Endogenous adenine is a potential driver of the cardiovascular-kidney-metabolic syndrome.

Mechanisms underlying the cardiovascular-kidney-metabolic (CKM) syndrome are unknown, although key small molecule metabolites may be involved. Bulk and spatial metabolomics identified adenine to be upregulated and specifically enriched in coronary blood vessels in hearts from patients with diabetes and left ventricular hypertrophy. Single nucleus gene expression studies revealed that endothelial methylthioadenosine phosphorylase (MTAP) was increased in human hearts with hypertrophic cardiomyopathy. The urine adenine/creatinine ratio in patients was predictive of incident heart failure with preserved ejection fraction. Heart adenine and MTAP gene expression was increased in a 2-hit mouse model of hypertrophic heart disease and in a model of diastolic dysfunction with diabetes. Inhibition of MTAP blocked adenine accumulation in the heart, restored heart dysfunction in mice with type 2 diabetes and prevented ischemic heart damage in a rat model of myocardial infarction. Mechanistically, adenine-induced impaired mitophagy was reversed by reduction of mTOR. These studies indicate that endogenous adenine is in a causal pathway for heart failure and ischemic heart disease in the context of CKM syndrome.

Glycolytic lactate in diabetic kidney disease.

Lactate elevation is a well-characterized biomarker of mitochondrial dysfunction, but its role in diabetic kidney disease (DKD) is not well defined. Urine lactate was measured in patients with type 2 diabetes (T2D) in 3 cohorts (HUNT3, SMART2D, CRIC). Urine and plasma lactate were measured during euglycemic and hyperglycemic clamps in participants with type 1 diabetes (T1D). Patients in the HUNT3 cohort with DKD had elevated urine lactate levels compared with age- and sex-matched controls. In patients in the SMART2D and CRIC cohorts, the third tertile of urine lactate/creatinine was associated with more rapid estimated glomerular filtration rate decline, relative to first tertile. Patients with T1D demonstrated a strong association between glucose and lactate in both plasma and urine. Glucose-stimulated lactate likely derives in part from proximal tubular cells, since lactate production was attenuated with sodium-glucose cotransporter-2 (SGLT2) inhibition in kidney sections and in SGLT2-deficient mice. Several glycolytic genes were elevated in human diabetic proximal tubules. Lactate levels above 2.5 mM potently inhibited mitochondrial oxidative phosphorylation in human proximal tubule (HK2) cells. We conclude that increased lactate production under diabetic conditions can contribute to mitochondrial dysfunction and become a feed-forward component to DKD pathogenesis.

High glucose-induced downregulation of PTEN-Long is sufficient for proximal tubular cell injury in diabetic kidney disease.

During the progression of diabetic kidney disease, proximal tubular epithelial cells respond to high glucose to induce hypertrophy and matrix expansion leading to renal fibrosis. Recently, a non-canonical PTEN has been shown to be translated from an upstream initiation codon CUG (leucine) to produce a longer protein called PTEN-Long (PTEN-L). Interestingly, the extended sequence present in PTEN-L contains cell secretion/penetration signal. Role of this non-canonical PTEN-L in diabetic renal tubular injury is not known. We show that high glucose decreases expression of PTEN-L. As a mechanism of its function, we find that reduced PTEN-L activates Akt-2, which phosphorylates and inactivate tuberin and PRAS40, resulting in activation of mTORC1 in tubular cells. Antibacterial agent acriflavine and antiviral agent ATA regulate translation from CUG codon. Acriflavine and ATA, respectively, decreased and increased expression of PTEN-L to altering Akt-2 and mTORC1 activation in the absence of change in expression of canonical PTEN. Consequently, acriflavine and ATA modulated high glucose-induced tubular cell hypertrophy and lamininγ1 expression. Importantly, expression of PTEN-L inhibited high glucose-stimulated Akt/mTORC1 activity to abrogate these processes. Since PTEN-L contains secretion/penetration signals, addition of conditioned medium containing PTEN-L blocked Akt-2/mTORC1 activity. Notably, in renal cortex of diabetic mice, we found reduced PTEN-L concomitant with Akt-2/mTORC1 activation, leading to renal hypertrophy and lamininγ1 expression. These results present first evidence for involvement of PTEN-L in diabetic kidney disease.

