Lori, who is an insulin guru, has explained the hard science behind insulin resistance below in Serious Bioscience Bits.
I've summarized it in a vastly simplified form in the green boxes throughout the text as needed for those who want it quick and easy.
When insulin levels are high most of the time it causes your body to be unable to switch from one fuel source (carbohydrates) to another fuel source (fats) quickly. This causes:
1) toxic lipids to build up and interfere with insulin cell signaling
2) less fat as fuel for mitochondria.
Table sugar is 1/2 glucose and 1/2 fructose. Your body controls blood glucose levels via insulin. Fructose is metabolized directly, mostly by the liver. It is not regulated by your body very well.
Carbohydrates are strings of glucose bound together. Enzymes in your body break simple carbohydrates into glucose.
Your body tracks glucose very closely since too little or too much glucose can be harmful to your health and even result in death.
Sustained high insulin levels or hyperinsulinemia and insulin resistance (IR) leads to changes in glucose and lipid metabolism in target tissues (adipose tissue, liver, and muscle). These conditions alter the state of metabolic flexibility which is the body’s ability to adapt fuel (carbohydrates and lipids) oxidation to the state of fuel availability (Goodpaster & Sparks, 2017). Due to altered lipid metabolism, excessive fatty acids limit fatty acid uptake into cells and to the mitochondria.
The mitochondrion is responsible for cellular energy production by using fat as a fuel source. However, limited availability of fatty acids leads to lower fat oxidation, an accumulation of intracellular lipids, and altered pathways that produce metabolites that lead to increased toxic lipid intermediates. These lipid intermediates can cause impairment of the major insulin signaling pathway (Akt/PIK3 pathway) which affects glucose uptake, synthesis, and homeostasis.
When people are metabolically healthy, insulin lets the body know it is time to take up excess glucose for use as energy or to store. This keeps blood glucose levels from getting too high. It also inhibits fat breakdown and causes the body to store fat.
When insulin is too high most of the time it can cause insulin resistance; this is when cells don't respond to insulin.
High insulin can also impair normal cell signals. This can cause the body to make glucose even when it already has too much glucose. As you can guess, this is not good. It is one of the first steps in metabolic diseases.
1) Normally insulin stimulates the storage of fats while inhibiting the breakdown of fats (lipolysis) in the adipose tissue. Lipolysis involves the breakdown of triglycerides (TG) into three fatty acids and the glycerol backbone. In IR, these metabolic processes are altered leading to increased lipolysis from adipose tissues, and increased release of non-esterified fatty acids.
2) Insulin mediates the process of glucose uptake in insulin sensitive tissues. In insulin resistance, insulin sensitive tissues become unresponsive, and glucose remains in the bloodstream, increasing plasma glucose concentration.
3) Impaired insulin signaling stems from alterations in the insulin receptor expression, ligand binding or changes in phosphorylation (the addition of a phosphate group) of insulin receptor proteins. Impaired insulin signaling leads to impairment of the translocation of intracellular GLUT4 transporter from the vesicles to the plasma membrane and reduces insulin-stimulated glucose uptake in skeletal muscle and adipose tissue.
4) Downstream insulin signaling is impaired leading to a decline in Akt activation. Akt activation leads to the phosphorylation of substrate and transcription factor, forkhead box 01 (FOX01) which normally would inhibit hepatic gluconeogenesis. In hepatic IR, decreased activation of Akt leads to increased transcription of FOX01 which turns on the process of gluconeogenesis. This process results in production of glucose molecules when conditions do not warrant more glucose.
In addition, metabolic disease and obesity creates an inflammatory milieu that along with chronic hyperglycemia and elevated free fatty acids desensitize insulin responsive tissues by interfering with the insulin signaling and eventually suppressing pancreatic insulin release leading to type 2 diabetes.
Dysfunctional inflamed fat produces free fatty acids (FFAs) which contribute to 1) fat deposits increasing through out the body 2) carbohydrates converted to fat instead of being used for energy 3) creation of toxic lipid intermediates which fuel more insulin resistance along with mitochondria stress and 4) inflammation in the liver.
The spillover of FFAs from the adipose tissue leads to fat deposits in other organs such as the liver, muscle, and pancreas. Continuous oversupply of dietary carbohydrates and fats plus hyperinsulinemia directs lipids towards increased synthesis of fat and storage in liver and muscle. Impairment of glucose uptake results in glucose traveling to the liver and becoming the substrate for hepatic de novo lipogenesis, increasing TG synthesis and plasma TG concentration, and lowering high density lipoprotein (HDL) concentration (Petersen et al., 2007). These metabolic outcomes characterize the dyslipidemia seen in Metabolic Syndrome.
