The Effect of SGLT2 Inhibition on Diabetic Kidney Disease in a Model of Diabetic Retinopathy

Abstract

Diabetic kidney disease (DKD) is a chronic disorder characterized by elevated urine albumin excretion, reduced glomerular filtration rate, or both. At present, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are the standard care for the treatment of DKD, resulting in improved outcomes. However, alternative treatments may be required because although the standard treatments have been found to slow the progression of DKD, they have not been found to halt the disease. In the past decade, sodium glucose co-transporter 2 (SGLT2) inhibitors have been widely researched in the area of cardiovascular disease and diabetes and have been shown to improve cardiovascular outcomes. SGLT2 inhibitors including canagliflozin and dapagliflozin have been shown to slow the progression of kidney disease. There is currently an omission of literature where three SGLT2 inhibitors have been simultaneously compared in a rodent diabetic model. After diabetic Akimba mice were treated with SGLT2 inhibitors for 8 weeks, there was not only a beneficial impact on the pancreas, signified by an increase in the islet mass and increased plasma insulin levels, but also on the kidneys, signified by a reduction in average kidney to body weight ratio and improvement in renal histology. These findings suggest that SGLT2 inhibition promotes improvement in both pancreatic and kidney health.

Determining the Role of SGLT2 Inhibition with Dapagliflozin in the Development of Diabetic Retinopathy

“…As expected, the normalized weight gain of nondiabetic WT and Kimba mice were similar in both DAPA and vehicle treated groups. The failure to thrive phenotype indicated by poor weight gain is a hallmark feature of uncontrolled type 1 diabetes in mice [20,[36][37][38]. The significant weight loss and muscle waste is possibly due to catabolic effects (accelerated protein catabolism and diminished protein synthesis) of insulin deficiency, as well as volume depletion associated with the osmotic diuresis in type 1 diabetes [36].…”

SGLT1/2 inhibition improves glycemic control and multi-organ protection in type 1 diabetes

“…Kidney hypertrophy is considered the earliest structural change noted in T1D associated kidney disease. 36 Similar to single SGLT2 inhibition, 10 SOTAG also showed a significant reduction in the KW/BW ratio in the setting of T1D, signifying that dual SGLT1/2i may improve renal health because of reduced renal hypertrophy.…”

“… 57 The Akimba mouse model displays hallmark retinal microvascular abnormalities representative of human DR and is shown to develop diabetic kidney disease. 10 , 18 , 58 , 59 DNA was isolated from tail clippings by using the Wizard Genomic DNA Purification Kit (Promega, Madison, WI). Genotyping of Kimba mice was carried out as described previously.…”

“… 4 Lately we and others have described pleiotropic effects of SGLT2i′s such as sympathoinhibition in a wide range of target tissues throughout the body. 5 , 6 , 7 , 8 , 9 , 10 …”

The Impact of SGLT2 Inhibitors in the Heart and Kidneys Regardless of Diabetes Status

“…Studies have shown that SGLT2i’s promote an upregulation of the family member SGLT1 in the kidneys ( Figure 4 ) and also cause a reduction in kidney size and an improvement in renal histology [ 88 ]. The compensatory upregulation of SGLT1 with SGLT2i’s warrants the use of dual SGLT1/2 inhibitors such as SOTA.…”