Protein N-glycans in Healthy and Sclerotic Glomeruli in Diabetic Kidney Disease.

BACKGROUND: Diabetes is expected to directly impact renal glycosylation, yet to date, there has not been a comprehensive evaluation of alterations in N-glycan composition in the glomeruli of patients with diabetic kidney disease (DKD). METHODS: We used untargeted mass spectrometry imaging to identify N-glycan structures in healthy and sclerotic glomeruli in FFPE sections from needle biopsies of five patients with DKD and three healthy kidney samples. Regional proteomics was performed on glomeruli from additional biopsies from the same patients to compare the abundances of enzymes involved in glycosylation. Secondary analysis of single nuclei transcriptomics (snRNAseq) data was used to inform on transcript levels of glycosylation machinery in different cell types and states. RESULTS: We detected 120 N-glycans, and among them identified twelve of these protein post-translated modifications that were significantly increased in glomeruli. All glomeruli-specific N-glycans contained an N-acetyllactosamine (LacNAc) epitope. Five N-glycan structures were highly discriminant between sclerotic and healthy glomeruli. Sclerotic glomeruli had an additional set of glycans lacking fucose linked to their core, and they did not show tetra-antennary structures that are common in healthy glomeruli. Orthogonal omics analyses revealed lower protein abundance and lower gene expression involved in synthesizing fucosylated and branched N-glycans in sclerotic podocytes. In snRNAseq and regional proteomics analyses, we observed that genes and/or proteins involved in sialylation and LacNAc synthesis were also downregulated in DKD glomeruli, but this alteration remained undetectable by our spatial N-glycomics assay. CONCLUSIONS: Integrative spatial glycomics, proteomics, and transcriptomics revealed protein N-glycosylation characteristic of sclerotic glomeruli in DKD.

Ketogenic diet induces p53-dependent cellular senescence in multiple organs.

A ketogenic diet (KD) is a high-fat, low-carbohydrate diet that leads to the generation of ketones. While KDs improve certain health conditions and are popular for weight loss, detrimental effects have also been reported. Here, we show mice on two different KDs and, at different ages, induce cellular senescence in multiple organs, including the heart and kidney. This effect is mediated through adenosine monophosphate-activated protein kinase (AMPK) and inactivation of mouse double minute 2 (MDM2) by caspase-2, leading to p53 accumulation and p21 induction. This was established using p53 and caspase-2 knockout mice and inhibitors to AMPK, p21, and caspase-2. In addition, senescence-associated secretory phenotype biomarkers were elevated in serum from mice on a KD and in plasma samples from patients on a KD clinical trial. Cellular senescence was eliminated by a senolytic and prevented by an intermittent KD. These results have important clinical implications, suggesting that the effects of a KD are contextual and likely require individual optimization.

Quinolinic acid links kidney injury to brain toxicity.

Kidney dysfunction often leads to neurological impairment, yet the complex kidney-brain relationship remains elusive. We employed spatial and bulk metabolomics to investigate a mouse model of rapid kidney failure induced by mouse double minute 2 ( Mdm2) conditional deletion in the kidney tubules to interrogate kidney and brain metabolism. Pathway enrichment analysis of focused plasma metabolomics panel pinpointed tryptophan metabolism as the most altered pathway with kidney failure. Spatial metabolomics showed toxic tryptophan metabolites in the kidneys and brains, revealing a novel connection between advanced kidney disease and accelerated kynurenine degradation. In particular, the excitotoxic metabolite quinolinic acid was localized in ependymal cells adjacent to the ventricle in the setting of kidney failure. These findings were associated with brain inflammation and cell death. A separate mouse model of acute kidney injury also had an increase in circulating toxic tryptophan metabolites along with altered brain inflammation. Patients with advanced CKD similarly demonstrated elevated plasma kynurenine metabolites and quinolinic acid was uniquely correlated with fatigue and reduced quality of life in humans. Overall, our study identifies the kynurenine pathway as a bridge between kidney decline, systemic inflammation, and brain toxicity, offering potential avenues for diagnosis and treatment of neurological issues in kidney disease.

Female Protection Against Diabetic Kidney Disease Is Regulated by Kidney-Specific AMPK Activity.

