scholarly journals SGLT2 Inhibitors: Physiology and Pharmacology

Kidney360 ◽  
2021 ◽  
pp. 10.34067/KID.0002772021
Author(s):  
Ernest M Wright
Keyword(s):  
Proximal Tubule ◽  
Glycosylated Hemoglobin ◽  
Blood Stream ◽  
Sglt2 Inhibitors ◽  
Luminal Membrane ◽  
Glucose Reabsorption ◽  
Lower Plasma Glucose ◽  
Glomerular Filtrate ◽  
Glucose Excretion

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.

Discovery of Natural SGLT2-Inhibitors for Type 2 Diabetes – Possible Way to Reduce Side Effects

2016 ◽  
Vol 15 (2) ◽  
pp. 86
Author(s):  
D. K. Semwal ◽  
R. B. Semwal
Keyword(s):  
Type 2 Diabetes ◽  
Side Effects ◽  
Sglt2 Inhibitors ◽  
Adult Onset ◽  
The Past ◽  
Glucose Reabsorption ◽  
Number Of Patients ◽  
The World ◽  
Glucose Excretion

The number of patients diagnosed with diabetes mellitus in all over the world has risen ominously in the past few decades, in which majority of cases belongs to type 2 diabetes. Previously, type 2 diabetes was known as adult-onset and noninsulin-dependent but now it can be seen at any stage including childhood. Various recent researches revealed that type 2 diabetes can be treated by inhibiting sodium-glucose co-transporter 2 (SGLT2), a protein which facilitates glucose reabsorption in the kidney. SGLT2 inhibitors can reduce the blood sugar level by blocking reabsorption of glucose in the kidney and increasing glucose excretion. In the past couple of years, many SGLT2 inhibitors have been discovered but owing to serious side effects, their use is completely banned. Hence, the discovery of natural SGLT2 inhibitors can be helpful in treating type 2 diabetes without any adverse effects.

scholarly journals Unexpected Pleiotropic Effects of SGLT2 Inhibitors: Pearls and Pitfalls of This Novel Antidiabetic Class

2021 ◽  
Vol 22 (6) ◽  
pp. 3062
Author(s):  
Hideaki Kaneto ◽  
Atsushi Obata ◽  
Tomohiko Kimura ◽  
Masashi Shimoda ◽  
Tomoe Kinoshita ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Cell Function ◽  
Sglt2 Inhibitors ◽  
Protective Effects ◽  
Glucose Reabsorption ◽  
Β Cell Function ◽  
Glucose Lowering Effect ◽  
Glucose Excretion

Sodium-glucose co-transporter 2 (SGLT2) inhibitors facilitate urine glucose excretion by reducing glucose reabsorption, leading to ameliorate glycemic control. While the main characteristics of type 2 diabetes mellitus are insufficient insulin secretion and insulin resistance, SGLT2 inhibitors have some favorable effects on pancreatic β-cell function and insulin sensitivity. SGLT2 inhibitors ameliorate fatty liver and reduce visceral fat mass. Furthermore, it has been noted that SGLT2 inhibitors have cardio-protective and renal protective effects in addition to their glucose-lowering effect. In addition, several kinds of SGLT2 inhibitors are used in patients with type 1 diabetes mellitus as an adjuvant therapy to insulin. Taken together, SGLT2 inhibitors have amazing multifaceted effects that are far beyond prediction like some emerging magical medicine. Thereby, SGLT2 inhibitors are very promising as relatively new anti-diabetic drugs and are being paid attention in various aspects. It is noted, however, that SGLT2 inhibitors have several side effects such as urinary tract infection or genital infection. In addition, we should bear in mind the possibility of diabetic ketoacidosis, especially when we use SGLT2 inhibitors in patients with poor insulin secretory capacity.

Mechanisms of Protective Effects of SGLT2 Inhibitors in Cardiovascular Disease and Renal Dysfunction

2019 ◽  
Vol 19 (20) ◽  
pp. 1818-1849 ◽  
Author(s):  
Ban Liu ◽  
Yuliang Wang ◽  
Yangyang Zhang ◽  
Biao Yan
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Renal Dysfunction ◽  
Sglt2 Inhibitors ◽  
Sodium Glucose Cotransporter ◽  
Glucose Reabsorption ◽  
Renal Glucose Reabsorption

