Trusii Hydrogen Water Mega Scam?
August 20, 2021BOOST Yourself, Reduce Fatigue and Falling Energy
September 12, 2021Insulin Resistance and Metabolic Dysfunction – The Ubiquitous Driver of Disease?
The emerging interest in low carbohydrate, ketogenic diets has created infamy for the hormone insulin, painting it as a villain. Herein will hopefully elucidate some of the misconceptions around insulin, and discuss the insidious biological phenomenon that appears to underlie a whole host of diseases.
What Is Insulin?
Insulin is a potent anabolic hormone that confers a variety of functions, most famously glucose homeostasis (lowering of blood glucose). It is secreted by the beta cells of the pancreas upon detection of insulinogenic substrates (i.e., elevated blood glucose) and subsequently binds to its receptor (IRS-1 or IRS-2) on the surface of the cell membrane of target tissues. The binding of insulin to its receptor triggers autophosphorylation and a signal transduction cascade. In the muscle and adipocyte (fat cell), glucose transporter-4 (GLUT 4) translocates to the cell membrane to foster uptake of glucose into the cell. Virtually every cell in the body has been shown to have insulin receptors. Proper functioning of insulin is essential for any cell to maintain homeostasis, and thus survival of the organism. Insulin tends to gets a bad rap in the low carbohydrate high fat (LCHF) community because it inhibits lipolysis and promotes fat storage, among many other downstream metabolic effects that are disadvantageous when chronically occurring.
Metabolic dysfunction reportedly plagues at least one third of the United States population, [1] and is intricately linked to cross-communication with various organ systems. Insulin resistance is a fundamental component of metabolic dysfunction and a key player in the pathogenesis of a myriad of seemingly unrelated diseases. Typically, one might associate insulin resistance with Type 2 Diabetes Mellitus (T2DM), but its pathophysiological effects are far more systemic and vast. It is even linked to cardiovascular disease (CVD), dementia, erectile dysfunction, and polycystic ovarian syndrome (PCOS). Insulin resistance can be defined as the cell becoming resistant to insulin’s signal concomitant with hyperinsulinemia. The insulin becomes chronically elevated to compensate for the cell’s muffled ability to respond to insulin, in order to maintain blood glucose homeostasis. Eventually, the beta cell can experience “burn out” from being overtaxed, and this manifests itself through prediabetes and eventually T2DM.
The Domino Effect of Insulin Resistance
What happens when insulin signaling becomes aberrant? Since insulin is a master regulator of so many difference biological processes, its failure to function properly has extensive consequences. Insulin resistance usually follows an order of operations whereby the adipocyte becomes resistant first, logically, as a survival mechanism to avoid necrosis. Adipose tissue is a highly malleable organ with immune-like characteristics that houses a substantial milieu of cells that collectively play an integral role in metabolic regulation. It is exquisitely sensitive to environmental cues and alters its composition in response to homeostatic changes (i.e., energy flux) or disease.[2] When adipocytes in white adipose tissue (WAT) hypertrophy beyond a threshold whereby they can sustain themselves, they prevent insulin from partitioning more energy into the fat cell so it doesn’t grow even bigger in size and explode; so, the adipocyte is leaking fat inappropriately (because lipolysis is not being switched off) and secreting pro-inflammatory adipokines into the circulation. The profile of the adipocyte becomes altered. Also, the fat cell is more prone to hypoxia as it deviates from proximity to the capillaries where it gets perfused with nutrients and gas exchange. In the process of becoming hypoxic, it becomes infiltrated with and releases pro-inflammatory cytokines, some of which stimulate angiogenesis because it’s trying to increase blood flow. Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a) inhibit lipoprotein lipase (LPL), which is an enzyme that is responsible for the degradation of triglycerides from circulating VLDL and chylomicrons.
Fatty acids liberated from the triglycerides are then stored in adipose tissue or utilized by other target tissues (cardiac or skeletal muscle) for fuel, and the chylomicron vestiges are endocytosed at the liver. When this mechanism is disturbed, the ability to clear triglycerides from the blood is impaired. Furthermore, these inflammatory molecules directly antagonize the insulin signaling cascade and cause destruction to tissues throughout the body. For instance, TNF-α and IL-6 inhibit the transcription of IRS-1 (insulin receptor substrate-1), GLUT-4, and PPAR- .
