Glucose Reabsorption Research Articles

SGLT2 inhibitors for heart and kidney

Sodium-glucose co-transporter 2 (SGLT2) inhibitors can block glucose reabsorption in the proximal tubule and thus play an important role in glycemic control in diabetes mellitus. In addition to glucosuric effects, surprisingly very extensive other positive effects were observed in chronic renal dysfunction and strong cardioprotective effects in heart failure. In the meantime, numerous mechanisms have been identified apart from the pure sugar-influencing effect of the SGLT2 inhibitors, which can have a direct positive influence heart and kidneys.In recent years there has been an extensive clinical study program, which has dealt with the effects of SGLT2 inhibitors on the progression of diabetic and non-diabetic chronic renal failure. It could be shown that patients with albuminuria have a significant benefit from the use of SGLT2 inhibitors. Therefore, the progression of renal dysfunction is slowed down significantly, while at the same time, positive cardiovascular endpoints could be influenced. Numerous studies have also been conducted in patients with and without diabetes or with heart failure, with and without, preserved ejection fraction. Impressive protection was also shown here, with the benefit of using SGLT2 inhibitors to reduce heart failure worsening.In a short period of 10 years, the use of SGLT2 inhibitors was established as an essential therapy for cardio-renal indications to inhibit the progression of renal failure as well as to protect against heart failure apart from pure diabetes therapy. In numerous guidelines (ESC heart failure, KDGIO diabetes, ESH hypertension), the early use of SGLT2 inhibitors is now recommended for protection against cardio-renal events and is an important first-line addition to the previously established therapies. Apart from diabetes therapy, it offers patients completely new options in cardio-renal protection.

How to optimize the use of diuretics in patients with heart failure?

Considering the pathophysiology and clinical presentation of heart failure, using diuretics or drugs with diuretic properties is indispensable for adequate management of heart failure patients. However, in clinical practice, fluid expansion is often undiagnosed, and diuretic therapy is not always adequately titrated. Today, several drug classes with diuretic properties are available in addition to classical thiazides, thiazide-like, and loop diuretics. The purpose of this short review is to discuss different ways to optimize diuretic therapy using currently available drugs. Several approaches are considered, including a combination of diuretics to obtain a sequential nephron blockade, use of a drug combining a blocker of the renin-angiotensin system (RAS) and an inhibitor of the metabolism of natriuretic peptides (ARNI), prescription of potassium binders to maintain and up-titrate RAS blockers and mineralocorticoid antagonists, and finally use of inhibitors of renal reabsorption of glucose through the sodium-glucose cotransporter 2 system. Optimal use of these various drug classes should improve the quality of life and reduce the need for hospital admissions and mortality in heart failure patients.

Role of SLC5A2 polymorphisms and effects of genetic polymorphism on sodium glucose cotransporter 2 inhibitorsinhibitor response.

Type 2 diabetes mellitus (T2DM) is a complex metabolic disease characterized by hyperglycaemia. T2DM is a highly heterogeneous polygenic disease. Due to genetic variation, variations in lifestyle and other environmental exposures, there are certain variations in the phenotype of T2DM patients. Sodium glucose cotransporter 2 (SGLT2) inhibitors are novel hypoglycaemic agents that increase urinary glucose excretion by inhibiting glucose reabsorption in the proximal tubules of the kidney. For glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, studies have confirmed a variety of gene variants that may modify their effects. For SGLT2 inhibitors, research has focused on the SLC5A2 gene encoding SGLT2 and UGT1A9 gene polymorphisms affecting SGLT2 inhibitor metabolism. The SLC5A2 polymorphism rs9934336 have been associated with decreased HbA1c during the oral glucose tolerance test. Common variants of the SLC5A2 gene are related to blood glucose and insulin concentrations, but not glucagon concentrations. SLC5A2 rs9934336 and rs3116150 are related to a lower risk of heart failure. SGLT2 inhibitor exposure of UGT1A9*3 carriers is commonly higher than that of noncarriers, while these effects commonly have no obvious clinical significance on SGLT2 inhibitor pharmacokinetics. In terms of efficacy, general SLC5A2 variants show no significant effect on the response to the SGLT2 inhibitor empagliflozin. At present, research on the relationship between genetic polymorphisms and the efficacy of SGLT2 inhibitors is limited. The main purpose of this review is to elucidate the general effects of SGLT2 polymorphisms and the association between polymorphisms and the treatment response to SGLT2 inhibitors.

