Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Integrity Is Required for Insulin Signaling and Is Implicated in Hepatic Insulin Resistance

Mitochondria and the endoplasmic reticulum (ER) are connected at multiple sites via what are known as mitochondria-associated ER membranes (MAMs). These associations are known to play an important role in maintaining cellular homeostasis. Impaired MAM signaling has wide-ranging effects in many diseases, such as obesity, diabetes, and neurodegenerative disorders. Accumulating evidence has suggested that MAMs influence insulin signaling through different pathways, including those associated with Ca2+ signaling, lipid metabolism, mitochondrial function, ER stress responses, and inflammation. Altered MAM signaling is a common feature of insulin resistance in different tissues, including the liver, muscle, and even the brain. In the liver, MAMs are key glucose-sensing regulators and have been proposed to be a hub for insulin signaling. Impaired MAM integrity has been reported to disrupt hepatic responses to changes in glucose availability during nutritional transition and to induce hepatic insulin resistance. Meanwhile, these effects can be rescued by the reinforcement of MAM interactions. In contrast, several studies have proposed that enhanced ER-mitochondria connections are detrimental to hepatic insulin signaling and can lead to mitochondrial dysfunction. Thus, given these contradictory results, the role played by the MAM in the regulation of hepatic insulin signaling remains elusive. Similarly, in skeletal muscle, enhanced MAM formation may be beneficial in the early stage of diabetes, whereas continuous MAM enhancement aggravates insulin resistance. Furthermore, recent studies have suggested that ER stress may be the primary pathway through which MAMs induce brain insulin resistance, especially in the hypothalamus. This review will discuss the possible mechanisms underlying MAM-associated insulin resistance as well as the therapeutic potential of targeting the MAM in the treatment of type 2 diabetes.

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Age and tissue specific differences in the development of acute insulin resistance following injury

Journal of Endocrinology ◽

10.1677/joe-09-0269 ◽

2009 ◽

Vol 203 (3) ◽

pp. 365-374 ◽

Cited By ~ 10

Author(s):

Lidong Zhai ◽

Joseph L Messina

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Signaling ◽

Intracellular Signaling ◽

Male Rats ◽

Hepatic Insulin Resistance ◽

Surgical Trauma ◽

Induce Insulin Resistance ◽

Old Rats ◽

Effect Of Age

Injuries, hemorrhage, sepsis, burn, and critical illnesses all induce insulin resistance, and insulin resistance is strongly associated with advancing age. However, the effect of age on injury induced insulin resistance is not well studied. We performed surgical trauma in male rats of three different ages (3-, 6-, and 10-weeks old). Rats were either hemorrhaged to a mean arterial pressure of 35–40 mmHg and subsequently maintained at that pressure for up to 90 min, or maintained without hemorrhage as controls. Results indicate that insulin-induced intracellular signaling was diminished in liver and skeletal muscle of 6- and 10-week old rats following trauma and hemorrhage. In even younger rats, immediately post-weaning (∼3 weeks of age), insulin signaling was lost in liver, but not in skeletal muscle. Glucocorticoids can play a role in the chronic development of insulin resistance. Our results demonstrate that corticosterone levels were increased in 6- and 10-week old animals following hemorrhage, but little change was measured in 3-week old animals. Blockade of glucocorticoid synthesis prevented the development of insulin resistance in skeletal muscle, but not in liver of 6- and 10-week old rats. Moreover, skeletal muscle glucocorticoid receptor levels increased dramatically between 3 and 6 weeks of age. These results indicate that trauma and hemorrhage-induced hepatic insulin resistance occurs at all ages tested. However, there is no development of insulin resistance following trauma and hemorrhage in skeletal muscle of post-weaning rats. In skeletal muscle of 6- and 10-week old rats, inhibition of glucocorticoid levels prevents the development of insulin resistance.

