Type 2 diabetes mellitus alters cardiac mitochondrial content and function in a non-obese mice model

Abstract

Type 2 diabetes mellitus (T2DM) is associated with an increase of premature appearance of several disorders such as cardiac complications. Thus, we test the hypothesis that a combination of a high fat diet (HFD) and low doses of streptozotocin (STZ) recapitulate a suitable mice model of T2DM to study the cardiac mitochondrial disturbances induced by this disease. Animals were divided in 2 groups: the T2DM group was given a HFD and injected with 2 low doses of STZ, while the CNTRL group was given a standard chow and a buffer solution. The combination of HFD and STZ recapitulate the T2DM metabolic profile showing higher blood glucose levels in T2DM mice when compared to CNTRL, and also, insulin resistance. The kidney structure/function was preserved. Regarding cardiac mitochondrial function, in all phosphorylative states, the cardiac mitochondria from T2DM mice presented reduced oxygen fluxes when compared to CNTRL mice. Also, mitochondria from T2DM mice showed decreased citrate synthase activity and lower protein content of mitochondrial complexes. Our results show that in this non-obese T2DM model, which recapitulates the classical metabolic alterations, mitochondrial function is impaired and provides a useful model to deepen study the mechanisms underlying these alterations.

Early exposure to high-fat diet impairs central and peripheral metabolic function: Impacts on cognition and mitochondrial function

“…Herein, we showed that feeding juvenile mice with HFD from weaning to adulthood, induce memory impairment and hippocampal dysfunction, as well as bioenergetic dysfunction in metabolic active tissues, leading to glucose intolerance, peripheral (BAT and liver) and central (hippocampus) mitochondrial dysfunction, despite not inducing overweight/obesity and changes in lipid profile. We used a combination of HFD with low STZ dose in order to increase the metabolic disturbance, consistent with high glucose levels and insulin resistance described elsewhere (Yurre et al, 2020). Similar dietary intervation starting from weaning also induced metabolic changes, such as dyslipidemia, hyperglycemia, and changes in leptin and insulin levels, in absence of obesity in juvenile mice (Boitard et al, 2012; Vinuesa et al, 2016).…”

“…Interestingly, our data did not indicate any cardiac bioenergetic change in juvenile HFD mice. Adult mice submitted to same hyperglycemic-HFD model, presented changes in cardiac mitochondrial function after normalizing the O 2 consumption by the citrate synthase activity, a notable marker of mitochondrial content, suggesting that the cardiac bioenergetic alterations were associated with reduced mitochondrial content, not mitochondrial dysfunction (Yurre et al, 2020).…”

“…Mice were fed with a standard rodent diet (CD; 15% fat) or a high-fat diet (HFD; 48% fat) (both from PRAGSOLUÇÕES Biociências®) for seven weeks (see complete nutritional composition on Table S1). To boost the metabolic changes, two consecutive intraperitoneal injections of streptozotocin (Sigma-Aldrich®) (40mg/kg) were administered to the HFD group, two weeks after the beginning of the diet (Yurre et al, 2020). Mice from CD group received citrate buffer 0.1M (vehicle).…”

Exacerbated post‐infarct pathological myocardial remodelling in diabetes is associated with impaired autophagy and aggravated NLRP3 inflammasome activation

“…Mice model of T2DM were induced by once daily Streptozotocin (STZ) 50 mg/kg by intraperitoneal injection (three continuous days) 15 . To induce insulin resistance, DM mice were fed with a high‐fat diet (D12492, Research Diets, New Brunswick, NJ, USA) during the study 16 . After 3 days of STZ administration, MI was induced surgically by chronic ligation of the left anterior descending coronary artery, as described previously 6 .…”

“… 15 To induce insulin resistance, DM mice were fed with a high‐fat diet (D12492, Research Diets, New Brunswick, NJ, USA) during the study. 16 After 3 days of STZ administration, MI was induced surgically by chronic ligation of the left anterior descending coronary artery, as described previously. 6 Mice in control group underwent sham‐operated surgery, but the left anterior descending coronary artery was not ligated.…”