Insulin resistance in the liver
المؤلف:
Holt, Richard IG, and Allan Flyvbjerg
المصدر:
Textbook of diabetes (2024)
الجزء والصفحة:
6th ed , page 242-243
2025-12-03
119
The liver plays a key role in the transition from the fasted to the fed state by its unique ability to switch rapidly from a glucose- producing organ to a glucose- storing organ. After ingestion of a mixed meal, the liver suppresses glucose production and takes up glucose for storage in the form of glycogen. In insulin- resistant individuals with type 2 diabetes, the excessive post- prandial hyperglycaemia results from impaired suppression of glucose production along with ~45% lower hepatic glycogen accumulation than in healthy people. This cannot be explained simply by the impaired prandial insulin secretion, but rather results from other mechanisms such as defective insulin- stimulated flux through glycogen synthase, because this abnormality persists during hyperinsulinaemic–hyperglycaemic clamps, which maximally favour glycogen synthesis. Insulin- mediated hepatic glycogen synthesis correlates inversely with ectopic lipid content in the liver not only in people with type 2 diabetes but also in those without, in line with a close link between hepatic lipid content and hepatic insulin resistance. Hepatic lipid accumulation, previously termed steatosis, is another form of ectopic lipid accumulation and is now included in the definition of non- alcoholic fatty liver disease (NAFLD). Steatosis relates closely to whole- body insulin resistance and is present in obesity, the metabolic syndrome, and women with a history of gestational diabetes or with type 2 diabetes. Although it has been discussed that NAFLD develops in the setting of or secondary to prevailing insulin resistance, increased lipid availability per se could also induce hepatic TAG storage and insulin resistance. This hypothesis is supported by human studies where short- term lipid infusions caused hepatic insulin resistance, as reflected by impaired insulin- mediated suppression of glucose production. Animal models indicate that lipid intermediates such as plasma membrane sn- 1,2- DAGs also inhibit insulin signalling in the liver, similarly to the mechanism of lipid- induced insulin resistance in skeletal muscle (Figure 1). One study in particular, inducing selective hepatic steatosis in rats by a three- day high- fat diet, found that hepatic insulin resistance corresponds to impaired tyrosine phosphorylation of IRS- 2 and increased activities of PKCε and c- Jun N- terminal kinase (JNK) 1, which act as serine/threonine kinases and can phosphorylate serine residues of IRS- 2. One study of human liver biopsies detected increases in some PKC isoforms (ε, α, and ζ) in people with type 2 diabetes and obesity. Another human liver biopsy studied found that stearoyl- CoA desaturase 1 (SCD1) activity and DAGs, but not ceramides, positively correlated with hepatic fat content. Recent intraoperative liver biopsy studies provided evidence that increases in hepatic DAG con tent and PKCε activity correlate negatively with hepatic insulin sensitivity in individuals with NAFLD and obesity, thereby underlining a critical role of the DAG/PKCε pathway also in hepatic insulin resistance in humans (Figure 1). More recently Petersen et al. demonstrated that PKCε- induced phosphorylation of the insulin receptor on threonine1160 (threonine1150 in mice) was necessary for lipid- induced hepatic insulin resistance, and using a cell fraction method Lyu et al. demonstrated that it was the plasma membrane–bound sn- 1,2- diaglycerols that were responsible for the activation of PKCε and that PKCε is both necessary and sufficient for mediating lipid- induced hepatic insulin resistance. This study also found that hepatic ceramide content did not consistently track with hepatic insulin resistance, suggesting that ceramides, like triglycerides, do not mediate hepatic insulin resistance.
Fig1. Cellular mechanism of insulin resistance in the human liver. An imbalance of intrahepatocellular fluxes gives rise to increases in plasma membrane sn- 1,2- diacylglyerols (sn- 1,2- DAGs), when DAG synthesis, from both fatty acid re- esterification and de novo lipogenesis, exceeds the rates of mitochondrial oxidation of long- chain fatty acyl- coenzyme A (CoA) and/or the rates of sn- 1,2- DAG incorporation into triglycerides (TAGs) and lipid droplets. Increases in plasma membrane sn- 1,2- DAGs leads to translocation and activation of protein kinase Cε (PKCε) to the plasma membrane, where it binds to the insulin receptor and phosphorylates it on threonine1160 (threonine1150 in mice), which in turn leads to inhibition of IRK activity and downstream insulin signalling events. In turn, phosphorylation of glycogen synthase kinase 3 (GSK3) increases, while that of forkhead box subgroup O (FOXO) decreases. This results in inhibition of glycogen synthase activity and thereby lowering insulin- stimulated glycogen storage, and in FOXO- mediated gene transcription of the gluconeogenic enzymes (e.g. phosphoenolpyruvate carboxykinase [PEP- CK] and glucose- 6- phosphate), with decreased insulin suppression of hepatic gluconeogenesis. It is also important to note that untargeted phosphoproteomic studies have identified many other proteins that are phosphorylated by activation of PKCε besides the insulin receptor, such as p70S6K, which will also cause insulin resistance downstream of the insulin receptor. Source: Shulman 2014. Copyright © 2014 Massachusetts Medical Society. Reprinted with permission.
