scholarly journals Dual-Target Compounds against Type 2 Diabetes Mellitus: Proof of Concept for Sodium Dependent Glucose Transporter (SGLT) and Glycogen Phosphorylase (GP) Inhibitors

2021 ◽  
Vol 14 (4) ◽  
pp. 364
Author(s):  
Ádám Sipos ◽  
Eszter Szennyes ◽  
Nikolett Éva Hajnal ◽  
Sándor Kun ◽  
Katalin E. Szabó ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Glycogen Phosphorylase ◽  
Glucose Transporter ◽  
Current Trend ◽  
Cell System ◽  
Synthetic Methods ◽  
Dual Inhibitor ◽  
Antidiabetic Therapy ◽  
Sodium Dependent ◽  
Dual Target

A current trend in the quest for new therapies for complex, multifactorial diseases, such as diabetes mellitus (DM), is to find dual or even multi-target inhibitors. In DM, the sodium dependent glucose cotransporter 2 (SGLT2) in the kidneys and the glycogen phosphorylase (GP) in the liver are validated targets. Several (β-D-glucopyranosylaryl)methyl (het)arene type compounds, called gliflozins, are marketed drugs that target SGLT2. For GP, low nanomolar glucose analogue inhibitors exist. The purpose of this study was to identify dual acting compounds which inhibit both SGLTs and GP. To this end, we have extended the structure-activity relationships of SGLT2 and GP inhibitors to scarcely known (C-β-D-glucopyranosylhetaryl)methyl arene type compounds and studied several (C-β-D-glucopyranosylhetaryl)arene type GP inhibitors against SGLT. New compounds, such as 5-arylmethyl-3-(β-D-glucopyranosyl)-1,2,4-oxadiazoles, 5-arylmethyl-2-(β-D-glucopyranosyl)-1,3,4-oxadiazoles, 4-arylmethyl-2-(β-D-glucopyranosyl)pyrimidines and 4(5)-benzyl-2-(β-D-glucopyranosyl)imidazole were prepared by adapting our previous synthetic methods. None of the studied compounds exhibited cytotoxicity and all of them were assayed for their SGLT1 and 2 inhibitory potentials in a SGLT-overexpressing TSA201 cell system. GP inhibition was also determined by known methods. Several newly synthesized (C-β-D-glucopyranosylhetaryl)methyl arene derivatives had low micromolar SGLT2 inhibitory activity; however, none of these compounds inhibited GP. On the other hand, several (C-β-D-glucopyranosylhetaryl)arene type GP inhibitor compounds with low micromolar efficacy against SGLT2 were identified. The best dual inhibitor, 2-(β-D-glucopyranosyl)-4(5)-(2-naphthyl)-imidazole, had a Ki of 31 nM for GP and IC50 of 3.5 μM for SGLT2. This first example of an SGLT-GP dual inhibitor can prospectively be developed into even more efficient dual-target compounds with potential applications in future antidiabetic therapy.

scholarly journals A new trend in the treatment of type 2 diabetes mellitus with the use of sodium-dependent glucose transporter-2 inhibitors

2014 ◽  
Vol 60 (4) ◽  
pp. 60-64
Author(s):  
V G Kadzharyan ◽  
N I Kapshitar’
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Glucose Transporter ◽  
Reverse Flow ◽  
Selective Inhibition ◽  
Antidiabetic Therapy ◽  
Glucose Transporter 2 ◽  
Sodium Dependent

Insulin is traditionally the main application point on which all methods for the management of type 2 diabetes mellitus are targeted. One of the new strategies for the treatment of this pathology utilizes sodium-dependent glucose transporter-2 (SGLT-2) inhibitors transforms this approach making kidneys the new point of application of antidiabetic therapy. SGLT-2 functions as a tunnel built into the epithelial wall of the initial segment of the proximal tubules in the nephron. When the channel is open, glucose is filtered into primary urine and can be reabsorbed in the proximal tubule. Based on this observation, the pharmaceutical companies began to search for the chemical substances that could be used to close the SGLT-2 tunnels and thereby interfere with the reverse flow of glucose from urine to blood, i.e. stimulate glycosuria. During the last decade, a few alternative molecules have been synthesized capable of selective inhibition of SGLT-2. At present, two of them, dapagliflozin and canagliflozin, are approved for the clinical application.