In silico Prediction of Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibition Activity by Allium Fistulosum Compound Based on SkelSpheres Molecular Descriptor

The Sodium-Glucose co-transporter-2 (SGLT2) inhibitor represents a novel agent for the treatment of type 2 diabetes. Drugs of this class function by inhibiting glucose reabsorption in the kidneys, thereby controlling blood glucose levels. It is known that SGLT2 inhibitors activate the AMPK signaling pathway by increasing the expression and activity of AMP-activated protein kinase (AMPK). In vivo tests have demonstrated that ethanolic and aqueous extracts of Welsh onion leaves (Allium fistulosum L) can reduce body weight, liver weight, adipocyte size, and enhance AMP-activated protein kinase (AMPK) expression. In this study, the inhibitory activity (IC50) of compounds within Allium fistulosum against SGLT2 was predicted using the Support Vector Regression (SVR) predictive model and the SkelSpheres descriptor. The results of the predicted IC50 measurements for compounds present in the 70% ethanol extract of Allium fistulosum in silico indicate that 4 tyramine derivatives and 1 decursidate compound exhibit Excellent or Potent inhibitor activity criteria (IC50 < 1 µM). Among these, the four tyramine group compounds are the isomers N-trans-feruloyltyramine and N-cis-feruloyltyramine, as well as the isomers N-trans-feruloyl-3'-methoxytyramine and N-cis-feruloyl-3'-methoxytyramine. The findings of this study suggest that the ability of Allium fistulosum to enhance AMPK expression is possibly achieved through the inhibition of SGLT2.

THU389 Euglycemic Diabetic Ketoacidosis With Prolonged Ketosis Due To SGLT-2 Inhibitor

Abstract Disclosure: N. Viera Feliciano: None. J. Johannan: None. E. Nosova: None. C.J. Levy: Advisory Board Member; Self; Eli Lilly & Company, Dexcom. Research Investigator; Self; NIH, Helmsley Foundation, Abbott, Dexcom, Insulet, Tandem. Background: Euglycemic Diabetic ketoacidosis is a known complication of Sodium-glucose cotransporter 2 inhibitor use. Prolonged ketosis is infrequently reported on this patient population. Clinical Case: A 67-year-old male with T2DM (HbA1c 8.3%) taking dapagliflozin, metformin and semaglutide presented with emesis, polydipsia and reduced oral intake for 2 weeks. Initial tests were consistent with euglycemic diabetic ketoacidosis (eDKA): glucose 193 (70-110 mg/dL), acidosis (pH on VBG 7.27), bicarbonate 10 mmol/L (22-26 mmol/L), anion gap of 25, beta-hydroxybutyrate >4.5, positive urine ketones and glycosuria. Insulin drip was initiated along with fluid resuscitation and intravenous dextrose, followed by transition to a basal/bolus regimen after anion gap closure. Despite overall clinical improvement, the patient’s labs demonstrated persistent metabolic derangements: glycosuria and ketosis that lasted 7 days after his last dose of dapagliflozin. Implementation of an insulin regimen in this insulin-naïve patient and a carbohydrate-rich diet resulted in subsequent resolution of the derangements. The patient was discharged on metformin and insulin. eDKA is defined by a blood glucose level below 200 mg/dL, metabolic acidosis and ketosis. The cause of eDKA in this case is attributed to SGLT-2 inhibitor (SGLT2i) use, which lead to a carbohydrate deficit and depletion of glycogen stores, increased glucagon/insulin ratio resulting in ketogenesis and decreased hepatic gluconeogenesis. SGLT-2i act on proximal tubules reducing reabsorption of glucose, thereby increasing urinary glucose excretion. Dapagliflozin has an approximate half-life of 12 hours; therefore, clinical recovery from SGLT2i-associated eDKA would be expected to take up to 2-3 days after cessation of the medication. Case reports have shown persistent glucosuria and ketonemia up to 10 days after discontinuation of the drug, but the data is sparse. Our patient’s laboratory tests remained consistent with eDKA for up to 7 days, suggesting a longer lasting effect of dapagliflozin. This was managed with more aggressive insulin doses and a higher carbohydrate intake which played a critical role in correction of the insulin deficit and repletion of glycogen stores for metabolic recovery. With the growing popularity of this medication class, additional controlled studies are needed for a better understanding of the pharmacodynamics as well as how to target management strategies when eDKA occurs. In this report, we highlight the prolonged clinical effects of SGLT-2i after discontinuation and resolution of symptoms with an aggressive insulin regimen and higher carbohydrate intake. Conclusion: Use of SGLT-2i therapy for diabetes has increased the incidence of eDKA. Providers should be aware of the possibility of prolonged eDKA and manage metabolic imbalances to achieve clinical recovery in an appropriate time frame. Presentation: Thursday, June 15, 2023

