Impaired Insulin Signaling is Associated with Hepatic Mitochondrial Dysfunction in IR+/−-IRS-1+/− Double Heterozygous (IR-IRS1dh) Mice

Saturated free fatty acids have been implicated in the increase of oxidative stress, mitochondrial dysfunction, apoptosis, and insulin resistance seen in type 2 diabetes. The purpose of this study was to determine whether palmitate-induced mitochondrial DNA (mtDNA) damage contributed to increased oxidative stress, mitochondrial dysfunction, apoptosis, impaired insulin signaling, and reduced glucose uptake in skeletal muscle cells. Adenoviral vectors were used to deliver the DNA repair enzyme human 8-oxoguanine DNA glycosylase/(apurinic/apyrimidinic) lyase (hOGG1) to mitochondria in L6 myotubes. After palmitate exposure, we evaluated mtDNA damage, mitochondrial function, production of mitochondrial reactive oxygen species, apoptosis, insulin signaling pathways, and glucose uptake. Protection of mtDNA from palmitate-induced damage by overexpression of hOGG1 targeted to mitochondria significantly diminished palmitate-induced mitochondrial superoxide production, restored the decline in ATP levels, reduced activation of c-Jun N-terminal kinase (JNK) kinase, prevented cells from entering apoptosis, increased insulin-stimulated phosphorylation of serine-threonine kinase (Akt) (Ser473) and tyrosine phosphorylation of insulin receptor substrate-1, and thereby enhanced glucose transporter 4 translocation to plasma membrane, and restored insulin signaling. Addition of a specific inhibitor of JNK mimicked the effect of mitochondrial overexpression of hOGG1 and partially restored insulin sensitivity, thus confirming the involvement of mtDNA damage and subsequent increase of oxidative stress and JNK activation in insulin signaling in L6 myotubes. Our results are the first to report that mtDNA damage is the proximal cause in palmitate-induced mitochondrial dysfunction and impaired insulin signaling and provide strong evidence that targeting DNA repair enzymes into mitochondria in skeletal muscles could be a potential therapeutic treatment for insulin resistance.

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Impaired insulin signaling accelerates cardiac mitochondrial dysfunction after myocardial infarction

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2009.02.014 ◽

2009 ◽

Vol 46 (6) ◽

pp. 910-918 ◽

Cited By ~ 47

Author(s):

Sandra Sena ◽

Ping Hu ◽

Dongfang Zhang ◽

Xiaohui Wang ◽

Benjamin Wayment ◽

...

Keyword(s):

Myocardial Infarction ◽

Mitochondrial Dysfunction ◽

Insulin Signaling ◽

Impaired Insulin

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Impaired Insulin Signaling Affects Renal Organic Anion Transporter 3 (Oat3) Function in Streptozotocin-Induced Diabetic Rats

PLoS ONE ◽

10.1371/journal.pone.0096236 ◽

2014 ◽

Vol 9 (5) ◽

pp. e96236 ◽

Cited By ~ 15

Author(s):

Anusorn Lungkaphin ◽

Phatchawan Arjinajarn ◽

Anchalee Pongchaidecha ◽

Chutima Srimaroeng ◽

Lisa Chatsudthipong ◽

...

Keyword(s):

Insulin Signaling ◽

Organic Anion ◽

Diabetic Rats ◽

Organic Anion Transporter ◽

Anion Transporter ◽

Impaired Insulin ◽

Organic Anion Transporter 3

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CaMKIV limits metabolic damage through induction of hepatic autophagy by CREB in obese mice

Journal of Endocrinology ◽

10.1530/joe-19-0251 ◽

2020 ◽

Vol 244 (2) ◽

pp. 353-367 ◽

Cited By ~ 2

Author(s):

Jiali Liu ◽

Yue Li ◽

Xiaoyan Zhou ◽

Xi Zhang ◽

Hao Meng ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Inflammatory Response ◽

