Sodium glucose cotransporter SGLT1 as a therapeutic target in diabetes mellitus

Song, Panai; Ōnishi, Akira; Koepsell, Hermann; Vallon, Volker

doi:10.1517/14728222.2016.1168808

Cited by 144 publications

(138 citation statements)

References 173 publications

(269 reference statements)

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“…Phlorizin competitively inhibits SGLT2 and SGLT1 and does so with a tenfold higher affinity for the former [9, 24]. However, SGLT1 is the primary pathway for glucose reabsorption in the intestine and is widely expressed throughout the body [25]. Thus oral administration of phlorizin is encumbered by extrarenal side effects, such as diarrhoea.…”

Section: Sglt2 Inhibitors Reduce Blood Glucose Levels In Diabetes Butmentioning

confidence: 99%

Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition

2016

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Healthy kidneys filter ~160 g/day of glucose (~30% of daily energy intake) under euglycaemic conditions. To prevent valuable energy from being lost in the urine, the proximal tubule avidly reabsorbs filtered glucose up to a limit of ~450 g/day. When blood glucose levels increase to the point that the filtered load exceeds this limit, the surplus is excreted in the urine. Thus, the kidney provides a safety valve that can prevent extreme hyperglycaemia as long as glomerular filtration is maintained. Most of the capacity for renal glucose reabsorption is provided by sodium glucose cotransporter (SGLT) 2 in the early proximal tubule. In the absence of SGLT2, the renal reabsorptive capacity for glucose declines to ~80 g/day (the residual capacity of SGLT1), i.e. the safety valve opens at a lower threshold, which makes it relevant to glucose homeostasis from day-to-day. Several SGLT2 inhibitors are now approved glucose lowering agents for individuals with type 2 diabetes and preserved kidney function. By inducing glucosuria, these drugs improve glycaemic control in all stages of type 2 diabetes, while their risk of causing hypoglycaemia is low because they naturally stop working when the filtered glucose load falls below ~80 g/day and they don’t otherwise interfere with metabolic counterregulation. Through glucosuria, SGLT2 inhibitors reduce body weight and body fat, and shift substrate utilisation from carbohydrates to lipids and, possibly, ketone bodies. Because SGLT2 reabsorbs sodium along with glucose, SGLT2 blockers are natriuretic and antihypertensive. Also, because they work in the proximal tubule, SGLT2 inhibitors increase delivery of fluid and electrolytes to the macula densa, thereby activating tubuloglomerular feedback and increasing tubular back pressure. This mitigates glomerular hyperfiltration, reduces the kidney’s demand for oxygen and lessens albuminuria. For reasons that are less well understood, SGLT2 inhibitors are also uricosuric. 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 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.

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Section: Sglt2 Inhibitors Reduce Blood Glucose Levels In Diabetes Butmentioning

confidence: 99%

Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition

2016

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“…Of note and in contrast to SGLT2, SGLT1 is expressed in various body tissues in addition to the renal tubules. This includes the small intestines where SGLT1 is expressed in the luminal membrane and responsible for glucose reabsorption [6]. As a result, phlorizin inhibition of SGLT1 can lead to extrarenal side effects such as diarrhea.…”

Section: Sglt2 Inhibitors Are Anti-hyperglycemic Drugs With Low Hypogmentioning

confidence: 99%

“…This is an added benefit of sotagliflozin compared to the more selective SGLT2 inhibitors. The inhibition of SGLT1 in the small intestine can also induce a sustained postprandial increase in glucagon-like peptide 1 (GLP1), which enhances glucose-dependent insulin secretion in type 2 diabetes [6]. This effect becomes irrelevant in the absence of endogenous insulin secretion.…”

Section: Use Of Sglt2 Inhibitors In Type 1 Diabetic Patients: Effectsmentioning

confidence: 99%

The Potential Role of SGLT2 Inhibitors in the Treatment of Type 1 Diabetes Mellitus

Fattah

Vallon

2018

Drugs

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Type 1 diabetes mellitus is a difficult disease to treat due to the relative paucity of therapeutic options other than injectable insulin. The latter, however, can induce hypoglycemia, which has been linked to enhanced cardiovascular risk. Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral anti-hyperglycemic medications that do not increase the hypoglycemia risk and are US Food and Drug Administration (FDA) approved in type 2 diabetes mellitus. SGLT2 inhibitors may also be of benefit in type 1 diabetic patients, in addition to insulin, although they have not yet been approved for this indication. By blocking SGLT2 in the early proximal tubules of the kidney, these drugs decrease renal glucose retention, which is enhanced in hyperglycemia, thereby improving blood glucose control, in type 1 and type 2 diabetic patents. Their low hypoglycemia risk is due to the compensating reabsorption capacity of another glucose transporter, SGLT1, in the downstream late proximal tubule and the body's metabolic counter-regulation, which remains intact during SGLT2 inhibition. When insulin dosage is lowered too much, SGLT2 inhibitors can enhance ketogenesis to the extent that the risk of diabetic ketoacidosis increases, particularly in type 1 diabetic patients. SGLT2 inhibitors improve the renal and cardiovascular outcome in type 2 diabetic patients. The mechanisms likely include a reduction in glomerular hyperfiltration, blood pressure, volume overload, and body weight, as well as lowering blood glucose without increasing the hypoglycemia risk. The same mechanistic effects are induced in type 1 diabetic patients. More studies are needed with SGLT2 inhibitors in type 1 diabetic patients, including renal and cardiovascular clinical outcome trials, to fully evaluate their therapeutic potential in this specific population.

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“…In short-term studies, inhibition of SGLT1 and combined SGLT1/SGLT2 inhibition appeared safe. However, more data is needed on long-term safety and cardiovascular consequences of SGLT1 inhibition [13].…”

Section: Introductionmentioning

confidence: 99%

Prescription Pattern Analysis of Antidiabetic Drugs in Diabetes Mellitus and Associated Comorbidities

Mahmood¹,

Reddy²,

Lahari³

et al. 2018

Clinical-Investigation

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Background: The treatment options for Diabetes mellitus and their prescribing has increased over years. This needs appropriate selection of drugs. The main objective of this study was to highlight the current prescribing trends in Diabetes mellitus patients with other co-morbid conditions. Methods:A prospective observational study was conducted on inpatients admitted to various wards in a tertiary care hospital for period of 6 months between October 2016-March 2017. Prescriptions of the patients are collected in a designed questionnaire form and the relevant information is recorded and analysed.Results: 235 patient prescription patterns were studied, out of which 62.97% were males and 37.02% were females. Most of the patients were in the age group of 41-60. Hypertension was the most commonly found co-morbid condition. Rapid acting insulin was mostly prescribed during hospital stay. Metformin was the commonly prescribed oral hypoglycemic agent followed by glimeperide. Conclusion:The adverse drug reactions can be minimized by replacing the drugs with novel therapeutic agents like Glucagon-like peptide agonist, Dipeptidyl peptidase inhibitors and Sodium-glucose transport inhibitors. The management of drug interactions should be done by clinical significance and correlation.

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Sodium glucose cotransporter SGLT1 as a therapeutic target in diabetes mellitus

Cited by 144 publications

References 173 publications

Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition

Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition

The Potential Role of SGLT2 Inhibitors in the Treatment of Type 1 Diabetes Mellitus

Prescription Pattern Analysis of Antidiabetic Drugs in Diabetes Mellitus and Associated Comorbidities

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