A Case of Congenital Glucose Galactose Malabsorption with a New Mutation in the SLC5A1 Gene

2020 ◽  
Author(s):  
Hasan Akduman ◽  
Dilek Dilli ◽  
Serdar Ceylaner
Keyword(s):  
Mutation Analysis ◽  
Autosomal Recessive ◽  
Glucose Transporter ◽  
Neonatal Period ◽  
Autosomal Recessive Disorder ◽  
Homozygous Mutation ◽  
New Mutation ◽  
Early Neonatal Period ◽  
Sodium Dependent ◽  
Hypernatremic Dehydration

AbstractCongenital glucose-galactose malabsorption (CGGM) is an autosomal recessive disorder originating from an abnormal transporter mechanism in the intestines. It was sourced from a mutation in the SLC5A1 gene, which encodes a sodium-dependent glucose transporter. Here we report a 2-day-old girl with CGGM who presented with severe hypernatremic dehydration due to diarrhea beginning in the first hours of life. Mutation analysis revealed a novel homozygous mutation NM_000343.3 c.127G > A (p.Gly43Arg) in the SLC5A1 gene. Since CGGM can cause fatal diarrhea in the early neonatal period, timely diagnosis of the disease seems to be essential.

The Worrying Trend of Diabetes Mellitus in Saudi Arabia: An Urgent Call to Action

2020 ◽  
Vol 16 (3) ◽  
pp. 204-210 ◽  
Author(s):  
Asirvatham A. Robert ◽  
Mohamed A. Al Dawish
Keyword(s):  
Diabetes Mellitus ◽  
Saudi Arabia ◽  
Present Report ◽  
Adult Population ◽  
Current Trend ◽  
Fold Increase ◽  
Developed Countries ◽  
Evidence Base ◽  
Small Sample ◽  
Cross Sectional

From last few years, the pervasiveness of diabetes mellitus (DM), in Saudi Arabia, is growing at a frightening rate. Overall, one-fourth of the adult population is affected by DM, which is further predicted to rise to more than double by the year 2030. The most alarming is possibly the escalation propensity of diabetes, in recent years, where a nearly ten-fold increase has been witnessed over the past thirty years in Saudi Arabia. However, the number of research arbitrations on the prevalence and incidence of DM is woefully inadequate, as compared to developed countries. Apart from this, most of the existing research data carried out in Saudi Arabia is cross-sectional, with small sample sizes, which most often involve only certain parts of the country. Consequently, the present scenario demands more multidimensional and multisectoral research to strengthen the evidence base and to accumulate greater knowledge as a basis for measures and programmes to confront diabetes and its complications. Thus, the present report makes an attempt to depict the current trend of diabetes as well as intends to put forward essential measures for controlling diabetes in Saudi Arabia.

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

2020 ◽  
Vol 13 ◽  
Author(s):  
Keshav Kumar ◽  
Tapan Behl ◽  
Arun Kumar ◽  
Sandeep Arora
Keyword(s):  
Diabetes Mellitus ◽  
Glucose Transporter ◽  
Clinical Trial Data ◽  
Cardiac Complications ◽  
Cardiac Inflammation ◽  
First Line Therapy ◽  
Glucose Transporter 2 ◽  
Specific Medication ◽  
Hba1c Levels

Background: A chronic metabolic disease, diabetes mellitus (DM), is associated with various comorbidity due to cardiac complications that considerably decreasing the quality of life, but there is no specific medication for this. The recent developed drugs Sodium glucose transporter 2 inhibitors (SGLT2-Is), have action on diabetes as well as on kidney. Current research and studies have shown that SGLT2-Is attenuated the risk of cardiac complication associated with morbidity and hospitalization in diabetes patients. Introduction: Sodium glucose linked transporter 2 (SGLT2) receptors are mainly situated in 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 SGLT2-Is which inhibit or lower the reabsorption of glucose. Objectives: The present review explores the mechanistic principle and the clinical trial data of SGLT2-Is which further support cardioprotective effects associated with these medications. Methods: The review collaborates PUBMED, Google Scholar and Research gate databases, which were explored using keywords and their combinations such as sodium glucose co-transporter 2 inhibitors, diabetes mellitus, cardioprotective effect, empagliflozin, canagliflozin, dapagliflozin and several others, to create an eclectic manuscript. Results: SGLT2-Is showed improvement in diabetes as well as in cardiac complications. These medications decreased HbA1c levels to control hyperglycemia. The mechanism of action of these drugs showed reduction in cardiac oxidative stress, cardiac apoptosis and cardiac inflammation. Besides, SGLT-2-Is showed improvement in cardiac structure and cardiac function. Conclusion: Anti-diabetic drugs, SGLT2-Is have a protective effect against cardiac complications. This indicates that these medication could become first line therapy for cardiac patients with DM.

scholarly journals Gliflozine – in Zukunft Kardioprotektiva?

