Kidney Week

Abstract: SA-PO0900

Renal Gluconeogenesis Regulates Systemic Glucose Metabolism and Sarcopenia in CKD

Session Information

• Health Maintenance, Nutrition, and Metabolism
  October 24, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Health Maintenance, Nutrition, and Metabolism

• 1500 Health Maintenance, Nutrition, and Metabolism

Authors

• Kojima, Mitsuharu, Nagoya Daigaku, Nagoya, Aichi Prefecture, Japan

Mitsuharu Kojima, MD

• Sato, Yuka, Fujita Ika Daigaku, Toyoake, Aichi Prefecture, Japan

Yuka Sato, MD, PhD

• Shibata, Katsuaki, Nagoya Daigaku, Nagoya, Aichi Prefecture, Japan

Katsuaki Shibata, MD

• Noda, Yuhei, Nagoya Daigaku, Nagoya, Aichi Prefecture, Japan

Yuhei Noda, MD, PhD

• Maeda, Kayaho, Nagoya Daigaku, Nagoya, Aichi Prefecture, Japan

Kayaho Maeda, MD

• Kato, Noritoshi, Nagoya Daigaku, Nagoya, Aichi Prefecture, Japan

Noritoshi Kato, MD, PhD

• Kosugi, Tomoki, Nagoya Daigaku, Nagoya, Aichi Prefecture, Japan

Tomoki Kosugi, MD, PhD

• Tsuboi, Naotake, Fujita Ika Daigaku, Toyoake, Aichi Prefecture, Japan

Naotake Tsuboi, MD, PhD

• Maruyama, Shoichi, Nagoya Daigaku, Nagoya, Aichi Prefecture, Japan

Shoichi Maruyama, MD, PhD

Background

Chronic kidney disease (CKD) is frequently complicated by sarcopenia and frailty, yet the mechanisms linking kidney dysfunction to aging-associated decline in physical function remain unclear, particularly from a metabolic perspective. Because the kidney contributes to endogenous glucose production via gluconeogenesis, we hypothesized that loss of renal gluconeogenic capacity disrupts inter-organ metabolic coordination, reducing systemic glucose availability, skeletal muscle energy supply, and ultimately leading to sarcopenia.

Methods

Renal tubular PCK1 expression was evaluated in human kidney biopsy specimens from older and younger individuals with comparable renal function. In mice, aging and nephron loss were examined using aged and subnephrectomized models, and systemic gluconeogenic capacity was assessed by lactate-pyruvate tolerance testing. Skeletal muscle function, mass, and myofiber cross-sectional area were analyzed. An aging-relevant metabolic stress model combining high-fat diet, nitric oxide synthase inhibition, and subnephrectomy was used to assess gluconeogenic adaptation. Multi-omics analyses of the liver and muscle were performed, and reversibility was tested by restoring glucose availability.

Results

In human kidney biopsy specimens, tubular PCK1 expression was significantly reduced in older individuals despite comparable renal function. In mice, aging attenuated the glycemic response to lactate-pyruvate challenge, and subnephrectomy further exacerbated this impairment in aged mice, whereas young nephrectomized mice preserved systemic gluconeogenic capacity. This reduction in gluconeogenic capacity was associated with decreased grip strength, treadmill endurance, muscle mass, myofiber cross-sectional area, and body weight, not explained by insulin resistance. In an aging-relevant metabolic stress model, subnephrectomy abolished compensatory renal gluconeogenesis and caused the most severe reduction in systemic gluconeogenic reserve, accompanied by hypoalbuminemia and frailty-like features. Multi-omics analyses identified impaired hepatic gluconeogenesis as a key alteration. Restoration of glucose availability improved both muscle and frailty phenotypes without altering renal function.

Conclusion

Renal gluconeogenesis contributes to systemic glucose availability and metabolic homeostasis. Impairment of systemic gluconeogenic reserve may promote sarcopenia and frailty in aging and CKD.

Funding

• Private Foundation Support