Summary Type 1 diabetes is a chronic autoimmune disease characterised by insulin deficiency and resultant hyperglycaemia. Knowledge of type 1 diabetes has rapidly increased over the past 25 years, resulting in a broad understanding about many aspects of the disease, including its genetics, epidemiology, immune and β-cell phenotypes, and disease burden. Interventions to preserve β cells have been tested, and several methods to improve clinical disease management have been assessed. However, wide gaps still exist in our understanding of type 1 diabetes and our ability to standardise clinical care and decrease disease-associated complications and burden. This Seminar gives an overview of the current understanding of the disease and potential future directions for research and care.

Type 1 diabetes

Exercise confers protection against obesity, type 2 diabetes and other cardiometabolic diseases1–5. However, the molecular and cellular mechanisms that mediate the metabolic benefits of physical activity remain unclear6. Here we show that exercise stimulates the production of N-lactoyl-phenylalanine (Lac-Phe), a blood-borne signalling metabolite that suppresses feeding and obesity. The biosynthesis of Lac-Phe from lactate and phenylalanine occurs in CNDP2+ cells, including macrophages, monocytes and other immune and epithelial cells localized to diverse organs. In diet-induced obese mice, pharmacological-mediated increases in Lac-Phe reduces food intake without affecting movement or energy expenditure. Chronic administration of Lac-Phe decreases adiposity and body weight and improves glucose homeostasis. Conversely, genetic ablation of Lac-Phe biosynthesis in mice increases food intake and obesity following exercise training. Last, large activity-inducible increases in circulating Lac-Phe are also observed in humans and racehorses, establishing this metabolite as a molecular effector associated with physical activity across multiple activity modalities and mammalian species. These data define a conserved exercise-inducible metabolite that controls food intake and influences systemic energy balance. A newly identified exercise-induced signalling metabolite—an amidated conjugate of lactate and phenylalanine—can reduce food intake and improve blood glucose homeostasis. 

An exercise-inducible metabolite that suppresses feeding and obesity

Myokines are muscle-derived cytokines and chemokines that act extensively on organs and exert beneficial metabolic functions in the whole-body through specific signal networks. Myokines as mediators provide the conceptual basis for a whole new paradigm useful for understanding how skeletal muscle communicates with other organs. In this review, we summarize and discuss classes of myokines and their physiological functions in mediating the regulatory roles of skeletal muscle on other organs and the regulation of the whole-body energy metabolism. We review the mechanisms involved in the interaction between skeletal muscle and nonmuscle organs through myokines. Moreover, we clarify the connection between exercise, myokines and disease development, which may contribute to the understanding of a potential mechanism by which physical inactivity affects the process of metabolic diseases via myokines. Based on the current findings, myokines are important factors that mediate the effect of skeletal muscle on other organ functions and whole-body metabolism.

Myokines mediate the cross talk between skeletal muscle and other organs.

Osteoarthritis (OA) is an age-related metabolic disease. Low-grade inflammation and oxidative stress are the last common pathway of OA. α-ketoglutarate (α-KG) is an essential physiological metabolite from the mitochondrial tricarboxylic acid (TCA) cycle, with multiple functions, including anti-inflammation and antioxidation, and exhibits decreased serum levels with age. Herein, we aimed to investigate the effect and mechanism of α-KG on OA. We first quantified the α-KG levels in human cartilage tissue and osteoarthritic chondrocytes induced by IL-1β. Besides, IL-1β-induced osteoarthritic chondrocytes were treated with different concentrations of α-KG. Chondrocyte proliferation and apoptosis, synthesis and degradation of extracellular matrix, and inflammation mediators were analyzed. RNA sequencing was used to explore the mechanism of α-KG, and mitophagy and oxidative stress levels were further detected. These results were verified in an anterior cruciate ligament transection (ACLT) induced age-related OA rat model. We found that α-KG content decreased by 31.32% in damaged medial cartilage than in normal lateral cartilage and by 36.85% in IL-1β-induced human osteoarthritic chondrocytes compared to control. α-KG supplementation reversed IL-1β-induced chondrocyte proliferation inhibition and apoptosis, increased the transcriptomic and proteinic expression of ACAN and COL2A1 in vivo and in vitro, but inhibited the expression of MMP13, ADAMTS5, IL-6, and TNF-α. In mechanism, α-KG promoted mitophagy and inhibited ROS generation, and these effects could be prevented by Mdivi-1 (a mitophagy inhibitor). Overall, α-KG content decreased in human OA cartilage and IL-1β-induced osteoarthritic chondrocytes. Moreover, α-KG supplementation could alleviate osteoarthritic phenotype by regulating mitophagy and oxidative stress, suggesting its potential as a therapeutic target to ameliorate OA. 

