New Insights into the Efficacy of Aspalathin and Other Related Phytochemicals in Type 2 Diabetes—A Review

In the pursuit of bioactive phytochemicals as a therapeutic strategy to manage metabolic risk factors for type 2 diabetes (T2D), aspalathin, C-glucosyl dihydrochalcone from rooibos (Aspalathus linearis), has received much attention, along with its C-glucosyl flavone derivatives and phlorizin, the apple O-glucosyl dihydrochalcone well-known for its antidiabetic properties. We provided context for dietary exposure by highlighting dietary sources, compound stability during processing, bioavailability and microbial biotransformation. The review covered the role of these compounds in attenuating insulin resistance and enhancing glucose metabolism, alleviating gut dysbiosis and associated oxidative stress and inflammation, and hyperuricemia associated with T2D, focusing largely on the literature of the past 5 years. A key focus of this review was on emerging targets in the management of T2D, as highlighted in the recent literature, including enhancing of the insulin receptor and insulin receptor substrate 1 signaling via protein tyrosine phosphatase inhibition, increasing glycolysis with suppression of gluconeogenesis by sirtuin modulation, and reducing renal glucose reabsorption via sodium-glucose co-transporter 2. We conclude that biotransformation in the gut is most likely responsible for enhancing therapeutic effects observed for the C-glycosyl parent compounds, including aspalathin, and that these compounds and their derivatives have the potential to regulate multiple factors associated with the development and progression of T2D.

Sodium-Glucose Cotransporter 2 Inhibitors Mechanisms of Action: A Review

Sodium-Glucose Cotransporter 2 inhibitors (SGLT2i), or gliflozins, are a group of antidiabetic drugs that have shown improvement in renal and cardiovascular outcomes in patients with kidney disease, with and without diabetes. In this review, we will describe the different proposed mechanisms of action of SGLT2i. Gliflozins inhibit renal glucose reabsorption by blocking the SGLT2 cotransporters in the proximal tubules and causing glucosuria. This reduces glycemia and lowers HbA1c by ~1.0%. The accompanying sodium excretion reverts the tubuloglomerular feedback and reduces intraglomerular pressure, which is central to the nephroprotective effects of SGLT2i. The caloric loss reduces weight, increases insulin sensitivity, lipid metabolism, and likely reduces lipotoxicity. Metabolism shifts toward gluconeogenesis and ketogenesis, thought to be protective for the heart and kidneys. Additionally, there is evidence of a reduction in tubular cell glucotoxicity through reduced mitochondrial dysfunction and inflammation. SGLT2i likely reduce kidney hypoxia by reducing tubular energy and oxygen demand. SGLT2i improve blood pressure through a negative sodium and water balance and possibly by inhibiting the sympathetic nervous system. These changes contribute to the improvement of cardiovascular function and are thought to be central in the cardiovascular benefits of SGLT2i. Gliflozins also reduce hepcidin levels, improving erythropoiesis and anemia. Finally, other possible mechanisms include a reduction in inflammatory markers, fibrosis, podocyte injury, and other related mechanisms. SGLT2i have shown significant and highly consistent benefits in renal and cardiovascular protection. The complexity and interconnectedness of the primary and secondary mechanisms of action make them a most interesting and exciting pharmacologic group.

Glucose Metabolism in Acute Kidney Injury and Kidney Repair

The kidneys play an indispensable role in glucose homeostasis via glucose reabsorption, production, and utilization. Conversely, aberrant glucose metabolism is involved in the onset, progression, and prognosis of kidney diseases, including acute kidney injury (AKI). In this review, we describe the regulation of glucose homeostasis and related molecular factors in kidneys under normal physiological conditions. Furthermore, we summarize recent investigations about the relationship between glucose metabolism and different types of AKI. We also analyze the involvement of glucose metabolism in kidney repair after injury, including renal fibrosis. Further research on glucose metabolism in kidney injury and repair may lead to the identification of novel therapeutic targets for the prevention and treatment of kidney diseases.

