Fractional Excretion Of Glucose Research Articles

Greater urinary calcium excretion is associated with diminished bone accrual in youth with type 1 diabetes

Abstract Context The adverse skeletal effects of type 1 diabetes (T1D) include deficient bone accrual and lifelong increased fracture risk. The contributors to impaired bone accrual in people with T1D are incompletely understood. Objective To determine if urinary calcium excretion is associated with impaired bone accrual in youth with T1D and to characterize the contribution of glycemic control and markers of bone mineral metabolism to urinary calcium excretion. Design Observational study. Participants 50 participants with T1D aged 6-20 years completed a 12-month longitudinal study of bone accrual. A second cohort of 99 similarly aged participants with T1D completed cross-sectional 24-hr urine and blood collections. Main Outcome Measure Whole body less head bone mineral content (WBLH BMC) velocity Z-score and fractional excretion of calcium (FeCa). Results Participants in the bone accrual cohort had lower WBLH BMC velocity compared to a healthy reference dataset (Z-score −0.3 ± 1.0, p=0.03). FeCa was negatively associated with WBLH BMC velocity Z-score, ρ= −0.47, p=0.001. In the urinary calcium excretion cohort, intact parathyroid hormone (β= −0.4, p=0.01), beta c-telopeptide (β=0.35, p=0.007), and either hemoglobin A1c (HbA1c, β=0.08, p=0.03) or urine fractional glucose excretion (β=0.07, p=0.03) were associated with FeCa in multivariable regression models that included known determinants of urinary calcium excretion. Conclusions Urinary calcium excretion was negatively associated with bone accrual in this cohort of youth with T1D. Mechanistic studies are needed to determine if interventions to reduce urinary calcium excretion could increase bone accrual and reduce skeletal fragility in people with T1D.

Effect of sodium-glucose cotransporter 2 inhibitor canagliflozin on interstitial glucose concentration in insulin-treated diabetic dogs.

The utility of sodium-glucose cotransporter 2 inhibitors (SGLT2i) has not been reported in insulin-treated diabetic dogs. Canagliflozin, a PO-administered SGLT2i, decreases interstitial glucose concentration (IG) in insulin-treated diabetic dogs. Five insulin-treated diabetic dogs. Uncontrolled open label longitudinal study. Canagliflozin (2-4 mg/kg/day PO) was added to an unchanged insulin dose for 7 days. Fractional excretion of glucose was calculated by dividing the product of urine glucose and serum creatinine concentrations by the product of serum glucose and urine creatinine concentrations. Hypoglycemia was defined as IG <60 mg/dL. Median IG in 2869 measurements obtained while dogs were treated with insulin and canagliflozin was 87 mg/dL (range, 40-500 mg/dL) and was significantly lower than median IG in 1426 measurements obtained while dogs were treated with insulin alone (212 mg/dL; range, 41-500 mg/dL; P < .001). Median fractional excretion of glucose when dogs were treated with insulin and canagliflozin was 1.1% (range, 0.9%-2.0%), significantly higher than when dogs were treated with insulin alone (0.3%; range, 0.01%-1.0%; P = .04). The frequency of hypoglycemia was higher in dogs treated with insulin and canagliflozin (544 of 2869 IG measurements, 19%) compared with the frequency of hypoglycemia in dogs treated with insulin alone (52 of 1426 IG measurements, 4%; P < .001). Canagliflozin may have a role in improving glycemic control in insulin-treated diabetic dogs, but the dose of insulin should be decreased when adding canagliflozin to insulin treatment.

The Uricosuric Effect of SGLT2 Inhibitors Is Maintained in the Long Term in Patients with Chronic Kidney Disease and Type 2 Diabetes Mellitus.

(1) Background: Sodium-glucose co-transporter 2 inhibitors (SGLT2is) increase uric acid excretion. The intensity of uricosuria is linked to glycosuria. (2) Methods: We aim to analyze the effect of SGLT2 inhibitors on urinary fractional excretion (FE) of uric acid and glucose in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) in a single-center retrospective study with patients with T2DM and CKD who started on treatment with SGLT2is. Patients on renal replacement therapy or with glucagon-like peptide-1 (GLP1) analogs were excluded. Subgroup analysis was performed according to the estimated glomerular filtration rate (eGFR), the SGLT2i molecule, the main comorbidities, and concomitant treatment. As a secondary objective, the study analyzed the effect of SGLT2 inhibitors on uricemia levels. (3) Results: Seventy-three patients were analyzed, with a mean follow-up of 1.2 years. Uric acid and glucose FE significantly increased after the initiation of SGLT2is. This increase remained stable during the follow-up without differences among eGFR groups. No significant reduction in uricemia was observed. However, a trend towards a decrease was observed. (4) Conclusion: The use of SGLT2is in patients with CKD and T2DM is associated with an increase in uric acid FE, which maintains stability irrespective of glomerular filtration loss at least during 24 months of follow-up.