Reduced kidney AMPK activity is associated with nutrient stress-induced chronic kidney disease (CKD) in male mice. In contrast, female mice resist nutrient stress-induced CKD. The role of kidney AMPK in sex-related organ protection against nutrient stress and metabolite changes was evaluated in diabetic kidney tubule-specific AMPKγ2KO (KTAMPKγ2ΚΟ) male and female mice. In wild-type (WT) males, diabetes increased albuminuria, urinary kidney injury molecule-1, hypertension, kidney p70S6K phosphorylation, and kidney matrix accumulation; these features were not exacerbated with KTAMPKγ2ΚΟ. Whereas WT females had protection against diabetes-induced kidney injury, KTAMPKγ2ΚΟ led to loss of female protection against kidney disease. The hormone 17ß-estradiol ameliorated high glucose-induced AMPK inactivation, p70S6K phosphorylation, and matrix protein accumulation in kidney tubule cells. The mechanism for female protection against diabetes-induced kidney injury is likely via an estrogen-AMPK pathway, as inhibition of AMPK led to loss of estrogen protection to glucose-induced mTORC1 activation and matrix production. RNA sequencing and metabolomic analysis identified a decrease in the degradation pathway of phenylalanine and tyrosine resulting in increased urinary phenylalanine and tyrosine levels in females. The metabolite levels correlated with loss of female protection. The findings provide new insights to explain evolutionary advantages to females during states of nutrient challenges.

Deliverables from Metabolomics in Kidney Disease: Adenine, New Insights, and Implication for Clinical Decision-Making.

BACKGROUND: Chronic kidney disease (CKD) presents a persistent global health challenge, characterized by complex pathophysiology and diverse progression patterns. Metabolomics has emerged as a valuable tool in unraveling the intricate molecular mechanisms driving CKD progression. SUMMARY: This comprehensive review provides a summary of recent progress in the field of metabolomics in kidney disease with a focus on spatial metabolomics to shed important insights to enhancing our understanding of CKD progression, emphasizing its transformative potential in early disease detection, refined risk assessment, and the development of targeted interventions to improve patient outcomes. KEY MESSAGE: Through an extensive analysis of metabolic pathways and small-molecule fluctuations, bulk and spatial metabolomics offers unique insights spanning the entire spectrum of CKD, from early stages to advanced disease states. Recent advances in metabolomics technology have enabled spatial identification of biomarkers to provide breakthrough discoveries in predicting CKD trajectory and enabling personalized risk assessment. Furthermore, metabolomics can help decipher the complex molecular intricacies associated with kidney diseases for exciting novel therapeutic approaches. A recent example is the identification of adenine as a key marker of kidney fibrosis for diabetic kidney disease using both untargeted and targeted bulk and spatial metabolomics. The metabolomics studies were critical to identify a new biomarker for kidney failure and to guide new therapeutics for diabetic kidney disease. Similar approaches are being pursued for acute kidney injury and other kidney diseases to enhance precision medicine decision-making.

Urine tricarboxylic acid cycle metabolites and risk of end stage kidney disease in patients with type 2 diabetes.

CONTEXT: Metabolites in tricarboxylic acid (TCA) pathway have pleiotropic functions. OBJECTIVE: To study the association between urine TCA cycle metabolites and the risk for chronic kidney disease (CKD) progression in individuals with type 2 diabetes. DESIGN, SETTING AND PARTICIPANTS: A prospective study in a discovery (n = 1826) and a validation (n = 1235) cohort of type 2 diabetes in a regional hospital and a primary care facility. EXPOSURE AND OUTCOME: Urine lactate, pyruvate, citrate, alpha-ketoglutarate, succinate, fumarate and malate were measured by mass spectrometry. CKD progression was defined as a composite of sustained eGFR below 15 ml/min/1.73 m2 , dialysis, renal death or doubling of serum creatinine. RESULTS: During a median of 9.2 (IQR 8.1-9.7) and 4.0 (3.2-5.1) years of follow-up, 213 and 107 renal events were identified. Cox regression suggested that urine lactate, fumarate and malate were associated with an increased risk (adjusted hazard ratio, aHR [95% CI] 1.63 [1.16-2.28], 1.82 [1.17-2.82] and 1.49 [1.05-2.11], per SD), while citrate was associated with a low risk (aHR 0.83 [0.72-0.96] per SD) for the renal outcome after adjustment for cardio-renal risk factors. These findings were reproducible in the validation cohort. Noteworthy, fumarate and citrate were independently associated with the renal outcome after additional adjustment for other metabolites. CONCLUSION: Urine fumarate and citrate predict the risk for progression to ESKD independent of clinical risk factors and other urine metabolites. These two metabolites in TCA cycle pathway may play important roles in the pathophysiological network underpinning progressive loss of kidney function in patients with type 2 diabetes.