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EET Analog Treatment Improves Insulin Signaling in a Genetic Mouse Model of Insulin Resistance

10.2337/figshare.16811251.v1 ◽

2021 ◽

Author(s):

Kakali Ghoshal ◽

Xiyue Li ◽

Dungeng Peng ◽

John R. Falck ◽

Raghunath Reddy Anugu ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Signaling ◽

Genetic Model ◽

Water Soluble ◽

Hepatic Insulin Resistance ◽

Epoxyeicosatrienoic Acid ◽

Genetic Mouse Model ◽

Hepatic Insulin Signaling ◽

Underlying Mechanisms

We previously showed that global deletion of the cytochrome P450 epoxygenase Cyp2c44, a major epoxyeicosatrienoic acid (EET) producing enzyme in mice, leads to impaired hepatic insulin signaling resulting in insulin resistance. This finding led us to investigate whether administration of a water soluble EET analog restores insulin signaling in vivo in Cyp2c44(-/-) mice and investigated the underlying mechanisms by which this effect is exerted. Cyp2c44(-/-) mice treated with the analog EET-A for 4 weeks improved fasting glucose and glucose tolerance compared to Cyp2c44(-/-) mice treated with vehicle alone. This beneficial effect was accompanied by enhanced hepatic insulin signaling, decreased expression of gluconeogenic genes and increased expression of glycogenic genes. Mechanistically, we show that insulin-stimulated phosphorylation of insulin receptor β (IRβ) is impaired in primary Cyp2c44(-/-) hepatocytes and this can be restored by cotreatment with EET-A and insulin. Plasma membrane fractionations of livers indicated that EET-A enhances the retention of IRβ in membrane rich fractions, thus potentiating its activation. Altogether, EET analogs ameliorate insulin signaling in a genetic model of hepatic insulin resistance by stabilizing membrane-associated IRβ and potentiating insulin signaling.

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Hepatic Insulin Resistance Is Not Pathway Selective in Humans With Nonalcoholic Fatty Liver Disease

10.2337/figshare.13150568 ◽

2020 ◽

Author(s):

Kasper W. ter Horst ◽

Daniel F. Vatner ◽

Dongyan Zhang ◽

Gary W. Cline ◽

Mariette T. Ackermans ◽

...

Keyword(s):

Insulin Resistance ◽

Bariatric Surgery ◽

Liver Disease ◽

Fatty Liver ◽

Insulin Signaling ◽

Fatty Liver Disease ◽

De Novo ◽

Glucose Production ◽

Hepatic Insulin Resistance ◽

Alcoholic Fatty Liver

Objective: Both glucose and triglyceride production are increased in Type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). For decades, the leading hypothesis to explain these paradoxical observations has been selective hepatic insulin resistance, wherein insulin drives de novo lipogenesis (DNL), while failing to suppress glucose production. Here, we aimed to test this hypothesis in humans. Research Design and Methods: We recruited obese subjects who met criteria for bariatric surgery with (n=16) or without (n=15) NAFLD and assessed: i) insulin-mediated regulation of hepatic and peripheral glucose metabolism using hyperinsulinemic-euglycemic clamps with [6,6-2H2]glucose, ii) fasting and carbohydrate-driven hepatic DNL using deuterated water (2H2O), and iii) hepatocellular insulin signaling in liver biopsies collected during bariatric surgery. Results: As compared with subjects without NAFLD, subjects with NAFLD demonstrated impaired insulin-mediated suppression of glucose production and attenuated -not increased- glucose-stimulated/high-insulin lipogenesis. Fructose-stimulated/low-insulin lipogenesis was intact. Hepatocellular insulin signaling, assessed for the first time in humans, exhibited a proximal block in insulin-resistant subjects: signaling was attenuated from the level of the insulin receptor through both glucose and lipogenesis pathways. The carbohydrate-regulated lipogenic transcription factor ChREBP was increased in subjects with NAFLD. Conclusions: Acute increases in lipogenesis in humans with NAFLD are not explained by altered molecular regulation of lipogenesis through a paradoxical increase in lipogenic insulin action; rather, increases in lipogenic substrate availability may be the key. <a></a>