THU244 Clinical Factors Affecting Dapagliflozin Response For Glycemic Control And Body Weight Reduction: Post-hoc Analysis Of BEYOND Study

Abstract Disclosure: K. Ahn: None. J. Ji Eun: None. J. In-Kyung: None. Background: Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, ameliorates hyperglycemia and obesity by inhibiting renal glucose reabsorption. However, significant heterogeneity exists in glucose-lowering efficacy and the magnitude of the weight loss among patients with type 2 diabetes. Herein, we aimed to evaluate the clinical factors affecting response to dapagliflozin treatment. Methods: We performed a post-hoc analysis of the BEYOND (Effects of Dapagliflozin Compared with Glimepiride on Body Composition in Patients with Type 2 Diabetes Inadequately Controlled with Metformin) randomized, double-blind, parallel-group trial. Patients were randomly assigned (1:1) to receive the addition of either dapagliflozin 10 mg per day or glimepiride 1∼2 mg per day to background metformin therapy for 52 weeks. Changes in HbA1c and body weight from baseline during the observation period were assessed for all patients. Responder to dapagliflozin was defined by >1% reduction in A1c and >3% reduction in body weight at week 52. Then, we classified the total subjects into 4 groups: non-responder of both A1c reduction and body weight reduction, responders of A1c reduction but non-responder of body weight reduction, non-responder of A1c reduction but responders of body weight reduction, and responders of both A1c reduction and body weight reduction. Results: Among 56 patients in a dapagliflozin arm, 55.4% (N = 31) and 57.1% (N = 32) experienced clinical responses as indicated by reductions in HbA1c and in body weight reduction, respectively. Younger age and higher HbA1c level at baseline were significantly associated with a greater HbA1c reduction, and a higher estimated glomerular filtration rate (eGFR) was significantly associated with a greater body weight reduction. However, there was no association between the change in HbA1c and the change in body weight (r = −0.133, P = 0.328). Responders of both A1c reduction and body weight reduction were most common (32.1%), non-responders of A1c reduction but responders of body weight reduction were second-most (25.0%), responders of A1c reduction but non-responders of body weight reduction were 23.2%, and non-responders of both A1c reduction and body weight reduction were 19.6%. Subjects with higher fasting plasma glucose (FPG) and HbA1c in addition to lower eGFR at baseline had a greater reduction in HbA1c, but less reduction in body weight. Conversely, those with lower FPG and HbA1c in addition to higher eGFR at baseline had a greater reduction in body weight, but less reduction in HbA1c level. Conclusion: Patients with type 2 diabetes actually exhibit a heterogeneous response to dapagliflozin treatment. Glucose-lowering efficacy of dapagliflozin was associated with worse baseline glycemic status, and body weight reduction was associated with baseline higher eGFR. Presentation: Thursday, June 15, 2023

Diabetes and Cardiorenal Complications: A Clinical Review of Existing Therapies and Novel Combinations, Focusing on SGLT2 Inhibitors.

