# Effects of losartan on mitochondria and prediabetes in rhesus monkeys (Macaca mulatta)

> **NIH NIH R36** · UNIVERSITY OF PUERTO RICO MED SCIENCES · 2020 · $45,320

## Abstract

Project Summary
 Prediabetes is an age-associated condition where glucose levels are not high enough to be diagnosed
as diabetes and is an important risk factor for the development of type 2 diabetes (T2D), cardiovascular
disease, kidney disease and stroke. Compelling evidence supports that oxidative stress and mitochondrial
dysfunction contribute significantly to the development of insulin resistance (IR). Activation of the renin-
angiotensin system (RAS) results in IR and T2D in part through the increased production of mitochondrial
radical oxygen species (mtROS) that may selectively damage mitochondrial DNA (mtDNA) and increase
mitochondrial dysfunction. Thus, mitochondrial dysfunction may play a role in the onset of prediabetes. In
rodents inhibition of RAS ameliorates mitochondrial dysfunction. However, the molecular mechanisms of RAS
inhibition by angiotensin receptor (AT1) blockers on precluding prediabetes in humans remain unknown. We
show that losartan significantly decreases insulin levels in prediabetic rhesus monkeys and glucose levels in
healthy/non-diabetic monkeys after 12 months of treatment. Thus, losartan is exerting beneficial effects in both
prediabetic and healthy middle-aged rhesus monkeys. In addition, our results show that healthy middle-age
monkeys exhibit increased levels of nDNA damage compared with young animals, and that treatment with
losartan significantly reduces lesion numbers to levels similar to young animals. These findings suggest that
losartan reverses the effects of aging on nuclear DNA damage. We will test the hypothesis that inhibition of
RAS reverses prediabetes by stimulating the insulin signaling pathway and by preventing mitochondrial
damage and mitochondrial dysfunction. To test our hypothesis we will use skeletal muscle and adipose tissue
from middle-age prediabetic rhesus monkeys (Macaca mulatta). This study may uncover mechanisms to delay
or prevent IR/T2D and will focus on a potential paradigmatic change in the current clinical application of RAS
blockade early in the prodromal phase of T2D.

## Key facts

- **NIH application ID:** 9877576
- **Project number:** 1R36AG065725-01
- **Recipient organization:** UNIVERSITY OF PUERTO RICO MED SCIENCES
- **Principal Investigator:** Janice Griselle Lozada Delgado
- **Activity code:** R36 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,320
- **Award type:** 1
- **Project period:** 2020-01-15 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9877576

## Citation

> US National Institutes of Health, RePORTER application 9877576, Effects of losartan on mitochondria and prediabetes in rhesus monkeys (Macaca mulatta) (1R36AG065725-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9877576. Licensed CC0.

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