Renal and Cardiovascular Metabolic Impact Caused by Ketogenesis of the SGLT2 Inhibitors.

Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) are glycosuric drugs that were originally developed for the treatment of type 2 diabetes mellitus (T2DM). There is a hypothesis that SGLT2i are drugs that are capable of increasing ketone bodies and free fatty acids. The idea is that they could serve as the necessary fuel, instead of glucose, for the purposes of cardiac muscle requirements and could explain antihypertensive effects, which are independent of renal function. The adult heart, under normal conditions, consumes around 60% to 90% of the cardiac energy that is derived from the oxidation of free fatty acids. In addition, a small proportion also comes from other available substrates. In order to meet energy demands with respect to achieving adequate cardiac function, the heart is known to possess metabolic flexibility. This allows it to switch between different available substrates in order to obtain the energy molecule adenosine triphosphate (ATP), thereby rendering it highly adaptive. It must be noted that oxidative phosphorylation in aerobic organisms is the main source of ATP, which is a result of reduced cofactors. These cofactors include nicotine adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2), which are the result of electron transfer and are used as the enzymatic cofactors that are involved in the respiratory chain. When there is an excessive increase in energy nutrients-such as glucose and fatty acids-which occur in the absence of a parallel increase in demand, a state of nutrient surplus (which is better known as an excess in supply) is created. The use of SGLT2i at the renal level has also been shown to generate beneficial metabolic alterations, which are obtained by reducing the glucotoxicity that is induced by glycosuria. Together with the reduction in perivisceral fat in various organs, such alterations also lead to the use of free fatty acids in the initial stages of the affected heart. Subsequently, this results in an increase in production with respect to ketoacids, which are a more available energy fuel at the cellular level. In addition, even though their mechanism is not fully understood, their vast benefits render them of incredible importance for the purposes of further research.

Safety and efficacy of Empagliflozin in Pakistani Muslim patients with type 2 diabetes (SAFE-PAK); a randomized clinical trial.

BACKGROUND: Sodium-Glucose-Co-Transporter 2 (SGLT2) inhibitor (Empagliflozin) is an effective drug in controlling blood glucose through predominantly glycosuria. Glycosuria increases the risk of genitourinary infections in diabetes. This study was aimed to establish the safety and efficacy of Empagliflozin (Group-A) versus standard care (Group-B) in Pakistani Muslim individuals with type 2 diabetes. METHODS: A multicenter, randomized clinical trial was conducted in five cities across Pakistan from July 2019 to August 2020. Patients of both genders aged 18-75 years, body mass index (BMI) ≤ 45 kg/m2, glycosylated hemoglobin (HbA1c) 7-10% (53 mmol/mol to 86 mmol/mol) and treatment-naive to Empagliflozin were included. Treatment was given for 24 weeks, and allocation was done through randomization. RESULTS: Out of 745 screened patients, 333 met the eligibility criteria, and a total of 244 (73.3%) patients were enrolled. More hypoglycemic events were reported in the standard care group, whereas positive urine culture, fungal infection, dehydration, and hypotension occurrence were comparable between the two groups. The 6 months mean HbA1c reduction was significant in both groups; (Group-A: 0.91 ± 0.15; p < 0.001 vs. Group-B2: 0.79 ± 0.14; p < 0.001). Efficacy comparison at 6 months revealed a significant reduction in weight and systolic blood pressure (SBP) in Group A only (Group-A: 1.4 ± 0.4 kg; p < 0.002 vs. Group-B: 0.01 ± 0.5 kg; p < 1.00), (Group-A: 5.1 ± 1.7 mmHg; p < 0.012 vs. Group-B: 2.3 ± 1.7 mmHg; p < 0.526). CONCLUSIONS: Empagliflozin was a safe drug compared to standard care in Pakistani Muslim patients with diabetes. It was as effective as standard care in the clinical setting but achieved glycemic control by reducing weight and SBP in type 2 diabetes patients. TRIAL REGISTRATION: This study was registered in the NIH US National Library of Medicine clinical trials registry at Clinicaltrials.gov with the registration number: NCT04665284 on 11/12/2020.

Non-diabetic urine glucose in idiopathic membranous nephropathy.