Sodium-Glucose Cotransporter-2 Inhibitors Improve Cardiovascular Dysfunction in Type 2 Diabetic East Asians

In East Asians, the incidence of type 2 DM (T2DM) has increased as a result of major alterations in life. Cardiovascular problems are more likely in those with T2DM. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are novel insulin-independent antihyperglycemic drugs that limit renal glucose reabsorption and thereby improve glycemic control. They are used alone or in combination with insulin and other antihyperglycemic medications to treat diabetes, and they are also helpful in protecting against the progression of complications. This review has evaluated the available evidence not only on the efficacy of SGLT2 inhibitors in T2DM, but also on their favourable cardiovascular events in East Asians. DM is an independent risk factor for cardiovascular diseases. As a result, in addition to glycemic control in diabetes management, the therapeutic goal in East Asian diabetic patients should be to improve adverse cardiovascular outcomes. Besides establishing antidiabetic effects, several studies have reported cardioprotective benefits of SGLT2 inhibitors via numerous pathways. SGLT2 inhibitors show promising antidiabetic drugs with potential cardiovascular advantages, given that a high number of diabetic patients in East Asia have co-existing cardiovascular disorders. Despite significant positive results in favour of SGLT2, more research is needed to determine how SGLT2 inhibitors exert these impressive cardiovascular effects.

Heart Failure Challenge in T2DM

Introduction Heart failure is a clinical syndrome caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress.1 There are 463 million patient with diabetes mellitus all over the world .2 People with diabetes have a 2- to 5-fold higher risk of developing HF3, On the other hand more than 30% of patients with heart failure also have diabetes. Patients with heart failure and diabetes have a worse prognosis than those without diabetes4. UKPDs, Accord and advance trials showed that Intensive glycaemic control has not been shown to significantly impact the risk of HF.5,6 SGLT2 inhibitor is a new class of drugs to treat diabetes by inhibiting SGT2 decreases glucose reabsorption and increases urinary glucose excretion, improving glucose control in the diabetic patient.7 At 2015 EMPA-REG OUTCOME trial showed that Empagliflozin in addition to reduction of HBa1c, reduced the 3MAC by 14%, CV death by 38% and HHF by 35%. Is these cardiovascular benefit were a chance? 8 Then DECLARE-TMI58, CNVAS and VIRTIS trials showed that Dapagliflizon, Canagliflozin and ertuglifozin respectively in addition to reduction of HBa1c, reduce HHFso it is a class effect. 9,10,11 Because in these trials starting treatment at the preclinical stage may prevent HF progression and improve outcomes. Objective We have 3 questions to be answered: There are 4 trials to answer these Questions DAPA HF, DELIVER, EMPEROR-Reduced and EMPEROR –Preserved. DAPA-HF and EMPEROR –Reduced include patients with HF with reduced ejection fraction, diabetic and non-diabetic the result of both was reduce the risk of worsening HF or death from cardiovascular causes regardless of the presence or absence of DM. 10,11 Conclusion The results of these trials FDA Approves Dapagliflozin for low EF-Heart Failure in diabetic and Non-diabetic. FDA had granted Fast Track status for empagliflozin. Waiting the result of other trials.12

SGLT2 Inhibitors: Physiology and Pharmacology

SGLTs are sodium glucose transporters found on the luminal membrane of the proximal tubule, where they reabsorb some 180 grams (one mole) of glucose from the glomerular filtrate each day. The natural glucoside phlorizin completely blocks glucose reabsorption. Oral SGLT2 inhibitors are rapidly absorbed into the blood stream where they remain in in the circulation for hours. On glomerular filtration, they bind specifically to SGLT2 in the luminal membrane of the early proximal tubule to reduce glucose reabsorption by 50-60%. Because of glucose excretion, these drugs lower plasma glucose and glycosylated hemoglobin levels in patients with type 2 diabetes mellitus. The drugs also protect against heart and renal failure. The aim of this review is to summarize what is currently known about the physiology of renal SGLTs and the pharmacology of SGLT drugs.

The effect of exogenous peroxiredoxin 6 on morphofunctional state of isolated rat kidney

Objective: to investigate the role of peroxiredoxin 6 (PRX6) in preserving the morphofunctional state of ischemic isolated kidney during perfusion.Materials and methods. The model of an isolated perfused rat kidney was used. Ischemia time was 5 and 20 minutes, perfusion was 50 minutes. To evaluate the effectiveness of PRX6 at different ischemia times, we used the conventional criteria of kidney function and histological methods.Results. During short warm ischemia times, exogenous PRX6 improves the morphofunctional state of an isolated kidney during perfusion. During this period, the main criteria for functioning of the isolated ischemic kidney reach acceptable values, renal parenchyma is without severe damage. By the end of perfusion, there was an increase in urine flow rate, glomerular filtration rate, fractional glucose reabsorption, urine urea concentration and proportion of primary urine from 1.5 to 2 times compared with the control lesion. At 20-minute ischemia, the isolated kidney can be recognized as non-viable according to the functioning criteria; the positive effect of PRX6 is leveled.Conclusion. The use of recombinant peroxiredoxin 6 for preserving the morphofunctional state of isolated kidneys can be an effective approach in preventing ischemia–reperfusion injury.

