Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance

Petersen, Max C.; Madiraju, Anila K.; Gassaway, Brandon M.; Marcel, Michael J.; Nasiri, Ali; Butrico, Gina M.; Marcucci, Melissa; Zhang, Dongyan; Abulizi, Abudukadier; Zhang, Xian‐Man; Philbrick, William M.; Hubbard, Stevan R.; Jurczak, Michael J.; Samuel, Varman T.; Rinehart, Jesse; Shulman, Gerald I.

doi:10.1172/jci86013

Cited by 180 publications

(219 citation statements)

References 59 publications

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“…PKC isoforms, JNK, p38 MAPK) leads to phosphorylation of the IR to reduce its kinase activity, or of IRS1 to elicit 14-3-3 protein binding and degradation. In support of this, ablation of a proposed PKCε-mediated feedback phosphorylation site on the IR protected mice from high-fat diet induced insulin resistance in liver (68), implicating a role for feedback involving the insulin receptor in altering insulin responses in this tissue. However, recent studies have shown that liver specific deletion of PKCε has no detectable effect on insulin resistance questioning the relevance of this pathway (Schmitz-Peiffer, personal communication).…”

Section: Diminished Signal Transduction Via Insulin Receptor/irs Is Umentioning

confidence: 73%

Muscle and adipose tissue insulin resistance: malady without mechanism?

Fazakerley

Krycer

Kearney

et al. 2019

Journal of Lipid Research

103

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Insulin resistance is a major risk factor for numerous diseases including Type 2 diabetes and cardiovascular disease. These disorders have dramatically increased in incidence with modern life, suggesting that excess nutrients and obesity are major causes of 'common' insulin resistance. Despite considerable effort, the mechanisms that contribute to 'common' insulin resistance are not resolved. There is universal agreement that extracellular perturbations such as nutrient excess, hyperinsulinemia, glucocorticoids or inflammation trigger intracellular stress in key metabolic target tissues, such as muscle and adipose tissue, and this impairs the ability of insulin to initiate its normal metabolic actions in these cells. Here we present evidence that the impairment in insulin action is independent of proximal elements of the insulin signaling pathway, but rather is likely specific to the glucoregulatory branch of insulin signaling. We propose that many intracellular stress pathways act in concert to increase mitochondrial reactive oxygen species to trigger insulin resistance. We speculate that this may be a physiological pathway to conserve glucose during specific states such as fasting, and that in the presence of chronic nutrient excess this pathway ultimately leads to disease. This review highlights key points in this pathway that require further research effort. Insulin resistance is a pathophysiological state where cells display reduced responsiveness to the glucose-lowering activity of insulin. While there are rare cases where mutations in genes associated with insulin signaling or lipodystrophy cause insulin resistance, for the most part insulin resistance is associated with obesity and thus a state of positive energy balance. This form of insulin resistance is frequently associated with hyperinsulinemia, increased waist circumference or visceral adiposity, metabolic dyslipidemia with high triglycerides and low HDL, and hepatic steatosis, features collectively referred to as the metabolic syndrome. We refer to this as "common insulin resistance". Here, both insulin-dependent glucose disposal and suppression of glucose output are impaired, albeit the relative degree of impairment in each process can vary between individuals (1-3).In this review we focus on the literature surrounding insulin resistance in muscle and adipose tissue, and specifically on insulin-stimulated glucose transport into myocytes and adipocytes within these tissues. Impaired insulin action in other tissues, most notably the liver (4, 5), brain (6, 7) and vasculature (8), also play a key role in whole body insulin resistance, and we direct readers to reviews that explore insulin resistance at these sites in detail. We will examine the evidence that common insulin resistance, in the context of muscle and adipose tissue, results from a defect in 'proximal' insulin signaling, which we define for the purposes of this review as the signaling intermediates that lead to the activation of Akt. We argue that common insulin resistance arises ...