Der Internist ◽  
2021 ◽  
Author(s):  
Ursula Rauch-Kröhnert ◽  
Ulf Landmesser
Keyword(s):  
Diabetes Mellitus ◽  
Sglt2 Inhibitor ◽  
Diabetes Mellitus Typ 2 ◽  
Sodium Dependent

ZusammenfassungGliflozine (Inhibitoren der „sodium-dependent glucose cotransporter“, SGLT) sind Arzneistoffe, die ursprünglich zur Behandlung des Diabetes mellitus eingesetzt und der Gruppe der Antidiabetika zugeordnet wurden. Seit November 2020 ist mit Dapagliflozin erstmalig ein SGLT2-Inhibitor zur Behandlung von Patienten mit Herzinsuffizienz (mit reduzierter linksventrikulärer Funktion), unabhängig vom Diabetesstatus, zugelassen worden. Das Präparat Empagliflozin hat gerade – im Juni 2021 – von der europäischen Arzneimittelbehörde (EMA) eine Zulassung für die Therapie der Herzinsuffizienz mit reduzierter Ejektionsfraktion erhalten. Somit stehen verschiedene Gliflozine nicht nur zur Behandlung des Diabetes mellitus, sondern auch der Herzinsuffizienz zur Verfügung. Der vorliegende Beitrag vermittelt Grundlagenkenntnisse zu den Gliflozinen und bietet eine Übersicht zur ihrer Bedeutung sowohl in der Behandlung des Diabetes mellitus Typ 2 als auch aufgrund ihrer kardio- und nephroprotektiven Funktion.

scholarly journals Roles of insulin, guanosine 5′-[γ-thio]triphosphate and phorbol 12-myristate 13-acetate in signalling pathways of GLUT4 translocation

1996 ◽  
Vol 315 (3) ◽  
pp. 875-882 ◽  
Author(s):  
Mikio TODAKA ◽  
Hideki HAYASHI ◽  
Takanobu IMANAKA ◽  
Yasumasa MITANI ◽  
Seika KAMOHARA ◽  
...  
Keyword(s):  
Binding Proteins ◽  
Glucose Transporter ◽  
Chinese Hamster ◽  
Specific Inhibitor ◽  
Cell System ◽  
Signalling Pathways ◽  
Dominant Negative Mutant ◽  
Glut4 Translocation ◽  
Gtp Binding Proteins ◽  
Gtp Binding

Insulin, guanosine 5´-[γ-thio]triphospate (GTP[S]) and phorbol 12-myristate 13-acetate (PMA) trigger the translocation of GLUT4 (type 4 glucose transporter; insulin-sensitive glucose transporter) from an intracellular pool to the cell surface. We have developed a highly sensitive and quantitative method to detect GLUT4 immunologically on the surface of intact 3T3-L1 adipocytes and Chinese hamster ovary (CHO) cells, using c-myc epitope-tagged GLUT4 (GLUT4myc). We examined the roles of insulin, GTP[S] and PMA in the signalling pathways of GLUT4 translocation in the CHO cell system. Among small molecular GTP-binding proteins, ras, rab3D, rad and rho seem to be candidates as signal transmitters of insulin-stimulated GLUT4 translocation. Overexpression of wild-type H-ras and the dominant negative mutant H-rasS17N in our cell system respectively enhanced and blocked insulin-stimulated activation of mitogen-activated protein kinase, but did not affect insulin-stimulated GLUT4 translocation. Overexpression of rab3D or rad in the cells did not affect GLUT4 translocation triggered by insulin, GTP[S] or PMA. Treatment with Botulinum C3 exoenzyme, a specific inhibitor of rho, had no effect on GLUT4 translocation induced by insulin, GTP[S] or PMA. Therefore these small molecular GTP-binding proteins are not likely to be involved in GLUT4 translocation. In addition, insulin, GTP[S] and PMA apparently stimulate GLUT4 translocation through independent pathways.

Sign in / Sign up

Export Citation Format

Share Document