Sodium-glucose Linked Transporter-2 Research Articles

Research progress on the effects of sodium-glucose linked transporter 2 inhibitors on multiple metabolic disorders in metabolic syndrome.

Metabolic syndrome is a complex group of metabolic disorders with an increasing global incidence rate, posing a serious threat to human health. Sodium-glucose linked transporter 2 (SGLT2) inhibitors are a new type of oral hypoglycemic drug. SGLT2 inhibitors not only lower blood glucose level in a non-insulin-dependent manner by inhibiting glucose reabsorption by renal proximal convoluted tubular epithelial cell to promote urinary glucose excretion, but also by improving islet β cell function, reducing inflammatory responses, and inhibiting oxidative stress. In addition, SGLT2 inhibitors can reduce body weight through osmotic diuresis and increase fat metabolism; reduce blood pressure by inhibiting excessive activation of sympathetic nervous system and by improving vascular function. They can also improve blood lipids by increasing degradation of triacylglycerol; reduce blood uric acid by promoting uric acid excretion in kidney and intestine, and by reducing uric acid synthesis. This article reviews the effects and mechanisms of SGLT2 inhibitors on multiple metabolic disorders in metabolic syndrome and explores their potential application in metabolic syndrome treatment.

Effects of Empagliflozin-Induced Glycosuria on Weight Gain, Food Intake and Metabolic Indicators in Mice Fed a High-Fat Diet.

Sodium glucose-linked transporter 2 (SGLT2) inhibitors promote glucose, and therefore calorie, excretion in the urine. Patients taking SGLT2 inhibitors typically experience mild weight loss, but the amount of weight loss falls short of what is expected based on caloric loss. Understanding the mechanisms responsible for this weight loss discrepancy is imperative, as strategies to improve weight loss could markedly improve type 2 diabetes management and overall metabolic health. Two mouse models of diet-induced obesity were administered the SGLT2 inhibitor empagliflozin in the food for 3 months. Urine glucose excretion, body weight, food intake and activity levels were monitored. In addition, serum hormone measurements were taken, and gene expression analyses were conducted. In both mouse models, mice receiving empagliflozin gained the same amount of body weight as their diet-matched controls despite marked glucose loss in the urine. No changes in food intake, serum ghrelin concentrations or activity levels were observed, but serum levels of fibroblast growth factor 21 (FGF21) decreased after treatment. A decrease in the levels of deiodinase 2 (Dio2) was also observed in the white adipose tissue, a primary target tissue of FGF21. These findings suggest that compensatory metabolic adaptations, other than increased food intake or decreased physical activity, occur in response to SGLT2 inhibitor-induced glycosuria that combats weight loss, and that reductions in FGF21, along with subsequent reductions in peripheral Dio2, may play a role.

Sodium-glucose linked transporter 2 inhibitors in liver cirrhosis: Beyond their antidiabetic use.

Type 2 diabetes mellitus (T2DM) and liver cirrhosis are clinical entities that frequently coexist, but glucose-lowering medication options are limited in cirrhotic patients. Sodium-glucose linked transporter 2 (SGLT2) inhibitors are a class of glucose-lowering medication that act independently of insulin, by causing glycosuria in the proximal convoluted tubule. In this review, we aimed to briefly present the main data and to provide insight into the pathophysiology and potential usefulness of SGLT2 inhibitors in cirrhotic patients with or without T2DM. SGLT2 inhibitors have been proven useful as antidiabetic treatment in patients with metabolic liver disease, with most robust data from patients with metabolic dysfunction-associated steatotic liver disease (MASLD), where they also showed improvement in liver function parameters. Moreover, it has been suggested that SGLT2 inhibitors may have effects beyond their antidiabetic action. Accordingly, they have exhibited cardioprotective effects, expanding their indication in patients with heart failure without T2DM. Since decompensated liver cirrhosis and congestive heart failure share common pathophysiological features, namely renin-angiotensin-aldosterone axis and sympathetic nervous system activation as well as vasopressin secretion, SGLT2 inhibitors could also be beneficial in patients with decompensated cirrhosis, even in the absence of T2DM.

