Effect of hyperglycemia and empagliflozin on markers of cardiorenal injury and inflammation in patients with type 1 diabetes.

AIMS: To investigate the effect of hyperglycemia and empagliflozin on cardiorenal injury and inflammation in patients with uncomplicated type 1 diabetes (T1D). METHODS: Serum cardiac (sST2, Gal-3, cTnT), kidney injury (KIM-1, NGAL), inflammatory (sTNFR1, sTNFR2), and hemodynamic (NT-proBNP, EPO) markers were assessed post-hoc in two separate T1D cohorts. The glycemic clamp trial (NCT02344602) evaluated 49 adults with T1D and 27 controls under euglycemic and acute hyperglycemic conditions. The crossover BETWEEN trial (NCT02632747) investigated empagliflozin 25 mg plus ramipril for 4 weeks compared to placebo-ramipril for 4 weeks in 30 adults with T1D. RESULTS: In the glycemic clamp study, hyperglycemia acutely increased levels of NT-proBNP (p = 0.0003) and sTNFR2 (p = 0.003). BETWEEN participants treated with empagliflozin exhibited a paradoxical subacute rise in NT-proBNP (p = 0.0147) compared to placebo, independent of hematocrit. Individuals with higher baseline levels of sST2 and sTNFR1 had greater empagliflozin-associated reductions in systolic blood pressure and greater activation of renin-angiotensin-aldosterone system (RAAS) mediators, whereas those with higher baseline levels of KIM-1 and sTNFR1 had greater glomerular filtration rate (GFR) dip. CONCLUSION: The protective mechanisms of SGLT2 inhibition on blood pressure, RAAS activation, and renal hemodynamics are apparent in the subset of people with uncomplicated T1D with adverse cardiorenal and inflammatory markers.

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.

Minireview: Understanding and targeting inflammatory, hemodynamic and injury markers for cardiorenal protection in type 1 diabetes.

The coexistence of cardiovascular disease (CVD) and diabetic kidney disease (DKD) is common in people with type 1 diabetes (T1D) and is strongly associated with an increased risk of morbidity and mortality. Hence, it is imperative to explore robust tools that can accurately reflect the development and progression of cardiorenal complications. Several cardiovascular and kidney biomarkers have been identified to detect at-risk individuals with T1D. The primary aim of this review is to highlight biomarkers of injury, inflammation, or renal hemodynamic changes that may influence T1D susceptibility to CVD and DKD. We will also examine the impact of approved pharmacotherapies for type 2 diabetes, including renin-angiotensin-aldosterone system (RAAS) inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) on candidate biomarkers for cardiorenal complications in people with T1D and discuss how these changes may potentially mediate kidney and cardiovascular protection. Identifying predictive and prognostic biomarkers for DKD and CVD may highlight potential drug targets to attenuate cardiorenal disease progression, implement novel risk stratification measures in clinical trials, and improve the assessment, diagnosis, and treatment of at-risk individuals with T1D.

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.

Endogenous adenine mediates kidney injury in diabetic models and predicts diabetic kidney disease in patients.

Diabetic kidney disease (DKD) can lead to end-stage kidney disease (ESKD) and mortality; however, few mechanistic biomarkers are available for high-risk patients, especially those without macroalbuminuria. Urine from participants with diabetes from the Chronic Renal Insufficiency Cohort (CRIC) study, the Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes (SMART2D), and the American Indian Study determined whether urine adenine/creatinine ratio (UAdCR) could be a mechanistic biomarker for ESKD. ESKD and mortality were associated with the highest UAdCR tertile in the CRIC study and SMART2D. ESKD was associated with the highest UAdCR tertile in patients without macroalbuminuria in the CRIC study, SMART2D, and the American Indian study. Empagliflozin lowered UAdCR in nonmacroalbuminuric participants. Spatial metabolomics localized adenine to kidney pathology, and single-cell transcriptomics identified ribonucleoprotein biogenesis as a top pathway in proximal tubules of patients without macroalbuminuria, implicating mTOR. Adenine stimulated matrix in tubular cells via mTOR and stimulated mTOR in mouse kidneys. A specific inhibitor of adenine production was found to reduce kidney hypertrophy and kidney injury in diabetic mice. We propose that endogenous adenine may be a causative factor in DKD.

Estimated glomerular filtration rate calculated by serum creatinine lacks precision and accuracy in adults with type 2 diabetes with preserved renal function.