Critical Analysis of the Effects of SGLT2 Inhibitors on Renal Tubular Sodium, Water and Chloride Homeostasis and Their Role in Influencing Heart Failure Outcomes.

SGLT2 (sodium-glucose cotransporter 2) inhibitors interfere with the reabsorption of glucose and sodium in the early proximal renal tubule, but the magnitude and duration of any ensuing natriuretic or diuretic effect are the result of an interplay between the degree of upregulation of SGLT2 and sodium-hydrogen exchanger 3, the extent to which downstream compensatory tubular mechanisms are activated, and (potentially) the volume set point in individual patients. A comprehensive review and synthesis of available studies reveals several renal response patterns with substantial variation across studies and clinical settings. However, the common observation is an absence of a large acute or chronic diuresis or natriuresis with these agents, either when given alone or combined with other diuretics. This limited response results from the fact that renal compensation to these drugs is rapid and nearly complete within a few days or weeks, preventing progressive volume losses. Nevertheless, the finding that fractional excretion of glucose and lithium (the latter being a marker of proximal sodium reabsorption) persists during long-term treatment with SGLT2 inhibitors indicates that pharmacological tolerance to the effects of these drugs at the level of the proximal tubule does not meaningfully occur. This persistent proximal tubular effect of SGLT2 inhibitors can be hypothesized to produce a durable improvement in the internal set point for volume homeostasis, which may become clinically important during times of fluid expansion. However, it is difficult to know whether a treatment-related change in the volume set point actually occurs or contributes to the effect of these drugs to reduce the risk of major heart failure events. SGLT2 inhibitors exert cardioprotective effects by a direct effect on cardiomyocytes that is independent of the presence of or binding to SGLT2 or the actions of these drugs on the proximal renal tubule. Nevertheless, changes in the volume set point mediated by SGLT2 inhibitors might potentially act cooperatively with the direct favorable molecular and cellular effects of these drugs on cardiomyocytes to mediate their benefits on the development and clinical course of heart failure.

Prolonged Controlled Oxygenated Rewarming Improves Immediate Tubular Function and Energetic Recovery of Porcine Kidneys During Normothermic Machine Perfusion.

Normothermic machine perfusion (NMP) is typically performed after a period of hypothermic preservation, which exposes the kidney to an abrupt increase in temperature and intravascular pressure. The resultant rewarming injury could be alleviated by gradual rewarming using controlled oxygenated rewarming (COR). This study aimed to establish which rewarming rate during COR results in the best protective effect on renal rewarming injury during subsequent NMP. Twenty-eight viable porcine kidneys (n = 7/group) were obtained from a slaughterhouse. After these kidneys had sustained 30 min of warm ischemia and 24 h of oxygenated HMP, they were either rewarmed abruptly from 4-8 °C to 37 °C by directly initiating NMP or gradually throughout 30, 60, or 120 min of COR (rate of increase in kidney temperature of 4.46%/min, 2.20%/min, or 1.10%/min) before NMP. Kidneys that were rewarmed during the course of 120 min (COR-120) had significantly lower fractional excretion of sodium and glucose at the start of NMP compared with rewarming durations of 30 min (COR-30) and 60 min (COR-60). Although COR-120 kidneys showed superior immediate tubular function at the start of normothermic perfusion, this difference disappeared during NMP. Furthermore, energetic recovery was significantly improved in COR-30 and COR-120 kidneys compared with abruptly rewarmed and COR-60 kidneys. This study suggests that a rewarming rate of 1.10%/min during COR-120 could result in superior immediate tubular function and energetic recovery during NMP. Therefore, it may provide the best protective effect against rewarming injury.

SGLT2 Inhibition and Uric Acid Excretion in Patients with Type 2 Diabetes and Normal Kidney Function.

