Muscle and adipose tissue insulin resistance: malady without mechanism?

Abstract

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 ...

Mitochondrial oxidants, but not respiration, are sensitive to glucose in adipocytes

“…Although mitoROS are implicated in insulin resistance (8), glucose-dependent mitoROS did not acutely lead to insulin resistance (Fig 3). In contrast, treatment with mPQ in a similarly short time-frame was sufficient to induce insulin resistance (8). We subsequently found that mitoROS needed to increase prior to the insulin stimulus to induce insulin resistance (Fig 4).…”

“…Insulin resistance in adipose tissue can be caused by numerous insults such as chronic hyperinsulinaemia, inflammation, and corticosteroids. Each of these have been examined in isolation through in vivo (mouse) and in vitro (adipocyte) models (e.g., (6,7)), revealing that they all produce mitochondrial oxidants (mitoROS) as a potential unifying cause of insulin resistance (reviewed in (8)). Although impaired mitochondrial function has been observed in insulin resistance (9,10), we have recently shown that acute treatment with mitochondrial-targeted paraquat (mPQ) increased mitoROS and caused insulin resistance, without impacting mitochondrial respiration (11).…”

The integrative biology of type 2 diabetes

“…Reduced insulin-stimulated glucose transport can be mainly attributed to defective insulin signalling at the level of IR and IRS-1-associated PI3K, which has been observed in one study to occur without altered AKT phosphorylation 80 . Whereas the majority of studies in humans point to proximal defects in insulin signalling, some experimental models provide evidence for distal abnormalities 81,82 . Glycogen synthase can also be stimulated via insulin regulation of glycogen synthase kinase-3 (GSK3) or independently via allosteric activation by glucose-6-phosphate 83 in skeletal muscle [75][76][77]84 and liver 38,85 , but its activity does not appear to regulate insulin-stimulated glucose disposal (Figs.…”

Thirty sweet years of GLUT4

“…The fact that insulin resistance is relatively specific to GLUT4 trafficking in muscle and fat cells is inconsistent with the disease phenotype arising from a generic defect in one of the signaling components proximal to the insulin receptor, as this would result in defects in all of the hormone's actions (132,133). Whereas numerous studies report a reduction in Akt phosphorylation in fat and muscle tissue of diabetic and obese prediabetic animals and humans, cellular studies show that, as a single defect, Akt must be reduced by over 80% or specifically at the plasma membrane to significantly impact on GLUT4 translocation (reviewed in 67,134).…”