Search for a Functional Genetic Variant Mimicking the Effect of SGLT2 Inhibitor Treatment

SGLT2 inhibitors (SGLT2i) block renal glucose reabsorption. Due to the unexpected beneficial observations in type 2 diabetic patients potentially related to increased natriuresis, SGLT2i are also studied for heart failure treatment. This study aimed to identify genetic variants mimicking SGLT2i to further our understanding of the potential underlying biological mechanisms. Using the UK Biobank resource, we identified 264 SNPs located in the SLC5A2 gene or within 25kb of the 5′ and 3′ flanking regions, of which 91 had minor allele frequencies >1%. Twenty-seven SNPs were associated with glycated hemoglobin (HbA1c) after Bonferroni correction in participants without diabetes, while none of the SNPs were associated with sodium excretion. We investigated whether these variants had a directionally consistent effect on sodium excretion, HbA1c levels, and SLC5A2 expression. None of the variants met these criteria. Likewise, we identified no common missense variants, and although four SNPs could be defined as 5′ or 3′ prime untranslated region variants of which rs45612043 was predicted to be deleterious, these SNPs were not annotated to SLC5A2. In conclusion, no genetic variant was found mimicking SGLT2i based on their location near SLC5A2 and their association with sodium excretion or HbA1c and SLC5A2 expression or function.

Efficacy and safety of remogliflozin etabonate in type 2 diabetes mellitus patients in a tertiary care hospital

Background: Incidence and prevalence of diabetes have been steadily increasing with a raise of global prevalence about 8.5%. The major types of diabetes are differentiated by insulin deficiency versus insulin resistance. SGLT2 inhibitors are a new class of drugs that act by inhibiting glucose reabsorption in the proximal renal tubules. Remogliflozin a prodrug of remogliflozin, which is a potent and selective sodium-glucose co-transporter-2 inhibitor was used for the study. The objective of the study was to evaluate the efficacy and safety of Remogliflozin etabonate in reducing HbA1C and serum glucose in type II diabetics.Methods: This was a prospective observational study was done for 3 months. HbA1C, FBS and PPBS readings were noted and then the subjects were introduced to Remoglifozin 100 mg twice a day. At the end of 12 weeks HbA1C, FBS and PPBS were noted. The obtained data was analysed for its efficacy and safety.Results: The study included 22 male subjects and 28 females. Before Remoglifzoin was given the mean HbA1C level was 8.23± 0.798, mean FBS was 179± 29.79 and PPBS was 299.38± 24.21. Remoglifozin 100 mg was given and the mean HbA1C level was 7.52± 0.765, mean FBS was 166.30± 32.13 and mean PPBS was 249.46± 18.21. Post 3 months of Remoglifzoin induction a reduction in HbA1C, FBS and PPBS was seen.Conclusions: This study concludes Remoglifozin etabonate of 100 mg when given twice daily reduced the HbA1C levels, FBS and PPBS levels significantly.

Inhibition of eIF5A hypusination reprogrammes metabolism and glucose handling in mouse kidney

Inhibition of the eukaryotic initiation factor 5A activation by the spermidine analogue GC7 has been shown to protect proximal cells and whole kidneys against an acute episode of ischaemia. The highlighted mechanism involves a metabolic switch from oxidative phosphorylation toward glycolysis allowing cells to be transiently independent of oxygen supply. Here we show that GC7 decreases protein expression of the renal GLUT1 glucose transporter leading to a decrease in transcellular glucose flux. At the same time, GC7 modifies the native energy source of the proximal cells from glutamine toward glucose use. Thus, GC7 acutely and reversibly reprogrammes function and metabolism of kidney cells to make glucose its single substrate, and thus allowing cells to be oxygen independent through anaerobic glycolysis. The physiological consequences are an increase in the renal excretion of glucose and lactate reflecting a decrease in glucose reabsorption and an increased glycolysis. Such a reversible reprogramming of glucose handling and oxygen dependence of kidney cells by GC7 represents a pharmacological opportunity in ischaemic as well as hyperglycaemia-associated pathologies from renal origin.