Sodium-glucose transporter 2 (SGLT2) inhibitor-induced uric acid lowering may contribute to kidney-protective effects of the drug class in people with type 2 diabetes. This study investigates mechanisms of plasma uric acid lowering by SGLT2 inhibitors in people with type 2 diabetes with a focus on urate transporter 1. We conducted an analysis of two randomized clinical trials. First, in the Renoprotective Effects of Dapagliflozin in Type 2 Diabetes study, 44 people with type 2 diabetes were randomized to dapagliflozin or gliclazide for 12 weeks. Plasma uric acid, fractional uric acid excretion, and hemodynamic kidney function were measured in the fasted state and during clamped euglycemia or hyperglycemia. Second, in the Uric Acid Excretion study, ten people with type 2 diabetes received 1 week of empagliflozin, urate transporter 1 blocker benzbromarone, or their combination in a crossover design, and effects on plasma uric acid, fractional uric acid excretion, and 24-hour uric acid excretion were measured. In the Renoprotective Effects of Dapagliflozin in Type 2 Diabetes study, compared with the fasted state (5.3±1.1 mg/dl), acute hyperinsulinemia and hyperglycemia significantly reduced plasma uric acid by 0.2±0.3 and 0.4±0.3 mg/dl (both P<0.001) while increasing fractional uric acid excretion (by 3.2%±3.1% and 8.9%±4.5%, respectively; both P<0.001). Dapagliflozin reduced plasma uric acid by 0.8±0.8 during fasting, 1.0±1.0 in hyperinsulinemic-euglycemic state, and 0.8±0.7 mg/dl during hyperglycemic conditions (P<0.001), respectively, whereas fractional uric acid excretion in 24-hour urine increased by 3.0%±2.1% (P<0.001) and 2.6%±4.5% during hyperinsulinemic-euglycemic conditions (P=0.003). Fractional uric acid excretion strongly correlated to fractional glucose excretion (r=0.35; P=0.02). In the Uric Acid Excretion study, empagliflozin and benzbromarone both significantly reduced plasma uric acid and increased fractional uric acid excretion. Effects of combination therapy did not differ from benzbromarone monotherapy. In conclusion, SGLT2 inhibitors induce uric acid excretion, which is strongly linked to urinary glucose excretion and is attenuated during concomitant pharmacologic blockade of urate transporter 1. Renoprotective Effects of Dapagliflozin in Type 2 Diabetes (RED), NCT02682563; SGLT2 Inhibition: Uric Acid Excretion Study (UREX), NCT05210517.

Dysfunction of the circadian clock in the kidney tubule leads to enhanced kidney gluconeogenesis and exacerbated hyperglycemia in diabetes

The circadian clock is a ubiquitous molecular time-keeping mechanism which synchronizes cellular, tissue, and systemic biological functions with 24-hour environmental cycles. Local circadian clocks drive cell type- and tissue-specific rhythms and their dysregulation has been implicated in pathogenesis and/or progression of a broad spectrum of diseases. However, the pathophysiological role of intrinsic circadian clocks in the kidney of diabetics remains unknown. To address this question, we induced type I diabetes with streptozotocin in mice devoid of the circadian transcriptional regulator BMAL1 in podocytes (cKOp mice) or in the kidney tubule (cKOt mice). There was no association between dysfunction of the circadian clock and the development of diabetic nephropathy in cKOp and cKOt mice with diabetes. However, cKOt mice with diabetes exhibited exacerbated hyperglycemia, increased fractional excretion of glucose in the urine, enhanced polyuria, and a more pronounced kidney hypertrophy compared to streptozotocin-treated control mice. mRNA and protein expression analyses revealed substantial enhancement of the gluconeogenic pathway in kidneys of cKOt mice with diabetes as compared to diabetic control mice. Transcriptomic analysis along with functional analysis of cKOt mice with diabetes identified changes in multiple mechanisms directly or indirectly affecting the gluconeogenic pathway. Thus, we demonstrate that dysfunction of the intrinsic kidney tubule circadian clock can aggravate diabetic hyperglycemia via enhancement of gluconeogenesis in the kidney proximal tubule and further highlight the importance of circadian behavior in patients with diabetes.

Angiotensin II up-regulates sodium-glucose co-transporter 2 expression and SGLT2 inhibitor attenuates Ang II-induced hypertensive renal injury in mice.

Clinical trials indicate that sodium/glucose co-transporter 2 (SGLT2) inhibitors (SGLT2i) improve kidney function, yet, the molecular regulation of SGLT2 expression is incompletely understood. Here, we investigated the role of the intrarenal renin-angiotensin system (RAS) on SGLT2 expression. In adult non-diabetic participants in the Nephrotic Syndrome Study Network (NEPTUNE, n=163), multivariable linear regression analysis showed SGLT2 mRNA was significantly associated with angiotensinogen (AGT), renin, and angiotensin-converting enzyme (ACE) mRNA levels (P<0.001). In vitro, angiotensin II (Ang II) dose-dependently stimulated SGLT2 expression in HK-2, human immortalized renal proximal tubular cells (RPTCs); losartan and antioxidants inhibited it. Sglt2 expression was increased in transgenic (Tg) mice specifically overexpressing Agt in their RPTCs, as well as in WT mice with a single subcutaneous injection of Ang II (1.44 mg/kg). Moreover, Ang II (1000 ng/kg/min) infusion via osmotic mini-pump in WT mice for 4 weeks increased systolic blood pressure (SBP), glomerulosclerosis, tubulointerstitial fibrosis, and albuminuria; canaglifozin (Cana, 15 mg/kg/day) reversed these changes, with the exception of SBP. Fractional glucose excretion (FeGlu) was higher in Ang II+Cana than WT+Cana, whereas Sglt2 expression was similar. Our data demonstrate a link between intrarenal RAS and SGLT2 expression and that SGLT2i ameliorates Ang II-induced renal injury independent of SBP.