Evaluation of Exploratory Fluid Biomarker Results from a Phase 1 Senolytic Trial in Mild Alzheimer's Disease.

Senescent cell accumulation contributes to the progression of age-related disorders including Alzheimer's disease (AD). Clinical trials evaluating senolytics, drugs that clear senescent cells, are underway, but lack standardized outcome measures. Our team recently published data from the first open-label trial to evaluate senolytics (dasatinib plus quercetin) in AD. After 12-weeks of intermittent treatment, we reported brain exposure to dasatinib, favorable safety and tolerability, and modest post-treatment changes in cerebrospinal fluid (CSF) inflammatory and AD biomarkers using commercially available assays. Herein, we present more comprehensive exploratory analyses of senolytic associated changes in AD relevant proteins, metabolites, lipids, and transcripts measured across blood, CSF, and urine. These analyses included mass spectrometry for precise quantification of amyloid beta (Aß) and tau in CSF; immunoassays to assess senescence associated secretory factors in plasma, CSF, and urine; mass spectrometry analysis of urinary metabolites and lipids in blood and CSF; and transcriptomic analyses relevant to chronic stress measured in peripheral blood cells. Levels of Aß and tau species remained stable. Targeted cytokine and chemokine analyses revealed treatment-associated increases in inflammatory plasma fractalkine and MMP-7 and CSF IL-6. Urinary metabolites remained unchanged. Modest treatment-associated lipid profile changes suggestive of decreased inflammation were observed both peripherally and centrally. Blood transcriptomic analysis indicated downregulation of inflammatory genes including FOS, FOSB, IL1ß, IL8, JUN, JUNB, PTGS2. These data provide a foundation for developing standardized outcome measures across senolytic studies and indicate distinct biofluid-specific signatures that will require validation in future studies. ClinicalTrials.gov: NCT04063124.

Understanding Heterogeneity in Individual Responses to Digital Lifestyle Intervention Through Self-Monitoring Adherence Trajectories in Adults With Overweight or Obesity: Secondary Analysis of a 6-Month Randomized Controlled Trial.

BACKGROUND: Achieving clinically significant weight loss through lifestyle interventions for obesity management is challenging for most individuals. Improving intervention effectiveness involves early identification of intervention nonresponders and providing them with timely, tailored interventions. Early and frequent self-monitoring (SM) adherence predicts later weight loss success, making it a potential indicator for identifying nonresponders in the initial phase. OBJECTIVE: This study aims to identify clinically meaningful participant subgroups based on longitudinal adherence to SM of diet, activity, and weight over 6 months as well as psychological predictors of participant subgroups from a self-determination theory (SDT) perspective. METHODS: This was a secondary data analysis of a 6-month digital lifestyle intervention for adults with overweight or obesity. The participants were instructed to perform daily SM on 3 targets: diet, activity, and weight. Data from 50 participants (mean age: 53.0, SD 12.6 y) were analyzed. Group-based multitrajectory modeling was performed to identify subgroups with distinct trajectories of SM adherence across the 3 SM targets. Differences between subgroups were examined for changes in clinical outcomes (ie, body weight, hemoglobin A1c) and SDT constructs (ie, eating-related autonomous motivation and perceived competence for diet) over 6 months using linear mixed models. RESULTS: Two distinct SM trajectory subgroups emerged: the Lower SM group (21/50, 42%), characterized by all-around low and rapidly declining SM, and the Higher SM group (29/50, 58%), characterized by moderate and declining diet and weight SM with high activity SM. Since week 2, participants in the Lower SM group exhibited significantly lower levels of diet (P=.003), activity (P=.002), and weight SM (P=.02) compared with the Higher SM group. In terms of clinical outcomes, the Higher SM group achieved a significant reduction in body weight (estimate: -6.06, SD 0.87 kg; P<.001) and hemoglobin A1c (estimate: -0.38, SD 0.11%; P=.02), whereas the Lower SM group exhibited no improvements. For SDT constructs, both groups maintained high levels of autonomous motivation for over 6 months. However, the Lower SM group experienced a significant decline in perceived competence (P=.005) compared with the Higher SM group, which maintained a high level of perceived competence throughout the intervention (P=.09). CONCLUSIONS: The presence of the Lower SM group highlights the value of using longitudinal SM adherence trajectories as an intervention response indicator. Future adaptive trials should identify nonresponders within the initial 2 weeks based on their SM adherence and integrate intervention strategies to enhance perceived competence in diet to benefit nonresponders. TRIAL REGISTRATION: ClinicalTrials.gov NCT05071287; https://clinicaltrials.gov/study/NCT05071287. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1016/j.cct.2022.106845.