SIRT1 mediates the inhibitory effect of Dapagliflozin on EndMT by inhibiting the acetylation of endothelium Notch1

BackgroundEndothelial–mesenchymal transition (EndMT) plays a crucial role in promoting myocardial fibrosis and exacerbating cardiac dysfunction. Dapagliflozin (DAPA) is a sodium–glucose-linked transporter 2 (SGLT-2) inhibitor that has been shown to improve cardiac function in non-diabetic patients with heart failure (HF). However, the precise mechanisms by which DAPA exerts its beneficial effects are yet to be fully elucidated.MethodsIsoproterenol (ISO) was used to generate a HF model in mice. For in vitro experiments, we used TGF-β1-stimulated human umbilical vein endothelial cells (HUVECs) and mouse aortic endothelial cells (MAECs).ResultsBoth our in vivo and in vitro results showed that EndMT occurred with decreased SIRT1 (NAD+-dependent deacetylase) protein expression, which could be reversed by DAPA therapy. We found that the protective effect of DAPA was significantly impaired upon SIRT1 inhibition. Mechanistically, we observed that SIRT1 phosphorylation, a required modification for its ubiquitination and degradation, was reduced by DAPA treatment, which induces the nucleus translocation of SIRT1 and promotes its binding to the active intracellular domain of Notch1 (NICD). This interaction led to the deacetylation and degradation of NICD, and the subsequent inactivation of the Notch1 signaling pathway which contributes to ameliorating EndMT.ConclusionsOur study revealed that DAPA can attenuate EndMT induced by ISO in non-diabetic HF mice. This beneficial effect is achieved through SIRT1-mediated deacetylation and degradation of NICD. Our findings provide greater insight into the underlying mechanisms of the therapeutic effects of DAPA in non-diabetic HF.Graphical

The effect of sglt-2 inhibitor dapagliflozin on adropin serum levels in patients with chronic heart failure and concomitant type 2 diabetes mellitus

Abstract Background adropin plays a protective role in cardiac remodeling through supporting energy metabolism and water homeostasis and suppressing inflammation. Low circulating levels of adropin were positively associated with the risk of cardiovascular diseases and type 2 diabetes mellitus (T2DM). We hypothesized that sodium–glucose linked transporter 2 (SGLT2) inhibitor dapagliflosin might represent cardiac protective effects in T2DM patients with known chronic heart failure (HF) through the modulation of adropin levels. Methods The study was an open-label, multicenter non-randomized cohort investigation. Patients of both sexes were included from October 2020 to July 2022 who were aged ≥18 years and had established T2DM with HbAc1 <6.9%, hemodynamically stable HF (I-III NYNA functional classes), and written consent to participate in the study. According to these criteria, we prospectively enrolled 417 patients with T2DM and HF. The eligible patients were treated with the recommended guided HF therapy according to their HF phenotypes, including the consumption of SGLT2 inhibitor dapagliflozin at a dose of 10 mg OD orally, along with standard therapy of HF. Anthropometry, clinical data, echocardiography / Doppler examinations, and measurements of biomarkers were performed at the baseline and over a 6-month interval of SGLT2 inhibitor administration. Results Over a 6-month period after the initial prescription of SGLT2 inhibitor dapagliflozin, the levels of adropin in the entire group demonstrated a significant increase of up to 26.6% (from 2.37 [25–75% IQR = 1.91–2.75] ng/mL to 3.00 [25−75% IQR = 2.68–3.36] ng/mL, p = 0.042). In the female subgroup, the increase in the circulating levels of adropin was sufficiently higher (Δ% = 35.6%, from 2.69 [25–75% IQR = 2.31–2.99] ng/mL to 3.65 [25–75% IQR = 3.40–3.89] ng/mL, p = 0.010)when compared with those of the male subgroup (Δ% = 22.7%, from 2.11 [25–75% IQR = 1.90–2.37] ng/mL to 2.60 [25–75% IQR = 2.07–3.21] ng/mL, p = 0.161). A multivariate linear regression analysis of the entire group showed that the relative changes (Δ) in the left ventricular (LV) ejection fraction (LVEF), left atrial volume index (LAVI), and E/e` were significantly associated with increased adropin levels. In the female subgroup, but not in the male subgroup, ΔLVEF (p = 0.046), ΔLAVI (p = 0.001), and ΔE/e` (p = 0.001) were independent predictive values for adropin changes. Conclusion the levels of adropin seem to be a predictor for the favorable modification of hemodynamic performances during SGLT2 inhibition, independent of N-terminal brain natriuretic pro-peptide levels.