Mitochondrial Dysfunction ◽

High Fat Diet ◽

Insulin Action ◽

Hepatic Insulin Resistance ◽

Obese Mice ◽

High Fat ◽

Impaired Insulin

High-fat diet (HFD) not only induces insulin resistance in liver, but also causes autophagic imbalance and metabolic disorders, increases chronic inflammatory response and induces mitochondrial dysfunction. Calcium/calmodulin-dependent protein kinase IV (CaMKIV) has recently emerged as an important regulator of glucose metabolism and skeletal muscle insulin action. Its activation has been involved in the improvement of hepatic and adipose insulin action. But the underlying mechanism is not fully understood. In the present study, we aimed to address the direct effects of CaMKIV in vivo and to evaluate the potential interaction of impaired insulin sensitivity and autophagic disorders in hepatic insulin resistance. Our results indicated obese mice receiving CaMKIV showed decreased blood glucose and serum insulin and improved insulin sensitivity as well as increased glucose tolerance compared with vehicle injection. Meanwhile, defective hepatic autophagy activity, impaired insulin signaling, increased inflammatory response and mitochondrial dysfunction in liver tissues which are induced by high-fat diet were also effectively alleviated by injection of CaMKIV. Consistent with these results, the addition of CaMKIV to the culture medium of BNL cl.2 hepatocytes markedly restored palmitate-induced hepatic insulin resistance and autophagic imbalance. These effects were nullified by blockade of cyclic AMP response element-binding protein (CREB), indicating the causative role of CREB in action of CaMKIV. Our findings suggested that CaMKIV restores hepatic autophagic imbalance and improves impaired insulin sensitivity via phosphorylated CREB signaling pathway, which may offer novel opportunities for treatment of obesity and diabetes.

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Uterine Insulin Sensitivity Defects Induced Embryo Implantation Loss Associated with Mitochondrial Dysfunction-Triggered Oxidative Stress

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6655685 ◽

2021 ◽

Vol 2021 ◽

pp. 1-18

Author(s):

Meixia Chen ◽

Jie Li ◽

Bo Zhang ◽

Xiangfang Zeng ◽

Xiangzhou Zeng ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Sensitivity ◽

Mitochondrial Dysfunction ◽

Insulin Signaling ◽

Embryo Implantation ◽

Fetal Loss ◽

Enrichment Analysis ◽

Uterine Receptivity ◽

Resistant Mouse

Scope. Implantation loss is a considerable cause of early pregnancy loss in humans and mammalian animals. It is not addressed how proliferative uterine defects implicate in implantation loss. Methods and Results. Herein, a comprehensive proteomic analysis was conducted on proliferative endometria from sows with low and normal reproductive performance (LRP and NRP, respectively). Enrichment analysis of differentially expressed proteins revealed alterations in endometrial remodeling, substance metabolism (mainly lipid, nitrogen, and retinol metabolism), immunological modulation, and insulin signaling in LRP sows. Importantly, aberrant lipid metabolite accumulation and dysregulation of insulin signaling were coincidently confirmed in endometria of LPR sows, proving an impaired insulin sensitivity. Furthermore, established high-fat diet- (HFD-) induced insulin-resistant mouse models revealed that uterine insulin resistance beginning before pregnancy deteriorated uterine receptivity and decreased implantation sites and fetal numbers. Mitochondrial biogenesis and fusion were decreased, and reactive oxygen species was overproduced in uteri from the HFD group during the implantation period. Ishikawa and JAR cells directly demonstrated that oxidative stress compromised implantation in vitro. Conclusions. This study demonstrated that uterine insulin sensitivity impairment beginning before pregnancy resulted in implantation and fetal loss associated with oxidative stress induced by mitochondrial dysfunction.