Decoding Heterogeneity in Data-Driven Self-Monitoring Adherence Trajectories in Digital Lifestyle Interventions for Weight Loss: A Qualitative Study.

Background: Data-driven trajectory modeling is a promising approach for identifying meaningful participant subgroups with various self-monitoring (SM) responses in digital lifestyle interventions. However, there is limited research investigating factors that underlie different subgroups. This qualitative study aimed to investigate factors contributing to participant subgroups with distinct SM trajectory in a digital lifestyle intervention over 6 months. Methods: Data were collected from a subset of participants (n = 20) in a 6-month digital lifestyle intervention. Participants were classified into Lower SM Group (n = 10) or a Higher SM (n = 10) subgroup based on their SM adherence trajectories over 6 months. Qualitative data were obtained from semi-structured interviews conducted at 3 months. Data were thematically analyzed using a constant comparative approach. Results: Participants were middle-aged (52.9 ± 10.2 years), mostly female (65%), and of Hispanic ethnicity (55%). Four major themes with emerged from the thematic analysis: Acceptance towards SM Technologies, Perceived SM Benefits, Perceived SM Barriers, and Responses When Facing SM Barriers. Participants across both subgroups perceived SM as positive feedback, aiding in diet and physical activity behavior changes. Both groups cited individual and technical barriers to SM, including forgetfulness, the burdensome SM process, and inaccuracy. The Higher SM Group displayed positive problem-solving skills that helped them overcome the SM barriers. In contrast, some in the Lower SM Group felt discouraged from SM. Both subgroups found diet SM particularly challenging, especially due to technical issues such as the inaccurate food database, the time-consuming food entry process in the Fitbit app. Conclusions: This study complements findings from our previous quantitative research, which used data-drive trajectory modeling approach to identify distinct participant subgroups in a digital lifestyle based on individuals' 6-month SM adherence trajectories. Our results highlight the potential of enhancing action planning problem solving skills to improve SM adherence in the Lower SM Group. Our findings also emphasize the necessity of addressing the technical issues associated with current diet SM approaches. Overall, findings from our study may inform the development of practical SM improvement strategies in future digital lifestyle interventions. Trial registration: The study was pre-registered at ClinicalTrials.gov (NCT05071287) on April 30, 2022.

Interactive Effects of Empagliflozin and Hyperglycemia on Urinary Amino Acids in Individuals With Type 1 Diabetes.

Optimizing energy use in the kidney is critical for normal kidney function. Here, we investigate the effect of hyperglycemia and sodium-glucose cotransporter 2 (SGLT2) inhibition on urinary amino acid excretion in individuals with type 1 diabetes (T1D). The open-label ATIRMA trial assessed the impact of 8 weeks of 25 mg empagliflozin orally once per day in 40 normotensive normoalbuminuric young adults with T1D. A consecutive 2-day assessment of clamped euglycemia and hyperglycemia was evaluated at baseline and posttreatment visits. Principal component analysis was performed on urinary amino acids grouped into representative metabolic pathways using MetaboAnalyst. At baseline, acute hyperglycemia was associated with changes in 25 of the 33 urinary amino acids or their metabolites. The most significant amino acid metabolites affected by acute hyperglycemia were 3-hydroxykynurenine, serotonin, glycyl-histidine, and nicotinic acid. The changes in amino acid metabolites were reflected by the induction of four biosynthetic pathways: aminoacyl-tRNA; valine, leucine, and isoleucine; arginine; and phenylalanine, tyrosine, and tryptophan. In acute hyperglycemia, empagliflozin significantly attenuated the increases in aminoacyl-tRNA biosynthesis and valine, leucine, and isoleucine biosynthesis. Our findings using amino acid metabolomics indicate that hyperglycemia stimulates biosynthetic pathways in T1D. SGLT2 inhibition may attenuate the increase in biosynthetic pathways to optimize kidney energy metabolism.