Advances in understanding and treating diabetic kidney disease: focus on tubulointerstitial inflammation mechanisms.

Diabetic kidney disease (DKD) is a serious complication of diabetes that can lead to end-stage kidney disease. Despite its significant impact, most research has concentrated on the glomerulus, with little attention paid to the tubulointerstitial region, which accounts for the majority of the kidney volume. DKD's tubulointerstitial lesions are characterized by inflammation, fibrosis, and loss of kidney function, and recent studies indicate that these lesions may occur earlier than glomerular lesions. Evidence has shown that inflammatory mechanisms in the tubulointerstitium play a critical role in the development and progression of these lesions. Apart from the renin-angiotensin-aldosterone blockade, Sodium-Glucose Linked Transporter-2(SGLT-2) inhibitors and new types of mineralocorticoid receptor antagonists have emerged as effective ways to treat DKD. Moreover, researchers have proposed potential targeted therapies, such as inhibiting pro-inflammatory cytokines and modulating T cells and macrophages, among others. These therapies have demonstrated promising results in preclinical studies and clinical trials, suggesting their potential to treat DKD-induced tubulointerstitial lesions effectively. Understanding the immune-inflammatory mechanisms underlying DKD-induced tubulointerstitial lesions and developing targeted therapies could significantly improve the treatment and management of DKD. This review summarizes the latest advances in this field, highlighting the importance of focusing on tubulointerstitial inflammation mechanisms to improve DKD outcomes.

Cost-Effectiveness of New Quadruple Therapy Compared With Standard Treatment for Patients With Heart Failure in China.

This study aimed to compare the cost-effectiveness of the new quadruple therapy regimen of adding sodium-glucose-linked transporter 2 (SGLT2) inhibitors, with standard treatment for patients with heart failure (HF) in China. From the payer's perspective, the dates of cardiovascular event recurrences were extracted from a meta-analysis including 6 trials, combined with the treatment cost for patients with HF in China to construct a Markov model. The outcomes included per capita medical costs and incremental cost-effectiveness ratio, using quality-adjusted life years (QALYs) data. Single-factor, probability sensitivity analysis, and scenario analysis were used to explore the potential uncertainties of the model. The per capita costs of the new quadruple therapy regimen and standard treatment were $87441.26 and $87087.54, respectively. The new regimen was associated with a mean of 21.44 QALYs gained, compared with 18.60 QALYs gained with the standard treatment. The incremental cost-effectiveness ratio was $124.03 per QALY gained. The sensitivity analysis revealed that changes in the parameters within the set range did not affect the model results. In China, compared with standard treatment, the new quadruple therapy regimen with SGLT2 inhibitors reduce the frequency of cardiovascular events among patients with HF, and it has economic advantages.

DAPAGLIFLOZIN MODULATES ADROPIN SERUM LEVELS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS AND CHRONIC HEART FAILURE