The physiological metabolite α-ketoglutarate ameliorates osteoarthritis by regulating mitophagy and oxidative stress

Increasing evidence indicates the involvement of myocardial oxidative injury and mitochondrial dysfunction in the pathophysiology of heart failure (HF). Alpha-ketoglutarate (AKG) is an intermediate metabolite of the tricarboxylic acid (TCA) cycle that participates in different cellular metabolic and regulatory pathways. The circulating concentration of AKG was found to decrease with ageing and is elevated after acute exercise and resistance exercise and in HF. Recent studies in experimental models have shown that dietary AKG reduces reactive oxygen species (ROS) production and systemic inflammatory cytokine levels, regulates metabolism, extends lifespan and delays the occurrence of age-related decline. However, the effects of AKG on HF remain unclear. In the present study, we explored the effects of AKG on left ventricular (LV) systolic function, the myocardial ROS content and mitophagy in mice with transverse aortic constriction (TAC). AKG supplementation inhibited pressure overload-induced myocardial hypertrophy and fibrosis and improved cardiac systolic dysfunction; in vitro, AKG decreased the Ang II-induced upregulation of β-MHC and ANP, reduced ROS production and cardiomyocyte apoptosis, and repaired Ang II-mediated injury to the mitochondrial membrane potential (MMP). These benefits of AKG in the TAC mice may have been obtained by enhanced mitophagy, which cleared damaged mitochondria. In summary, our study suggests that AKG improves myocardial hypertrophy remodelling, fibrosis and LV systolic dysfunction in the pressure-overloaded heart by promoting mitophagy to clear damaged mitochondria and reduce ROS production; thus, AKG may have therapeutic potential for HF.

Alpha-ketoglutarate ameliorates pressure overload-induced chronic cardiac dysfunction in mice.

Beneficial effects of resistance exercise on metabolic health and particularly muscle hypertrophy and fat loss are well established, but the underlying chemical and physiological mechanisms are not fully understood. Here, we identified a myometabolite-mediated metabolic pathway that is essential for the beneficial metabolic effects of resistance exercise in mice. We showed that substantial accumulation of the tricarboxylic acid cycle intermediate α-ketoglutaric acid (AKG) is a metabolic signature of resistance exercise performance. Interestingly, human plasma AKG level is also negatively correlated with BMI. Pharmacological elevation of circulating AKG induces muscle hypertrophy, brown adipose tissue (BAT) thermogenesis, and white adipose tissue (WAT) lipolysis in vivo. We further found that AKG stimulates the adrenal release of adrenaline through 2-oxoglutarate receptor 1 (OXGR1) expressed in adrenal glands. Finally, by using both loss-of-function and gain-of-function mouse models, we showed that OXGR1 is essential for AKG-mediated exercise-induced beneficial metabolic effects. These findings reveal an unappreciated mechanism for the salutary effects of resistance exercise, using AKG as a systemically derived molecule for adrenal stimulation of muscle hypertrophy and fat loss.

Exercise-induced α-ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1-dependent adrenal activation.