Cross-talk between the adipose tissue and macrophages instigates a vicious inflammatory cycle. Necrotic cells from the adipose tissue recruit macrophages to clear the debris. The macrophages engulf the dead cells resulting in lipid-laden macrophages designated as “foam cells” due to their foamy-appearing cytosol. This process further recruits more inflammatory molecules and coagulation factors perpetuating a signaling cascade that contributes to the pathogenesis of atherosclerosis (through vascular insult, atheromatous change, etc.). [3][4][5]
When the fat cell becomes resistant to insulin, it spreads its sickness to the other organs, depositing ectopic fat in places where you don’t want it — such as the liver, heart, and muscle. The increased fatty acid flux to the liver increases triglyceride-rich VLDL production and, consequently, blood triglycerides. A high triglyceride-to-HDL ratio is indicative that someone is insulin resistant. Contrary to the muscle and fat cell, the liver does not need insulin to pull glucose into the hepatocytes (liver cells), but glucose output is unable to be shut off when needed (insulin inhibits gluconeogenesis). Consequently, there is elevated glucose concurrent with elevated fatty acids in the blood.
So, glucose and fatty acid metabolism become disrupted, and uptake by the insulin-dependent fat and muscle cells are impaired. The muscle serves as the biggest reservoir to lower blood glucose. The glucose transporter (GLUT-4) for the muscle has an insulin-dependent mechanism to uptake glucose into the myocyte (muscle cell); so, when the muscle becomes insulin resistant, the predominant blood glucose buffer is no longer available, except during exercise when the muscle is able to consume glucose without the presence of insulin. Chronic hyperglycemia occurs resulting in cross-linking of proteins, advanced glycation end products (aptly known as AGEs[6]), oxidative stress, inflammation, and cell damage. This also triggers endothelial dysfunction, which initiates the sequence of events leading up to cardiovascular disease. Aberrant lipid metabolism results in dyslipidemia: hypertriglyceridemia, lower high-density lipoprotein (HDL), and increased small dense lipoprotein (LDL) — the LDL profile that has been shown to be more atherogenic. This, in turn, promotes atherosclerotic plaque formation.[7]
What Are Some of the Causes of Insulin Resistance?
There are three primary causes of insulin resistance that have been validated across the main biomedical models: cells, rodents and humans; 1) Inflammation, 2) stress hormones (namely epinephrine and cortisol), and 3) elevated insulin, which is reflective of a basic biological principle — a cell that becomes inundated with a signal (i.e., insulin) will become desensitized to that signal. A secondary link to insulin resistance may be the excessive consumption of refined seed oils such as soybean oil, corn oil, cottonseed oil, canola oil, safflower oil, and sunflower oil.
Firstly, due to the chemical composition of these oils, they are probably almost always highly oxidized (which is further exacerbated when they’re heated). This, in turn, results in oxidative stress in the body — in particular, formation of lipid peroxides (which are highly damaging to cell membranes).
Furthermore, linoleic acid, which refined seed oils are rich in, makes the fat cell grow through hypertrophy. As I mentioned earlier, this can make the fat cell hypoxic, ultimately driving insulin resistance throughout the body through a variety of avenues. It is worth noting that mitochondrial dysfunction confers a pathological effect in a multitude of ways. Insulin resistance itself will directly affect mitochondrial functionality — it prevents it from undergoing fusion and fission, which is essential for the mitochondria to perform their jobs, a primary one being the catabolism of nutrients.
The Link Between Insulin Resistance, Alzheimer’s Disease, and Neurodegenerative Diseases
The brain is perhaps the most metabolically demanding organ. One of the underlying themes of dementia is an energy deficit governed by insulin resistance in the brain. The brain is able to use ketones and lactate as an alternative source of fuel; however, hyperinsulinemia prevents the liver from making ketones, and the brain is left starving for energy. Elevated insulin can also prevent the brain from clearing amyloid plaques, which are one of the damaging proteins that accumulate and cause Alzheimer’s disease. One of the ways it can do this is by downregulating the enzymes that regularly help degrade and clear amyloid plaques. Collectively, it’s the combinatorial effect of high inflammation (insulin resistance is an intrinsically inflammatory condition), impaired glucose processing, and excess insulin that gives way to neurodegenerative diseases. Fifty percent of type 2 diabetics comorbidly have neurodegenerative conditions.
What Are Some Actionable, Practical Steps We Can Take to Mitigate Insulin Resistance?
Diet, exercise, sleep quality, and stress management.
Diet
This is going to look different for everybody; but generally, people become insulin-resistant when they inundate the cells with insulinogenic substrates. You can think of insulinogenic foods as being on a spectrum, and while diet should be customized to the individual, there are some general principles to consider.
Out of the three macronutrients, fat has the least impact on insulin secretion (hence ketogenic diets). However, not all dietary fats exert the same effects on cellular energy metabolism. For instance, dietary omega 3 fatty acids have been shown to attenuate insulin resistance development by modulating mitochondrial bioenergetics and endoplasmic reticulum stress.[8] As I alluded to before, limit fat from industrial seed oils and highly refined fats.
Limit glycemic variability, and maintain stable blood sugar. Hyper-palatable, carbohydrate-dense (a high carbohydrate-to-fiber ratio), sugar-laden, hyper-processed foods will generally have the biggest impact on your blood sugar, and thus insulin — whatever spikes your blood sugar the most is going to spike your insulin.
