Scientists have discovered novel molecular mechanisms that contribute to recovery from diabetic kidney disease following bariatric surgery in adolescents with type 2 diabetes and obesity, mechanisms that may serve as potential targets for non-surgical treatments for diabetic kidney disease, according to a multi-institutional study published in The Journal of Clinical Investigation.
The number of adolescents with type 2 diabetes and obesity has steadily increased over the last two decades, according to a recent report from the Centers for Disease Control and Prevention, with rates expected to continually rise over the next 40 years.
Adolescents with type 2 diabetes and obesity also are more likely than adults with type 2 diabetes to develop insulin resistance and, consequently, develop diabetic kidney disease more quickly. Diabetic kidney disease develops when chronic high glucose levels induce metabolic, hemodynamic and inflammatory changes that damage the basic filtration units of the kidney, leading to urinary protein loss and progressive loss of kidney filtration functions.
“Type 2 diabetes in kids is a much more aggressive disease than in the adult form,” said Thomas Inge, MD, PhD, the Lydia J. Fredrickson Board Designated Professor of Pediatric Surgery and a co-author of the study. “They progress to a need for insulin therapy five times faster than adults do and the multi-organ damage also comes faster.”
Bariatric surgery has been shown to be an effective treatment for some adolescents with type 2 diabetes. The most common bariatric operation today is sleeve gastrectomy, in which the majority of the stomach is removed and dramatically decreases appetite, resulting in reduced food consumption and calorie intake.
In the current study, the scientists aimed to identify the structural and molecular changes in the kidneys of adolescents with diabetic kidney disease who had undergone vertical sleeve gastrectomy surgery.
Using a combination of metabolic profiling, kidney volume assessment, histological evaluation and single-cell RNA sequencing techniques, the scientists studied kidney biopsy samples from five adolescents with type 2 diabetes and obesity taken before and 12 months after the procedure.
Circulating proteomics with kidney transcriptomics data were compared with data from 64 adolescents with obesity with or without type 2 diabetes who had bariatric surgery and were enrolled in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study, of which Inge is the principal investigator.
All participants lost weight and showed improvements in insulin sensitivity and metabolism following bariatric surgery. Post-surgery, the scientists identified several structural and molecular changes in the kidneys, including a reduction in renal hyperfiltration, total kidney volume and microalbuminuria (the presence of small amounts of the protein albumin in the urine, indicating early-stage kidney damage).
Single-cell RNA sequencing of proximal tubule cells and thick ascending limb cells, which reabsorb filtered nutrients back into the blood, showed molecular changes indicating the downregulation of glycolysis, gluconeogenesis and tricarboxylic acid cycle genes as well as the upregulation of AMPK and FOXO3 proteins, which help maintain cellular energy homeostasis.
The scientists also observed a decrease in metabolic signaling suggesting reduced mTORC1 activity, which under normal conditions helps cells produce proteins to grow and proliferate.
These molecular signatures promote both autophagy and energy conservation in the kidney cells, according to the authors.
“There’s a lot of reprogramming of the kidney cells that seems to be independent of the weight loss and that drives some of the downstream mechanisms that we see in kidney function, reduced inflammation and these energy conservation pathways,” said Justin Ryder, PhD, associate professor of Surgery in the Division of Pediatric General Surgery and of Pediatrics, who was also a co-author of the study.
“The energy conservation that you get with these interventions for surgical patients is believed to be more durable long-term because while you’re restricting the calories, you are doing so in a way that doesn’t evoke a powerful compensatory response to be hungry and eat more to reverse it. That’s what really stood out to me,” said Inge, who is also a professor of Pediatrics.
The findings encourage future studies to evaluate non-surgical treatments that could address or prevent early kidney injury in adolescents with type 2 diabetes and obesity without surgery, according to the authors.
“Some of these specific targets that we identified could potentially be targets for future medications or combinations of medications to treat diabetic kidney disease, potentially without the need for surgery. However, surgery should always be part of the treatment discussion until we have therapies that can mimic the same results that we get from surgery,” Ryder said.
This work is supported, in part, by the National Institute of Diabetes and Digestive and Kidney Diseases grant UM1DK072493.