Ketone production and excretion even during mild hyperglycemia and the impact of sodium-glucose co-transporter inhibition in type 1 diabetes.

AIMS: We aimed to determine if ketone production and excretion are increased even at mild fasting hyperglycemia in type 1 diabetes (T1D) and if these are modified by ketoacidosis risk factors, including sodium-glucose co-transporter inhibition (SGLTi) and female sex. METHODS: In secondary analysis of an 8-week single-arm open-label trial of empagliflozin (NCT01392560) we evaluated ketone concentrations during extended fasting and clamped euglycemia (4-6 mmol/L) and mild hyperglycemia (9-11 mmol/L) prior to and after treatment. Plasma and urine beta-hydroxybutyrate (BHB) concentrations and fractional excretion were analyzed by metabolomic analysis. RESULTS: Forty participants (50 % female), aged 24 ± 5 years, HbA1c 8.0 ± 0.9 % (64 ± 0.08 mmol/mol) with T1D duration of 17.5 ± 7 years, were studied. Increased BHB production even during mild hyperglycemia (median urine 6.3[3.5-13.6] vs. 3.5[2.2-7.0] µmol/mmol creatinine during euglycemia, p < 0.001) was compensated by increased fractional excretion (0.9 % [0.3-1.6] vs. 0.4 % [0.2-0.9], p < 0.001). SGLTi increased production and attenuated the increased BHB fractional excretion (decreased to 0.3 % during mild hyperglycemia, p < 0.001), resulting in higher plasma concentrations (increased to 0.21 [0.05-0.40] mmol/L, p < 0.001), particularly in females (interaction p < 0.001). CONCLUSIONS: Even mild hyperglycemia is associated with greater ketone production, compensated by urinary excretion, in T1D. However, SGLTi exaggerates production and partially reduces compensatory excretion, particularly in women.

Metabolomic profiles associated with physical activity in White and African American adult men.

BACKGROUND: Physical activity (PA) is associated with various health benefits, especially in improving chronic health conditions. However, the metabolic changes in host metabolism in response to PA remain unclear, especially in racially/ethnically diverse populations. OBJECTIVE: This study is to assess the metabolic profiles associated with the frequency of PA in White and African American (AA) men. METHODS: Using the untargeted metabolomics data collected from 698 White and AA participants (mean age: 38.0±8.0, age range: 20-50) from the Louisiana Osteoporosis Study (LOS), we conducted linear regression models to examine metabolites that are associated with PA levels (assessed by self-reported regular exercise frequency levels: 0, 1-2, and ≥3 times per week) in White and AA men, respectively, as well as in the pooled sample. Covariates considered for statistical adjustments included race (only for the pooled sample), age, BMI, waist circumstance, smoking status, and alcohol drinking. RESULTS: Of the 1133 untargeted compounds, we identified 7 metabolites associated with PA levels in the pooled sample after covariate adjustment with a false discovery rate of 0.15. Specifically, compared to participants who did not exercise, those who exercised at a frequency ≥3 times/week showed higher abundances in uracil, orotate, 1-(1-enyl-palmitoyl)-2-oleoyl-GPE (P-16:0/18:1) (GPE), threonate, and glycerate, but lower abundances in salicyluric glucuronide and adenine in the pooled sample. However, in Whites, salicyluric glucuronide and orotate were not significant. Adenine, GPE, and threonate were not significant in AAs. In addition, the seven metabolites were not significantly different between participants who exercised ≥3 times/week and 1-2 times/week, nor significantly different between participants with 1-2 times/week and 0/week in the pooled sample and respective White and AA groups. CONCLUSIONS: Metabolite responses to PA are dose sensitive and may differ between White and AA populations. The identified metabolites may help advance our knowledge of guiding precision PA interventions. Studies with rigorous study designs are warranted to elucidate the relationship between PA and metabolites.