Type 2 diabetes mellitus (T2DM) is a set of metabolic disorders specified by hyperglycemia as a result of abnormalities in insulin secretion or sensitivity. Chronic kidney disease (CKD) and cardiovascular disease (CVD) are the widespread co-morbidities of T2DM and share risk factors for onset and progression. Despite numerous mono- and combination therapies exist, the progression of diabetes complications remains a global health concern. Treatment options for diabetic- CKD and CVD include drugs targeting hyperglycemia, hypertension, albuminuria, hyperlipidemia and the renin-angiotensin aldosterone system (RAAS). The sodium-glucose co-transporter 2 channel (SGLT2) is abundantly present in proximal tubules of the kidney and its capacity to recover glucose and sodium from the glomerular filtrate limits urinary glucose and sodium excretion. SGLT2 inhibitors (SGLT2i) reduce sodium and glucose reabsorption in the proximal and thus increase urinary glucose excretion in T2DM. SGLT2i monotherapy can improve but dual SGLT2/RAAS inhibition or SGLT2i along with other classes of drugs are more effective in protecting the kidneys and the cardiovascular system in patients with and without diabetes. Combinations such as empagliflozin and linagliptin, ertugliflozin and metolazone, dapagliflozin and sacubitril- valsartan and many more show promising results. Here, we have reviewed the ongoing and completed clinical trials, addressed current theories, and discussed necessary future research to explain the possible risks and benefits of using an SGLT2i alone and in combination with existing antidiabetic drugs and drugs acting on the cardiovascular system.

Sodium-glucose Cotransporter 2 Inhibitors and Pathological Myocardial Hypertrophy.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new type of oral hypoglycemic drugs that exert a hypoglycemic effect by blocking the reabsorption of glucose in the proximal renal tubules, thus promoting the excretion of glucose from urine. Their hypoglycemic effect is not dependent on insulin. Increasing data shows that SGLT2 inhibitors improve cardiovascular outcomes in patients with type 2 diabetes. Previous studies have demonstrated that SGLT2 inhibitors can reduce pathological myocardial hypertrophy with or without diabetes, but the exact mechanism remains to be elucidated. To clarify the relationship between SGLT2 inhibitors and pathological myocardial hypertrophy, with a view to providing a reference for the future treatment thereof, this study reviewed the possible mechanisms of SGLT2 inhibitors in attenuating pathological myocardial hypertrophy. We focused specifically on the mechanisms in terms of inflammation, oxidative stress, myocardial fibrosis, mitochondrial function, epicardial lipids, endothelial function, insulin resistance, cardiac hydrogen and sodium exchange, and autophagy.

Cardiorenal Protections of SGLT2 Inhibitors in the Treatment of Type 2 Diabetes.

Cardiovascular disease and renal complications raise the risk of death and morbidity in patients with type 2 diabetes (T2D). Sodium/glucose cotransporter-2 inhibitors (SGLT2i) are a novel class of glucose-lowering drug that increases urine glucose excretion while decreasing blood glucose levels in type 2 diabetes patients by inhibiting glucose reabsorption. In the present article, we review the discovery and development of SGLT2i as a new T2D treatment approach for T2D; thereafter, we consider different cell-based methods for the evaluation of SGLT2i. Finally, we provide evidences from both clinical and experimental studies which bring up the cardio-renal protective effects of SGLT2i. We performed a literature search using PubMed, Google Scholar, and Web of Science to identify publications on preclinical and clinical studies of cardiorenal protective action of SGLT2i and their suggested mechanisms. SGLT2i have shown good effects in the improvement of cardiovascular and renal complications independent of glucose lowering effects. Besides controlling blood glucose levels, SGLT2i were found to exhibit therapeutic benefits on the kidney and cardiovascular system by lowering diabetic glomerular hyperfiltration, blood pressure (BP), body weight, uric acid concentrations, lipid peroxidation, inflammation, etc. As a result of their distinct mode of action, SGLT2i have emerged as a promising treatment option for T2D and maybe T1D due to their increased urine excretion of glucose. It has been demonstrated that SGLT2i have considerable protective effects on diabetic nephropathy (DN) and cardiomyopathy in well-designed experimental and clinical investigations.

Comparison of SGLT1, SGLT2, and Dual Inhibitor biological activity in treating Type 2 Diabetes Mellitus.

Diabetes Mellitus Type 2 (T2D) is an emerging health burden in the USand worldwide, impacting approximately 15% of Americans. Current front-line therapeutics for T2D patients include sulfonylureas that act to reduce A1C and/or fasting blood glucose levels, or Metformin that antagonizes the action of glucagon to reduce hepatic glucose production. Next generation glucomodulatory therapeutics target members of the high-affinity glucose transporter Sodium-Glucose-Linked-Transporter (SGLT) family. SGLT1 is primarily expressed in intestinal epithelium, whose inhibition reduces dietary glucose uptake, whilst SGLT2 is highly expressed in kidney - regulating glucose reabsorption. A number of SGLT2 inhibitors are FDA approved whilst SGLT1 and dual SGLT1 & 2 inhibitor are currently in clinical trials. Here, we discuss and compare SGLT2, SGLT1, and dual inhibitors' biochemical mechanism and physiological effects.