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POST-BURN HEPATIC INSULIN RESISTANCE IS ASSOCIATED WITH ENDOPLASMIC RETICULUM (ER) STRESS

Shock ◽

10.1097/shk.0b013e3181b2f439 ◽

2010 ◽

Vol 33 (3) ◽

pp. 299-305 ◽

Cited By ~ 38

Author(s):

Gerd G. Gauglitz ◽

Stefanie Halder ◽

Darren F. Boehning ◽

Gabriela A. Kulp ◽

David N. Herndon ◽

...

Keyword(s):

Insulin Resistance ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Hepatic Insulin Resistance

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Ethno-pharmacological insulin signaling induction of aqueous extract of Syzygium paniculatum fruits in a high-fat diet induced hepatic insulin resistance

Journal of Ethnopharmacology ◽

10.1016/j.jep.2020.113576 ◽

2020 ◽

pp. 113576

Author(s):

Prabhakar Yellanur Konda ◽

Vidyasagar Chennupati ◽

Sreenivasulu Dasari ◽

Nishesh Sharma ◽

Muthukumaran Muthulingam ◽

...

Keyword(s):

Insulin Resistance ◽

Aqueous Extract ◽

Insulin Signaling ◽

High Fat Diet ◽

Hepatic Insulin Resistance ◽

High Fat

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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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PKCε contributes to lipid-induced insulin resistance through cross talk with p70S6K and through previously unknown regulators of insulin signaling

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1804379115 ◽

2018 ◽

Vol 115 (38) ◽

pp. E8996-E9005 ◽

Cited By ~ 20

Author(s):

Brandon M. Gassaway ◽

Max C. Petersen ◽

Yulia V. Surovtseva ◽

Karl W. Barber ◽

Joshua B. Sheetz ◽

...

Keyword(s):

Insulin Resistance ◽

Protein Phosphorylation ◽

Cross Talk ◽

Insulin Signaling ◽

High Fat Diet ◽

Large Scale ◽

Kinase Assay ◽

Hepatic Insulin Resistance ◽

High Fat ◽

The Impact

Insulin resistance drives the development of type 2 diabetes (T2D). In liver, diacylglycerol (DAG) is a key mediator of lipid-induced insulin resistance. DAG activates protein kinase C ε (PKCε), which phosphorylates and inhibits the insulin receptor. In rats, a 3-day high-fat diet produces hepatic insulin resistance through this mechanism, and knockdown of hepatic PKCε protects against high-fat diet-induced hepatic insulin resistance. Here, we employed a systems-level approach to uncover additional signaling pathways involved in high-fat diet-induced hepatic insulin resistance. We used quantitative phosphoproteomics to map global in vivo changes in hepatic protein phosphorylation in chow-fed, high-fat–fed, and high-fat–fed with PKCε knockdown rats to distinguish the impact of lipid- and PKCε-induced protein phosphorylation. This was followed by a functional siRNA-based screen to determine which dynamically regulated phosphoproteins may be involved in canonical insulin signaling. Direct PKCε substrates were identified by motif analysis of phosphoproteomics data and validated using a large-scale in vitro kinase assay. These substrates included the p70S6K substrates RPS6 and IRS1, which suggested cross talk between PKCε and p70S6K in high-fat diet-induced hepatic insulin resistance. These results identify an expanded set of proteins through which PKCε may drive high-fat diet-induced hepatic insulin resistance that may direct new therapeutic approaches for T2D.