This study aims to analyze the characteristics of idiopathic membranous nephropathy (iMN) with nondiabetic urine glucose during the follow-up. We retrospectively analyzed the data of 1313 patients who were diagnosed iMN. The prevalence of nondiabetic urine glucose during follow-up was 10.89%. There were significant differences between the patients with nondiabetic urine glucose and those without urine glucose in gender, hypertension ratio, proteinuria, N-acetyl-ß-glucosaminidase, retinol binding protein, serum albumin, serum creatinine (Scr), cholesterol, triglyceride and positive anti-phospholipase A2 receptor antibody ratio, glomerular sclerosis ratio, acute and chronic tubular injury lesion at baseline. To exclude the influence of the baseline proteinuria and Scr, case control sampling of urine glucose negative patients was applied according to gender, baseline proteinuria and Scr. The proteinuria nonremission (NR) ratio was 45.83 versus 12.50% of the urine glucose positive group and case control group. Partial remission (PR) ratio of the two groups was 36.46 versus 23.96% and complete remission (CR) ratio was 19.79% versus 63.54%, respectively. Patients with urine glucose had higher risk of 50% estimated glomerular filtration rate (eGFR) reduction. Cox regression showed that urine glucose and baseline Scr were risk factors of 50% reduction of eGFR. Urine glucose remission ratio of the patients with proteinuria NR, PR, and CR was 13.33, 56.25, and 94.73% (p < 0.005). Patients who got urine glucose remission also had better renal survival. In conclusion, non-diabetic urine glucose was closely related to proteinuria. It could be applied as a tubular injury marker to predict renal function.

Evaluation of Renal Function in COVID-19 Patients by Using Urinalysis Following the Administration of Vancomycin.

BACKGROUND: The aim of this study was to evaluate renal function by urinalysis in COVID-19 patients following the administration of vancomycin. METHODS: A retrospective observational study was performed between October 2020 and January 2021, during which time patients were hospitalized in the Prince Mohammed Bin Abdulaziz Hospital in Riyadh, Saudi Arabia. The patients were free of kidney disease. Urinalysis was performed by an automated laboratory system, and the collected results were based upon age, gender, diabetic status, whether the patients had received vancomycin, the mortality rate, and the urinalysis panel including coinfection by bacteria and yeast. RESULTS: A total of 227 patients were included in this study, 147 (64.75%) of whom were male and 80 (35.25%) of whom were female; 54.63% were diabetic, 11.89% were prediabetic, and 33.48% were non-diabetic patients. Proteinuria, hematuria, glycosuria, coinfection, and ketonuria were detected among all participants within the study group, specifically among diabetic patients. The mortality rate was 16.2% among the study group; 6.6% had re-ceived vancomycin, and 9.6% had not received vancomycin. No significant correlation was found between nephrotoxicity and abnormalities in the urine and the mortality rate among members of our study group. CONCLUSIONS: Proteinuria, hematuria, glycosuria, ketonuria, and coinfection were common among members of our study group, especially in the diabetic group. Urinalysis abnormalities were less frequent in the vancomycin group than in the others, except the prediabetic group. No correlation between mortality and vancomycin was identified.

8-Aminoinosine and 8-Aminohypoxanthine Inhibit Purine Nucleoside Phosphorylase and Exert Diuretic and Natriuretic Activity.