Pump-Less Platform Enables Long-Term Recirculating Perfusion of 3D Printed Tubular Tissues.

The direction and pattern of fluid flow affect vascular structure and function, in which vessel-lining endothelial cells exhibit variable cellular morphologies and vessel remodeling by mechanosensing. To recapitulate this microenvironment, some approaches have been reported to successfully apply unidirectional flow on endothelial cells in organ-on-a-chip systems. However, these platforms encounter drawbacks such as the dependency on pumps or confinement to closed microfluidic channels. These constraints impede their synergy with advanced biofabrication techniques like 3D bioprinting, thereby curtailing the potential to introduce greater complexity into engineered tissues. Herein, a pumpless recirculating platform (UniPlate) that enables unidirectional media recirculation through 3D printed tubular tissues, is demonstrated.The device is made of polystyrene via injection molding in combination with 3D printed sacrifical gelatin templates. Tubular blood vessels with unidirectional perfusion are firstly engineered. Then the design is expanded to incorporate duo-recirculating flow for culturing vascularized renal proximal tubules with glucose reabsorption function. In addition to media recirculation, human monocyte recirculation in engineered blood vessels is also demonstrated for over 24h, with minimal loss of cells, cell viability, and inflammatory activation. UniPlate can be a valuable tool to more precisely control the cellular microenvironment of organ-on-a-chip systems for drug discovery.

The Impact of SGLT2 Inhibitors in the Heart and Kidneys Regardless of Diabetes Status.

Chronic Kidney Disease (CKD) and Cardiovascular Disease (CVD) are two devastating diseases that may occur in nondiabetics or individuals with diabetes and, when combined, it is referred to as cardiorenal disease. The impact of cardiorenal disease on society, the economy and the healthcare system is enormous. Although there are numerous therapies for cardiorenal disease, one therapy showing a great deal of promise is sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors. The SGLT family member, SGLT2, is often implicated in the pathogenesis of a range of diseases, and the dysregulation of the activity of SGLT2 markedly effects the transport of glucose and sodium across the luminal membrane of renal cells. Inhibitors of SGLT2 were developed based on the antidiabetic action initiated by inhibiting renal glucose reabsorption, thereby increasing glucosuria. Of great medical significance, large-scale clinical trials utilizing a range of SGLT2 inhibitors have demonstrated both metabolic and biochemical benefits via numerous novel mechanisms, such as sympathoinhibition, which will be discussed in this review. In summary, SGLT2 inhibitors clearly exert cardio-renal protection in people with and without diabetes in both preclinical and clinical settings. This exciting class of inhibitors improve hyperglycemia, high blood pressure, hyperlipidemia and diabetic retinopathy via multiple mechanisms, of which many are yet to be elucidated.

An Overview on Analytical Method Development and Validation for Ertugliflozin in Bulk and Pharmaceutical Dosage form

Diabetes mellitus (DM) is a metabolic condition characterized by hyperglycemia, glycosuria, hyperglycemia, a negative nitrogen balance, and occasionally ketonemia. The type 2 sodium-dependent glucose co-transporters (SGLT), which are in charge of roughly 90% of the reabsorption of glucose from the glomerulus, are subject to strong and selective inhibition by ertugliflozin. This review's primary objective is to highlight the development and validation of analytical methods employing chromatographic and spectrophotometric techniques for ertugliflozin and combination products in bulk and pharmaceutical dose forms. RP-HPLC, UV, UPLC, and LC-MS techniques are used to determine the dosage of ertugliflozin when it is combined with metformin and sitagliptin. Spectrometric techniques for ertugliflozin in combination with metformin or sitagliptin contain parameters like solvent, wavelength, linearity, LOD, LOQ, etc., and HPLC methods for ertugliflozin in combination with metformin or sitagliptin include parameters like stationary phase, mobile phase, RT, detection wavelength, LOD, LOQ, etc. Discussions on the separation requirements for ertugliflozin in combination with metformin or sitagliptin are also addressed throughout this review.