Factors that predict glycaemic response to sodium-glucose linked transporter (SGLT) inhibitors.

To determine the clinical and biochemical variables associated with change in HbA1c in patients with type 2 diabetes who start sodium-glucose linked transporter (SGLT) inhibitor therapy. We performed a prospective cohort study (ACTRN12616000833460) of 48 adults (30 male, 18 female) with type 2 diabetes who attended a tertiary hospital diabetes clinic. Fasting serum and urine samples, collected during clinic visits prior to and at 1, 12 and 24 weeks after commencing SGLT inhibitor treatment, were analysed for HbA1c, electrolytes, urea, creatinine and glucose. After 12 weeks, SGLT inhibitor therapy was associated with respective median (97% CI) decreases in weight, blood pressure, HbA1c and urine albumin/creatinine ratio of 3.0 (1.7-3.4) kg, 8 (2-16)/4 (3-9) mmHg, 6 (3-14) mmol/mol and 0.69 (0.18-1.8) mg/mmol. These effects persisted to 24 weeks. Urinary frequency and genitourinary infection were common adverse effects. Baseline HbA1c and eGFR independently predicted ΔHbA1c at 12 weeks whereas only baseline HbA1c independently predicted ΔHbA1c at 24 weeks. Urinary fractional glucose excretion and change in fasting glucose 1 week after starting SGLT inhibitor did not contribute to prediction of glycaemic response. SGLT inhibitor therapy in a hospital clinic setting was associated with clinical improvements comparable to those observed in clinical trials but with higher incidence of genitourinary side-effects. Baseline HbA1c and eGFR, but not urine fractional glucose excretion, predicted glycaemic response.

Effects of empagliflozin on renal sodium and glucose handling in patients with acute heart failure.

AimsSodium–glucose co‐transporter 2 (SGLT2) inhibitors improve clinical outcome in patients with heart failure (HF), but the mechanisms behind their beneficial effects are not yet fully understood. We examined the effects of empagliflozin on renal sodium and glucose handling in patients with acute HF.Methods and resultsThis study was a pre‐defined sub‐study of a double‐blind, randomized, placebo‐controlled, multicentre study (EMPA‐RESPONSE‐AHF). Patients were allocated within 24 h of an acute HF admission to either empagliflozin 10 mg/day (n = 40) or placebo (n = 39) for 30 days. Markers of glucose and sodium handling were measured daily during the first 96 h and at day 30. Patients were 76 (range 38–89) years old and 33% had diabetes. The use of loop diuretics during the first 96 h was similar in both groups. Empagliflozin increased fractional glucose excretion with a peak after 24 h (21.8% vs. 0.1%; P < 0.001), without affecting plasma glucose concentration, while fractional sodium and chloride excretion and urinary osmolality remained unchanged (P >0.3 for all). However, empagliflozin increased plasma osmolality (delta osmolality at 72 h: 5 ± 8 vs. 2 ± 5 mOsm/kg; P = 0.049). Finally, there was an early decline in estimated glomerular filtration rate with empagliflozin vs. placebo (−10 ± 12 vs. −2 ± 12 mL/min/1.73 m2; P = 0.009), which recovered within 30 days.ConclusionIn patients with acute HF, empagliflozin increased fractional glucose excretion and plasma osmolality, without affecting fractional sodium excretion or urine osmolality and caused a temporary decline in estimated glomerular filtration rate. This suggests that empagliflozin stimulates osmotic diuresis through increased glycosuria rather than natriuresis in patients with acute HF.

