A rat model of enhanced glycation mimics cardiac phenotypic components of human type 2 diabetes : A translational study using MRI.

BACKGROUND: The success of translational research depends on how well animal models mimic the pathophysiology of the human phenotype, and on the identification of disease mechanisms such as enhanced glycation. METHODS: Here, we studied cardiac MRI and metabolic phenotypes in human type 2 diabetes (N = 106; 55 patients+51 controls) and animal models with distinct levels of fat diet and end glycation products, to model the role of these factors in the cardiac phenotype. We included four groups of rats, designed to evaluate the role of lipid load and glucotoxicity in cardiac function and to correlate these with the cardiac phenotype observed in humans. We also aimed to assess into which extent phenotypes were related to specific risk factors. RESULTS: Stroke Volume (SV) and Peak Filling Rate (PFR) measures were similarly discriminative both in humans and animal models, particularly when enhanced glycation was present. Factorial analysis showed that reduction of multidimensionality into common main explanatory factors, in humans and animals, revealed components that equally explained the variance of cardiac phenotypes (87.62% and 83.75%, respectively). One of the components included, both in humans and animals, SV, PFR and peak ejection rate (PER). The other components included in both humans and animals are the following: ESV (end systolic volume), left ventricular mass (LVM) and ejection fraction (EF). These components were useful for between group discrimination. CONCLUSIONS: We conclude that animal models of enhanced glycation and human type 2 diabetes share a striking similarity of cardiac phenotypic components and relation with metabolic changes, independently of fact content in the diet, which reinforces the role of glucose dysmetabolism in left ventricular dysfunction and provides a potentially useful approach for translational research in diabetes, in particular when testing new therapies early on during the natural history of this condition.

High-fat diet induces a neurometabolic state characterized by changes in glutamate and N-acetylaspartate pools associated with early glucose intolerance: An in vivo multimodal MRI study.

BACKGROUND: Type-2 diabetes mellitus (T2DM) is a metabolic disorder with a broad range of complications in the brain that depend on the conditions that precede its onset, such as obesity and metabolic syndromes. It has been suggested that neurotransmitter and metabolic perturbations may emerge even before the early stages of T2DM and that high-caloric intake could adversely influence the brain in such states. Notwithstanding, evidence for neurochemical and structural alterations in these conditions are still sparse and controversial. PURPOSE: To evaluate the influence of high-fat diet in the neurochemical profile and structural integrity of the rodent brain. STUDY TYPE: Prospective. SUBJECTS: Wistar rats (n = 12/group). FIELD STRENGTH/SEQUENCE: A PRESS, ISIS, RARE, and EPI sequences were performed at 9.4T. ASSESSMENT: Neurochemical and structural parameters were assessed by magnetic resonance spectroscopy, voxel-based morphometry, volumetry, and diffusion tensor imaging. STATISTICAL TESTS: Measurements were compared through Student and Mann-Whitney tests. Pearson correlation was used to assess relationships between parameters. RESULTS: Animals submitted to high-caloric intake gained weight (P = 0.003) and developed glucose intolerance (P < 0.001) but not hyperglycemia. In the hippocampus, the diet induced perturbations in glutamatergic metabolites reflected by increased levels of glutamine (P = 0.016) and glutamatergic pool (Glx) (P = 0.036), which were negatively correlated with glucose intolerance (glutamine, r = -0.804, P = 0.029), suggesting a link with neurometabolic dysregulation. At caudate-putamen, high-fat diet led to a surprising increase in the pool of N-acetylaspartate (P = 0.028). A relation with metabolic changes was again suggested by the negative correlation between glucose intolerance and levels of glutamatergic metabolites in this region (glutamate, r = -0.845, P = 0.014; Glx, r = -0.834, P = 0.020). Neither changes in phosphate compounds nor major structural alterations were observed for both regions. DATA CONCLUSION: We found evidence that high-fat diet-induced obesity leads to distinct early and region-specific metabolic/neurochemical imbalances in the presence of early glucose intolerance even when structural alterations or T2DM are absent. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018.

Methylglyoxal-induced glycation changes adipose tissue vascular architecture, flow and expansion, leading to insulin resistance.

Microvascular dysfunction has been suggested to trigger adipose tissue dysfunction in obesity. This study investigates the hypothesis that glycation impairs microvascular architecture and expandability with an impact on insulin signalling. Animal models supplemented with methylglyoxal (MG), maintained with a high-fat diet (HFD) or both (HFDMG) were studied for periepididymal adipose (pEAT) tissue hypoxia and local and systemic insulin resistance. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to quantify blood flow in vivo, showing MG-induced reduction of pEAT blood flow. Increased adipocyte size and leptin secretion were observed only in rats feeding the high-fat diet, without the development of hypoxia. In turn, hypoxia was only observed when MG was combined (HFDMG group), being associated with impaired activation of the insulin receptor (Tyr1163), glucose intolerance and systemic and muscle insulin resistance. Accordingly, the adipose tissue angiogenic assay has shown decreased capillarization after dose-dependent MG exposure and glyoxalase-1 inhibition. Thus, glycation impairs adipose tissue capillarization and blood flow, hampering its expandability during a high-fat diet challenge and leading to hypoxia and insulin resistance. Such events have systemic repercussions in glucose metabolism and may lead to the onset of unhealthy obesity and progression to type 2 diabetes.