8-Aminoguanine and 8-aminoguanosine (via metabolism to 8-aminoguanine) are endogenous 8-aminopurines that induce diuresis, natriuresis, and glucosuria by inhibiting purine nucleoside phosphorylase (PNPase); moreover, both 8-aminopurines cause antikaliuresis by other mechanisms. Because 8-aminoinosine and 8-aminohypoxanthine are structurally similar to 8-aminoguanosine and 8-aminoguanine, respectively, we sought to define their renal excretory effects. First, we compared the ability of 8-aminoguanine, 8-aminohypoxanthine, and 8-aminoinosine to inhibit recombinant PNPase. These compounds inhibited PNPase with a potency order of 8-aminoguanine > 8-aminohypoxanthine = 8-aminoinosine. Additional studies showed that 8-aminoinosine is a competitive substrate that is metabolized to a competitive PNPase inhibitor, namely 8-aminohypoxanthine. Administration of each 8-aminopurine (33.5 µmol/kg) reduced the guanine-to-guanosine and hypoxanthine-to-inosine ratios in urine, a finding confirming their ability to inhibit PNPase in vivo. All three 8-aminopurines induced diuresis, natriuresis, and glucosuria; however, the glucosuric effects of 8-aminohypoxanthine and 8-aminoinosine were less pronounced than those of 8-aminoguanine. Neither 8-aminohypoxanthine nor 8-aminoinosine altered potassium excretion, whereas 8-aminoguanine caused antikaliuresis. In vivo administration of 8-aminoinosine increased 8-aminohypoxanthine excretion, indicating that 8-aminohypoxanthine mediates, in part, the effects of 8-aminoinosine. Finally, 8-aminohypoxanthine was metabolized to 8-aminoxanthine by xanthine oxidase. Using ultraperformance liquid chromatography-tandem mass spectrometry, we identified 8-aminoinosine as an endogenous 8-aminopurine. In conclusion, 8-aminopurines have useful pharmacological profiles. To induce diuresis, natriuresis, glucosuria, and antikaliuresis, 8-aminoguanine (or its prodrug 8-aminoguanosine) would be preferred. If only diuresis and natriuresis, without marked glucosuria or antikaliuresis, is desired, 8-aminohypoxanthine or 8-aminoinosine might be useful. Finally, here we report the in vivo existence of another pharmacologically active 8-aminopurine, namely 8-aminoinosine. SIGNIFICANCE STATEMENT: Here, we report that a family of 8-aminopurines affects renal excretory function: effects that may be useful for treating multiple diseases including hypertension, heart failure, and chronic kidney disease. For diuresis and natriuresis accompanied by glucosuria and antikaliuresis, 8-aminoguanine (or its prodrug 8-aminoguanosine) would be useful; if only diuresis and natriuresis is called for, 8-aminohypoxanthine or 8-aminoinosine would be useful. Previously, we identified 8-aminoguanine and 8-aminoguanosine as endogenous 8-aminopurines; here, we extend the family of endogenous 8-aminopurines to include 8-aminoinosine.

Bimetallic nanozyme mediated urine glucose monitoring through discriminant analysis of colorimetric signal.

The ability to detect glucose concentrations in human urine offers a non-invasive approach to monitor changes in blood glucose, kidney health and vascular complications associated with diabetes. We show the potential of employing catalytically active nanoparticles directly grown on textiles to produce a dose-dependent colorimetric sensor for glucose. We use a galvanic replacement (GR) reaction for the synthesis of bimetallic nanoparticles. Here, Cu nanoparticles act as a sacrificial template that undergoes a spontaneous electroless GR reaction when exposed to metal ions of gold, silver, platinum, and palladium to form bimetallic Cu-M nanoparticles (M = Au, Ag, Pt, or Pd). The evaluation of their intrinsic peroxidase-mimicking catalytic activity ("nanozyme") in comparison to that of the Cu nanozyme revealed that the bimetallic systems show a higher catalytic rate with the Cu-Pt nanozyme showing the highest catalytic efficiency. This property of the Cu-Pt nanozyme was then utilized to detect glucose in human urine using the glucose oxidase enzyme as a molecular recognition element. A key outcome of our study is the ability to detect urine glucose without requiring sample dilution which is an advantage over the gold standard GOx-POx method and significantly more reliable performance over commercial urine glucose dipsticks. The difference in the intensity of the colorimetric response between different glucose concentrations further allowed this sensor system to be combined with digital imaging tools for multivariate analysis.

Glycosuria Alters Uropathogenic Escherichia coli Global Gene Expression and Virulence.

