Insulin resistance in skeletal and cardiac muscle also impairs their ability to transport glucose for fuel in part by the inhibition of the Glut4 transporter. Because circulating triglycerides and FFA are also high in accord with WAT release and impaired insulin action, muscle deposits of fat are also seen on pathological specimens (myocellular steatosis). The impairment of normal uptake of glucose by adipocytes and muscle cells and the paradoxical storage of FFA in muscles and release from adipocytes perpetuates peripheral IR. These metabolic perturbations are intimately involved with the concept of hepatocyte IR (Fig. 2).44
Figure 2. Biochemistry of normal insulin sensitivity and insulin resistance.43 (a) Physiological state. Normal glucose levels are maintained by insulin action which effectively stimulates glucose uptake in adipose tissue and skeletal muscles and inhibits hepatic glucose output. Moreover, insulin contributes to normal plasma lipid levels by stimulating lipid storage in the adipose tissue through inhibition of the activity of hormone-sensitive lipoprotein lipase. (b) Insulin-resistant state. Hyperglycemia and compensatory hyperinsulinemia result from decreased glucose uptake by peripheral tissues and decreased inhibition of hepatic glucose output. Moreover, atherogenic hyperlipidemia results from impaired inhibition of lipoprotein lipase, leading to lipotoxicity, namely tissue malfunction and damage from excess lipid depots in non-adipose tissues such as liver, muscles and kidney. In addition, adipocytokines are unbalanced so contribute to perpetuating insulin resistance. Reprinted with permission.44
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Hepatocyte IR: molecular insights into the initiator of systemic IR
The exact mechanisms of hepatocyte IR tend to be more and more precisely elucidated. In addition to the role of WAT, adipocytokines, the microbiome and inflammation most likely contribute to hepatocyte IR. Lifestyle – specifically diet and exercise – is involved. Although physical exercise, by reversing muscle IR, decreases hepatic de novo lipogenesis and hepatic triglyceride synthesis after a carbohydrate-rich meal in experimental conditions,45 diet ameliorated central adiposity and liver enzymes and exercise training did not confer significant incremental benefits in a recent study mimicking clinical conditions more closely.46 Consumption of the highly lipogenic sugar fructose is associated with IR, MS, NAFLD and NASH.47–51 Smoking favors hepatic lipogenesis and fibrotic progression in NAFLD52–54 as well as the development of T2D.55
Conversely, moderate alcohol56,57 and coffee consumption58–60 may prevent the development of both NAFLD and T2D. These findings, however, do not translate into specific lifestyle suggestions so far. Consumption of dairy products may be associated, via increased Trans-palmitoleate (trans-16:1n-7) serum levels, with improved glicolipidic metabolic profile and diabetes prevention;61 nonetheless, the role of dairy products in association with NAFLD, if any, is unsettled. Hepatic protein kinase C (PKC) isoforms promote hepatocyte IR by inhibiting insulin signaling in human liver biopsy samples.62 In a study published by Shulman's group, antisense oligonucleotide (ASO) against PKCε markedly improved clinical parameters of MS associated with a significant reduction in hepatocyte IR, including intrahepatic triglycerides and fasting plasma insulin concentrations. Their work provides a molecular explanation for the derangements associated with hepatocyte IR by demonstrating that PKCε ASO restores insulin receptor substrate-2 (IRS-2) phosphorylation and protein-serine-threonine kinase activity.63 A more recent study by the same group64 developed this line of research further by demonstrating that hepatic diaglycerol content in cytoplasmic lipid droplets, which was strongly associated with activation of hepatic PKCε activity, was the best predictor of IR, being responsible for 64% of the variability in insulin sensitivity. Gupta et al. recently published the effect of exendin-4, a glucagon-like peptide 1 (GLP-1) analog as promoting insulin-sensitizing effects by way of PKCζ.65 Finally, FFA, which are causally linked to the development of steatosis, have been recognized as inductors of IR via activation of protein kinases.66,67 Although requiring further study, this line of research underscores the importance of fatty liver as a precursor lesion to the development of systemic IR accounting for the finding that NAFLD individuals are twice as likely to develop T2D as those without NAFLD.5 Clearly, the mechanisms leading from hepatic steatosis to long-lasting IR and, in predisposed individuals, to T2D are critical.
Lipotoxicity remains key to the pathogenesis of T2D.1 Stated otherwise, the presence of long-standing IR per se is not sufficient to lead to full-blown T2D in the absence of β-cell failure.
Therefore, morphological evidence of fatty changes in the pancreas could be a better marker of pancreatic lipotoxicity. Recent studies suggest that steatosis of the pancreas is visible through endoscopic ultrasound. Interestingly, risk factors for “fatty pancreas” tend to overlap with those for fatty liver68,69 suggesting a shared pathogenesis in lipotoxicity, the ectopic, extra-adipose tissue storage of lipids eventually conducive to tissue damage and organ dysfunction.
Assessment of mediators of IR is of critical importance: Fetuin-A and IL-6 could be such mediators. Fetuin-A, a protein secreted by the liver and associated with the development of IR in animals and with fatty liver in humans, has been proposed as one such mediator. Stefan et al.70 in a large prospective case cohort – EPIC-Potsdam study –observed fetuin-A to be an independent predictor of T2D. IL-6 – a major pro-inflammatory cytokine, the expression of which is increased in experimental NAFLD, resulting in systemic IR – could be another mediator. Wieckowska et al. reported that the expression of IL-6 in the hepatocytes, which is selectively induced by saturated FFA, is positively correlated with hepatic inflammatory fibrotic changes and systemic.71 These data account for the well-known matching of IR with hepatic fibrosis observed, for instance, in chronic hepatitis C virus infection72 and explain why blockade of IL-6 signaling improves liver injury in a rodent model of NASH.73
Hepatocyte apoptosis and the potential for dysfunctional ER stress response
Czaja and colleagues clearly implicated Janus Kinase 1 (JNK1) as a principal player in driving the pathogenesis of NASH and hepatocyte apoptosis.79 Death by apoptosis is currently felt to be the major player resulting in progression of NASH.80 While this discussion cannot review the details of ER stress, the reader is referred to other sources.81–83 Three key trans-membrane proteins in the ER – PERK, ATF-4 and XBP-1 – manage misfolded proteins. If, however, XBP-1 and ATF-6 cannot induce the key ER chaperone GRP78 or BIP, then c-β homologous protein, or CHOP, will be expressed which leads to downstream effectors of apoptosis. It should be mentioned, however, that the role of CHOP in human NASH as a driver of hepatocyte apoptosis is in dispute.80,84