Sodium glucose cotransporter 2 inhibition in the diabetic kidney

Novikov, Aleksandra; Vallon, Volker

doi:10.1097/mnh.0000000000000187

Cited by 96 publications

(71 citation statements)

References 50 publications

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“…Throughout the progression of diabetes, the kidney undergoes adaptive changes to accommodate and manage the increased filtered glucose load. These changes not only impact glucose handling but also contribute to the development and progression of renal damage and functional decline . The diabetic kidney is subject to tubular interstitial oxidative stress and inflammation with associated adaptive changes in renal function, biochemistry and pathology.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the urinary glucose excretion contributions of SGLT2 and SGLT1: A quantitative systems pharmacology analysis in healthy individuals and patients with type 2 diabetes treated with SGLT2 inhibitors

Yakovleva¹,

Соколов²,

Chu

et al. 2019

Diabetes Obesity Metabolism

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Aim To develop a quantitative drug‐disease systems model to investigate the paradox that sodium‐glucose co‐transporter (SGLT)2 is responsible for >80% of proximal tubule glucose reabsorption, yet SGLT2 inhibitor treatment results in only 30% to 50% less reabsorption in patients with type 2 diabetes mellitus (T2DM). Materials and methods A physiologically based four‐compartment model of renal glucose filtration, reabsorption and excretion via SGLT1 and SGLT2 was developed as a system of ordinary differential equations using R/IQRtools. SGLT2 inhibitor pharmacokinetics and pharmacodynamics were estimated from published concentration‐time profiles in plasma and urine and from urinary glucose excretion (UGE) in healthy people and people with T2DM. Results The final model showed that higher renal glucose reabsorption in people with T2DM versus healthy people was associated with 54% and 28% greater transporter capacity for SGLT1 and SGLT2, respectively. Additionally, the analysis showed that UGE is highly dependent on mean plasma glucose and estimated glomerular filtration rate (eGFR) and that their consideration is critical for interpreting clinical UGE findings. Conclusions Quantitative drug‐disease system modelling revealed mechanistic differences in renal glucose reabsorption and UGE between healthy people and those with T2DM, and clearly showed that SGLT2 inhibition significantly increased glucose available to SGLT1 downstream in the tubule. Importantly, we found that the findings of lower than expected UGE with SGLT2 inhibition are explained by the shift to SGLT1, which recovered additional glucose (~30% of total).

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Section: Discussionmentioning

confidence: 99%

Comparison of the urinary glucose excretion contributions of SGLT2 and SGLT1: A quantitative systems pharmacology analysis in healthy individuals and patients with type 2 diabetes treated with SGLT2 inhibitors

Yakovleva¹,

Соколов²,

Chu

et al. 2019

Diabetes Obesity Metabolism

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“…69 Interestingly, Pessoa et al recently reported that NHE3 activity is stimulated by luminal glucose, and that NHE3 co-localizes and may functionally interact with SGLT2 in the proximal tubule. Thus, it is possible that SGLT2 inhibition may inhibit NHE3 transport activity.…”

Section: Summary and Future Directionsmentioning

confidence: 99%

ISN Forefronts Symposium 2015: Maintaining Balance Under Pressure—Hypertension and the Proximal Tubule

McDonough

2016

Kidney International Reports

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Renal control of effective circulating volume is key for circulatory performance. When renal Na+ excretion is inadequate, blood pressure rises and serves as a homeostatic signal to drive natriuresis to re-establish effective circulating volume (ECV). Recognizing that hypertension involves both renal and vascular dysfunction, this report concerns proximal tubule Na+/H+ exchanger 3 (PT NHE3) regulation during acute and chronic hypertension. NHE3 is distributed in tall microvilli (MV) in the PT where it reabsorbs a significant fraction of the filtered Na+. NHE3 redistributes, in the plane of the MV membrane, between the MV body, where NHE3 is active, and MV base where NHE3 is less active. High salt diet and acute hypertension both retract NHE3 to the base and reduce PT Na+ reabsorption independent of a change in abundance. The renin angiotensin system provokes NHE3 redistribution independent of blood pressure: the ACE inhibitor captopril redistributes NHE3 to the base and subsequent AngII infusion returns NHE3 to the body of the microvilli and restores reabsorption. Chronic AngII infusion presents simultaneous AngII stimulation and hypertension: NHE3 remains in the body of the MV, due to the high local AngII and inflammation, and exhibits a compensatory decrease in abundance, driven by the hypertension. Genetically modified mice with blunted hypertensive responses to chronic AngII infusion (due to lack of PT AngII receptors, IL-17A or IFN-γ expression) exhibit reduced local AngII accumulation and inflammation and larger decreases in NHE3 abundance which improve the pressure natriuresis responses and reduces the need for elevated BP to facilitate circulating volume balance.

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“…SGLT2 inhibitors work independent of insulin and have little hypoglycemia risk. The compounds induce a modest diuresis/natriuresis, urinary calorie loss, and activation of lipolysis, which are associated with a modest reduction in body fat, body weight, and blood pressure [12]. Ongoing long-term clinical trials explore the safety and the clinical efficacy of SGLT2 inhibitors in the prevention of diabetic renal and cardiovascular complications [7-9, 11, 13].…”

Section: Introductionmentioning

confidence: 99%

Sodium glucose cotransporter SGLT1 as a therapeutic target in diabetes mellitus

Song

Ōnishi

Koepsell

et al. 2016

Expert Opinion on Therapeutic Targets

Self Cite

153

126

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Introduction Glycemic control is important in diabetes mellitus to minimize the progression of the disease and the risk of potentially devastating complications. Inhibition of the sodium–glucose cotransporter SGLT2 induces glucosuria and has been established as a new anti-hyperglycemic strategy. SGLT1 plays a distinct and complementing role to SGLT2 in glucose homeostasis and, therefore, SGLT1 inhibition may also have therapeutic potential. Areas covered This review focuses on the physiology of SGLT1 in the small intestine and kidney and its pathophysiological role in diabetes. The therapeutic potential of SGLT1 inhibition, alone as well as in combination with SGLT2 inhibition, for anti-hyperglycemic therapy are discussed. Additionally, this review considers the effects on other SGLT1-expressing organs like the heart. Expert opinion SGLT1 inhibition improves glucose homeostasis by reducing dietary glucose absorption in the intestine and by increasing the release of gastrointestinal incretins like glucagon-like peptide-1. SGLT1 inhibition has a small glucosuric effect in the normal kidney and this effect is increased in diabetes and during inhibition of SGLT2, which deliver more glucose to SGLT1 in late proximal tubule. In short-term studies, inhibition of SGLT1 and combined SGLT1/SGLT2 inhibition appeared to be safe. More data is needed on long-term safety and cardiovascular consequences of SGLT1 inhibition.

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Sodium glucose cotransporter 2 inhibition in the diabetic kidney

Cited by 96 publications

References 50 publications

Comparison of the urinary glucose excretion contributions of SGLT2 and SGLT1: A quantitative systems pharmacology analysis in healthy individuals and patients with type 2 diabetes treated with SGLT2 inhibitors

Comparison of the urinary glucose excretion contributions of SGLT2 and SGLT1: A quantitative systems pharmacology analysis in healthy individuals and patients with type 2 diabetes treated with SGLT2 inhibitors

ISN Forefronts Symposium 2015: Maintaining Balance Under Pressure—Hypertension and the Proximal Tubule

Sodium glucose cotransporter SGLT1 as a therapeutic target in diabetes mellitus

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