Uropathogenic Escherichia coli (UPEC) is the principal etiology of more than half of urinary tract infections (UTI) in humans with diabetes mellitus. Epidemiological data and studies in mouse model of ascending UTI have elucidated various host factors responsible for increasing the susceptibility of diabetic hosts to UPEC-UTI. In contrast, diabetic urinary microenvironment-mediated alterations in UPEC physiology and its contributions to shaping UPEC-UTI pathogenesis in diabetes have not been examined. To address our central hypothesis that glycosuria directly induces urinary virulence of UPEC, we compared virulence characteristics and gene expression in human UPEC strains UTI89 (cystitis) and CFT073 (pyelonephritis), exposed for 2 h in vitro to urine from either male or female donors that was either plain or supplemented with glucose to mimic glycosuria. Compared to control UPEC exposed to nutrient-rich culture medium, lysogeny broth, glycosuria-exposed UPEC exhibited significant increase in biofilm formation and reduction in the hemagglutination of Guinea pig erythrocytes (a measure of type 1 piliation). In addition, the analysis of UTI89 transcriptome by RNA sequencing revealed that 2-h-long, in vitro exposure to glycosuria also significantly alters expression of virulence and metabolic genes central to urinary virulence of UPEC. Addition of galactose as an alternative carbon source affected biofilm formation and gene expression profile of UPEC to an extent similar to that observed with glucose exposure. In summary, our results provide novel insights into how glycosuria-mediated rapid changes in UPEC fitness may facilitate UTI pathogenesis in the diabetic urinary microenvironment. IMPORTANCE Uropathogenic Escherichia coli (UPEC) is an important causative agent of urinary tract infections in diabetic humans. We examined the effects of in vitro exposure to glycosuria (presence of glucose in urine) on the virulence and gene expression by UPEC. Our results show that glycosuria rapidly (in 2 h) alters UPEC gene expression, induces biofilm formation, and suppresses type 1 piliation. These results offer novel insights into the pathogenesis of UPEC in the urinary tract.

Loss of function of renal Glut2 reverses hyperglycaemia and normalises body weight in mouse models of diabetes and obesity.

AIMS/HYPOTHESIS: Renal GLUT2 is increased in diabetes, thereby enhancing glucose reabsorption and worsening hyperglycaemia. Here, we determined whether loss of Glut2 (also known as Slc2a2) specifically in the kidneys would reverse hyperglycaemia and normalise body weight in mouse models of diabetes and obesity. METHODS: We used the tamoxifen-inducible CreERT2-Lox system in mice to knockout Glut2 specifically in the kidneys (Ks-Glut2 KO) to establish the contribution of renal GLUT2 to systemic glucose homeostasis in health and in insulin-dependent as well as non-insulin-dependent diabetes. We measured circulating glucose and insulin levels in response to OGTT or IVGTT under different experimental conditions in the Ks-Glut2 KO and their control mice. Moreover, we quantified urine glucose levels to explain the phenotype of the mice independently of insulin actions. We also used a transcription factor array to identify mechanisms underlying the crosstalk between renal GLUT2 and sodium-glucose cotransporter 2 (SGLT2). RESULTS: The Ks-Glut2 KO mice exhibited improved glucose tolerance and massive glucosuria. Interestingly, this improvement in blood glucose control was eliminated when we knocked out Glut2 in the liver in addition to the kidneys, suggesting that the improvement is attributable to the lack of renal GLUT2. Remarkably, induction of renal Glut2 deficiency reversed hyperglycaemia and normalised body weight in mouse models of diabetes and obesity. Longitudinal monitoring of renal glucose transporters revealed that Sglt2 (also known as Slc5a2) expression was almost abolished 3 weeks after inducing renal Glut2 deficiency. To identify a molecular basis for this crosstalk, we screened for renal transcription factors that were downregulated in the Ks-Glut2 KO mice. Hnf1α (also known as Hnf1a) was among the genes most downregulated and its recovery restored Sglt2 expression in primary renal proximal tubular cells isolated from the Ks-Glut2 KO mice. CONCLUSIONS/INTERPRETATION: Altogether, these results demonstrate a novel crosstalk between renal GLUT2 and SGLT2 in regulating systemic glucose homeostasis via glucose reabsorption. Our findings also indicate that inhibiting renal GLUT2 is a potential therapy for diabetes and obesity.

The differential effects of ertugliflozin on glucosuria and natriuresis biomarkers: Prespecified analyses from VERTIS CV.

