Autophagic adaptations in diabetic cardiomyopathy differ between type 1 and type 2 diabetes

Abstract

Abbreviations: AMPK, AMP-activated protein kinase; CTSD, cathepsin D; DM, diabetes mellitus; GFP, green fluorescent protein; HBA1c, glycated hemoglobin a 1; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; LV, left ventricular; MTOR, mechanistic target of rapamycin; SIRT1, sirtuin 1; Mn-SOD, superoxide dismutase 2, mitochondrial; STZ, streptozotocin; SQSTM1/p62, sequestosome 1.Little is known about the association between autophagy and diabetic cardiomyopathy. Also unknown are possible distinguishing features of cardiac autophagy in type 1 and type 2 diabetes. In hearts from streptozotocin-induced type 1 diabetic mice, diastolic function was impaired, though autophagic activity was significantly increased, as evidenced by increases in microtubule-associated protein 1 light chain 3/LC3 and LC3-II/-I ratios, SQSTM1/p62 (sequestosome 1) and CTSD (cathepsin D), and by the abundance of autophagic vacuoles and lysosomes detected electronmicroscopically. AMP-activated protein kinase (AMPK) was activated and ATP content was reduced in type 1 diabetic hearts. Treatment with chloroquine, an autophagy inhibitor, worsened cardiac performance in type 1 diabetes. In addition, hearts from db/db type 2 diabetic model mice exhibited poorer diastolic function than control hearts from db/C mice. However, levels of LC3-II, SQSTM1 and phosphorylated MTOR (mechanistic target of rapamycin) were increased, but CTSD was decreased and very few lysosomes were detected ultrastructurally, despite the abundance of autophagic vacuoles. AMPK activity was suppressed and ATP content was reduced in type 2 diabetic hearts. These findings suggest the autophagic process is suppressed at the final digestion step in type 2 diabetic hearts. Resveratrol, an autophagy enhancer, mitigated diastolic dysfunction, while chloroquine had the opposite effects in type 2 diabetic hearts. Autophagy in the heart is enhanced in type 1 diabetes, but is suppressed in type 2 diabetes. This difference provides important insight into the pathophysiology of diabetic cardiomyopathy, which is essential for the development of new treatment strategies.

Mitochondrial quality control in the diabetic heart

“…Another recent study claimed an increased autophagy in STZ diabetic mouse hearts as shown by increased LC3-II levels and GFP-LC3 puncta. However, chloroquine treatment reduced rather than further increased the LC3-II levels[129], suggesting that cardiac autophagic flux was actually inhibited. Cardiac autophagy is also reduced in several forms of metabolic syndrome and type 2 diabetic animal models[127–129], but it is not as consistent since other studies reported either increased[130] or unchanged autophagy in the type 2 diabetic hearts[127, 128].…”

“…However, chloroquine treatment reduced rather than further increased the LC3-II levels[129], suggesting that cardiac autophagic flux was actually inhibited. Cardiac autophagy is also reduced in several forms of metabolic syndrome and type 2 diabetic animal models[127–129], but it is not as consistent since other studies reported either increased[130] or unchanged autophagy in the type 2 diabetic hearts[127, 128]. These different conclusions could be attributed partly to the fact that not all studies have followed the suggested guidelines to determine autophagic flux [84, 85].…”

Activation of IGF-1 receptors and Akt signaling by systemic hyperinsulinemia contributes to cardiac hypertrophy but does not regulate cardiac autophagy in obese diabetic mice

“…Thus, inhibition of autophagy through Rheb overexpression and mTORC1 activation in the heart increased infarct size following ischemia [16], suggesting a protective role. Similarly, enhancement of autophagy using resveratrol restored cardiac diastolic function, while inhibition of autophagy using chloroquine worsened both cardiac diastolic and systolic function in leptin receptor-deficient ( db/db ) mice [39]. Furthermore, autophagy insufficiency occurs in sustained cardiac hypertrophy as seen in chronic left ventricular hypertrophy and recent reports suggest that improving autophagy could alleviate cardiac hypertrophy [47].…”

Myocardial stress and autophagy: mechanisms and potential therapies

“…In support of the contention that autophagy plays a beneficial role in the diabetic heart, studies have shown that activation of autophagy via fenofibrate, 132 metformin, 123, 133 ghrelin, 134 or resveratrol, 135 rescues diabetes-induced cardiac dysfunction; and inhibition of autophagy via chloroquine 135 exacerbates diabetes-induced diastolic dysfunction. In contrast, other studies have shown that autophagy may play a detrimental role in the diabetic heart: inhibition of autophagy via Epigallocatechin-3-gallate, 136 chloroquine, 137 global Beclin1 haploinsufficiency 127 or global Atg16L deficiency 127 rescues diabetes-induced cardiac pathology.…”