The Association between Urinary Glucose and Renal Uric Acid Excretion in Non-diabetic Patients with Stage 1-2 Chronic Kidney Disease

ABSTRACT Aims: To test the hypothesis that in non-diabetic patients with early-stage chronic kidney disease (CKD), the renal excretion of urate and glucose transportation are coupled and interconnected. Methods: A cross-sectional study of 255 non-diabetic participants with stage 1–2 CKD recruited from our department was conducted. Spearman’s correlation and multiple linear regression analyses were used to study the correlation between urinary glucose and renal uric acid excretion. ANOVA was used to compare urinary uric acid excretion among three tertiles of urinary glucose (UG; UG1: UG<0.24 mmol/24 h/1.73 m2, UG2: 0.24 mmol/24 h/1.73 m2≤ UG≤0.55 mmol/24 h/1.73 m2, and UG3: UG>0.55 mmol/24 h/1.73 m2), the fractional excretion of glucose (FEG; FEG1: FEG<0.04%, FEG2: 0.04%≤FEG≤0.09%, and FEG3: FEG>0.09%) and the excretion of glucose per volume of glomerular filtration (EgGF; EgGF1: EgGF<1.95 μmol/L, EgGF2: 1.95 μmol/L≤ EgGF≤3.99 μmol/L, and EgGF3: EgGF>3.99 μmol/L). Results: According to the multiple linear regression analysis, FEG and EgGF were positively correlated with the excretion of uric acid per volume of glomerular filtration (EurGF) after adjusting for confounding factors. The EurGF levels in the highest tertiles of UG, FEG and EgGF were higher than those in the lowest tertiles of UG, FEG and EgGF. Conclusion: Urinary glucose excretion is closely related to renal excretion of uric acid in non-diabetic patients with stage 1–2 CKD.

Pathophysiological mechanisms underlying a rat model of triple whammy acute kidney injury

AbstractSimultaneous administration of certain antihypertensive (renin–angiotensin system inhibitors and diuretics) and nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a renal toxicity syndrome known as “triple whammy” acute kidney injury (TW-AKI), yet poorly characterized at the pathophysiological level, as no specific experimental model exists on which to conduct preclinical research. Herein, we generated and characterized a rat model of TW-AKI (0.7 mg/kg/day trandolapril +400 mg/kg/day ibuprofen +20 mg/kg/day furosemide). Double treatments involving the NSAID caused a subclinical acute kidney injury, as they reduced glomerular filtration rate to a significant but not sufficient extent to increase Crpl concentration. Only the triple treatment generated an overt AKI with increased Crpl provided that animals were under partial water ingestion restriction. Histological examination revealed no evidence of tissue renal injury, and no proteinuria or makers of renal damage were detected in the urine. These findings, along with a normal fractional excretion of sodium and glucose, indicated that these drug combinations produce a prerenal type of AKI. In fact, blood pressure and renal blood flow were also reduced (most markedly following the triple combination), although renal dysfunction was more pronounced than expected for the corresponding pressure drop, supporting a key pathological role of the interference with renal autoregulation mechanisms. In summary, prerenal TW-AKI only occurs when volemia is challenged (i.e., by furosemide in partially water-deprived animals) under the effects of renin–angiotensin system inhibitors and NSAIDs. This model will facilitate further pathophysiological knowledge for a better diagnosis and clinical handling of this syndrome.Combination of antihypertensive drugs with NSAID analgesics may cause a syndrome called triple whammy (TW) acute kidney injury (AKI), most often in the elderly. A rat model reveals that the TW-AKI is a prerenal form of AKI, only occurring in previously dehydrated rats, a condition particularly rife among the aged.

Insulin enhances renal glucose excretion: relation to insulin sensitivity and sodium-glucose cotransport

IntroductionInsulin regulates renal glucose production and utilization; both these fluxes are increased in type 2 diabetes (T2D). Whether insulin also controls urinary glucose excretion is not known.MethodsWe applied the pancreatic...

1127-P: SGLT2 Inhibition (SGLT2i) Mediated Urinary Glucose Excretion (UGE) Associations with Metabolic and Renal Hemodynamic Parameters

