Empagliflozin Ameliorates Type 2 Diabetes-Induced Ultrastructural Remodeling of the Neurovascular Unit and Neuroglia in the Female db/db Mouse

Abstract

Type 2 diabetes is associated with diabetic cognopathy. Anti-hyperglycemic sodium glucose transporter 2 (SGLT2) inhibitors have shown promise in reducing cognitive impairment in mice with type 2 diabetes mellitus. We recently described marked ultrastructural (US) remodeling of the neurovascular unit (NVU) in type 2 diabetic db/db female mice. Herein, we tested whether the SGLT-2 inhibitor, empagliflozin (EMPA), protects the NVU from abnormal remodeling in cortical gray and subcortical white matter. Ten-week-old female wild-type and db/db mice were divided into lean controls (CKC, n = 3), untreated db/db (DBC, n = 3), and EMPA-treated db/db (DBE, n = 3). Empagliflozin was added to mouse chow to deliver 10 mg kg−1 day−1 and fed for ten weeks, initiated at 10 weeks of age. Brains from 20-week-old mice were immediately immersion fixed for transmission electron microscopic study. Compared to CKC, DBC exhibited US abnormalities characterized by mural endothelial cell tight and adherens junction attenuation and/or loss, pericyte attenuation and/or loss, basement membrane thickening, glia astrocyte activation with detachment and retraction from mural cells, microglia cell activation with aberrant mitochondria, and oligodendrocyte–myelin splitting, disarray, and axonal collapse. We conclude that these abnormalities in the NVU were prevented in DBE. Empagliflozin may provide neuroprotection in the diabetic brain.

Type 2 Diabetes Mellitus Increases The Risk of Late-Onset Alzheimer’s Disease: Ultrastructural Remodeling of the Neurovascular Unit and Diabetic Gliopathy

“…As mentioned earlier in section 1.2, obesity seems to be the driver of both the Hyper "H" and "E" phenomenon and the Met S. (Fig.2, 3 In this figure we propose that these above precursors are more of a continuum of progression from various stages, one to the next; however, some have posited that they could each represent separate pathologies that may be differentially expressed over time and thus, remain age-related . The three boxes on the right side of this figure refer to our independent findings in the brains of the diet induced obesity, insulin resistant model with impaired glucose tolerance or prediabetes Western mouse model [8], the streptozotocin induced type 1 diabetic mouse model [9] and the db/db mouse model of obesity, insulin resistance and T2DM [4][5][6][7]. Note the intersects between #10 in Box 2 to the red dashed outline protected these NVU remodeling changes as well as increased permeability [9].…”

“…is a result of the relative or complete impairment of insulin actions, signaling, and associated with a progressive decline in pancreatic beta cell function [4,5,6,7,8,9,11,12,13,14,15,16].…”

“…Note the intersects between #10 in Box 2 to the red dashed outline protected these NVU remodeling changes as well as increased permeability [9]. The most recent model studied was the obese, insulin resistant, T2DM female db/db mouse model [4][5][6][7]. This model demonstrated marked NVU, microglia cell(s) (MGC) and oligodendrocyte(s) OL and myelin remodeling that was protected utilizing a 10-week treatment period with the glucose lowering antidiabetic sodium glucose transporter 2 (SGLT2) inhibitor from 10 -20 weeks of age [7].…”

“…The most recent model studied was the obese, insulin resistant, T2DM female db/db mouse model [4][5][6][7]. This model demonstrated marked NVU, microglia cell(s) (MGC) and oligodendrocyte(s) OL and myelin remodeling that was protected utilizing a 10-week treatment period with the glucose lowering antidiabetic sodium glucose transporter 2 (SGLT2) inhibitor from 10 -20 weeks of age [7]. In this diabetic obese db/db model we were also able to demonstrate a marked expansion in aortic visceral perivascular adipose tissue that contained hypertrophic unilocular adipocytes that were rupturing with the spillage of neurotoxic proinflammatory free fatty acids (unpublished data).…”

“…Additionally, there are mural vascular cells coursing throughout the brain consisting of endothelial cell(s) (EC), pericyte(s) (Pcs) and vascular smooth muscles cells. Each of these cells have multiple unique identifying ultrastructural forms and functions [4][5][6][7][8][9]. This review focuses on type 2 diabetes mellitus (T2DM) and the increased risk of late-onset Alzheimer's disease (LOAD) and the capillary neurovascular unit(s) (NVU) and neuroglia.…”