AIMS: We evaluated the performance of creatinine-based equations that are currently used to estimate glomerular filtration rate (GFR) in people with type 2 diabetes compared to measured GFR using gold-standard methods. METHODS: In this post-hoc analysis, 32 participants underwent repeated measurement of GFR by inulin clearance (mGFR). GFR was estimated by serum creatinine using the MDRD (eGFRMDRD) and CKD-EPI (eGFRCKD-EPI) equations four times over the course of one month. Performance was evaluated using measurements of bias (mean difference), precision (SD), and inaccuracy (proportion of eGFR that differed by >20 % of mGFR). Treatment and time effects on bias were evaluated using linear mixed effects models. RESULTS: At baseline, participants (38 % female) were age 60 ± 8 years, had diabetes duration of 9 ± 7 years, HbA1c 56 ± 9 mmol/mol (7.2 ± 0.8 %), and BMI 31.0 ± 6.2 kg/m2. Mean mGFR was 113 ± 24, mean eGFRMDRD was 93 ± 12, and mean eGFRCKD-EPI was 94 ± 9 mL/min/1.73 m2. When 128 observations (32 participants measured 4 times) were evaluated, both equations substantially underestimated mGFR. For eGFRMDRD, mean bias was -21.5 mL/min/1.73 m2, precision was 22.7 mL/min/1.73 m2, and 46 % of observations differed by >20 %. Results were similar for eGFRCKD-EPI. No time or treatment effects on bias were observed. CONCLUSIONS: In adults with type 2 diabetes and preserved renal function, eGFR equations underestimated mGFR, lacked precision and accuracy, and performance was lower at higher ranges of mGFR. Current eGFR equations by serum creatinine are inaccurate in adults with type 2 diabetes with preserved renal function, highlighting the necessity to develop new methods to measure kidney function at earlier stages of diabetic kidney disease.

Role of endogenous adenine in kidney failure and mortality with diabetes.

Diabetic kidney disease (DKD) can lead to end-stage kidney disease (ESKD) and mortality, however, few mechanistic biomarkers are available for high risk patients, especially those without macroalbuminuria. Urine from participants with diabetes from Chronic Renal Insufficiency Cohort (CRIC), Singapore Study of Macro-Angiopathy and Reactivity in Type 2 Diabetes (SMART2D), and the Pima Indian Study determined if urine adenine/creatinine ratio (UAdCR) could be a mechanistic biomarker for ESKD. ESKD and mortality were associated with the highest UAdCR tertile in CRIC (HR 1.57, 1.18, 2.10) and SMART2D (HR 1.77, 1.00, 3.12). ESKD was associated with the highest UAdCR tertile in patients without macroalbuminuria in CRIC (HR 2.36, 1.26, 4.39), SMART2D (HR 2.39, 1.08, 5.29), and Pima Indian study (HR 4.57, CI 1.37-13.34). Empagliflozin lowered UAdCR in non-macroalbuminuric participants. Spatial metabolomics localized adenine to kidney pathology and transcriptomics identified ribonucleoprotein biogenesis as a top pathway in proximal tubules of patients without macroalbuminuria, implicating mammalian target of rapamycin (mTOR). Adenine stimulated matrix in tubular cells via mTOR and stimulated mTOR in mouse kidneys. A specific inhibitor of adenine production was found to reduce kidney hypertrophy and kidney injury in diabetic mice. We propose that endogenous adenine may be a causative factor in DKD.

The anti-hypertensive effects of sodium-glucose cotransporter-2 inhibitors.

INTRODUCTION: Hypertension is a well-established risk factor for cardiovascular (CV) events in patients with chronic kidney disease (CKD), heart failure, obesity, and diabetes. Despite the usual prescribed antihypertensive therapies, many patients fail to achieve the recommended blood pressure (BP) targets. AREAS COVERED: This review summarizes the clinical BP-lowering data presented in major CV and kidney outcome trials for sodium-glucose cotransporter-2 (SGLT2) inhibitors, as well as smaller dedicated BP trials in high-risk individuals with and without diabetes. We have also highlighted potential mechanisms that may contribute to the antihypertensive effects of SGLT2 inhibitors, including natriuresis and hemodynamic changes, a loop diuretic-like effect, and alterations in vascular physiology. EXPERT OPINION: The antihypertensive properties of SGLT2 inhibitors are generally modest but may be larger in certain patient populations. SGLT2 inhibitors may have an additional role as an adjunctive BP-lowering therapy in patients with hypertension at high risk of CV disease or kidney disease.