Summary Beneficial effects of resistance exercise on metabolic health and particularly muscle hypertrophy and fat loss are well established, but the underlying chemical and physiological mechanisms are not fully understood. Here we identified a myometabolite-mediated metabolic pathway that is essential for the beneficial metabolic effects of resistance exercise in vivo. We showed that substantial accumulation of the tricarboxylic acid cycle intermediate α-ketoglutaric acid (AKG) is a metabolic signature of resistance exercise performance. Interestingly, human plasma AKG level is also negatively correlated with BMI. Pharmacological elevation of circulating AKG induces muscle hypertrophy, brown adipose tissue (BAT) thermogenesis, and white adipose tissue (WAT) lipolysis in vivo. We further found that AKG stimulates the adrenal release of adrenaline through 2-oxoglutarate receptor 1 (OXGR1) expressed in adrenal glands. Finally, by using both loss-of-function and gain-of-function mouse models, we showed that OXGR1 is essential for AKG-mediated exercise-induced beneficial metabolic effects. These findings reveal an unappreciated mechanism for the salutary effects of resistance exercise, using AKG as a systemically-derived molecule for adrenal stimulation of muscle hypertrophy and fat loss.

/pdf/a-ketoglutaric-acid-stimulates-muscle-hypertrophy-and-fat-3phe6lor3q.pdf

α-ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1-dependent adrenal activation


 While resistance exercise effectively improves overall health in diabetic patients, the underlying biological mechanism by which resistance exercise improves metabolic function and glucose homeostasis remain mostly unknown. Previously, we identified a myometabolite-mediated metabolic pathway that is essential for the beneficial effects of resistance exercise on metabolic function. We found that resistance exercise-induced α-ketoglutaric acid (AKG) stimulates muscle hypertrophy and fat loss through 2-oxoglutarate receptor 1 (OXGR1)-dependent adrenal activation. Here, we provided evidence for the beneficial effects of AKG on glucose homeostasis in a diet-induced obesity (DIO) mouse model, which are independent of OXGR1. We showed that circulating AKG levels are negatively correlated with the fraction of blood glycated hemoglobin (HbA1c) in both humans and mice and significantly decreased in DIO mice. Consistently, pharmacological elevation of AKG effectively decreased body weight, blood glucose, and hepatic gluconeogenesis without changing insulin sensitivity and glucose tolerance in DIO mice. Notably, OXGR1KO blocked the inhibitory effects of AKG on body weight but failed to affect AKG’s suppression on blood glucose and hepatic gluconeogenesis, indicating distinct mechanisms for AKG’s regulation on energy balance and glucose homeostasis. In supporting this view, we showed that serpina1e, a member of protease inhibitor serpins superfamily, mediates the direct inhibitory effects of AKG on gluconeogenesis in both in vitro hepatocytes and liver slice. By using a liver-specific serpina1e deletion mouse model, we further demonstrated that liver serpina1e is required for the inhibitory effects of AKG on hepatic gluconeogenesis and hyperglycemia in DIO mice. Finally, we provided in vitro evidence to support a model in which AKG decreases hepatic gluconeogenesis by targeting trimethylation of lysine 27 on histone 3 (H3K27me3) in seprina1e promoter region. Our studies established an important role of AKG in glucose homeostasis, and identified the AKG-serpina1e pathway as potential therapeutic targets to attenuate hyperglycemia.

/pdf/alpha-ketoglutaric-acid-ameliorates-hyperglycemia-in-lvkvssuzzj.pdf

Alpha-ketoglutaric acid ameliorates hyperglycemia in diabetes by inhibiting hepatic gluconeogenesis via serpina1e signaling

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Exercise-induced α-ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1-dependent adrenal activation.

α-ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1-dependent adrenal activation

Alpha-ketoglutaric acid ameliorates hyperglycemia in diabetes by inhibiting hepatic gluconeogenesis via serpina1e signaling