AIMS: This prespecified exploratory analyses from VERTIS CV (NCT01986881) aimed to assess the effects of the sodium-glucose cotransporter-2 (SGLT2) inhibitor ertugliflozin on glucosuria-related (glycated haemoglobin [HbA1c], uric acid, body weight) and natriuresis-related (blood pressure, haemoglobin, haematocrit, serum albumin) biomarkers according to kidney function risk category. MATERIALS AND METHODS: Patients with type 2 diabetes and atherosclerotic cardiovascular disease were randomized to placebo, ertugliflozin 5 mg, or ertugliflozin 15 mg (1:1:1). Analyses compared placebo (n = 2747) versus ertugliflozin (pooled; n = 5499) on glucosuria- and natriuresis-related biomarkers according to baseline estimated glomerular filtration rate (eGFR) subgroup and Kidney Disease: Improving Global Outcomes in Chronic Kidney Disease (KDIGO CKD) risk category. RESULTS: Patients were classified according to KDIGO CKD low- (49%), moderate- (32%) and high-/very-high-risk categories (19%), and eGFR groups 1 (25%), 2 (53%) and 3 (19%). At Week 18, the high-/very-high-risk category had a smaller placebo-subtracted least squares mean (LSM) change from baseline (95% confidence interval) in HbA1c (-0.34 [-0.43, -0.25]) compared with the low- and moderate-risk categories (-0.54 [-0.60, -0.49] and - 0.47 [-0.54, -0.40], respectively). This pattern was maintained throughout the study (Pinteraction  = 0.0001). Similar patterns based on baseline eGFR G stage were observed. Placebo-subtracted LSM changes from baseline in uric acid were lowest in the high-/very-high-risk category at Weeks 6 and 18, but the pattern was not maintained after Week 156 (Pinteraction  = 0.15). Effects of ertugliflozin on body weight and natriuresis-related biomarkers did not differ across KDIGO CKD categories. CONCLUSIONS: In VERTIS CV, ertugliflozin was associated with physiologically favourable changes in glucosuria- and natriuresis-related biomarkers. Glycaemic efficacy of ertugliflozin was attenuated in patients with higher chronic kidney disease (CKD) risk. Effects on other biomarkers were consistent, regardless of CKD risk stage.

Stx2 Induces Differential Gene Expression and Disturbs Circadian Rhythm Genes in the Proximal Tubule.

Shiga toxin-producing Escherichia coli (STEC) causes proximal tubular defects in the kidney. However, factors altered by Shiga toxin (Stx) within the proximal tubules are yet to be shown. We determined Stx receptor Gb3 in murine and human kidneys and confirmed the receptor expression in the proximal tubules. Stx2-injected mouse kidney tissues and Stx2-treated human primary renal proximal tubular epithelial cell (RPTEC) were collected and microarray analysis was performed. We compared murine kidney and RPTEC arrays and selected common 58 genes that are differentially expressed vs. control (0 h, no toxin-treated). We found that the most highly expressed gene was GDF15, which may be involved in Stx2-induced weight loss. Genes associated with previously reported Stx2 activities such as src kinase Yes phosphorylation pathway activation, unfolded protein response (UPR) and ribotoxic stress response (RSR) showed differential expressions. Moreover, circadian clock genes were differentially expressed, suggesting Stx2-induced renal circadian rhythm disturbance. Circadian rhythm-regulated proximal tubular Na+-glucose transporter SGLT1 (SLC5A1) was down-regulated, indicating proximal tubular functional deterioration, and mice developed glucosuria confirming proximal tubular dysfunction. Stx2 alters gene expression in murine and human proximal tubules through known activities and newly investigated circadian rhythm disturbance, which may result in proximal tubular dysfunctions.

Glucose biosensors in clinical practice: principles, limits and perspectives of currently used devices.

The demand of glucose monitoring devices and even of updated guidelines for the management of diabetic patients is dramatically increasing due to the progressive rise in the prevalence of diabetes mellitus and the need to prevent its complications. Even though the introduction of the first glucose sensor occurred decades ago, important advances both from the technological and clinical point of view have contributed to a substantial improvement in quality healthcare. This review aims to bring together purely technological and clinical aspects of interest in the field of glucose devices by proposing a roadmap in glucose monitoring and management of patients with diabetes. Also, it prospects other biological fluids to be examined as further options in diabetes care, and suggests, throughout the technology innovation process, future directions to improve the follow-up, treatment, and clinical outcomes of patients.

Reduction of susceptibility to azoles and 5-fluorocytosine and growth acceleration in Candida albicans in glucosuria.