Use of Oral Empagliflozin to Obtain Optimal Blood Sugar Levels for Conducting 18 F-FDG PET-CT in Patients with Hyperglycemia-A Pilot Study.

Background Flourine-18 fluorodeoxyglucose positron emission tomography-computed tomography ( 18 F-FDG PET-CT) is a well-established imaging modality for the evaluation of patients with oncological and nononcological conditions. The underlying principle of imaging is the preferentially increased glucose consumption by cancer cells, due to overexpression of glucose type 1 receptors that are insulin independent. Thus, one of the factors that leads to decreased sensitivity of an 18 F-FDG PET-CT is elevated blood sugar levels, leading to decreased glucose uptake by cancer cells due to competitive inhibition. A significant percentage of patients scheduled for PET-CT scan has diabetes mellitus type II as a comorbid condition and often has elevated random blood sugar (RBS) precluding an upfront PET-CT evaluation. Such cases must be rescheduled. This causes delay in the evaluation and management of such patients. Empagliflozin is a novel sodium glucose type 2 inhibitor that prevents tubular reabsorption of glucose and increases renal glycosuria resulting in decreased blood sugar. This drug does not cause significant hypoglycemia or increase endogenous insulin secretion. This study was undertaken to evaluate a potential role for empagliflozin in facilitating optimal blood sugar control in patients with hyperglycemia on the day of the scheduled PET scan. Methods This is an interventional prospective study and patients detected to have RBS more than 200 mg/dL on the day of the scheduled scan were included in the study. The patients were administered two tablets of 10 mg empagliflozin and kept under observation. Samples for RBS were taken at approximately 2nd and 4th hour post administration by bedside method. These patients underwent scan on the same day after adequate sugar control and when an RBS of less than 200 mg/dL was achieved. The primary outcome studied was change in RBS values in the patient cohort and evaluation of PET SUV (standardized uptake value) compared with the rest of the patients scheduled on the same day. Secondary outcome was assessment of any side effects in the patients. Results Total of 10 patients were found to have elevated blood sugar (RBS > 200 mg/dL; irrespective of being on medication) and did not meet the evaluation criteria for a PET-CT scan on the scheduled day. Following administration of the drug, all 10 patients were able to attain blood sugar levels and fulfill the criteria for undergoing a PET-CT scan. No obvious side effect was noted in any of the patient. The SUV values of the patient cohort were comparable with the rest of the patient scanned on the day. Conclusion In this pilot study, 20 mg of empagliflozin (2 tablets of 10 mg) appears to be a safe and effective method for achieving optimal decrease in the RBS without causing hypoglycemia or hyperinsulinemia. It can be safely employed in the subset of population with RBS between 201 and 300 mg/dL to adequately bring the sugar levels at acceptable levels RBS less than 200 mg/dl and fulfill the FDG PET-CT criteria as per European Association of Nuclear Medicine (EANM) norms.

Sodium-dependent glucose co-transporter-2 inhibitor empagliflozin exerts neuroprotective effects in rotenone-induced Parkinson’s disease model in zebrafish; mechanism involving ketogenesis and autophagy

Sodium-dependent glucose co-transporter-2 (SGLT2) inhibitor empagliflozin (EMP), is the new class of oral hypoglycemic agent approved as a treatment for Type 2 diabetes. SGLT2 inhibitors may induce ketogenesis through inhibiting the renal reabsorption of glucose. In recent years, positive effects of ketogenic diets on neurodegenerative diseases such as Parkinson's disease (PD) have been reported by improving autophagy. We aimed to evaluate the effects of EMP treatment as a SGLT2 inhibitor that can mimic the effects of ketogenic diet, in rotenone induced PD model in zebrafish focusing on ketogenesis, autophagy, and molecular pathways related with PD progression including oxidative stress and inflammation. Adult zebrafish were exposed to rotenone and EMP for 30 days. Y-Maze task and locomotor analysis were performed. Neurotransmitter levels were determined by liquid chromatography tandem- mass spectrometry (LC-MS/MS). Lipid peroxidation (LPO), nitric oxide (No), alkaline phosphatase, superoxide dismutase, glutathione, glutathione S-transferase (GST), sialic acid, acetylcholinesterase, and the expressions of autophagy, ketogenesis and PD-related genes were determined. Immunohistochemical staining was performed for the microglial marker L-plastin (Lcp1) and tyrosine hydroxylase (Th). EMP treatment improved DOPAC/DA ratio, Y-Maze task, locomotor activity, expressions of Th and Lcp-1, autophagy and inflammation related (mTor, atg5, tnfα, sirt1, il6, tnfα); PD-related (lrrk2, park2, park7, pink1), and ketone metabolism-related genes (slc16a1b, pparag, and pparab), and oxidant-damage in brain in the rotenone group as evidenced by decreased LPO, No, and improved antioxidant molecules. Our results showed benefical effects of EMP as a SGLT2 inhibitor in neurotoxin-induced PD model in zebrafish. We believe our study, will shed light on the mechanism of the effects of SGLT2 inhibitors, ketogenesis and autopahgy in PD.