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Hemorrhage induces the rapid development of hepatic insulin resistance

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00217.2002 ◽

2003 ◽

Vol 284 (1) ◽

pp. G107-G115 ◽

Cited By ~ 38

Author(s):

Yuchen Ma ◽

Ping Wang ◽

Joachim F. Kuebler ◽

Irshad H. Chaudry ◽

Joseph L. Messina

Keyword(s):

Insulin Resistance ◽

Insulin Signaling ◽

Metabolic Response ◽

Rapid Development ◽

Convincing Evidence ◽

Pi3 Kinase ◽

Hepatic Insulin Resistance ◽

Adult Rats ◽

Male Adult ◽

Hepatic Insulin Signaling

Hyperglycemia is an early metabolic response to trauma and hemorrhage. The role of hepatic insulin resistance to the development of this hyperglycemia is not well understood. The aim of this study was to determine whether the liver becomes insulin resistant and to identify the particular hepatic insulin signaling pathways that may be compromised following trauma and hemorrhage. Male adult rats were bled to a mean arterial pressure of 40 mmHg and maintained at that pressure for 90 min followed by resuscitation with Ringer lactate. Data showed that trauma and hemorrhage rapidly induced profound hyperinsulinemia in combination with significant hyperglycemia, suggesting the development of insulin resistance. After trauma and hemorrhage, hepatic insulin signaling via the insulin-induced phosphatidylinositol 3 (PI3)-kinase-Akt pathway was abolished, whereas ERK1/2 signaling was relatively normal. The regulation (inhibition) of a hepatic-, insulin-, and the PI3-kinase-dependent gene, IGF binding protein-1, was also lost. The present study provides convincing evidence of a rapid onset hepatic insulin resistance following a combination of trauma and hemorrhage.

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Palmitate Attenuates Insulin Signaling and Induces Endoplasmic Reticulum Stress and Apoptosis in Hypothalamic Neurons: Rescue of Resistance and Apoptosis through Adenosine 5′ Monophosphate-Activated Protein Kinase Activation

Endocrinology ◽

10.1210/en.2009-1122 ◽

2010 ◽

Vol 151 (2) ◽

pp. 576-585 ◽

Cited By ~ 133

Author(s):

Christopher M. Mayer ◽

Denise D. Belsham

Keyword(s):

Insulin Resistance ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Insulin Signaling ◽

Caspase 3 ◽

Saturated Fatty Acids ◽

Amp Kinase ◽

Hypothalamic Neurons ◽

Peripheral Tissues ◽

Short Term Exposure

Hypothalamic insulin signaling is essential to the maintenance of glucose and energy homeostasis. During pathological states, such as obesity and type 2 diabetes mellitus, insulin signaling is impaired. One key mechanism involved in the development of insulin resistance is lipotoxicity, through increased circulating saturated fatty acids. Although many studies have begun to determine the underlying mechanisms of lipotoxicity in peripheral tissues, little is known about the effects of excess lipids in the brain. We used a hypothalamic, neuronal cell model, mHypoE-44, to understand how the highly prevalent nonesterified fatty acid, palmitate, affects neuronal insulin signaling. Through Western blot analysis, we discerned that prolonged exposure to palmitate impairs insulin activation, as assessed by phosphorylation of Akt. We investigated the role of endoplasmic reticulum (ER) stress, which is known to promote cellular insulin resistance and apoptosis in peripheral tissues. Palmitate treatment induced ER stress through a c-Jun N-terminal kinase (JNK)-dependent pathway because a selective JNK inhibitor blocked palmitate activation of the ER stress pathways eIF2α and X-box binding protein-1. Interestingly, JNK inhibition did not prevent the palmitate-mediated cleaved caspase-3 increase, an apoptotic marker, or insulin signaling attenuation. However, pretreatment with the AMP kinase activator, aminoimidazole carboxamide ribonucleotide, blocked JNK phosphorylation and importantly prevented caspase-3 cleavage and restored insulin signaling during short-term exposure to palmitate. Thus, activation of AMP kinase prevents the deleterious effects of palmitate on hypothalamic neurons by inhibiting the onset of insulin resistance and apoptosis.

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