Diabetes mellitus is a chronic metabolic disease characterized by hyperglycemia and glucosuria, and is a risk factor for Candida infections. To reveal the potential effects of glucosuria on Candida spp., we investigated their growth and antifungal susceptibilities in normal human urine to which glucose was added. The viable cell numbers of Candida spp. were more than 10 fold higher in the urine added 3000 mg/dL glucose than in plain urine. In antifungal susceptibility, more than 80% of Candida albicans clinical isolates increased minimum inhibitory concentrations of azoles and 5-fluorocytosine with the addition of glucose, and exceeded their breakpoints. In most of the C. albicans clinical isolates, the mRNA expression of the azole resistance genes ERG11, CDR1, CDR2, and MDR1 in the presence of glucose in urine. These observations provide valuable information about the clinical course and therapeutic effects of azoles against C. albicans infections in patients with diabetes mellitus and hyperglucosuria.

Factors Influencing Change in Serum Uric Acid After Administration of the Sodium-Glucose Cotransporter 2 Inhibitor Luseogliflozin in Patients With Type 2 Diabetes Mellitus.

Although sodium-glucose cotransporter 2 (SGLT2) inhibitors lower serum uric acid, their long-term effect on uric acid metabolism is not well understood. We analyzed pooled data from studies wherein patients with type 2 diabetes mellitus received luseogliflozin, an SGLT2 inhibitor. Upon stratifying patients by baseline glycated hemoglobin (HbA1c ) or serum uric acid, lower HbA1c or higher serum uric acid level was associated with a greater reduction in serum uric acid after treatment. At week 12 of treatment, significant increases in urinary glucose/creatinine (Cr) ratio and urinary uric acid clearance/Cr clearance ratio (CUA /CCr ratio) and a significant reduction in serum uric acid were observed. Comparison of the subgroups of patients with a reduction or an increase in serum uric acid showed that the increase subgroup had a higher estimated glomerular filtration rate (eGFR) at baseline, and the eGFR was significantly reduced, associated with a significant reduction in the CUA /CCr ratio. Multiple regression analysis showed that the reduction in serum uric acid in the luseogliflozin group was strongly associated with baseline high serum uric acid, low HbA1c levels, and an increase in eGFR. Luseogliflozin was shown to reduce serum uric acid by enhancing urinary uric acid excretion in association with increased urinary glucose. Treatment with luseogliflozin resulted in increased serum uric acid in some patients, which may be due to reduced glomerular filtration of uric acid via the tubuloglomerular feedback. SGLT2 inhibitors reduced serum uric acid desirably in patients with type 2 diabetes mellitus with low HbA1c and high serum uric acid.

Glycosuria in primary glomerulopathies: prevalence and prognostic significance.

INTRODUCTION: Tubular damage is common in glomerular diseases (GD). Glycosuria is a marker of tubular dysfunction and may be used to detect tubular lesion and CKD progression. The aim of this study was to evaluate the prevalence and prognostic value of glycosuria at the time of diagnosis in primary glomerulopathies (PG). METHODS: We conducted a 24-month retrospective study in patients diagnosed with PG in our center between 2009 and 2020. We excluded diabetic patients, use of SGLT2 inhibitors, transplant patients, and secondary GD. Patients were divided in two groups according to their glycosuria status at diagnosis. RESULTS: We studied 115 patients. Global prevalence of glycosuria was 10% (n=11) and membranous nephropathy (MN) had the highest prevalence (n=5, 17.9%). We found that patients with glycosuria had higher serum creatinine (2.4 vs. 1.2 mg/dL, p=0.030), higher albuminuria (4.8 vs. 1.9 g/g, p=0.004), and lower serum albumin (2.3 vs. 3.2 g/dL, p=0.021). We did not find association with histological prognostic factors. At the end of follow-up, patients with glycosuria had higher prevalence of the composite outcome of stage 5D CKD or 50% increase in basal SCr (45.5% vs. 17.3%, p=0.037). In patients with MN, results were similar but we were able to find an association of glycosuria with more severe interstitial fibrosis and tubular atrophy (25.0 vs. 0.0 %, p=0.032). CONCLUSION: Ten percent of our patients with PG have glycosuria. Glycosuria at the time of diagnosis was associated with more severe clinical presentation and worst renal outcome. The association with higher albuminuria suggests that tubular function has an impact on the severity and outcomes of PG.

