ABSTRACT
Autoreactivity of the complement system may escalate the development of diabetic nephropathy. We used the BTBR OB mouse model of type 2 diabetes to investigate the role of the complement factor mannan-binding lectin (MBL) in diabetic nephropathy. Female BTBR OB mice (n = 30) and BTBR non-diabetic WT mice (n = 30) were included. Plasma samples (weeks 12 and 21) and urine samples (week 19) were analyzed for MBL, C3, C3-fragments, SAA3, and markers for renal function. Renal tissue sections were analyzed for fibrosis, inflammation, and complement deposition. The renal cortex was analyzed for gene expression (complement, inflammation, and fibrosis), and isolated glomerular cells were investigated for MBL protein. Human vascular endothelial cells cultured under normo- and hyperglycemic conditions were analyzed by flow cytometry. We found that the OB mice had elevated plasma and urine concentrations of MBL-C (p < 0.0001 and p < 0.001, respectively) and higher plasma C3 levels (p < 0.001) compared to WT mice. Renal cryosections from OB mice showed increased MBL-C and C4 deposition in the glomeruli and increased macrophage infiltration (p = 0.002). Isolated glomeruli revealed significantly higher MBL protein levels (p < 0.001) compared to the OB and WT mice, and no renal MBL expression was detected. We report that chronic inflammation plays an important role in the development of DN through the binding of MBL to hyperglycemia-exposed renal cells.
Subject(s)
Diabetes Mellitus, Type 2 , Diabetic Nephropathies , Disease Models, Animal , Inflammation , Mannose-Binding Lectin , Animals , Mannose-Binding Lectin/metabolism , Mannose-Binding Lectin/genetics , Mannose-Binding Lectin/blood , Mice , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Inflammation/metabolism , Inflammation/pathology , Female , Humans , Kidney/metabolism , Kidney/pathology , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathologyABSTRACT
BACKGROUND: The indication for treatment of type 1 diabetes(T1D) with the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin has been withdrawn in Europe likely because of concern for diabetic ketoacidosis (DKA). We calculated the incidence of DKA in people with T1D treated with SGLT2i in Denmark. METHODS: Clinical data from adults with T1D in Denmark were collected from nine outpatient clinics. Electronic health records made the search for DKA accurate. RESULTS: From a population of 10.500 we observed 134 people treated with SGLT2i over a total period of 222 patient-years. Of those 72% were female, mean age (SD) was 51.4 (13.6) years and median duration of treatment (median, IQR) with an SGLT2i were 12.0 (6.0-29.0) months. The incidence of DKA was zero%. CONCLUSION: In 134 people with T1D treated with SGLT2i we found that none of the participants developed DKA during the treatment.