: Type 2 diabetes mellitus is one of the most common forms of the disease worldwide. Hyperglycemia and insulin resistance play key roles in type 2 diabetes mellitus. Renal glucose reabsorption is an essential feature in glycaemic control. Kidneys filter 160 g of glucose daily in healthy subjects under euglycaemic conditions. The expanding epidemic of diabetes leads to a prevalence of diabetes-related cardiovascular disorders, in particular, heart failure and renal dysfunction. Cellular glucose uptake is a fundamental process for homeostasis, growth, and metabolism. In humans, three families of glucose transporters have been identified, including the glucose facilitators GLUTs, the sodium-glucose cotransporter SGLTs, and the recently identified SWEETs. Structures of the major isoforms of all three families were studied. Sodium-glucose cotransporter (SGLT2) provides most of the capacity for renal glucose reabsorption in the early proximal tubule. A number of cardiovascular outcome trials in patients with type 2 diabetes have been studied with SGLT2 inhibitors reducing cardiovascular morbidity and mortality. : The current review article summarises these aspects and discusses possible mechanisms with SGLT2 inhibitors in protecting heart failure and renal dysfunction in diabetic patients. Through glucosuria, SGLT2 inhibitors reduce body weight and body fat, and shift substrate utilisation from carbohydrates to lipids and, possibly, ketone bodies. These pleiotropic effects of SGLT2 inhibitors are likely to have contributed to the results of the EMPA-REG OUTCOME trial in which the SGLT2 inhibitor, empagliflozin, slowed down the progression of chronic kidney disease and reduced major adverse cardiovascular events in high-risk individuals with type 2 diabetes. This review discusses the role of SGLT2 in the physiology and pathophysiology of renal glucose reabsorption and outlines the unexpected logic of inhibiting SGLT2 in the diabetic kidney.

scholarly journals Diabetes Research Open Access: Sodium Glucose Cotransporter2 (SGLT2) Inhibitors

2020 ◽  
Vol 2 (S1) ◽  
pp. 14
Author(s):  
Kuşkonmaz SM
Keyword(s):  
Sglt2 Inhibitors ◽  
Diabetes Research ◽  
Oral Antidiabetics ◽  
First Line ◽  
Glucose Lowering ◽  
Sodium Glucose Cotransporter ◽  
Glucose Reabsorption ◽  
New Guidelines ◽  
Renal Glucose Reabsorption

Sodium glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) are a group of glycosuric drugs approved in the management of type 2 diabetes mellitus. They act on the sodium glucose cotransporter and inhibit renal glucose reabsorption. Canagliflozin dapagliflozin and empagliflozin are members of the SGLT2i group. SGLT2 is supposed to be unique to the kidney. Recent studies showed the benefits of these agents beyond and independent from glucose lowering. New guidelines emphasize these pleiotropic effects such as cardioprotective and renoprotective effects of SGLT2i and suggest them as first line oral antidiabetics in patients with coronary heart disease.

The Beneficial Hemodynamic Actions of SGLT-2 Inhibitors beyond the Management of Hyperglycemia

2020 ◽  
Vol 27 (39) ◽  
pp. 6682-6702 ◽  
Author(s):  
Charalampos Loutradis ◽  
Eirini Papadopoulou ◽  
Elena Angeloudi ◽  
Asterios Karagiannis ◽  
Pantelis Sarafidis
Keyword(s):  
Proximal Tubule ◽  
Public Health Burden ◽  
The Metabolic Syndrome ◽  
Type 2 Dm ◽  
Glucose Reabsorption ◽  
Oral Agents ◽  
Stage Renal Disease ◽  
End Stage ◽  
Existing Data

Type 2 diabetes mellitus (DM) is a public health burden and its co-existence with hypertension is long established in the context of the metabolic syndrome. Both DM and hypertension are major risk factors, for end-stage renal disease, cardiovascular events and mortality. Strict blood pressure (BP) control in diabetics has been associated with a cardiovascular and renal risk decrease. Inhibitors of the sodium-glucose co-transporter 2 (SGLT-2) in the proximal tubule is a relatively novel class of agents for the treatment of type 2 DM. Inhibition of SGLT-2 co-transporter combines proximal tubule diuretic and osmotic diuretic action leading to glucose reabsorption reduction and mild natriuretic and diuretic effects. On this basis, several studies showed that treatment with SGLT-2 inhibitors can effectively decrease hyperglycemia but also increase BP control and reduce renal outcomes and cardiovascular mortality. Based on such evidence, the recent guidelines for the management of type 2 DM now suggest that SGLT-2 inhibitors should be preferred among oral agents in combination with metformin, in patients at increased cardiovascular risk, chronic kidney disease or heart failure. This review summarizes the existing data from studies evaluating the effect of SGLT-2 inhibitors on BP, and its potential value for cardio- and nephroprotection.

Micropuncture studies of glucose transport in the dog: mechanism of renal glycosuria

1976 ◽  
Vol 231 (2) ◽  
pp. 468-475 ◽  
Author(s):  
SF Wen
Keyword(s):  
Proximal Tubule ◽  
Maleic Acid ◽  
Volume Expansion ◽  
Low Dose ◽  
High Dose ◽  
Urinary Glucose Excretion ◽  
Renal Glycosuria ◽  
Glucose Reabsorption ◽  
Urinary Glucose ◽  
Glucose Excretion

Clearance and micropuncture studies were performed in 23 dogs without glucose loading to examine the tubule mechanism of renal glycosuria. Studies were carried out in three groups of animals before and after 10% extracellular volume expansion, and administration of maleic acid in low dose at 150 mumol/kg and in high dose at 300 mumol/kg. Specific hexokinase methods were used for the determination of glucose in tubule fluid and urine. Under control conditios, glucose reabsorption occurred predominantly in the proximal tubule. In all three groups, proximal tubule reabsorption of both sodium and glucose was inhibited in the second phase, showing a good correlation between the two. In contrast, fractional urinary glucose excretion remained unchanged after volume expansion and low-dose maleic acid, indicating reabsorption of virtually all the increased glucose load at a further "distal" site. On the other hand, significant glycosuria developed after high-dose maleic acid that was a result of reduced glucose reabsorption in the distal nephron, in addition to the proximal effect. It was concluded that distal glucose transport plays a significant role in regulating urinary glucose excretion and maintains renal thershold for glucose,

scholarly journals Renal olfactory receptor 1393 contributes to the progression of type 2 diabetes in a diet-induced obesity model