Antifibrotic effects of low dose SGLT2 Inhibition with empagliflozin in comparison to Ang II receptor blockade with telmisartan in 5/6 nephrectomised rats on high salt diet.

To date, the lowest protective SGLT2 inhibitor dose is unknown. We initially performed a dose-response pilot study in normal rats. Based on the results of this pilot study we compared the cardio-renal effects of the SGLT-2 inhibitor empagliflozin, with placebo or telmisartan in rats with 5/6 nephrectomy (5/6 Nx) on a high salt diet (HSD). The experimental set up was as follows: Sham operation (Sham) with normal diet and placebo; 5/6 Nx with 2% HSD and placebo; 5/6 Nx with HSD and empagliflozin (0.6 mg/kg/day, bid); 5/6 Nx with HSD and telmisartan (5 mg/kg/day, qd). Empagliflozin treatment increased urinary glucose excretion, in parallel to empagliflozin plasma levels, in a dose-dependent manner starting at doses of 1 mg/kg in the pilot study. 5/6Nx rats on HSD treated with this low empagliflozin dose showed significantly reduced cardiac (-34.85%; P < 0.05) and renal (-33.68%; P < 0.05) fibrosis in comparison to 5/6Nx rats on HSD treated with placebo. These effects were comparable to the effects observed when implementing the standard dose (5 mg/kg/day) of telmisartan (cardiac fibrosis: -36.37%; P < 0.01; renal fibrosis; -43.96%; P < 0.01). RNA-sequencing followed by confirmatory qRT-PCR revealed that both telmisartan and empagliflozin exert their cardiac effects on genes involved in vascular cell stability and cardiac iron homeostasis, whereas in the kidneys expression of genes involved in endothelial function and oxidative stress were differentially expressed. Urinary adenosine excretion, a surrogate marker of the tubuloglomerular feedback (TGF) mechanism, was not affected. In conclusion, the antifibrotic properties of low dose empagliflozin were comparable to a standard dose of telmisartan. The underlying pathways appear to be TGF independent.

Urinary liver-type fatty acid-binding protein in two dogs with acquired Fanconi syndrome: A case report.

Background: Fanconi syndrome (FS) is defined as multiple defects of the proximal tubules and is diagnosed by clinical symptoms. However, in dogs with FS, the damage in the proximal tubules that is responsible for the clinical symptoms has not been evaluated. Among FS cases, tubular damage in acquired FS is reversible following the elimination of a causative factor. Liver-type fatty acid-binding protein (L-FABP) is a biomarker of tubular damage in various animals including dogs. Urinary L-FABP measurement may be useful for the diagnosis and follow-up evaluation in canine FS. Case Description: At the first visit, two Toy Poodles that had no remarkable findings on physical examination presented with glycosuria without hyperglycemia, hypokalemia, hyperchloremia, increased levels of plasma alkaline phosphatase, and metabolic acidosis. Considering all the factors involved, the dogs were clinically diagnosed with acquired FS. The owner reported that they routinely fed the dog with chicken jerky, a recently considered cause of acquired FS. Following the withdrawal of the jerky, abnormalities including glycosuria improved in both dogs. Moreover, urinary L-FABP levels, which were high at diagnosis, presented a decreasing trend during the follow-up. However, in one dog, the elevated urinary L-FABP level did not return to normal. Conclusion: Although the clinical symptoms of acquired FS in dogs could be improved by the elimination of a causative factor, the severity of tubular damage described by urinary L-FABP may not be necessarily linked to the degree of functional deterioration. Therefore, the evaluation of proximal tubular damage by L-FABP may be of clinical value during the follow-up of acquired FS in canines.

Tubular Injury Causing Protracted Glycosuria Following Withdrawal of a Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor: A Possible Role in the Development of Protracted Hypoglycemia and Ketoacidosis.