The generation of FFAs also stems from lipolysis of dietary fat packaged as chylomicrons. In addition, hyperinsulinemia stimulates the conversion of carbohydrates to fat via the process of de novo lipogenesis in the liver (Basaranoglu et al., 2015) and uncontrolled lipolysis of adipose tissue. High concentrations of fatty acids and glucose results in reduced fat utilization by reduced β-oxidation and promote the esterification of fatty acids (Li et al., 2008; Ruderman & Prentki 2004). Abundant FFAs are either stored in the lipid droplet of the hepatocyte or repackaged as very low lipoprotein-triglyceride (VLDL-TG) for circulation (Saponaro et al., 2015; Gastaldelli 2011). The imbalance of reduced β-oxidation and elevated VLDL-TG production promotes fat storage which results in lipotoxicity in the liver.
Lipotoxicity is an accumulation of lipid intermediates (diacylglycerols (DAG), ceramides) that cause cellular stress and promote the development of insulin resistance in the liver, adipose tissue, and skeletal muscle (DaSilva Rosa et al., 2020). The accumulation of intrahepatic fats disrupts insulin signaling, fails to suppress hepatic glucose production (gluconeogenesis) and is associated with hepatic IR (Gastaldelli et al., 2007; Kotronen & Yki-Jarvinen 2008; Petersen et al., 2005; Seppala-Lindroos 2002). Elevated hepatic VLDL-TG levels and impaired clearance of VLDL results in increased plasma TG and low density lipoprotein (LDL) levels and reduced HDL levels or dyslipidemia seen in Metabolic Syndrome (Tchernof & Despres 2013; NCEP-ATP III, 2001).
In addition, hyperinsulinemia and hyperglycemia promote the synthesis of lipids or lipogenesis in the liver during a time when energy intake exceeds energy expenditure (Sidossis et al., 1996; Schwarz et al., 2003; Schwarz et al., 1995). Activation of transcription factors, sterol response element-binding protein 1c (SREBP-1c) and carbohydrate response element-binding protein (ChREBP) promote de novo lipogenesis by inhibiting FOX O1 and upregulating hepatic lipogenic enzymes, fatty acid synthase and acetyl CoA carboxylase (Steneberg et al., 2015; Postic & Girard 2008; Ido-Kitamura et al., 2012; Geisler & Renquist 2017). Most of the lipid accumulation in the liver comes from the adipose tissue with approximately 25% from de novo lipogenesis.
The breakdown of triglycerides in the liver results in the lipid intermediates of acyl CoA, DAG, and ceramides. These intermediates act as signaling molecules to activate protein kinase C isoforms (Samuel et al., 2010). PKC isoforms phosphorylate serine and threonine residues of the insulin receptor and IRS-1. The result is impairment of insulin signaling pathway through decreased activity of PIK3 (Samuel et al., 2010; Yu et al., 2002; Erion & Shulman 2010).
Altered hepatic lipid metabolism leads to the development of fatty liver disease. Fatty liver disease is the accumulation of intrahepatic fat greater than 5% of hepatocytes without hepatocellular injury and in the absence of excessive use of alcohol or liver disease (Chalasani et al., 2012).
Intrahepatic fat and its lipid toxic state place metabolic stress on hepatocytes and its organelles contributing ER stress, mitochondrial dysfunction, and apoptosis (Hirsova et al., 2016; Mota et al., 2016). The mitochondria produce cellular energy via substrate oxidation, the tricarboxylic acid cycle, and adenosine triphosphate (ATP) synthesis via oxidative phosphorylation (Ryan & Hoogenraad, 2007). Fatty liver subjects exhibited increased mitochondrial oxidation and tricarboxylic acid cycle activity that strongly correlated with liver fat content (Sunny et al., 2011). Early in obesity-related IR, upregulation of hepatic mitochondrial respiration compensates for altered bioenergetic demands and attempts to restrain further hepatic lipid accumulation (Koliaki et al., 2015; Begriche et al., 2013.) Researchers found that obese subjects with and without fatty liver exhibited increased lipid peroxidation but reduced hepatic ATP production due to impaired mitochondrial coupling (Koliaki et al., 2015). Mitochondrial coupling is the process by which the electron transport drives ATP synthesis. Despite this increase in respiration, Koliaki and colleagues (2015) found that individuals with fatty liver had lower hepatic gene expression indicative of impaired mitochondrial biogenesis compared to those without fatty liver. Obese individuals with fatty liver exhibit elevated mitochondrial respiration despite the inefficiency of oxidative phosphorylation (Sunny et al., 2011). Other mechanisms that compromise the mitochondria include lipid intermediates. During DNL, ceramides produced from palmitic acid cause impairment of the mitochondrial respiratory chain and increased permeability of the mitochondrial membrane increasing programmed cell death or apoptosis (Chalasani et al., 2012).
