sglt2 inhibition
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2021 ◽  
Vol 13 (12) ◽  
pp. 676-694
Author(s):  
Mouhamed Nashawi ◽  
Mahmoud S Ahmed ◽  
Toka Amin ◽  
Mujahed Abualfoul ◽  
Robert Chilton

2021 ◽  
Author(s):  
Kim Connelly ◽  
Ellen Wu ◽  
Aylin Visram ◽  
Mark K. Friedberg ◽  
Sri Nagarjun Batchu ◽  
...  

Abstract Background— 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 might be similarly efficacious in the treatment and prevention of right heart failure has not been unexplored. Hypothesis: We hypothesized that SGLT2 inhibition would reduce the structural, functional and molecular responses to pressure overload of the right ventricle. Methods: 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 six weeks of treatment, animals underwent transthoracic echocardiography and invasive hemodynamic studies. Animals were then terminated, and their hearts harvested for structural and molecular analyses. Results: 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, AMPkinase and LC3I/II ratio expression (all p<0.05). Significance: 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.


2021 ◽  
Author(s):  
Anita Layton

The kidney plays an essential role in regulating the homeostasis of electrolytes, acid-base species, and fluids. Kidney structure and function are significantly affected in diabetes. These pathophysiological changes include glomerular hyperfiltration and tubular hypertrophy, and ultimately leading to diabetic kidney disease. A class of medications that have shown promise in slowing the progression to diabetic kidney disease are the sodium-glucose cotransporter 2 (SGLT2) inhibitors. SGLT2 inhibitors target Na+ and glucose reabsorption along the proximal convoluted tubule, enhance urinary glucose, Na+ and fluid excretion, and lower hyperglycemia in diabetes. We postulate that both diabetes-induced and SGLT2 inhibition-induced changes in kidney may exhibit significant sex differences, because the distribution of renal transporters along the nephron may be markedly different between women and men, as recently shown in rodents. The goals of this study are to (i) analyze how kidney function is altered in male and female patients with diabetes, (ii) assess the renal effects, in women and men, of an anti-hyperglycemic therapy that inhibits the sodium-glucose cotransporter 2 (SGLT2) in the proximal convoluted tubules, and (iii) study how those renal effects are altered in uninephrectomy. To accomplish these goals, we have developed computational models of kidney function, separate for male and female patients with diabetes and/or uninephredctomy. The simulation results indicate that by inducing osmotic diuresis in the proximal tubules, SGLT2 inhibition reduces paracellular transport, eventually leading to diuresis and natriuresis.


2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Sameer Leley ◽  
Qianyi Luo ◽  
Ashay Bhatwadekar

Background and Hypothesis: Diabetic retinopathy (DR), a microvascular complication of diabetes, is the leading cause of blindness in the working-age population, and its prevalence is increasing. New treatment modalities must be developed to slow the progression of DR. SGLT2 inhibition has shown promise in treating other diabetic complications; however, its effect on DR remains unknown, therefore, for this study, we hypothesize that SGLT2 inhibition will reduce the harmful effects of DR. Methods: Diabetic (db/db) mice were fed 10 mg/kg of the SGLT2 inhibitor dapagliflozin in their diet for 6 months, non-diabetic (db/m) mice on a regular diet served as controls. In parallel, human retinal endothelial cells (HREC) were used as in-vitro models and treated with dapagliflozin to assess glucose uptake via a 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2-NBDG) assay. Results: Our studies show that db/db mice with dapagliflozin had significantly fewer acellular capillaries compared to untreated db/db mice. Furthermore, Dapagliflozin treatment at 1 and 10 µM concentrations of dapagliflozin yielded a significant decrease in glucose uptake compared to respective vehicle controls. Conclusion: Our study shows that SGLT2 inhibition has a promise in treating DR by reducing acellular capillaries and retinal glucose transport suggesting the potential of dapagliflozin treatment in DR.


2021 ◽  
Author(s):  
Schafer C. Boeder ◽  
Justin M. Gregory ◽  
Erin R. Giovannetti ◽  
Jeremy H. Pettus

Individuals with type 1 diabetes have an impaired glucagon counterregulatory response to hypoglycemia. Sodium-glucose cotransporter (SGLT) inhibitors increase glucagon concentrations. We evaluated whether SGLT inhibition restores the glucagon counterregulatory hormone response to hypoglycemia. Adults with type 1 diabetes (<i>n</i> = 22) were treated with the SGLT2 inhibitor dapagliflozin (5 mg daily) or placebo for 4 weeks in a randomized, double-blind, crossover study. After each treatment phase, participants underwent a hyperinsulinemic hypoglycemic clamp. Basal glucagon concentrations were 32% higher following dapagliflozin versus placebo, with a median within-participant difference of 2.75 pg/mL (95% CI 1.38-12.6). However, increased basal glucagon levels did not correlate with decreased rates of hypoglycemia, and thus do not appear to be protective in avoiding hypoglycemia. During hypoglycemic clamp, SGLT2 inhibition did not change counterregulatory hormone concentrations, time to recovery from hypoglycemia, hypoglycemia symptoms, or cognitive function. Thus, despite raising basal glucagon concentrations, SGLT inhibitor treatment did not restore the impaired glucagon response to hypoglycemia. We propose that clinical reduction in hypoglycemia associated with these agents is a result of changes in diabetes care (e.g., lower insulin doses or improved glycemic variability) as opposed to a direct, physiologic effect of these medications on alpha cell function.


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