Role of SGLT2 Inhibitors in Diabetes Management: Focus on HbA1c Levels, Weight Loss and Genetic Variation

Sodium Glucose Co-transporters-2 (SGLT2) inhibitors are the recent addition to treatment strategies for Type 2 Diabetes Mellitus (T2DM). It is a non-insulin dependent anti-diabetic therapeutic approach that eliminates plasma glucose by urination. The study was carried out with the aim of evaluating the effect of SGLT2 inhibitors on HbA1c levels and weight loss in responders and non-responders. In addition, the role of two significant variants, SLC5A2 (rs9934336) and UGT1A9 (rs72551330), affecting the inter-individual variation in response to SGLT2 inhibitors was evaluated in the study population. 200 confirmed T2DM patients on SGLT2 inhibitors were enrolled for the study. Patients with decreased HbA1c levels and body weight were categorized as responders, whereas the ones who did not show a significant decrease in these two parameters after treatment were categorised as non-responders. Association of HbA1c levels and weight loss before as well as after treatment with responders and non-responders was evaluated. Patients were screened for two significant variants, SLC5A2 (rs9934336) and UGT1A9 (rs72551330), affecting the inter-individual variation in response to SGLT2 inhibitors by Sanger Sequencing. A significant difference in HbA1c levels and weight was found in responders and non-responders before and after the treatment. However, both of the variants, SLC5A2 (rs9934336) and UGT1A9 (rs72551330), were not found to be significantly associated with the drug response. In conclusion, SGLT2 inhibitors reduced HbA1c levels and weight effectively in responders. However, the targeted gene variants need not to be involved in genetic testing before prescribing this class of drugs to T2DM patients from Malwa region of Punjab. Highlights: Treatment of Type 2 diabetes mellitus (T2DM) with Sodium Glucose co-transporter-2 (SGLT2) inhibitors is an insulin-independent method of reducing blood glucose levels by lowering renal tubular glucose reabsorption. Significant decrease in HbA1c levels and weight loss in responders was observed after the treatment with SGLT2 inhibitors. Pharmacogenetic analysis was carried out for two gene variants, SLC5A2 (rs9934336) and UGT1A9 (rs72551330), reported to be involved in inter-individual response to SGLT2 inhibitors. None of the tested variants were found to be significantly associated with inter-individual response to SGLT2 inhibitors. Pharmacogenetic testing for the two most commonly reported variants is not required for the T2DM patients on SGLT2 inhibitors from the Malwa region of Punjab.

SGLT2 inhibitors for patients with type 2 diabetes and CKD: a narrative review.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have recently emerged as an effective means to protect kidney function in people with type 2 diabetes and chronic kidney disease (CKD). In this review, we explore the role of SGLT2 inhibition in these individuals. SGLT2 inhibitors specifically act to inhibit sodium and glucose reabsorption in the early proximal tubule of the renal nephron. Although originally developed as glucose-lowering agents through their ability to induce glycosuria, it became apparent in cardiovascular outcome trials that the trajectory of kidney function decline was significantly slowed and the incidence of serious falls in kidney function was reduced in participants receiving an SGLT2 inhibitor. These observations have recently led to specific outcome trials in participants with CKD, including DAPA-CKD, CREDENCE and EMPA-KIDNEY, and real-world studies, like CVD-REAL-3, that have confirmed the observation of kidney benefits in this setting. In response, recent KDIGO Guidelines have recommended the use of SGLT2 inhibitors as first-line therapy in patients with CKD, alongside statins, renin-angiotensin-aldosterone system inhibitors and multifactorial risk factor management as indicated. However, SGLT2 inhibitors remain significantly underutilized in the setting of CKD. Indeed, an inertia paradox exists, with patients with more severe disease less likely to receive an SGLT2 inhibitor. Concerns regarding safety appear unfounded, as acute kidney injury, hyperkalaemia, major acute cardiovascular events and cardiac death in patients with CKD appear to be lower following SGLT2 inhibition. The first-in-class indication of dapagliflozin for CKD may begin a new approach to managing kidney disease in type 2 diabetes.