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Section: Diminished Signal Transduction Via Insulin Receptor/irs Is Umentioning

confidence: 73%

Muscle and adipose tissue insulin resistance: malady without mechanism?

Fazakerley

Krycer

Kearney

et al. 2019

Journal of Lipid Research

103

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“…Chronic leptin treatment lowered both water drinking, consistent with lower plasma glucose concentrations throughout the day, and food intake, similar to its effect in humans with poorly controlled diabetes due to lipodystrophy (18), but did not affect activity or energy expenditure. As ectopic lipid content and, more importantly, intracellular DAG content have been strongly implicated in causing insulin resistance in liver and skeletal muscle, the lower plasma glucose concentrations in chronic leptin-infused mice can be attributed, at least in part, to lower liver and muscle DAG content and reversal of insulin resistance in these tissues (19)(20)(21).…”

Section: Discussionmentioning

confidence: 99%

Mechanism for leptin’s acute insulin-independent effect to reverse diabetic ketoacidosis

Perry¹,

Peng²,

Abulizi³

et al. 2017

Journal of Clinical Investigation

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IntroductionRecent studies have demonstrated that leptin, administered either systemically or into the cerebroventricular or hypothalamic space, can lower plasma glucose concentrations and prolong life in insulinopenic rodent models of poorly controlled type 1 diabetes (T1D) (1-4). However, the mechanism by which this occurs has been the subject of recent debate and has been attributed to suppression of hyperglucagonemia or glucagon responsiveness (1, 2, 5-8), improvements in insulin sensitivity (7,9), and activation of Creb-regulated transcription coactivator 1 signaling (10). Furthermore, even less is known regarding the mechanism by which leptin reverses ketaoacidosis in diabetic rodents. In this regard, hepatic ketogenesis is thought to be regulated mostly by malonyl CoA, a key regulator of carnitine palmitoyl transferase-I (CPT-I) activity, which in turn regulates fatty acid transport into the mitochondria (11). However, until recently, the small pool size and lability of hepatic malonyl CoA have prevented direct measurements of malonyl CoA concentrations, making it difficult to examine the role of malonyl CoA in ketogenesis as well as to determine whether leptin-induced increases in hepatic malonyl CoA concentrations are responsible for leptin's ability to reverse ketoacidosis in rodent models of diabetic ketoacidosis (DKA). In a recent study, we found that acute leptin replacement therapy reduces plasma glucose concentrations by suppressing plasma corticosterone concentrations, resulting in lower rates of lipolysis, which in turn leads to reductions in hepatic acetyl CoA content and hepatic gluconeogenesis in 3 rat models of poorly controlled diabetes (12). However, the role of leptin-mediated suppression of hypercorticosteronemia as necessary or sufficient to mediate leptin's acute, insulin-independent effect in T1D has recently been called into question (13) by Morton et al. They found that leptin as well as glucocorticoid receptor blockade had no effect on plasma glucose concentrations in a streptozotocin-treated (STZ-treated) rat model of T1D and that adrenalectomized T1D rats did not exhibit lower plasma glucose concentrations than nonadrenalectomized T1D rats. From these results, they concluded that lowering plasma corticosterone concentrations is neither necessary nor sufficient to mediate leptin's effects to lower plasma glucose concentrations in T1D rodents. However, there are major differences in the STZ-treated T1D rat model that Morton et al. used in their studies compared with the STZ-treated T1D rat model of DKA used in our studies, which could account for these different results. Specifically, Morton et al. used rats that are less insulinopenic than ours and performed mostly chronic studies in fed rats, whereas we performed primarily acute experiments in fasted rats with 5-fold lower plasma insulin concentrations.In order to further characterize the mechanism by which leptin replacement therapy acutely reverses both the increased rates of hepatic glucose production and hepatic ketogenesis a...