Plasma Tryptophan-Kynurenine Pathway Metabolites and Risk for Progression to End-Stage Kidney Disease in Patients With Type 2 Diabetes.

OBJECTIVE: We sought to study the associations between plasma metabolites in the tryptophan-kynurenine pathway and the risk of progression to end-stage kidney disease (ESKD) in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Plasma tryptophan, kynurenine, 3-hydroxykynurenine, kynurenic acid, and xanthurenic acid concentrations were measured in discovery (n = 1,915) and replication (n = 346) cohorts. External validation was performed in Chronic Renal Insufficiency Cohort (CRIC) participants with diabetes (n = 1,312). The primary outcome was a composite of incident ESKD (progression to estimated glomerular filtration rate [eGFR] <15 mL/min/1.73 m2, sustained dialysis, or renal death). The secondary outcome was annual eGFR decline. RESULTS: In the discovery cohort, tryptophan was inversely associated with risk for ESKD, and kynurenine-to-tryptophan ratio (KTR) was positively associated with risk for ESKD after adjustment for clinical risk factors, including baseline eGFR and albuminuria (adjusted hazard ratios [HRs] 0.62 [95% CI 0.51, 0.75] and 1.48 [1.20, 1.84] per 1 SD). High levels of kynurenic acid and xanthurenic acid were associated with low risks of ESKD (0.74 [0.60, 0.91] and 0.74 [0.60, 0.91]). Consistently, high levels of tryptophan, kynurenic acid, and xanthurenic acid were independently associated with a slower eGFR decline, while a high KTR was predictive of a faster eGFR decline. Similar outcomes were obtained in the replication cohort. Furthermore, the inverse association between kynurenic acid and risk of ESKD was externally validated in CRIC participants with diabetes (adjusted HR 0.78 [0.65, 0.93]). CONCLUSIONS: Accelerated catabolism of tryptophan in the kynurenine pathway may be involved in progressive loss of kidney function. However, shunting the kynurenine pathway toward the kynurenic acid branch may potentially slow renal progression.

SUPPRESION OF MITOCHONDRIAL RESPIRATION IS A FEATURE OF CELLULAR GLUCOSE TOXICITY.

Glucose toxicity is central to the myriad complications of diabetes and is now believed to encompass neurodegenerative diseases and cancer as well as microvascular and macrovascular disease. Due to the widespread benefits of SGLT2 inhibitors, which affect glucose uptake in the kidney proximal tubular cell, a focus on cell metabolism in response to glucose has important implications for overall health. We previously found that a -Warburg-type effect underlies diabetic kidney disease and involves metabolic reprogramming. This is now supported by quantitative measurements of superoxide measurement in the diabetic kidney and systems biology analysis of urine metabolites in patients. Further exploration of mechanisms underlying mediators of mitochondrial suppression will be critical in understanding the chronology of glucose-induced toxicity and developing new therapeutics to arrest the systemic glucose toxicity of diabetes.

Adherence to ketogenic diet in lifestyle interventions in adults with overweight or obesity and type 2 diabetes: a scoping review.

BACKGROUND/OBJECTIVES: Despite the evidence supporting the efficacy of the ketogenic diet (KD) on weight and type 2 diabetes (T2D) management, adherence to the KD is challenging. Additionally, no studies have reported changes in PA among individuals with overweight/obesity and T2D who have followed KD. We mapped out the methods used to assess adherence to the KD and level of physical activity (PA) in lifestyle interventions for weight and T2D management in individuals with overweight/obesity and T2D and compared levels of KD adherence and PA in these interventions. METHODS: Articles published between January 2005 and March 2022 were searched in MEDLINE, CINAHL, and Scopus. Studies that included KD in lifestyle interventions for adults with T2D and overweight/obesity and measured ketone levels were included. RESULTS: The eleven included studies comprised eight randomized controlled trials. They mainly used self-reported measures to evaluate adherence to the KD and level of PA. We found studies reported higher carbohydrate intake and lower fat intake than the KD regimen. Great inconsistencies were found among studies on the measurement and reporting of ketone and PA levels. CONCLUSION: Our results demonstrated the need to develop intervention strategies to improve adherence to the KD, as well as the necessity of developing standardized diet and PA assessment tools to establish a stronger evidence base for including KD in lifestyle interventions for weight and T2D management among adults with overweight/obesity and T2D.