A Role of Glucose Overload in Diabetic Cardiomyopathy in Nonhuman Primates

Abstract

Type 2 diabetes (T2D) plays a major role in the development of heart failure. Patients with T2D have an increased risk to develop HF than healthy subjects, and they always have very poor outcomes and survival rates. However, the underlying mechanisms for this are still unclear. To help develop new therapeutic interventions, well-characterized animal models for preclinical and translational investigations in T2D and HF are urgently needed. Although studies in rodents are more often used, the research findings in rodents have often failed to be translated into humans due to the significant metabolic differences between rodents and humans. Nonhuman primates (NHPs) serve as valuable translational models between basic studies in rodent models and clinical studies in humans. NHPs can recapitulate the natural progress of these diseases in humans and study the underlying mechanism due to their genetic similarity and comparable spontaneous T2D rates to humans. In this review, we discuss the importance of using NHPs models in understanding diabetic cardiomyopathy (DCM) in humans with aspects of correlations between hyperglycemia and cardiac dysfunction progression, glucose overload, and altered glucose metabolism promoting cardiac oxidative stress and mitochondria dysfunction, glucose, and its effect on cardiac resynchronization therapy with defibrillator (CRT-d), the currently available diabetic NHPs models and the limitations involved in the use of NHP models.

Signaling Pathways Related to Oxidative Stress in Diabetic Cardiomyopathy

“…The accumulation of advanced glycation end-products (AGEs) and greater activation of the hexosamine biosynthesis pathway (HBP) have been shown to make an important contribution to mitochondrial damage induced by high glucose concentrations. AGEs are produced non-enzymatically from glycosylation reactions between glucose and protein or lipids, and are involved in the pathogenesis of DCM ( 14 ). The binding of AGEs to the receptor for AGEs (RAGEs) activates the nuclear factor (NF)-κB signaling pathway, which causes inflammatory cells to release a series of proinflammatory cytokines, chemokines, and exosomes.…”

Research('s) Sweet Hearts: Experimental Biomedical Models of Diabetic Cardiomyopathy

“…Spontaneous diabetes has been detected in cynomolgus macaques (Macaca fascicularis), rhesus macaques (Macaca mulatta), black Celebes macaques (Macaca nigra), bonnet macaques (Macaca radiata), Formosan rock macaques (Macaca cyclopis) and pigtailed macaques (Macaca nemestrina) (32). However, mainly the cynomolgus and rhesus macaques have become the object of study (91). Approximately 30 % of cynomolgus macaques develop hyperinsulinemia and glucose tolerance in old age (from 15 years on), and the monkeys with transition from glucose intolerance to T2DM are usually obese.…”