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“…In the four human studies that have measured hepatic diacylglycerol content and hepatic insulin sensitivity, diacylglycerol content was strongly correlated with hepatic insulin resistance in all four, whereas other potential mediators of hepatic insulin resistance (such as ceramides) showed an inconsistent relationship 21,28–30 . An increase in the level of hepatic diacylglycerol activates protein kinase Cε (PKCε), which impairs the tyrosine kinase activity of the insulin receptor (INSR) 31,32 through inhibitory phosphorylation of INSR at Thr1160; mice homozygous for a Thr1150Ala (the homologous residue to human Thr1160) mutation in Insr were protected from lipid-induced hepatic insulin resistance 33 .…”

Section: Hepatosteatosis and Insulin Resistancementioning

confidence: 99%

“…Insulin-dependent stimulation of hepatic glycogen synthesis would be a useful readout of direct hepatic insulin action, but under hyperinsulinaemic–euglycaemic conditions both glycogen synthesis and glycogenolysis are active, which results in glycogen cycling and attenuated net hepatic glycogen synthesis 10 . Thus, a hyperinsulinaemic–hyperglycaemic clamp is necessary to achieve maximal net hepatic glycogen synthesis and, accordingly, this technique has been used to measure absolute rates of hepatic glycogen synthesis through both direct and indirect glycogen synthesis pathways in rodents 33 and dogs 140 . The prevention of lipid-induced hepatic insulin resistance in Insr T1150A mice (which are insensitive to INSR inhibition by PKCε) was associated with improvements in insulin-stimulated hepatic glycogen synthesis compared with HFD-fed wild-type controls during hyperinsulinaemic–hyperglycaemic clamp studies 33 .…”

Section: Control Of Hepatic Glycogen Metabolismmentioning

confidence: 99%

“…Thus, a hyperinsulinaemic–hyperglycaemic clamp is necessary to achieve maximal net hepatic glycogen synthesis and, accordingly, this technique has been used to measure absolute rates of hepatic glycogen synthesis through both direct and indirect glycogen synthesis pathways in rodents 33 and dogs 140 . The prevention of lipid-induced hepatic insulin resistance in Insr T1150A mice (which are insensitive to INSR inhibition by PKCε) was associated with improvements in insulin-stimulated hepatic glycogen synthesis compared with HFD-fed wild-type controls during hyperinsulinaemic–hyperglycaemic clamp studies 33 . Although they are infrequently used, these in vivo measurements of net hepatic glycogen synthesis probably provide the best direct readout of hepatic insulin action.…”

Section: Control Of Hepatic Glycogen Metabolismmentioning

confidence: 99%

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Regulation of hepatic glucose metabolism in health and disease

2017

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The liver is crucial for the maintenance of normal glucose homeostasis — it produces glucose during fasting and stores glucose postprandially. However, these hepatic processes are dysregulated in type 1 and type 2 diabetes mellitus, and this imbalance contributes to hyperglycaemia in the fasted and postprandial states. Net hepatic glucose production is the summation of glucose fluxes from gluconeogenesis, glycogenolysis, glycogen synthesis, glycolysis and other pathways. In this Review, we discuss the in vivo regulation of these hepatic glucose fluxes. In particular, we highlight the importance of indirect (extrahepatic) control of hepatic gluconeogenesis and direct (hepatic) control of hepatic glycogen metabolism. We also propose a mechanism for the progression of subclinical hepatic insulin resistance to overt fasting hyperglycaemia in type 2 diabetes mellitus. Insights into the control of hepatic gluconeogenesis by metformin and insulin and into the role of lipid-induced hepatic insulin resistance in modifying gluconeogenic and net hepatic glycogen synthetic flux are also discussed. Finally, we consider the therapeutic potential of strategies that target hepatosteatosis, hyperglucagonaemia and adipose lipolysis.

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Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance

Cited by 180 publications

References 59 publications

Muscle and adipose tissue insulin resistance: malady without mechanism?

Muscle and adipose tissue insulin resistance: malady without mechanism?

Mechanism for leptin’s acute insulin-independent effect to reverse diabetic ketoacidosis

Regulation of hepatic glucose metabolism in health and disease

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