Objective: To investigate an effect of sodium glucose linked transporter 2 (SGLT2) inhibitor dapagliflosin on the levels of adropin in patients with type 2 diabetes mellitus (T2DM) with chronic heart failure (HF). Design and method: The study is open label multicenter (private hospital Vita-Centre, Zaporozhye, Ukraine, EliteMedService, Zaporozhye, Ukraine and City Hospital #7, Zaporozhye, Ukraine) non-randomized cohort investigation. We prospectively enrolled 417 patients with T2DM and HF from entire cohort of 612 T2DM pa-tients. The eligible patients were treated with guided-recommended HF therapy de-pending on HF phenotypes, which included SGLT2 inhibitor dapagliflozin in a dose of 10 mg OD orally along with angiotensin receptor-neprilysin inhibitor (ARNI) / ACE inhibitors / angiotensin-II receptor blockers (ARBs), mineralocorticoid receptor antag-onist (MRA), beta-blockers. Anthropometrics, clinical data, Echocardiography / Doppler examinations and biomarkers assessments were performed at the baseline and over 6-month interval. Results: Over 6-month period after initial prescription of SGLT2 inhibitor dapagliflozin the levels of adropin in entire group demonstrated a significant growth up to 26.6% (from 237.4 [25%-75% IQR = 190.50–275.30] ng/mL to 300.2 [25%-75% IQR = 267.80–335.70] ng/mL, P = 0.04). In female subgroup, an increase in circulating level of adropin was sufficiently higher (from 269.5 [25%-75% IQR = 231.20–299.20] ng/mL to 365.2 [25%-75% IQR = 340.10–388.60] ng/mL, P = 0.01), when com-pared with male subgroup (from 211.2 [25%-75% IQR = 190.40–237.50] ng/mL to 259.6 [25%-75% IQR = 206.50–321.40] ng/mL, P = 0.16). Multivariate logistic regression analysis of entire group showed that relative changes of left ventricular (LV) ejection fraction (LVEF), left atrial volume index (LAVI), and E/e` were significantly associated with increased adropin levels. In fe-male subgroup, but not in male subgroup, relative changes of LVEF (P = 0.046), LAVI (P = 0.001) and E/e` (P = 0.001) exhibited their independent predictive values for adropin changes. Conclusions: The levels of adropin seem to be a predictor for favorable modification of hemodynamic perfor-mances that is independent from N-terminal brain natriuretic pro-peptide.

Therapieoptionen bei diabetischer Nephropathie

Diabetic nephropathy is a serious complication of diabetes mellitus caused by metabolic and hemodynamic changes. Both supportive and drug therapies have been limited to treatment of cardiovascular risk factors and blockade of the renin–angiotensin–aldosterone system. With the development of sodium–glucose linked transporter 2 (SGLT2) inhibitors and nonsteroidal mineralocorticoid receptor blockers, two classes of drugs that suppress the proinflammatory and profibrotic nature of diabetic nephropathy are available after years of stagnation. In addition, glucagon-like peptide 1 (GLP-1) receptor agonists may soon expand the therapeutic portfolio. Atrasentan, selonsertib, and stimulators and activators of soluble guanylate cyclase present themselves as promising future therapeutic options.

The Impact of SGLT2 Inhibitor Dapagliflozin on Adropin Serum Levels in Men and Women with Type 2 Diabetes Mellitus and Chronic Heart Failure

adropin plays a protective role in cardiac remodeling through supporting energy metabolism and water homeostasis and suppressing inflammation. Low circulating levels of adropin were positively associated with the risk of cardiovascular diseases and type 2 diabetes mellitus (T2DM). We hypothesized that sodium-glucose linked transporter 2 (SGLT2) inhibitor dapagliflosin might represent cardiac protective effects in T2DM patients with known chronic HF through the modulation of adropin levels. we prospectively enrolled 417 patients with T2DM and HF from an entire cohort of 612 T2DM patients. All eligible patients were treated with the recommended guided HF therapy according to their HF phenotypes, including SGLT2 inhibitor dapagliflozin 10 mg, daily, orally. Anthropometry, clinical data, echocardiography/Doppler examinations, and measurements of biomarkers were performed at the baseline and over a 6-month interval of SGLT2 inhibitor administration. in the entire group, dapagliflozin led to an increase in adropin levels by up to 26.6% over 6 months. In the female subgroup, the relative growth (Δ%) of adropin concentrations was sufficiently higher (Δ% = 35.6%) than that in the male subgroup (Δ% = 22.7%). A multivariate linear regression analysis of the entire group showed that the relative changes (Δ) in the left ventricular (LV) ejection fraction (LVEF), left atrial volume index (LAVI), and E/e' were significantly associated with increased adropin levels. In the female subgroup, but not in the male subgroup, ΔLVEF (p = 0.046), ΔLAVI (p = 0.001), and ΔE/e' (p = 0.001) were independent predictive values for adropin changes. the levels of adropin seem to be a predictor for the favorable modification of hemodynamic performances during SGLT2 inhibition, independent ofN-terminal brain natriuretic pro-peptide levels.

