Dietary Resistant Starch, RAS Inhibitor Demonstrate Protective Effect on Kidney for Type 2 Diabetes

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In diabetic rats, investigators found a decrease in urine biomarkers and expression of proteins that play a part in renin-angiotensin system (RAS).

A combination of dietary resistant starch (RS) and renin-angiotensin system (RAS) inhibitors protected kidney integrity in rats who had type 2 diabetes (T2D), according to results of a study presented at 2024 American Physiology Summit, the conference of The American Physiological Society, held from April 4 to April 7, 2024, in Long Beach, California. Investigators found that there was a “decrease of biomarkers in the urine and expression of proteins that play a part in the RAS and increase in serum biomarkers and expression of glomerular structural proteins,” according to the abstract of the study.1

Medical concept on virtual screen | Image Credit: WrightStudio - stock.adobe.com

Image Credit: WrightStudio - stock.adobe.com

“Our lab’s previous studies suggested that a diet high in [RS], where 35% to 50% of the carbohydrates were resistant to digestion, prevented urinary vitamin D and protein loss in both type I and type II diabetic animals, but the cellular mechanism remained unknown,” Claudia Carrillo, graduate student at Iowa State University and presenting author, said in an email interview with Pharmacy Times®. “Our group chose to investigate the combined dietary and drug intervention to provide a more practical dosage of RS than before, with only 5% to 10% of the carbohydrates being resistant to digestion, with a blood pressure medication that has been shown to elicit the same effect on kidney health in the literature.”

Carrillo added that the goal of the study was to determine if RS could elicit kidney protection by regulating RAS as a drug-diet intervention for T2D. The investigators hypothesized that the combination would decrease renal biomarkers that were associated complications and progression of disease.1

Investigators of the study used 4-week-old Zucker Diabetic Fatty (ZDF) rates and Zucker lean rats and were acclimated for 1 week. The ZDF rats were randomly assigned to a diet of AIN-93G diet with 0% resistant starch (RS) (the control arm), AIN-93G diet with 5% RS, or AIN-93 with 10% resistant starch for a total of 8 weeks, according to the study abstract. At 6 weeks, investigators randomly assigned daily intraperitoneal injection of captopril in saline water and ascorbic acid or the placebo solution (containing just the vehicle) until the end of the 8 weeks. The lean rats received the control RS and daily placebo injection for the same timeframe.Urine, feces, and tissue samples were gathered.Urine and serum samples were used to detect biomarkers, and investigators measured 25-hydroxy-vitamin D, albumin, and creatinine. Protein was extracted from kidney samples.1

“When kidney integrity and health is compromised, especially during diabetic nephropathy, we see an increase of protein, particularly albumin, and vitamin D loss in the urine,” Carrillo said. “A decrease of urinary vitamin D, along with an increase in nephrin protein expression and other proteins related to kidney function and the RAS, suggest that the kidney health is being protected by our intervention.”

For the ZDF receiving 10% and the captopril injection, investigators found that they had a decrease of 62.5% in urinary protein creatinine ratio, 29% in albumin levels, and 18% in 25-hydroxy vitamin D level compared to the control group. Further, the same cohort also had a 62% increase in serum 25-hydroxy vitamin D levels and the 5% and captopril cohort at 8.6% in 1,25-dihydroxy-vitamin D levels. The 10% group also had an increase of 5.5% in relative abundance of nephrin and a decrease in angiotensin II receptor 1 and aldosterone synthase relative abundance at 4.9% and 33.3%, respectively, when compared to the control group.1

“Nephrin angiotensin II receptor I and aldosterone synthase are all proteins expressed in the kidney that are impacted by the health and function of the kidney. Nephrin is a renal structural protein expressed in the filtration barrier so higher levels indicate better kidney filtration. Aldosterone synthase is the enzyme involved in the biosynthesis of the hormone aldosterone, which is secreted by the adrenal cortex of the kidney in response to blood pressure levels via signaling of the RAS,” Carrillo said.

She added that lower levels of aldosterone synthase show less activity for RAS signaling. When Nephrin angiotensin II receptor I regulate aldosterone secretion at binding, the result can be an elevation in blood pressure. When it decreases, like in the study, indicates lower activity of angiotensin II, according to Carrillo.

Although other mechanisms cannot be ruled out, the results showed that the effects of nephroprotective occurs through the modulation of proteins and genes in RAS, Carrillo said.

“One thing our lab has recurrently seen in our RS interventions with diabetic animals are enlarged livers and abnormal triglyceride levels. Though this could be associated with the disease state of the animal, or the rodent model we use, our group is currently performing further analyses to rule out that the RS intervention is not what is causing this effect on the liver and triglyceride levels,” Carrillo said.

Key Takeaways

  1. The combination of resistant starch (RS), a type of dietary fiber, and a blood pressure medication (captopril) offered kidney protection in rats with type 2 diabetes.
  2. The intervention reduced urinary protein and vitamin D loss, while increasing serum vitamin D levels - all indicators of improved kidney health.
  3. The researchers observed changes in proteins associated with the renin-angiotensin system (RAS), suggesting the intervention may work through this pathway to protect the kidneys.

Carrillo added that their lab specializes in pre-clinical models, but the investigators are hoping to collaborate with other teams in the future to bring these results to a human population. This summer, the investigators will conduct a follow-up study for rates with type 1 diabetes to determine if the results could also be seen for a model that is insulin deficient. Other studies planned include how other fibers, including whole oats, could play a role in kidney health for diabetes.

As for limitations, Carrillo said that there were 7 intervention groups with 8 rats in a group, which is considered the minimum number of animals needed for statistical power but can still be considered a small sample size.

“Diabetic kidney disease is one of the most prevalent diabetes complications and the leading cause of end stage kidney failure worldwide. Thus, investigating pathological mechanisms and dietary interventions that can help decrease the risk of these is crucial to understanding the disease better and improving people’s health,” Carrillo said.

Reference

Carrillo C. Low to moderate doses of dietary resistant starch and a renin angiotensin system inhibitor exhibit nephroprotective effects through similar mechanisms in a preclinical model of diabetes. Presented at: American Physiology Summit. April 2024. Long Beach, California.

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