The metabolic and hemodynamic correlates of SGLT2i-mediated UGE in patients with diabetes are not well understood. Accordingly, in this post hoc analysis, we measured UGE in 66 T2D, 37 T1D, and 25 nondiabetic (ND) participants under baseline conditions and following treatment with an SGLT2i (empagliflozin, 25 mg/d, EMPA). Measurements were taken during 3 h of fasting and 5 h of a mixed meal absorption (T2D and ND) or under usual clinical conditions in patients with T1D. Fractional glucose excretion (FEGlu) was obtained as the ratio of UGE to the filtered glucose load (=GFR x plasma glucose concentration [G]). In T1D participants only, ERPFPAH and GFRINULIN were measured and intraglomerular pressure (PGLO) estimated. With EMPA, FEGlu was 38±12% and 46±11% in T2D (fasting and post meal, respectively), 26±11% and 36±8% in ND, and 45±21% in T1D. In the pooled T1D, T2D and ND cohort, overall effect of EMPA on FEGlu was 39±11%; in this model, [G] was a positive determinant (FEGlu=34% at a [G] of 100 mg/dL and 44% at a [G] of 200 mg/dL, r=0.38, p&amp;lt;0.0001), whereas presence of T1D, T2D or ND was not. After adjusting for [G], plasma insulin concentration was also a positive determinant of FeGlu (r=0.12, p=0.01), adding 3% to FEGlu at the mean post meal plasma insulin of 50 µU/mL in T2D and ND; likewise, in T1D, FEGlu was related to the mean daily insulin dose (r=0.41, p&amp;lt;0.01). As described in previous work, in T1D, EMPA decreased ERPF and increased renal vascular resistance (p&amp;lt;0.01). Estimated PGLO was reduced (59.0±6.7 to 56.5±4.6 mmHg, p=0.038), and its change from baseline was associated with a larger increment in FEGlu (r=0.48, p=0.003. In conclusion, SGLT2i effects on renal glucose reabsorption are consistent across the spectrum of glucose tolerance. Moreover, FEGlu is a function of ambient hyperglycemia and, to a lesser extent, insulinemia. Finally, in T1D, decrements in renal hyperfiltration are related to greater glycosuria, possibly as a function of natriuresis. Disclosure Y. Lytvyn: None. A. Lytvyn: None. E.O. Muscelli: None. B.A. Perkins: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Boehringer Ingelheim International GmbH, Insulet Corporation. Research Support; Self; Boehringer Ingelheim International GmbH. Other Relationship; Self; Abbott, Boehringer Ingelheim International GmbH, Lilly Diabetes, Medtronic, Novo Nordisk Inc., Sanofi. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Mitsubishi Tanabe Pharma Corporation, Prometic Life Sciences Inc., Sanofi. E. Ferrannini: None.

What does sodium-glucose co-transporter 1 inhibition add: Prospects for dual inhibition.

Epithelial glucose transport is accomplished by Na+ -glucose co-transporters, SGLT1 and SGLT2. In the intestine, uptake of dietary glucose is for its majority mediated by SGLT1, and humans with mutations in the SGLT1 gene show glucose/galactose malabsorption. In the kidney, both transporters, SGLT1 and SGLT2, are expressed and recent studies identified that SGLT2 mediates up to 97% of glucose reabsorption. Humans with mutations in the SGLT2 gene show familial renal glucosuria. In the last three decades, significant progress was made in understanding the physiology of these transporters and their potential as therapeutic targets. Based on the structure of phlorizin, a natural compound acting as a SGLT1/2 inhibitor, initially several SGLT2, and later SGLT1 and dual SGLT1/2 inhibitors have been developed. Interestingly, SGLT2 knockout or treatment with SGLT2 selective inhibitors only causes a fractional glucose excretion in the magnitude of ∼60%, an effect mediated by up-regulation of renal SGLT1. Based on these findings the hypothesis was brought forward that dual SGLT1/2 inhibition might further improve glycaemic control via targeting two distinct organs that express SGLT1: the intestine and the kidney. Of note, SGLT1/2 double knockout mice completely lack renal glucose reabsorption. This review will address the rationale for the development of SGLT1 and dual SGLT1/2 inhibitors and potential benefits compared to sole SGLT2 inhibition.

Acute saccharin infusion has no effect on renal glucose handling in normal rats invivo.

Artificial sweeteners are extensively used by the food industry to replace sugar in food and beverages and are widely considered to be a healthy alternative. However, recent data suggest that artificial sweeteners may impact intestinal glucose absorption and that they might lead to glucose intolerance. Moreover, chronic consumption of artificial sweeteners has also been linked to detrimental changes in renal function. Using an in vivo approach, our study aimed to determine if short‐term infusion of the artificial sweetener saccharin can alter renal function and renal glucose absorption. We show that saccharin infusion does not induce any major change in GFR or urine flow rate at either the whole kidney or single nephron level, suggesting that any reported change in renal function with artificial sweeteners must depend on chronic consumption. As expected for a nondiabetic animal, glucose excretion was low; however, saccharin infusion caused a small, but significant, decrease in fractional glucose excretion. In contrast to the whole kidney data, our micropuncture results did not show any significant difference in fractional glucose reabsorption in either the proximal or distal tubules, indicating that saccharin does not influence renal glucose handling in vivo under euglycemic conditions. In keeping with this finding, protein levels of the renal glucose transporters SGLT1 and SGLT2 were also unchanged. In addition, saccharin infusion in rats undergoing a glucose tolerance test failed to induce a robust change in renal glucose excretion or renal glucose transporter expression. In conclusion, our results demonstrate that saccharin does not induce acute physiologically relevant changes in renal function or renal glucose handling.