Dapagliflozin-Loaded Exosome Mimetics Facilitate Diabetic Wound Healing by HIF-1α-Mediated Enhancement of Angiogenesis.

Angiogenesis plays a critical role in diabetic wound healing. However, no effective strategies have been developed to target endothelial cells (ECs) to facilitate diabetic wound healing. Dapagliflozin (DA) as a sodium-glucose linked transporter 2 (SGLT2) inhibitor, may promote neovascularization in diabetic mice via HIF-1α-mediated enhancement of angiogenesis. Here, the bioinspired nanovesicles (NVs) prepared from induced pluripotent stem cells-derived ECs through an extrusion approach are reported, which can function as exosome mimetics to achieve targeted deliver of DA. Abundant membrane C-X-C motif chemokine receptor 4 conferred the EC-targeting ability of these NVs and the endothelial homology facilitated the accumulation in ECs. Furthermore, these DA-loaded induced pluripotent stem cells (iPSC)-EC NVs can facilitate angiogenesis and diabetic wound healing by HIF-1α/VEGFA pathway. Taken together, this study indicated that targeting ECs and regulating angiogenesis may be a promising strategy for the treatment of diabetic wound healing.

The SGLT2i Dapagliflozin Reduces RV Mass Independent of Changes in RV Pressure Induced by Pulmonary Artery Banding.

Sodium glucose linked transporter 2 (SGLT2) inhibition not only reduces morbidity and mortality in patients with diagnosed heart failure but also prevents the development of heart failure hospitalization in those at risk. While studies to date have focused on the role of SGLT2 inhibition in left ventricular failure, whether this drug class is efficacious in the treatment and prevention of right heart failure has not been explored. We hypothesized that SGLT2 inhibition would reduce the structural, functional, and molecular responses to pressure overload of the right ventricle. Thirteen-week-old Fischer F344 rats underwent pulmonary artery banding (PAB) or sham surgery prior to being randomized to receive either the SGLT2 inhibitor: dapagliflozin (0.5mg/kg/day) or vehicle by oral gavage. After 6weeks of treatment, animals underwent transthoracic echocardiography and invasive hemodynamic studies. Animals were then terminated, and their hearts harvested for structural and molecular analyses. PAB induced features consistent with a compensatory response to increased right ventricular (RV) afterload with elevated mass, end systolic pressure, collagen content, and alteration in calcium handling protein expression (all p < 0.05 when compared to sham + vehicle). Dapagliflozin reduced RV mass, including both wet and dry weight as well as normalizing the protein expression of SERCA 2A, phospho-AMPK and LC3I/II ratio expression (all p < 0.05). Dapagliflozin reduces the structural, functional, and molecular manifestations of right ventricular pressure overload. Whether amelioration of these early changes in the RV may ultimately lead to a reduction in RV failure remains to be determined.

Therapie des metabolischen Syndroms

Metabolic syndrome is defined by the simultaneous presence of abdominal obesity, atherogenic dyslipoproteinemia, high blood pressure and increased fasting blood glucose. It is an important precursor of cardiovascular disease sequelae and shows epidemic proportions, not only in western countries. Modifications of lifestyle are central for treatment: negative energy balance with increased physical activity, a prudent balance of nutrients with carbohydrates, proteins and fats, considering atherogenic lipid profiles, blood pressure and the glycemic index of nutrients. Decisive for the implementation is the incorporation of long-term programs with continuous guidance, preferably in group therapy and targeting all individual risk factors. The introduction of sodium-glucose linked transporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 (GLP1) receptor agonists and modern mineralocorticoid receptor blockers has resulted in new options for the effective prevention of sequelae.