We herein present the case of a 45-year-old diabetic woman who developed diabetic ketoacidosis following the administration of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor. The patient had been diagnosed with diabetes three years previously and was being treated with multiple daily injections of insulin. Metformin hydrochloride and dapagliflozin were added seven months and 11 months later, respectively. Her clinical course was uneventful until the onset of influenza. She then discontinued insulin and oral medications voluntarily. On arrival at the hospital, she was found to be in a state of ketoacidosis, and promptly received insulin and saline infusion. In retrospect, the initial amount of glucose infused was insufficient, and the hypoglycemia was thought to have been prolonged. This phenomenon may also have affected her long-term urinary glucose excretion. Her urinary L-type fatty acid-binding protein (L-FABP) level was found to be markedly elevated (48.8 µg/g·Cr, reference value < 8.4 µg/g·Cr) as was her urinary ß2-microglobulin level (9,230 µg/L, reference value < 230 µg/L). Patients with SGLT-2 inhibitor-associated diabetic ketoacidosis often exhibit protracted hyperglycosuria, in which acute proximal renal tubular dysfunction is considered to be etiologically implicated.

Determinación niveles de glucosa por medio de espectroscopía como método no invasivo / Determination of glucose levels by means of spectroscopy as a non-invasive method

Introducción: la diabetes mellitus es uno de los problemas más graves de salud pública que enfrenta México. El factor más preocupante es la falta de control de la misma, lo que incide de manera directa, causando daños severos a la salud y la calidad de vida del paciente y familiares, así como una carga económica al país. Por lo tanto, el desarrollo de un método no invasivo para la medición de la glucemia proporcionaría a los pacientes una forma sencilla e indolora de monitoreo y, en consecuencia, un mejor control de la diabetes. Objetivo: investigar, desarrollar y validar un sensor no invasivo por medio de la espectroscopía para la estimación del nivel de glucosa en sangre. Material y métodos: se realizó un análisis de estudio transversal analítico de correlación realizado en las instalaciones del laboratorio de la UMAE No 1, Bajío. Se incluyeron pacientes adultos voluntarios que acudieron al laboratorio de dicha unidad para la toma de niveles de glucosa sérica y de manera simultánea se realizó la medición a través de método no invasivo por espectroscopía y, posteriormente, se compararon ambos resultados para demostrar la validez del dispositivo. Resultados: mediante el análisis de la diferencia de medias de Bland-Altman, se identificó que solamente un paciente tuvo un valor extremo, y que el método para medir la glucosa de manera no invasiva sobreestima hasta un 10.2% del valor de glucosa central. Conclusión: comparando dichos resultados con las normas para glucómetros digitales se concluye que nuestro dispositivo es capaz de proporcionar niveles de glucosa certeros.

Background: Diabetes mellitus is one of the most serious public health problems in Mexico. The most worrying factor is the lack of control of it, which has a direct impact, causing severe damage to the health and quality of life of the patient and its family, as well as an economic burden to the health system. Therefore, the development of a non-invasive method for measuring blood glucose would provide to patients a simple and painless way of monitoring and consequently better control of diabetes. Objective: Research, development and validation of a non-invasive sensor by means of spectroscopy for the estimation of the blood glucose level. Material and methods: An analysis of a cross-sectional analytical correlation study was carried out in the facilities of the laboratory at the UMAE No. 1, Bajío. Voluntary adult patients who attended the laboratory of the UMAE to take serum glucose levels were included, and simultaneously the measurement was carried out through a non-invasive method by spectroscopy and, later, both results were compared to demonstrate the validity of the device. Results: By the Bland-Altman mean difference analysis, it was identified that only one patient had an extreme value, and that the method to measure glucose non-invasively overestimates up to 10.2% of the central glucose value. Conclusion: Comparing these results with the standards for digital glucometers, it is concluded that our device is capable of providing accurate glucose levels.

Mass urine sugar testing to tackle post-COVID mucormycosis epidemic in India-MUSTARD concept.

BACKGROUND: Post-Covid mucormycosis is associated with very high morbidity and reasonably high mortality. The three main causes seem to be covid infection, excessive steroid usage and uncontrolled diabetes. METHODS: Of the three risk factors causing post-Covid mucormycosis, the only risk factor which can be modified quickly is uncontrolled diabetes. Checking urine-sugar levels of susceptible population asymptomatic for mucormycosis can be done rapidly and at a relatively low cost. Urine sugar positive persons can then be investigated and managed for uncontrolled diabetes. RESULTS: None CONCLUSIONS: Mass urine sugar testing to assess and regulate diabetes(MUSTARD) can help identify and manage uncontrolled diabetes in populations with high prevalence of diabetes.