Absence of the Na‐Glucose Cotransporter SGLT1 Ameliorates Kidney Recovery in a Murine Model of Acute Kidney Injury

The renal Na‐glucose cotransporter SGLT1 reabsorbs ~3% of the filtered glucose in the late proximal tubule, a hypoxia‐sensitive tubular segment that enters the outer medulla. Pharmacological blockade of SGLT2, which in the early proximal tubule reabsorbs most of the filtered glucose, was found protective in a mouse model of acute kidney injury (AKI) induced by ischemia‐reperfusion (IR). Since little is known about the role of SGLT1 in this context, we determined whether lack of SGLT1 affects kidney injury or recovery following IR.SGLT1‐knockout (KO) and WT mice (C57BL/6J males) underwent IR or sham surgery. IR was induced by 20 minutes of bilateral renal artery clamping, while body temperature was maintained at 36–37□. Sham operation was similar to IR surgery without artery clamping. All groups (WT Sham, WT IR, SGLT1‐KO Sham and SGLT1‐KO IR, n=7–8/group) were fed a low‐glucose high‐protein diet to prevent diarrhea in SGLT1‐KO. Urine and blood were collected at several time points during recovery. GFR was measured 14 days after IR by plasma elimination kinetics of FITC‐sinistrin in conscious mice. Kidneys were harvested on day 16.On day 1 after IR, plasma creatinine (by LC‐MS‐MS) increased to similar levels in SGLT1‐KO and WT (0.554±0.08 vs. 0.470±0.1 mg/dL, p=0.351), indicating similar initial kidney impairment. In accordance, IR reduced urine osmolality and increased plasma osmolality to similar levels in SGLT1‐KO and WT on day 1, possibly as a consequence of impaired urine concentration or renal retention of waste products. This was associated with a greater increase in fractional glucose excretion in SGLT1‐KO (1 to 19%) vs WT (0.1 to 7%) (p=0.003) indicating a prominent role of SGLT1 in glucose reabsorption at this time point. On day 14, GFR was significantly lower in WT IR vs SGLT1‐KO IR (6.56±0.6 vs. 9.13±0.8 μL/min/g BW, p&lt;0.05), associated with higher plasma creatinine levels on harvest day (0.130±0.016 vs. 0.093±0.009 mg/dL, p&lt;0.05). Moreover, plasma osmolality remained elevated in WT IR but was normalized in SGLT1‐KO IR on day 16 (345±11 vs. 316±4 mosm/kg, p=0.006). On day 16, plasma urea levels in sham groups were higher in SGLT1 KO vs WT (18.0±0.3 vs. 13.2±0.9 mmol/L, p=0.028), possibly reflecting a proposed role of SGLT1 in renal urea secretion, unmasked by high protein diet. Plasma urea was strongly increased in WT IR vs sham (24.6±2.2 vs. 13.2±0.9 mmol/L, p&lt;0.001), whereas levels were preserved in SGLT1‐KO IR vs sham. RT‐qPCR analyses on whole kidney tissue revealed that Na‐2Cl‐K cotransporter NKCC2 mRNA expression was decreased in WT IR but preserved in SGLT1‐KO IR, whereas renal mRNA expression of markers of injury, fibrosis and inflammation (KIM‐1, type 1 collagen, MCP‐1) was lower in SGLT1‐KO IR vs WT IR.Lack of SGLT1 improved kidney recovery in a mouse model of IR‐induced AKI. The results may reflect a deleterious role of SGLT1 activity in the late proximal tubule for outer medullary integrity in the aftermath of IR‐induced AKI. This may impair tubular function (reduced NKCC2) with consequences on GFR, kidney integrity, and body homeostasis, and have therapeutical implications.Support or Funding InformationNIH R01DK106102, R01DK112042, P30DK079337, and the Department of Veterans AffairsThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Organic anion transporter OAT3 enhances the glucosuric effect of the SGLT2 inhibitor empagliflozin

