in the hypertension group only (P < 0.001). Our findings provide first evidence for a strong relationship between distinct patterns of PFAAs and elevated UA with reduced eGFR in hypertension. The findings may appear useful in developing effective strategies for the prevention or early detection and treatment of declined kidney function in hypertension.