Insulin resistance in adipose tissue Adipose tissue
المؤلف:
Holt, Richard IG, and Allan Flyvbjerg
المصدر:
Textbook of diabetes (2024)
الجزء والصفحة:
6th ed , page 244-245
2025-12-03
104
is highly sensitive to the action of insulin on lipolysis in healthy humans, but not in states of insulin resistance and type 2 diabetes, which are also characterized by elevations in plasma concentrations of TAGs and fatty acids. These alterations will contribute to lipid- mediated effects on insulin sensitivity in other organs such as liver and skeletal muscle. By contrast, obesity and the metabolic syndrome have been linked to a state of so- called subclinical inflammation, arising from adipose tissue and leading to an imbalance of the secretion of adipocytokines with anti- inflammatory and insulin- sensitizing properties such as adiponectin and proinflammatory cytokines such as leptin, tumour necrosis factor- α, and interleukin- 6 (IL- 6), and many others (Figure 1). The latter adipocytokines may cause insulin resistance in liver and muscle by stimulating increased serine phosphorylation of IRS1 by activation of JNK1 and activation of Iκ kinase β (IKKβ)–nuclear factor- κB (NF- κB) kinase β, both of which are involved in chronic insulin resistance. Anti- inflammatory treatment, either acutely with acetyl salicylate or chronically with salsalate, promotes a modest improvement in glycaemic levels and insulin resistance in people with type 2 diabetes and obesity, indicating that activation of inflammatory pathways can contribute to obesity- associated insulin resistance and hyperglycaemia in type 2 diabetes. Endoplasmic reticulum stress may serve as another cause of cellular inflammation and insulin resistance via JNK activation. In humans, weight loss following bariatric surgery improves insulin sensitivity, which has been further associated with altered gut microbiota or hormone secretion and also with reductions in endoplasmic reticulum stress. These hypotheses are currently under further investigation. Finally, chronically increased lipid availability may also cause mitochondrial and endoplasmic reticulum stress with release of ROS, which in turn activate proinflammatory NF- κB. Under these conditions, intracellular lipid metabolites (DAGs, ceramides, acyl- CoA) may also contribute to the resulting insulin resistance. In support of the latter possibility, Lyu et al. recently demonstrated that increases in plasma membrane sn- 1,2- DAGs and activation of PKCε leading to insulin receptor threonine1150 phosphorylation were responsible for lipid- induced white adipose tissue insulin resistance following short- term high- fat feeding in rodent. These findings underline the relevance of the plasma membrane sn- 1,2- DAG/PKCε/IRKT1160 pathway in mediating lipid- induced insulin resistance in multiple insulin- responsive tissues (liver, skeletal muscle, white adipose tissue).
Fig1. Hypothesis of macrophage- induced lipolysis in the pathogenesis of fasting hyperglycaemia and insulin resistance. During the development of obesity, macrophage infiltration of white adipose tissue results in increased lipolysis by release of macrophage- derived cytokines such as interleukin- 6. Increased rates of lipolysis lead to accelerated rates of hepatic gluconeogenesis by two mechanisms. (a) First, increased fatty acid delivery to the liver leads to higher hepatic acetyl- coenzyme A (CoA) levels when its production through fat oxidation exceeds its rates of oxidation in the tricarboxylic acid cycle. This leads to increased pyruvate carboxylase activity. (b) Second, increased delivery of glycerol promotes its conversion to dihydroxyacetone (glyceraldehyde) 3- phosphate, which serves as a precursor of glucose. Source: Shulman 2014. Copyright © 2014 Massachusetts Medical Society. Reprinted with permission.
Syndromes of lipodystrophy or lipoatrophy made it possible to study the roles of peripheral or visceral adipose tissues for insulin resistance and ectopic lipid deposition. Both inherited and acquired forms of generalized lipodystrophy are devoid of relevant amounts of adipose tissue and develop excessive hypertriglyceridaemia and ectopic fat deposition owing to fat overflow from the negligible triglyceride storage in adipocytes. Furthermore, these individuals have lower levels of inflammatory cytokines and leptin, resulting in hyperphagia. Individuals with severe, generalized lipodystrophy have severe steatosis along with hepatic and muscle insulin resistance or even overt type 2 diabetes, which completely resolves after 3–8 months of leptin replacement therapy, as demonstrated previously in rodent models of lipodystrophy. Thus, visceral lipid content is likely more of a marker of hepatic steatosis rather than a causal player in the development of insulin resistance.
Although these findings also demonstrate that the important role of lipid- induced alterations at the onset of insulin resistance can be dissociated from inflammation, they do not exclude the operation of other mechanisms promoting the progression to impaired glucose tolerance and fasting hyperglycaemia. According to the canonical view, impaired pancreatic β- and α- cell function first leads to reduced hepatic activation of Akt and exclusion of forkhead box (FOXO1) from the nucleus of the hepatocyte, with consequent transcription- mediated hepatic gluconeogenesis. Second, subclinical inflammation would diminish insulin action through secreted (adipo)cytokines, which subsequently interfere with insulin signalling and increase hepatic gluconeogenic protein transcription by activating the NF- κB/JNK/ceramide pathways. Recently, an alternative mechanism has been proposed, by which macrophage- induced lipolysis may regulate hepatic gluconeogenesis independently of canonical insulin receptor signalling and thereby link subclinical inflammation to the onset of fasting hyperglycaemia (Figure 1). Using a novel in vivo metabolomics approach in rodent models, it was demonstrated that IL- 6 and TNF- α, released from macrophages within adipose tissue, inhibit insulin- mediated lipolysis in white adipose tissue with augmented delivery of fatty acids and glycerol to the liver. This resulted in increased hepatic acetyl- CoA concentrations, due to increased fatty acid β- oxidation, which stimulated hepatic gluconeogenesis through allosteric activation of pyruvate carboxylase as well as increased glycerol conversion to glucose in the liver by a substrate push mechanism. In line with these studies in rodents, insulin- resistant adolescents with obesity displayed increased circulating IL- 6 concentrations and a more marked, 50% rise in IL- 6 concentration in white adipose tissue, along with impaired insulin- mediated suppression of white adipose tissue lipolysis and endogenous glucose production compared with age- and body mass–matched insulin- sensitive humans. These studies collectively support the concept of an indirect action of insulin on hepatic glucose production via adipocytes. Some further observations underline that transcriptional control of hepatic gluconeogenesis cannot be due simply to direct insulin action on the liver to suppress glucose release. Insulin- mediated reduction in endogenous glucose production occurs rapidly, within minutes, even in individuals with type 2 diabetes, and there is a lack of any relationship between hepatic expression of gluconeogenic protein and fasting hyperglycaemia in humans with obesity, with and without type 2 diabetes.
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