Update Typ-2-Diabetes

Important advances in 2021/2022 in the diagnosis and treatment of type 2 diabetes are discussed in this article. A new national guideline for pharmacotherapy of type 2 diabetes was recently published in Germany. In patients with pre-existing cardiovascular disease, drug treatment of type 2 diabetes should be started with a combination of metformin and a sodium glucose linked transporter 2 (SGLT-2) inhibitor or a glucagon-like peptide 1 (GLP-1) receptor agonist with proven benefit in cardiovascular safety trials, respectively. Differential effects of antidiabetic compounds were analyzed in several large cohorts that included a high percentage of patients of lower cardiovascular risk. SGLT‑2 inhibitors and GLP‑1 receptor agonists appeared to be beneficial compared to sulfonylurea or dipeptidylpeptidase 4 (DPP-4) inhibitors. Current guidelines encourage physicians to de-escalate insulin therapy, especially in the elderly, when possible. Due to a focus on therapeutic safety and stable metabolism, continuous glucose monitoring is of increasing relevance also for patients with type 2 diabetes.

Neues zu Hypertonie und Diabetes

Hypertonie und Diabetes treten oft gemeinsam auf und erhöhen die kardiovaskuläre Mortalität. Beide Erkrankungen sind bei COVID-19-Patienten (COVID-19: „coronavirus disease 2019“) mit schweren Verläufen gehäuft anzutreffen. Hinsichtlich der Kausalität für COVID-19 ist die Datenlage widersprüchlich. Sicher ist ein Surrogateffekt, da meiste ältere COVID-19-Patienten einen schweren Verlauf aufgrund der Vorschäden aufweisen. Hemmer des Renin-Angiotensin-Aldosteron-Systems (RAAS-Blocker) erhöhen nicht die Wahrscheinlichkeit der positiven SARS-CoV-2-Testung (SARS-CoV-2: „severe acute respiratory syndrome coronavirus 2“). Sie haben keinen Einfluss auf die Schwere des Verlaufs und die Mortalität und sollten daher unter COVID-19 nicht pausiert/abgesetzt werden. Die renale Denervierung erfreut sich einer Renaissance, nachdem sich die Studiendesigns und Technologien stark weiterentwickelt haben. Bei den SGLT-2-Hemmern (SGLT-2: „sodium glucose linked transporter 2“) ist der Wissenszuwachs enorm. In den ersten beiden großen randomisierten kontrollierten Studien mit primären renalen Endpunkten verzögerten sie die Progression der chronischen Niereninsuffizienz (CKD) bis zum Dialysebeginn deutlich um zusätzliche ca. 12–13 Jahre. Sie sind prinzipiell bei Typ‑2- sowie Typ-1-Diabetes und auch bei herzinsuffizienten Patienten mit und ohne Diabetes einsetzbar und reduzieren den systolischen Blutdruck. Der nichtsteroidale Mineralokortikoidrezeptorantagonist (MRA) Finerenon wirkt bei Typ‑2-Diabetes reno- und kardioprotektiv bezüglich kardiovaskulärer Mortalität und Niereninsuffizienz. Wie bei den klassischen MRA kann es auch hier zur Hyperkaliämie in höheren CKD-Bereichen kommen. Größere Vergleichsstudien zu den klassischen MRA liegen nicht vor. Die Zulassung in Deutschland steht noch aus.