The sodium-glucose cotransporter SGLT2 inhibitor empagliflozin (plasma protein binding ~88%) may reach its target in the brush border of the early proximal tubule by glomerular filtration and tubular secretion. Here we determined whether empagliflozin is secreted by renal tubules in mice and whether genetic knockout of the basolateral organic anion transporter 3 ( Oat3-/-) affects its tubular secretion or glucosuric effect. Renal clearance studies in wild-type (WT) mice showed that tubular secretion accounted for 50-70% of empagliflozin urinary excretion. Immunostaining indicated that SGLT2 and OAT3 localization partially overlapped in proximal tubule S1 and S2 segments. Glucosuria in metabolic cage studies was reduced in Oat3-/- vs. WT mice for acute empagliflozin doses of 1, 3, and 10 mg/kg, whereas 30 mg/kg induced similar maximal glucosuria in both genotypes. Chronic application of empagliflozin (~25 mg·kg-1 ·day-1) in Oat3-/- mice was associated with lower urinary glucose-to-creatinine ratios despite maintaining slightly higher blood glucose levels than WT. On a whole kidney level, renal secretion of empagliflozin was largely unchanged in Oat3-/- mice. However, the absence of OAT3 attenuated the influence of empagliflozin on fractional glucose excretion; higher levels of plasma or filtered empagliflozin were needed to induce similar increases in fractional renal glucose excretion. We conclude that empagliflozin is excreted into the urine to similar extent by glomerular filtration and tubular secretion. The latter can occur largely independent of OAT3. However, OAT3 increases the glucosuric effect of empagliflozin, which may relate to the partial overlap of its localization with SGLT2 and thus OAT3-mediated tubular secretion of empagliflozin in the early proximal tubule.

Renal Handling of Ketones in Response to Sodium-Glucose Cotransporter 2 Inhibition in Patients With Type 2 Diabetes.

Pharmacologically induced glycosuria elicits adaptive responses in glucose homeostasis and hormone release, including decrements in plasma glucose and insulin levels, increments in glucagon release, enhanced lipolysis, and stimulation of ketogenesis, resulting in an increase in ketonemia. We aimed at assessing the renal response to these changes. We measured fasting and postmeal urinary excretion of glucose, β-hydroxybutyrate (β-HB), lactate, and sodium in 66 previously reported patients with type 2 diabetes and preserved renal function (estimated glomerular filtration rate ≥60 mL · min-1 · 1.73 m-2) and in control subjects without diabetes at baseline and following empagliflozin treatment. With chronic (4 weeks) sodium-glucose cotransporter 2 inhibition, baseline fractional glucose excretion (<2%) rose to 38 ± 12% and 46 ± 11% (fasting vs. postmeal, respectively; P < 0.0001) over a range of BMIs (range 23-41 kg/m2) and creatinine clearance (65-168 mL · min-1 · m-2). Excretion of β-HB (median [interquartile range]: 0.08 [0.10] to 0.31 [0.43] µmol · min-1), lactate (0.06 [0.06] to 0.28 [0.25] µmol · min-1), and sodium (0.27 [0.22] to 0.36 [0.16] mEq · min-1) all increased (P ≤ 0.001 for all) and were each positively related to glycosuria (P ≤ 0.001). These parameters changed in the same direction in subjects without diabetes, but changes were smaller than in the patients with diabetes. Although plasma N-terminal pro-B-type natriuretic peptide levels were unaltered, plasma erythropoietin concentrations increased by 31 (64)% (P = 0.0078). We conclude that the sodium-glucose cotransporter 2 inhibitor-induced increase in β-HB is not because of reduced renal clearance but because of overproduction. The increased lactate excretion contributes to lower plasma lactate levels, whereas the increased natriuresis may help in normalizing the exchangeable sodium pool. Taken together, glucose loss through joint inhibition of glucose and sodium reabsorption in the proximal tubule induces multiple changes in renal metabolism.

Novel role of insulin in the regulation of glucose excretion by mourning doves (Zenaida macroura)

In mammals, insulin primarily lowers plasma glucose (PGlu) by increasing its uptake into tissues. Studies have also shown that insulin lowers PGlu in mammals by modulating glomerular filtration rate (GFR). Birds have naturally high PGlu and, although insulin administration significantly decreases glucose concentrations, birds are resistant to insulin-mediated glucose uptake into tissues. Since prior work has not examined the effects of insulin on GFR in birds, the purpose of the present study was to assess whether insulin can augment renal glucose excretion and thereby lower PGlu. Therefore, the hypothesis of the present study was that insulin lowers PGlu in birds by augmenting GFR, as estimated by inulin clearance (CIn). Adult mourning doves (Zenaida macroura) were used as experimental animals. Doves were anesthetized and the brachial vein was cannulated for administration of [14C]-inulin and insulin and the brachial artery was cannulated for blood collections. Ureteral urine was collected via a catheter inserted into the cloaca. Ten minutes following administration of exogenous insulin (400μg/kg body mass, i.v.) plasma glucose was significantly decreased (p=0.0003). Twenty minutes following insulin administration, increases in GFR (p=0.016) were observed along with decreases in urine glucose concentrations (p=0.008), glucose excretion (p=0.028), and the fractional excretion of glucose (p=0.003). Urine flow rate (p=0.051) also tended to increase after administration of insulin. These data demonstrate a significant role for insulin in modulating GFR in mourning doves, which may in part explain the lower PGlu measured following insulin administration.