Although NAFLD is most often associated with obesity, there are important exceptions where NAFLD and hepatic insulin resistance coexist in lean individuals. Healthy, young, lean Asian Indian men have a markedly greater risk of hepatic steatosis associated with hepatic insulin resistance than men of other ethnic groups. Two polymorphisms (rs2854116 and rs2854117) in the apolipoprotein C3 (ApoC3) gene seem to predispose these individuals and lean men of Asian ethnic backgrounds to NAFLD and insulin resistance [134]. In these carriers of the APOC3 variant alleles (C- 482T, T- 455C, or both), higher fasting plasma apolipo protein C3 and plasma TAG concentrations are 30% and 60% higher, respectively, than in wild- type homozygous humans. These findings can be explained in part by the inhibitory effect of apolipo protein C3 on LPL activity, resulting in reduced plasma triglyceride clearance, leading to increases in post- prandial hypertriglyceridaemia and increased post- prandial chylomicron remnants. This mechanism was validated genetically in transgenic mice with hepatic overexpression of human ApoC3, which were more prone to develop hepatic steatosis than their wild- type littermate counter parts when fed a high- fat diet. This ApoC3 gene–environment interaction has only been observed in male individuals, likely reflecting a protective effect of oestradiol on inhibition of LPL activity. Furthermore, this ApoC3 gene–environment interaction is not observed in individuals with obesity, in whom this relatively subtle gene–environment effect to promote hepatic steatosis in lean individuals is masked by the dominant effect of obesity and insulin resistance to promote NAFLD.
A genome- wide association study identified a missense mutation I148M within patatin- like phospholipase domain containing 3 (PNPLA3/adiponutrin) that is more prevalent in Hispanic individuals and associates with NAFLD. The rs738409 polymorphism of PNPLA3 also leads to impaired TAG hydrolysis. Although the association between this polymorphism and hepatic steatosis has been reproduced in other populations, there is no association with insulin resistance, with the limitation of these studies that all the participants had obesity and were likely insulin resistant. Individuals with the severe insulin- resistant diabetes endotype more likely carry the risk allele of this PNPLA3 polymorphism. These individuals also feature markedly higher adipose tissue insulin resistance, suggesting a role of PNPLA3 for adipose tissue function. Finally, alterations in other genes that regulate lipogenesis leading to lipodystrophy (e.g. AGPAT2, PPARγ) or lipolysis (e.g. perilipin, ATGL, CGI- 58) may also lead to ectopic lipid deposition and insulin resistance. Hence there is growing evidence that gene–environment interactions can predispose even lean individuals to hepatic insulin resistance, NAFLD, and type 2 diabetes. There are a few exceptions in which ectopic lipid content dissociates from insulin resistance. A mutation in the ABHD5 gene with consecutive deficiency in the protein comparative gene identification 58 (CGI- 58) leads to Chanarin–Dorfman syndrome, which is characterized by excessive lipid deposition in the liver, muscle weakness, and central nervous symptoms in the absence of insulin resistance. In this condition, DAGs are restricted to storage in lipid droplets (and not the plasma membrane) and thereby cannot promote PKCε translocation to the plasma membrane, which is required for its binding to the insulin receptor and inhibition of IRK activity/ insulin signalling in the liver.
Similar to skeletal muscle, people with type 2 diabetes but without obesity also show reductions in hepatocellular ATP concentrations as measured with non- invasive 31P NMR methods compared with age- matched and young people without diabetes. Hepatocellular ATP and inorganic phosphate levels differently change in type 2 diabetes and type 1 diabetes over the initial five years after clinical diabetes onset. Even with adjustments for liver fat content, hepatic ATP concentrations correlated closely with hepatic insulin sensitivity, but not with whole- body insulin sensitivity. People with type 2 diabetes but without obesity also had 40% lower flux rates through hepatic ATP synthase, which relate to both peripheral and hepatic insulin sensitivity but negatively with body fat content. Nevertheless, other features of hepatic mitochondrial function are not uniformly impaired in insulin- resistant humans [148–150]. Using high- resolution respirometry to quantify directly mitochondrial respiration in liver biopsies, it was found that, despite similar mitochondrial contents, people with obesity with or without steatosis had 4.3–5.0- fold higher maximal respiration rates in isolated mitochondria than lean people, whereas people with non- alcoholic steatohepatitis (NASH) featured 30–40% lower maximal respiration associated with greater hepatic insulin resistance (Figure 2). These individuals also had higher degrees of mitochondrial uncoupling and leaking activity, together with augmented hepatic oxidative stress paralleled by reduced antioxidant defence capacity and increased inflammatory response. These findings suggest an adaptation of the liver at early stages of obesity- related insulin resistance, which is subsequently lost during the progression of NAFLD and insulin resistance. In line with this hypothesis, insulin- resistant individuals with steatosis and obesity had a sixfold greater increase in hepatic ATP concentrations than in lean insulin- sensitive individuals after ingestion of a single mixed meal.
Fig2. Hypothesis of adaptation of hepatic energy metabolism in the pathogenesis of non- alcoholic fatty liver disease and progression of hepatic insulin resistance. (a) In states of obesity, increased fatty acid delivery upregulates hepatic mitochondrial oxidative capacity, which prevents excessive storage of triacylglycerols (TAGs), but promotes the accumulation of reactive oxygen species and lipid peroxides, which are scavenged by hepatic catalase activity. (b) During the development of non- alcoholic fatty liver disease (NAFLD), the efficiency of mitochondrial coupling fails, which accelerates the generation of hydrogen peroxide (H2O2) in the face of decreasing catalase activity. Finally, oxidative stress decreases mitochondrial biogenesis, but increases leakage of mitochondria and activates c- Jun N- terminal kinase (JNK), which drives cellular inflammation and progression to steatohepatitis (NASH). Source: Koliaki et al. 2015. Copyright 2015 Elsevier.
Taken together, these findings suggest that loss of adaptation of hepatic energy metabolism to increased lipid flux from large visceral adipose tissue depots and/or adaptation- related hepatic oxidative stress could cause hepatic lipid accumulation and subsequent hepatic insulin resistance in the context of type 2 diabetes.
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