Current aspects of heart-kidney interactions : Summary of important clinical studies from 2020

Chronisch nierenkranke Patienten weisen eine erhöhte kardiovaskuläre Morbidität und Sterblichkeit auf. Im letzten Jahr sind einige wichtige Studien zur Herz-Nieren-Interaktion veröffentlicht worden, die im Folgenden zusammengefasst und diskutiert werden. In der DAPA-CKD-Studie sowie in der SCORED-Studie konnten 2 unterschiedliche SGLT2(„sodium-glucose linked transporter 2“)-Inhibitoren (Dapagliflozin und Sotagliflozin) die Prognose von chronisch nierenkranken Patienten mit und ohne Diabetes nachweislich verbessern. Auch die Ergebnisse der randomisierten Studie zum neuen Mineralokortikoidrezeptorantagonisten Finerenon – FIDELIO-DKD – liefern einen vielversprechenden neuen Therapieansatz für Patienten mit diabetischer Nephropathie. Die veröffentlichten Daten der ISCHEMIA-CKD-Studie bei Patienten mit koronarer Herzkrankheit und Untersuchungen zum Einfluss einer TAVI („transcatheter aortic valve implantation“) auf die Nierenfunktion sowie eine weitere Studie zum akuten Nierenversagen nach MitraClip®-Implantation (Abbott, Chicago, IL, USA) geben wichtige Hinweise zu zukünftigen Handlungsempfehlungen. Der optimale Zeitpunkt der Einleitung einer Nierenersatztherapie bei Patienten mit akuter Nierenschädigung in der Intensivmedizin wurde in 2 randomisierten Studien untersucht, die entsprechend diskutiert werden.

Volume Management in Chronic kidney disease

Understanding the (patho-)physiology of volume regulation and osmoregulation is fundamental to guide patient advice and therapy in chronic kidney disease (CKD). Volume regulation primarily impacts the amount of sodium in the body, and it mainly affects the extracellular space, while osmoregulation primarily impacts the amount of free water, and it affects both the intra- and extracellular space. The kidneys control water and sodium homeostasis both through their sensor (e. g. tubuloglomerular feedback) and regulator systems (e. g. sodium reabsorption). Many CKD patients are advised by non-nephrologists to a high fluid intake, although they often do not require a daily intake of more than 1.5 litres. Many CKD patients are hypervolemic, and sodium restriction is of key importance in patients' effort to utilize lifestyle changes as therapeutic means. Pharmacologically, (particularly loop) diuretics are the basis of therapy, increasing sodium excretion. Recent developments shift the focus towards classes of drugs ameliorating prognosis in CKD: sodium-glucose linked transporter 2 (SGLT2) inhibitors have proven beneficial in heart and renal failure - by sodium and fluid excretion, among others; additionally, a novel mineralocorticoid receptor antagonist (MRA), finerenone, was recently shown to improve prognosis in CKD.

The Effect of Alpha-Lipoic Acid on Diabetic Peripheral Neuropathy and the Upcoming Depressive Disorders of Type II Diabetics.

IntroductionPeripheral neuropathy is one of the possible complications of diabetes. Alpha-lipoic acid (a-lipoic acid or ALA) is a powerful antioxidant cofactor synthesized in mitochondria that could help stimulate nerves and regenerate nerve fibers, thus preventing disease progression. Moreover, the possible feeling of oppression from the lifestyle changes needed to avoid the complications of diabetes may contribute to the development of depressive symptoms. ALA increases insulin sensitivity, which could increase serotonin synthesis and thus reduce the manifestations of depressive disorder.AimThe aim of this study is to investigate the therapeutic effect after oral administration of a-lipoic acid in patients with type II diabetes mellitus, regarding the possibility of developing peripheral neuropathy and the possibility of developing depressive disorder due to the existence of diabetes type II.MethodsThe study sample consisted of 148 Greek patients, type II diabetics, 68 men and 80 women, aged 50-75 years. All of them were non-smokers and did not consume alcohol. Their treatment was a combination of gliclazide, sodium-glucose-linked transporter 2 (SGLT-2) inhibitors, metformin, and glucagon-like peptide 1 (GLP-1) analogs. None of them were under insulin administration. Any other treatment received chronically from the patients for other comorbidities was not altered or paused. All patients were in regular monitoring of renal, hepatic, and ocular function, which was normal. Patients were monitored with a balanced diet, based on equivalents, in order to maintain an almost constant body mass index (BMI). All were given one tablet of 600 mg a-lipoic acid, two hours before a meal, for eight months, and the incidence of developing peripheral neuropathy and depressive disorder was assessed, using the Subjective Peripheral Neuropathy Screen Questionnaire (SPNSQ) and Beck Depression Inventory (BDI) questionnaire.ResultsALA administration after both four and eight months resulted in statistically significant results and, specifically, the peripheral neuropathy development mean score was reduced by 4.79 at four months and 6.22 after eight months. Concerning the incidence of depressive disorder, an average decrease of 4.43 in the related depression score was observed at the four-month milestone and 7.56 at eight months, both statistically significant.ConclusionA-lipoic acid is a powerful antioxidant and, when used with conventional treatment, has shown to significantly decrease the incidence of depression and peripheral neuropathy in patients with type 2 diabetes mellitus.

