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Mitochondria play a pivotal role in energy metabolism, but whether insulin signaling per se could regulate mitochondrial function has not been identified yet. To investigate whether mitochondrial function is regulated by insulin signaling, we analyzed muscle and liver of insulin receptor (IR)+/--insulin receptor substrate-1 (IRS-1)+/- double hetero...
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... mice demonstrated less body weight and decreased fasting blood glucose levels at both ages (6 and 12 months old) compared to age-matched wild-type (wt) controls (Table 1). Body weight (BW), fasting blood glucose (BG), random fed serum insulin, leptin, and insulin-like growth factor 1 (IGF-1) levels, mo denotes the age of mice in months. ...
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... insulin was elevated, but insulin-like growth factor 1 (IGF-1) remained unchanged in IR-IRS1dh mice (Table 1). Serum leptin level was lower in 12-month-old IR-IRS1dh mice compared to age-matched controls (Table 1). ...
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... insulin was elevated, but insulin-like growth factor 1 (IGF-1) remained unchanged in IR-IRS1dh mice (Table 1). Serum leptin level was lower in 12-month-old IR-IRS1dh mice compared to age-matched controls (Table 1). To study glucose metabolism, we performed glucose and insulin tolerance tests. ...
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... +/− -IRS-1 +/− double heterozygous (IR-IRS1dh) mice showed attenuated insulin signaling in skeletal muscle and liver [12], which caused a pancreatic β-cell hyperplasia [9,11], in parallel with the elevated insulin levels (Table 1). These data suggest that the overproduction of insulin could be a compensatory mechanism counteracting peripheral insulin resistance in IR-IRS1dh mice, which also led to lower fasting blood glucose levels [9]. ...
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Citations
... Later, no changes were observed in the protein levels of PGC1α, complex I, II and V of the ETC in those with insulin resistance in a study which induced a transitory insulin resistance by overfeeding the sedentary non-obese individuals, showing that insulin resistance occurred ahead of mitochondrial dysfunction (Sergi et al., 2019). Furthermore, genetic deletion of IRS1/2 in mice exhibiting liver mitochondrial dysfunction (Franko et al., 2017), which underlined the direct association between insulin resistance and mitochondrial dysfunction. Further study revealed that insulin resistance suppressed the transcription factor foxhead box O1(FOXO1), whose downstream protein directly disrupted the mitochondrial ETC complexes (Cheng et al., 2009). ...
Energic deficiency of cardiomyocytes is a dominant cause of heart failure. An antianginal agent, trimetazidine improves the myocardial energetic supply. We presumed that trimetazidine protects the cardiomyocytes from the pressure overload-induced heart failure through improving the myocardial metabolism. C57BL/6 mice were subjected to transverse aortic constriction (TAC). After 4 weeks of TAC, heart failure was observed in mice manifested by an increased left ventricular (LV) chamber dimension, an impaired LV ejection fraction evaluated by echocardiography analysis, which were significantly restrained by the treatment of trimetazidine. Trimetazidine restored the mitochondrial morphology and function tested by cardiac transmission electron microscope and mitochondrial dynamic proteins analysis. Positron emission tomography showed that trimetazidine significantly elevated the glucose uptake in TAC mouse heart. Trimetazidine restrained the impairments of the insulin signaling in TAC mice and promoted the translocation of glucose transporter type IV (GLUT4) from the storage vesicle to membrane. However, these cardioprotective effects of trimetazidine in TAC mice were notably abolished by compound C (C.C), a specific AMPK inhibitor. The enlargement of neonatal rat cardiomyocyte induced by mechanical stretch, together with the increased expression of hypertrophy-associated proteins, mitochondria deformation and dysfunction were significantly ameliorated by trimetazidine. Trimetazidine enhanced the isolated cardiomyocyte glucose uptake in vitro. These benefits brought by trimetazidine were also removed with the presence of C.C. In conclusion, trimetazidine attenuated pressure overload-induced heart failure through improving myocardial mitochondrial function and glucose uptake via AMPK.
... Increased intracellular lipid accumulation resulting from reduced oxidative capacity of mitochondria in liver was previously reported in IR rats. [46][47][48] On the other hand, higher resting metabolic rate has also been reported in mice of HFD induced IR compared with chow fed mice. [49] In addition, higher mitochondrial respiration was observed in liver of obese subjects with non-alcoholic fatty liver diseases compared with lean subjects, while significant higher proton leak was detected in obese subjects with non-alcoholic steatohepatitis but not obese subjects with non-alcoholic fatty liver diseases and lean individuals. ...
Scope
We aimed at evaluating the effect of dietary ellagic acid (EA) and its microbial metabolite urolithin A (UA) on glucose metabolism and insulin resistance (IR) in mice with diet‐induced IR.