SGLT2: A PERSPECTIVE ON PATHOPHYSIOLOGY AND IMPACT OF SGLT2 INHIBITION ON RENAL FUNCTION

In individuals with diabetes, kidney size and glomerular filtration rate (GFR) tend to increase, and elevated GFR is a risk factor for diabetic kidney disease. Hyperfiltration occurs when high glucose levels in the glomerular filtrate causes increased reabsorption of glucose and sodium by the sodium-glucose cotransporters SGLT2 and SGLT1 in the proximal tubule. This hyperfiltration puts additional stress on the filtration barrier and increases the oxygen demand for reabsorption. Tubular growth is associated with a molecular signature that leads to inflammation and fibrosis. SGLT2 inhibitors play a significant role in mitigating hyperfiltration by reducing sodium and glucose reabsorption, normalizing feedback signals, and alleviating the physical stress on the filtration barrier. This tubule-centered model of diabetic kidney physiology explains the positive effects of SGLT2 inhibitors on renal outcomes, as demonstrated in large-scale clinical trials. Although these medications primarily target glucose reabsorption , patients with type 2 diabetes mellitus benefit from reduced blood glucose levels along with various other physiological advantages. Data support their use for modifying risk of kidney disease progression and acute kidney injury, not only in patients with type 2 diabetes at high cardiovascular risk, but also in patients with chronic kidney disease or heart failure irrespective of diabetes status, primary kidney disease, or kidney function.

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.

A pharmacokinetic study to correlate the hypoglycemic effect of phlorizin in rats: Identification of metabolites as inhibitors of sodium/glucose cotransporters.

Phlorizin (PRZ) is a natural product that belongs to a class of dihydrochalcones. The unique pharmacological property of PRZ is to block glucose absorption or reabsorption through specific and competitive inhibitors of the sodium/glucose cotransporters (SGLTs) in the intestine (SGLT1) and kidney (SGLT2). This results in glycosuria by inhibiting renal reabsorption of glucose and can be used as an adjuvant treatment for type 2 diabetes. The pharmacokinetic profile, metabolites of the PRZ, and efficacy of metabolites towards SGLTs are unknown. Therefore, the present study on the characterization of hitherto unknown in vivo metabolites of PRZ and pharmacokinetic profiling using liquid chromatography-electrospray ionization tandem mass spectrometry (LC/ESI/MS/MS) and accurate mass measurements is undertaken. Plasma, urine, and feces samples were collected after oral administration of PRZ to Sprague-Dawley rats to identify in vivo metabolites. Furthermore, in silico efficacy of the identified metabolites was evaluated by docking study. PRZ at an intraperitoneal dose of 400 mg/kg showed maximum concentration in the blood to 439.32 ± 8.84 ng/mL at 1 h, while phloretin showed 14.38 ± 0.33 ng/mL at 6 h. The pharmacokinetic profile of PRZ showed that the maximum concentration lies between 1 and 2 h after dosing. Decreased blood glucose levels and maximum excretion of glucose in the urine were observed when the PRZ and metabolites were observed in plasma. The identification and characterization of PRZ metabolites by LC/ESI/MS/MS further revealed that the phase I metabolites of PRZ are hydroxy (mono-, di-, and tri-) and reduction. Phase II metabolites are O-methylated, O-acetylated, O-sulfated, and glucuronide metabolites of PRZ. Further docking study revealed that the metabolites diglucuronide metabolite of mono-hydroxylated PRZ and mono-glucuronidation of PRZ could be considered novel inhibitors of SGLT1 and SGLT2, respectively, which show better binding affinities than their parent compound PRZ and the known inhibitors.