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Mechanisms of impaired insulin signaling in calcineruin A‐alpha knockout mice

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.597.10 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Jennifer L Gooch ◽

Tiffany K Roberts ◽

Russ Price ◽

Ramesh N Reddy

Keyword(s):

Insulin Signaling ◽

Knockout Mice ◽

Impaired Insulin

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Metabolism: A Novel Shared Link between Diabetes Mellitus and Alzheimer’s Disease

Journal of Diabetes Research ◽

10.1155/2020/4981814 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12 ◽

Cited By ~ 7

Author(s):

Yanan Sun ◽

Cao Ma ◽

Hui Sun ◽

Huan Wang ◽

Wei Peng ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Metabolic Disease ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mitochondrial Dysfunction ◽

Diabetic Patients ◽

Increased Risk ◽

Impaired Insulin ◽

The Brain

As a chronic metabolic disease, diabetes mellitus (DM) is broadly characterized by elevated levels of blood glucose. Novel epidemiological studies demonstrate that some diabetic patients have an increased risk of developing dementia compared with healthy individuals. Alzheimer’s disease (AD) is the most frequent cause of dementia and leads to major progressive deficits in memory and cognitive function. Multiple studies have identified an increased risk for AD in some diabetic populations, but it is still unclear which diabetic patients will develop dementia and which biological characteristics can predict cognitive decline. Although few mechanistic metabolic studies have shown clear pathophysiological links between DM and AD, there are several plausible ways this may occur. Since AD has many characteristics in common with impaired insulin signaling pathways, AD can be regarded as a metabolic disease. We conclude from the published literature that the body’s diabetic status under certain circumstances such as metabolic abnormalities can increase the incidence of AD by affecting glucose transport to the brain and reducing glucose metabolism. Furthermore, due to its plentiful lipid content and high energy requirement, the brain’s metabolism places great demands on mitochondria. Thus, the brain may be more susceptible to oxidative damage than the rest of the body. Emerging evidence suggests that both oxidative stress and mitochondrial dysfunction are related to amyloid-β (Aβ) pathology. Protein changes in the unfolded protein response or endoplasmic reticulum stress can regulate Aβ production and are closely associated with tau protein pathology. Altogether, metabolic disorders including glucose/lipid metabolism, oxidative stress, mitochondrial dysfunction, and protein changes caused by DM are associated with an impaired insulin signal pathway. These metabolic factors could increase the prevalence of AD in diabetic patients via the promotion of Aβ pathology.

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PGRN Induces Impaired Insulin Sensitivity and Defective Autophagy in Hepatic Insulin Resistance

Molecular Endocrinology ◽

10.1210/me.2014-1266 ◽

2015 ◽

Vol 29 (4) ◽

pp. 528-541 ◽

Cited By ~ 21

Author(s):

Jiali Liu ◽

Huixia Li ◽

Bo Zhou ◽

Lin Xu ◽

Xiaomin Kang ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Insulin Signaling ◽

Nuclear Factor Κb ◽

Hepatic Insulin Resistance ◽

Causative Role ◽

Dependent Manner ◽

Nuclear Factor ◽

Impaired Insulin

Abstract Progranulin (PGRN) has recently emerged as an important regulator for glucose metabolism and insulin sensitivity. However, the underlying mechanisms of PGRN in the regulation of insulin sensitivity and autophagy remain elusive. In this study, we aimed to address the direct effects of PGRN in vivo and to evaluate the potential interaction of impaired insulin sensitivity and autophagic disorders in hepatic insulin resistance. We found that mice treated with PGRN for 21 days exhibited the impaired glucose tolerance and insulin tolerance and hepatic autophagy imbalance as well as defective insulin signaling. Furthermore, treatment of mice with TNF receptor (TNFR)-1 blocking peptide-Fc, a TNFR1 blocking peptide-Fc fusion protein to competitively block the interaction of PGRN and TNFR1, resulted in the restoration of systemic insulin sensitivity and the recovery of autophagy and insulin signaling in liver. Consistent with these findings in vivo, we also observed that PGRN treatment induced defective autophagy and impaired insulin signaling in hepatocytes, with such effects being drastically nullified by the addition of TNFR1 blocking peptide -Fc or TNFR1-small interference RNA via the TNFR1-nuclear factor-κB-dependent manner, indicating the causative role of PGRN in hepatic insulin resistance. In conclusion, our findings supported the notion that PGRN is a key regulator of hepatic insulin resistance and that PGRN may mediate its effects, at least in part, by inducing defective autophagy via TNFR1/nuclear factor-κB.

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