SGLT-2 Inhibitors: Ideal Remedy for Cardioprotection in Diabetes Mellitus.

A chronic metabolic disease, diabetes mellitus (DM), is associated with various comorbidities that considerably decrease the quality of life. Sodium glucose linked transporter 2 (SGLT2) receptors are mainly situated in the proximal tubule of nephron. About 90% of glucose concentration is reabsorbed by these receptors in the nephron. The advanced remedy for the management of DM is sodium glucose co-transporter 2 inhibitors (SGLT2-Is), which inhibits or lowers the reabsorption of glucose. Furthermore, SGLT2-Is enhance the elimination of glucose level in urine (glycosuria). Empagliglozin, canagliflozin, ertugliflozin and dapagliflozin are the standard medications which have been authorized recently, for the management of DM by The Food and Drug Administration (FDA). Besides, having optimistic efficacy to attenuate blood glucose level, these medications have exhibited impressive cardioprotective and renoprotective effects in major clinical trials. Unlike other hypoglycaemic medications, it is found that these agents help in a consistent reduction in hospitalization, due to heart failure with probably multifactorial mechanisms. The cardioprotective efficacy of SGLT2-Is is characterized by enhancement in ventricular loading condition, in metabolism of cardiac cell, adipokines alteration, cardiac fibrosis, and reduction in the necrosis of cardiac cell. Recently confirmed results depict that dapagliflozin gradually decreases the frequency of co-morbidity and mortality in heart failure patients. The present review explores the mechanistic principle and the clinical trial data of SGLT2-Is, which further support cardioprotective effects associated with these medications.

Antidiabetic drug therapy alleviates type 1 diabetes in mice by promoting pancreatic α-cell transdifferentiation

Gut incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), enhance secretion of insulin in a glucose-dependent manner, predominantly by elevating cytosolic levels of cAMP in pancreatic β-cells. Successful targeting of the incretin pathway by several drugs, however, suggests the antidiabetic mechanism is likely to span beyond the acute effect on hormone secretion and include, for instance, stimulation of β-cell growth and/or proliferation. Likewise, the antidiabetic action of kidney sodium-glucose linked transporter-2 (SGLT-2) inhibitors exceeds simple increase glucose excretion. Potential reasons for these ‘added benefits’ may lie in the long-term effects of these signals on developmental aspects of pancreatic islet cells. In this work, we explored if the incretin mimetics or SGLT-2 inhibitors can affect the size of the islet α- or β-cell compartments, under the condition of β-cell stress.To that end, we utilised mice expressing YFP specifically in pancreatic α-cells, in which we modelled type 1 diabetes by injecting streptozotocin, followed by a 10-day administration of liraglutide, sitagliptin or dapagliflozin.We observed an onset of diabetic phenotype, which was partially reversed by the administration of the antidiabetic drugs. The mechanism for the reversal included induction of β-cell proliferation, decrease in β-cell apoptosis and, for the incretin mimetics, transdifferentiation of α-cells into β-cells.Our data therefore emphasize the role of chronic incretin signalling in induction of α-/β-cell transdifferentiation. We conclude that incretin peptides may act directly on islet cells, making use of the endogenous local sites of ‘ectopic’ expression, whereas SGLT-2 inhibitors work via protecting β-cells from chronic hyperglycaemia.