Methods and results
DBA2J mice were fed a high fat/high sucrose diet (HF/HS) for 8 weeks to induce IR and then 0.1% EA, UA, or EA and UA combined (EA+UA) were added to the HF/HS‐diet for another 8 weeks. UA significantly decreased fasting glucose and increased serum adiponectin compared with HF/HS‐controls. During intraperitoneal insulin tolerance test, EA+UA significantly improved insulin‐mediated glucose lowering effects at 15 and 120 min and reduced blood triglycerides compared with HF/HS‐controls. Serum free fatty acids were significantly decreased by EA, UA and EA+UA. We observed differential expression of genes related to mitochondrial function by EA, UA and EA+UA in liver and skeletal muscle. Primary hepatocytes from IR‐mice had higher proton leak, basal and ATP‐linked oxygen consumption rates compared with healthy controls. EA and EA+UA but not UA reduced the proton leak in hepatocytes from IR‐mice.
Conclusion
EA and UA induced different metabolic benefits in HF/HS diet induced IR mice. The effects of EA and UA on mitochondrial function suggest a potentially novel mechanism modulating metabolism.
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... 8 In this scenario, one of the most popular hypotheses states that mitochondrial dysfunction and oxidative stress, resulting from an increased production of mitochondrial ROS in response to hyperglycemia, are early and crucial events involved in the multiorgan damage associated to diabetes and/or obesity. 63,64 Under the rationale that mitochondrial dysfunction in peripheral tissues is an intervening factor for impaired insulin signaling, 65,66 Peng et al. 67 looked into whether and how glucose levels, comparable to the extracellular levels found in diabetic brains, affect insulin signaling and mitochondrial function in cultured cortical neurons. In close agreement with observations made on peripheral organs, authors observed that hyperglycemia-induced mitochondrial function decline is the initiating step contributing to the alteration of insulin signaling in primary cortical neurons. ...
In developed and developing countries, the adoption of high calorie diets and a sedentary lifestyle have been major contributors in the inflating number of obese and/or type 2 diabetic (T2D) individuals. In spite of the strong will to promote and increase the awareness of the importance of an active healthy life and aging, the current obesity and T2D epidemics across the world show no signs of dwindling. This comes with severe consequences, including an increased likelihood for people to suffer from cognitive deficits and neurodegenerative maladies. In this framework, as research progresses, it is becoming clear that mitochondrial anomalies are inextricably implicated in glucose metabolism and insulin action (deficiency and/or resistance) abnormalities that characterize T2D and obesity, and associated complications. In this chapter, we address how obesity and T2D are capable of disrupting nervous system homeostasis. Also, we highlight how obesity and T2D-related alterations in mitochondrial function can impair neuronal and brain function, increasing the risk of neurodegenerative events. Special focus will be given to peripheral diabetic neuropathy and to two major neurodegenerative illnesses, Alzheimer’s and Parkinson’s diseases.
Diabetes and Alzheimer’s disease are common chronic illnesses in the United States and lack clearly demonstrated therapeutics. Mitochondria, the “powerhouse of the cell”, is involved in the homeostatic regulation of glucose, energy, and reduction/oxidation reactions. The mitochondria has been associated with the etiology of metabolic and neurological disorders through a dysfunction of regulation of reactive oxygen species. Mitochondria-targeted chemicals, such as the Szeto-Schiller-31 peptide, have advanced therapeutic potential through the inhibition of oxidative stress and the restoration of normal mitochondrial function as compared to traditional antioxidants, such as vitamin E. In this article, we summarize the pathophysiological relevance of the mitochondria and the beneficial effects of Szeto-Schiller-31 peptide in the treatment of Diabetes and Alzheimer’s disease.
Muscle stem cells undergo a dramatic metabolic switch to oxidative phosphorylation during differentiation, which is achieved by massively increased mitochondrial activity. Since expression of the muscle-specific miR-1/133a gene cluster correlates with increased mitochondrial activity during muscle stem cell (MuSC) differentiation, we examined the potential role of miR-1/133a in metabolic maturation of skeletal muscles in mice. We found that miR-1/133a downregulate Mef2A in differentiated myocytes, thereby suppressing the Dlk1-Dio3 gene cluster, which encodes multiple microRNAs inhibiting expression of mitochondrial genes. Loss of miR-1/133a in skeletal muscles or increased Mef2A expression causes continuous high-level expression of the Dlk1-Dio3 gene cluster, compromising mitochondrial function. Failure to terminate the stem cell-like metabolic program characterized by high-level Dlk1-Dio3 gene cluster expression initiates profound changes in muscle physiology, essentially abrogating endurance running. Our results suggest a major role of miR-1/133a in metabolic maturation of skeletal muscles but exclude major functions in muscle development and MuSC maintenance.