Lastly, secretion of pro-inflammatory cytokines from the adipose tissue promotes inflammation in the liver. TNF-α and MCP-1 impair insulin action by failing to inhibit lipolysis and promote greater release of FFAs. Experimental data showed that mice fed a high-fat diet induced the expression of pro-inflammatory cytokines, TNF-α and INF-γ (interferon-gamma) (Tang et al., 2013). Further, saturated fatty acids such as palmitic acid and lipid intermediates activate hepatic Kupffer cells which bolster the over-activation of natural killer cells (NKT) and cause hepatic cell death (Tang et al., 2013 ). NKT cells are T-cells which regulate the production of pro- and anti-inflammatory cytokines (Geissman et al., 2005). This action plus the activation of TLR-4 gene expression contributes to local inflammation and insulin resistance within the liver and spurs other leukocytes towards the production of pro-inflammatory substances (Tang et al., 2013).
When fat cells obtain too much energy (through overeating or insulin dysfunctions) they become inflamed in most people. This causes the fat cells to change in appearance (phenotype) and start producing more inflammatory chemicals. The chemicals attract immune cells and all of this contributes to whole body inflammation.
The adipose tissue is an endocrine and storage organ which regulates energy homeostasis through the uptake of fatty acids and synthesis of triglycerides, inhibition of lipolysis, gene regulation of expression of lipid uptake and storage, and the process of synthesis of new adipocytes or adipogenesis (Kahn & Flier 2000; Berry et al.,2014; Kersten 2001; Czech 2013).
Obesity affects the structure of the adipose tissue. Overnutrition spurs adipocytes to become laden with fat (hypertrophic) and inflamed. As hypertrophic adipocytes expand, the innate immune cells such as macrophages are recruited, increase in numbers, and surround the adipocyte to form crown-like structures. Resident macrophages engulf dying adipocytes, cellular debris, and lipids. They secrete pro-inflammatory cytokines such as tumor necrosis factor (TNF-α), interleukin 6 (IL-6), and interleukin-1β (IL-1β) (Apovian et al., 2008; Bai et al., 2015; Lumeng et al., 2007) while secreting less of anti-inflammatory and beneficial adipokine, adiponectin. Adiponectin regulates insulin sensitivity through stimulation of fatty acid oxidation and glucose uptake in the muscle and liver (Jung & Choi 2014; Oda et al., 2008).
Studies show…
Individuals with obesity, metabolic syndrome and type 2 diabetes have diminished adiponectin levels (Coelho et al., 2013). Other studies show that obese, diabetic, and non-diabetic individuals with hypertrophic adipocytes were associated with decreased insulin sensitivity and a high concentration of circulating insulin (Arner et al., 2010). Furthermore, adipocyte hypertrophy was positively correlated with HOMA-IR analysis (homeostatic model of assessment for insulin resistance) and increased lipolytic responsiveness (Michaud et al., 2016; Verboven et al., 2018).
HOWEVER,…
Some obese individuals will develop insulin resistance but not all insulin resistance individuals are overweight or obese (Iacobini et al, 2019). Metabolic profiles of obese metabolically health individuals include less accumulation of visceral fat, less systemic inflammation, and improved oxidative capacity (Samocha-Bonet et al., 2014). Metabolically unhealthy obese individuals are more likely to develop insulin resistance may exhibit lower fat utilization (Pujia et al., 2016), greater abdominal fat deposition (Tchernof & Despres, 2013; Ross et al, 2002), greater amounts of large adipose cells in the abdomen, and defective adipogenesis (McLaughlin et al, 2011).
The imbalance of pro-inflammatory and anti-inflammatory substances leads to decreased insulin sensitivity via disruption in insulin signaling and insulin’s action on lipid metabolism. The secretion of pro-inflammatory cytokines (TNF-α) activates serine kinases, c-Jun N-terminal kinase (JNK), Ikβ kinase (IKKβ), and protein kinase C (PKC), which phosphorylate serine residues on the insulin receptor substrate. This action inhibits the normal tyrosine phosphorylation affecting the downstream insulin signaling. Activation of JNK disrupts insulin sensitivity, promotes inflammation in adipose tissue, and impairs insulin -stimulated vasodilation of arterioles in adipose tissue during obesity (Farb et al., 2016).
As insulin sensitivity of the adipose tissue declines, insulin fails to suppress lipolysis, resulting in stored triglycerides being hydrolyzed into free fatty acids (FFAs) and glycerol by hormone sensitive lipase. Inflamed hypertrophic adipocytes secrete TNF-α and monocytes chemoattractant protein-1 (MCP-1) which impaired insulin from inhibiting lipolysis thus a release of free fatty acids. High release of saturated fatty acids activates JNK and the inhibitor IKKβ which affect downstream insulin signaling. In addition, FFAs have been shown to act as signaling molecules which bind to toll-like receptors (TLR) on macrophages in mice (Nguyen et al., 2007). In turn, TLR activates nuclear factor-kappa B (NF-kB) and JNK to mediate both inflammation and insulin resistance. Release of excess FFAs and glycerol travel through the bloodstream to the liver causing harmful effects (Snel et al., 2012; Landgraf et al., 2015; Kissebah et al., 1982).
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