Epidemiology, Pathophysiology and Treatment of Diabetic Nephropathy

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

Linked publications, trials & patents

Abstract

This project, in part, represents an extension of work previously reported as Project Numbers Z01 DK69037, Z01 DK069097 and Z01 DK069000. It also reports on continuation of work previously reported under Project Numbers DK069036-23, DK069063-17, and DK069100-06. All work related to diabetic kidney disease, except for the genetics of diabetic kidney disease, is now reported under this single project. Below are described some representative studies that were published in the past year. A study conducted in collaboration with the University of Michigan and the University of Florida demonstrated the relationship between the serum lipidomic profile and neuropathy in type 2 diabetes. Serum measures of 435 species of serum lipids from 18 different classes were performed and neuropathy was assessed 10 years later with the combined Michigan Neuropathy Screening Instrument examination and questionnaire scores. We found that a serum lipidomics signature that included decreased baseline serum medium-chain acylcarnitines and increased free fatty acids associated with peripheral neuropathy 10 years later. Impaired mitochondrial beta-oxidation was found in those who developed peripheral neuropathy, suggesting the possible need for therapeutics that optimize fatty acid metabolism and enhance mitochondrial beta-oxidation. A study conducted in collaboration with the University Hospital of North Norway, the University of Munich, the University of Colorado, and the University of Michigan identified molecular programs associated with glomerular hyperfiltration in early diabetic kidney disease. A glomerular 1240-gene transcriptional signature identified in those with hyperfiltration was enriched for endothelial stress response signaling genes, with the majority of the transcripts mapped to endothelial and inflammatory cell clusters in kidney single cell transcriptional data. Importantly, these associations were identified through the use of an individuals peak measured GFR to classify hyperfiltration rather than an arbitrary, absolute hyperfiltration threshold that does not allow for individual variations. These findings provide a framework for exploring existing and new therapeutic targets for hyperfiltration in diabetic kidney disease. In collaboration with an international group of investigators, we wrote a comprehensive review describing the course, determinants, and management of youth-onset type 2 diabetes in an invited review published in Nature Reviews Nephrology. In collaboration with the University of Colorado, the University of Michigan, and the University of Arizona, we conducted a study that examined the molecular mechanisms of sodium-glucose cotransporter-2 (SGLT2i) inhibitors in the management of diabetic kidney disease in type 2 diabetes. Transcriptional profiles showed SGLT2 expression exclusively in the proximal tubules, but with transcriptional alterations across nephron segments, and in particular the distal nephron. SGLT2i treatment was associated with suppression of transcripts in the glycolysis, gluconeogenesis, and tricarboxylic acid cycle pathways in the proximal tubule, but the opposite effect in the thick ascending limb. Among those treated with type 2 diabetes treated with SGLT2i, transcripts in the energy-sensitive mTORC1-signaling pathway returned toward levels found in healthy controls in all tubular segments. We proposed that SGLT2i treatment benefited the kidneys by mitigating diabetes-induced metabolic perturbations via suppression of mTORC1 signaling in kidney tubules. In collaboration with the University of Waterloo, the University of Southern California, the University of Colorado, and Poitiers University, we examined the role of permselective defects in the glomerular capillary in the progression of diabetic kidney disease. We demonstrated that early loss of glomerular size selectivity with the expansion of a shunt was strongly associated with progression to kidney failure in American Indians with type 2 diabetes independent of the usual risk factors.