2019 ◽  
Vol 316 (2) ◽  
pp. F372-F381 ◽  
Author(s):  
Blythe D. Shepard ◽  
Hermann Koepsell ◽  
Jennifer L. Pluznick
Keyword(s):  
Type 2 Diabetes ◽  
Proximal Tubule ◽  
High Fat Diet ◽  
Olfactory Receptor ◽  
Early Stage ◽  
Fasting Blood Glucose ◽  
Olfactory Receptors ◽  
High Fat ◽  
Glucose Reabsorption

Olfactory receptors are G protein-coupled receptors that serve to detect odorants in the nose. Additionally, these receptors are expressed in other tissues, where they have functions outside the canonical smell response. Olfactory receptor 1393 (Olfr1393) was recently identified as a novel regulator of Na+-glucose cotransporter 1 (Sglt1) localization in the renal proximal tubule. Glucose reabsorption in the proximal tubule (via Sglt1 and Sglt2) has emerged as an important contributor to the development of diabetes. Inhibition of Sglt2 is accepted as a viable therapeutic treatment option for patients with type 2 diabetes and has been shown to delay development of diabetic kidney disease. We hypothesized that Olfr1393 may contribute to the progression of type 2 diabetes, particularly the development of hyperfiltration, which has been linked to increased Na+ reabsorption in the proximal tubule via the Sglts. To test this hypothesis, Olfr1393 wild-type (WT) and knockout (KO) mice were challenged with a high-fat diet to induce early-stage type 2 diabetes. After 16 wk on the high-fat diet, fasting blood glucose values were increased and glucose tolerance was impaired in the male WT mice. Both of these effects were significantly blunted in the male KO mice. In addition, male and female WT mice developed diabetes-induced hyperfiltration, which was attenuated in the Olfr1393 KO mice and corresponded with a reduction in luminal expression of Sglt2. Collectively, these data indicate that renal Olfr1393 can contribute to the progression of type 2 diabetes, likely as a regulator of Na+-glucose cotransport in the proximal tubule.

Effect of metabolic acidosis on glucose reabsorption in rats with acute hyperglycemia

1990 ◽  
Vol 68 (1) ◽  
pp. 79-83 ◽  
Author(s):  
P. O. Magner ◽  
M. L. Halperin
Keyword(s):  
Proximal Tubule ◽  
Fractional Excretion ◽  
Electrochemical Gradient ◽  
Osmotic Diuresis ◽  
Acute Hyperglycemia ◽  
Luminal Membrane ◽  
Glucose Reabsorption ◽  
Other Substances ◽  
Hyperglycemic Hyperosmolar Nonketotic Coma ◽  
Filtered Load

The rate of reabsorption of glucose in the kidney is a factor to consider with respect to the degree of hyperglycemia in poorly controlled diabetics. The rate of reabsorption of glucose in the proximal tubule is driven by the electrochemical gradient for sodium across the luminal membrane. This gradient in the proximal tubule is also used to reabsorb a number of other substances, quantitatively the most important being bicarbonate. We wished to explore the hypothesis that acidosis, by reducing the filtered load of bicarbonate and therefore the reabsorption of bicarbonate in the proximal tubule, might permit an increased rate of reabsorption of glucose. Hyperglycemia was induced in rats by the infusion of hypertonic glucose. Reabsorption of glucose was measured by clearance methods and factored for glomerular filtration rate (GFR), which has a direct effect on the reabsorption of glucose. The reabsorption of glucose was increased in the kidney when the reabsorption of bicarbonate in the proximal tubule was decreased by either HCl-induced acidosis or the administration of a carbonic anhydrase inhibitor. This effect was independent of a change in GFR and the fractional excretion of Na, factors that may also lead to changes in the reabsorption of glucose by the kidney.Key words: diabetes mellitus, hyperglycemic hyperosmolar nonketotic coma, diabetic ketoacidosis, proximal convoluted tubule, hyperglycemia, glucosuria, osmotic diuresis.

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

Metabolites ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 794
Author(s):  
Muhammad Afzal ◽  
Fahad A. Al-Abbasi ◽  
Muhammad Shahid Nadeem ◽  
Sultan Alshehri ◽  
Mohammed M. Ghoneim ◽  
...  
Keyword(s):  
Glycemic Control ◽  
Diabetes Management ◽  
Cardiovascular Effects ◽  
Sglt2 Inhibitors ◽  
Diabetic Patients ◽  
East Asians ◽  
Sodium Glucose Cotransporter ◽  
Glucose Reabsorption ◽  
Renal Glucose Reabsorption

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.

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