Stepwise development of tissue- specific insulin resistance
المؤلف:
Holt, Richard IG, and Allan Flyvbjerg
المصدر:
Textbook of diabetes (2024)
الجزء والصفحة:
6th ed , page 246-247
2025-12-03
100
The close association between obesity, ectopic fat accumulation, and insulin resistance makes it difficult to identify skeletal muscle, liver, or adipose tissue as the primary cause of insulin resistance. Indeed, ingestion of one energy- dense high- fat meal can cause simultaneous insulin resistance in these tissues both in humans and in mice. Nevertheless, in humans the earliest development of insulin resistance most likely occurs in the adipose tissue. The observation of rapid reversibility of hepatic but not muscle insulin resistance with moderate weight loss in individuals with NAFLD, and leptin replacement in generalized lipodystrophy and type 2 diabetes, is in agreement with this contention. As detailed earlier, the principal mechanism involves tissue- specific accumulation of plasma membrane sn- 1,2- DAGs, which occurs owing to an imbalance between substrate influx and oxidation (mitochondrial activity) and/or synthesis of TAGs in insulin- responsive tissues. Accordingly, any situation that will disrupt the balance between delivery and removal of plasma membrane sn- 1,2- DAGs to the muscle, liver, and white adipose tis sue will lead to the accumulation of these lipid species, resulting in activation of PKCε (as well as PKCθ in skeletal muscle) and insulin resistance. This likely explains the high prevalence of obesity- associated insulin resistance, where lipid delivery exceeds storage and oxidation, the impaired adipocyte storage capacity in lipodystrophy, and the decreased substrate oxidation in certain forms of inherited insulin resistance such as lean, insulin- resistant relatives of individuals with type 2 diabetes or in acquired insulin resistance occurring during ageing.
Evidence for the specific role of inefficient substrate oxidation during the onset of insulin resistance comes from the human model of lean, young, severely insulin- resistant relatives of people with type 2 diabetes, who are devoid of any other confounding factors such as obesity, hyperglycaemia, or subclinical inflammation. In these individuals, inherited abnormalities in muscle mitochondrial biogenesis and/or function can cause or at least contribute to muscle insulin resistance due to decreased mitochondrial fatty acid oxidation and subsequent accumulation of intracellular lipid metabolites (plasma membrane sn- 1,2- DAGs) with diminished insulin signalling. The impaired adaptation of insulin sensitivity to exercise training in carriers of the rs540467 polymorphism of the NDUFB6 gene in such relatives of people with type 2 diabetes is in line with this hypothesis. Likewise, the rs2267668 A/G SNP in the PPARD gene and the Gly482Ser SNP in the PGC1A gene also have independent and additive effects on the effectiveness of aerobic exercise training to increase physical fitness and insulin sensitivity in humans at risk for type 2 diabetes. Impaired mitochondrial function as assessed from ATP synthesis was also found in other non- obese groups at increased risk for type 2 diabetes, such as individuals with previous acromegaly or gestational diabetes. All these alterations in skeletal muscle metabolism would lead to lower rates of insulin- stimulated glucose disposal and accelerated rates of anaerobic glycolysis with release of lactate and alanine as substrates of hepatic gluconeogenesis.
Chronic overnutrition will increase the size of white adipose tis sue and recruit macrophages to adipose tissue. Local inflammation of adipose tissue leads to macrophage- induced lipolysis with release of TAGs and fatty acids, which in turn elevate the white adipose tissue–derived hepatic acetyl- CoA pool and drive hepatic gluconeogenesis. This mechanism could potentiate the transition from whole- body insulin resistance to impaired glucose tolerance and type 2 diabetes. Chronic increases in hepatic gluconeogenesis would then impair insulin secretion by the pancreatic β cells and inappropriate glucagon secretion by the α cells due to glucose toxicity, and ultimately exacerbate both fasting and post- prandial hyperglycaemia in the context of overt type 2 diabetes.
Finally, excessive flux of fatty acids to the liver will promote NAFLD through increased hepatic esterification, which occurs in a mostly insulin- independent manner and therefore is not dependent on postulating selective hepatic insulin resistance. Hepatic mitochondria may transiently adapt to the increased substrate availability by upregulating their oxidative capacity at the expense of decreased coupling efficiency until NAFLD develops. Ongoing substrate overloading will blunt the liver’s antioxidant capacity and increase hepatic oxidative stress, with subsequent leakage of mitochondria and decreased mitochondrial biogenesis, resulting in NASH and aggravated insulin resistance.
Several studies provided experimental support for the concept of the stepwise development of insulin resistance in humans (Figure 1). Monitoring energy distribution employing 13C/1H NMR spectroscopy and hepatic de novo lipogenesis after ingestion of a high- carbohydrate meal revealed that post- prandial muscle glycogen synthesis was reduced by ~60% in insulin- resistant compared with insulin- sensitive young, lean individuals. On the other hand, liver TAG content and hepatic de novo lipogenesis were doubled in the insulin- resistant group. This was accompanied by 60% higher plasma TAG and uric acid contents and 20% lower fasting HDL- C, but with no changes in circulating adipocytokines. These data confirmed that muscle insulin resistance per se shifts the distribution of post- prandial energy storage away from muscle glycogen and leads to upregulation of hepatic lipid synthesis and hepatic lipid storage and export of VLDL, thereby contributing to the development of atherogenic dyslipidaemia; these are features of the metabolic syn drome independently of visceral obesity or subclinical inflammation. Meal- dependent increases in liver glycogen synthesis were comparable in insulin- resistant and insulin- sensitive individuals, which is in accordance with the low amount of liver lipids and normal hepatic insulin sensitivity in these individuals with muscle insulin resistance. It is noteworthy that a single bout of moderate- intensity exercise abrogated the abnormal pattern of energy storage, which pro moted muscle glycogen synthesis after carbohydrate ingestion through increased glucose transport activity (Figure 1). Moreover, non- obese insulin- resistant women with a history of gestational diabetes also feature doubled fasting liver TAGs without NAFLD, which correlates with insulin resistance and fat mass. Hepatic, but not visceral, fat mass relates to hepatic insulin resistance and increased TAG release. Finally, loss of adaptation of hepatic mitochondria to excessive substrate delivery may accelerate steatosis and promote the progression of NAFLD, which is a major and independent predictor of cardiovascular morbidity and mortality in the context of type 2 diabetes.
Fig1. Concept of the stepwise development of insulin resistance from skeletal muscle to atherogenic dyslipidaemia and non- alcoholic fatty liver disease. In healthy, young, lean people, selective insulin resistance in skeletal muscle results in the diversion of ingested carbohydrates from muscle glycogen synthesis to the liver. Combined with compensatory hyperinsulinaemia, this stimulates hepatic de novo lipogenesis, synthesis of triglycerides, and secretion of very low- density lipoproteins (VLDL), resulting in hypertriglyceridaemia and reduced plasma high- density lipoprotein (HDL) levels. It is of note that even one bout of exercising is able to restore the abnormal pattern of energy storage after carbohydrate ingestion by stimulating glucose uptake and glycogen synthesis in muscle through insulin- independent adenosine 5′- monophosphate- activated protein kinase (AMPK) activation of glucose transporter 5 (GLUT4) recruitment, and further improves hepatic carbohydrate and lipid metabolism. Source: Shulman 2014. Copyright © 2014 Massachusetts Medical Society. Reprinted with permission.
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