There is data in rodent models and humans that demonstrates that adding polyphenol-rich compounds to an obesogenic diet modulates several metabolic parameters, including insulin sensitivity and blood glucose levels. This may be due, in part, to the metabolites that are produced by the gut microbiota. [9] [10]
Carbohydrates have the biggest impact on blood sugar, but not all carbohydrates are created equal. Resistant starch, which is present in foods like whole grains, beans, legumes, and potatoes, is a prebiotic that lowers the impact the food has on your blood sugar while being fermented to butyrate and other metabolites by commensal gut microbiota. As the name implies, the starch is resistant to digestion. Cooking (don’t overcook) and cooling these foods for 8+ hours augments the resistant starch and thus less of the carbohydrates get broken down into glucose.
Consuming protein and fiber (i.e., a salad/non-starchy vegetables) before something carbohydrate-dense may help buffer the blood glucose spike that would otherwise occur if you consumed the carbohydrate-dense food alone.
Embarking on fasting protocols may be helpful, and would be necessary to stop burdening the cells with insulin along with overtaxing the beta cells to secrete insulin. You want to train your body to become more metabolically flexible and activate its fat-burning machinery so that it’s not solely dependent on burning sugar as fuel.
Sleep
This is critical, and one of the biggest stressors for many people. One night of poor quality sleep can give you the phenotype of a type 2 diabetic and perturbs metabolic homeostasis.[11] The single most effective habit for lowering stress hormones (namely cortisol and epinephrine) is good sleep hygiene.
Exercise
Recall I mentioned that muscle has an insulin-dependent mechanism to consume glucose, with the exception being exercise. When the muscle contracts through exercise, it is able to suck up glucose without insulin, therefore placing less of a burden on your beta cells to produce insulin and clear glucose out of the blood. This, in turn, lowers the amount of insulin needed to manage blood glucose (making one more insulin-sensitive).
Sedentary behaviors, irrespective of how much fat mass one has, promote white adipose tissue (WAT) inflammation (recall that this directly antagonizes the insulin signaling cascade), which is attenuated by exercise.[12]
Exercise has been shown to activate the fuel sensing AMP-activated protein kinase (AMPK).
Photo credit: Ruderman et al (2013). Figure 1. Journal of Clinical Investigation. Boston University School of Medicine. [13]
Furthermore, molecular hydrogen has been demonstrated to regulate redox status of the cell and selectively modulate inflammation. Recall that one of the primary inducers of insulin resistance is inflammation. High-dose hydrogen water has even been shown to significantly improve insulin sensitivity in prediabetic individuals. [14]
Further Reading
- https://drinkhrw.com/blog/part-2-can-you-prevent-advanced-glycation-end-product-formation/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696539/
References
[1] https://www.healthline.com/health-news/more-than-one-third-of-americans-have-dangerous-metabolic-syndrome
[2] Chan, C. C., Damen, M. S. M. A., Alarcon, P. C., Sanchez-Gurmaches, J., & Divanovic, S. (2019). Inflammation and immunity: From an adipocyte’s perspective. Journal of Interferon & Cytokine Research, 39(8), 459–471.
[3] Berg, A. H., & Scherer, P. E. (2005). Adipose tissue, inflammation, and cardiovascular disease. Circulation Research, 96(9), 939–949.
[4] Stolarczyk, E. (2017). Adipose tissue inflammation in obesity: A metabolic or immune response? Current Opinion in Pharmacology, 37, 35–40.
[5] Ormazabal, V., Nair, S., Elfeky, O., Aguayo, C., Salomon, C., & Zuñiga, F. A. (2018). Association between insulin resistance and the development of cardiovascular disease. Cardiovascular Diabetology, 17, 122.
[6] https://drinkhrw.com/blog/part-1-advanced-glycation-end-product-crosslinking/
[7] Samuel, V. T., & Shulman, G. I. (2016). The pathogenesis of insulin resistance: Integrating signaling pathways and substrate flux. The Journal of Clinical Investigation, 126(1), 12–22.
[8] Lepretti, M., Martucciello, S., Burgos Aceves, M. A., Putti, R., & Lionetti, L. (2018). Omega-3 fatty acids and insulin resistance: Focus on the regulation of mitochondria and endoplasmic reticulum stress. Nutrients, 10(3), 350.
[9] Roopchand, D. E., Carmody, R. N., Kuhn, P., Moskal, K., Rojas-Silva, P., Turnbaugh, P. J., Raskin, I. (2015). Dietary polyphenols promote growth of the gut bacterium akkermansia muciniphila and attenuate high-fat diet-induced metabolic syndrome. Diabetes, 64(8), 2847–58.
[10] Liu, J., He, Z., Ma, N., & Chen, Z.-Y. (2020). Beneficial effects of dietary polyphenols on high-fat diet-induced obesity linking with modulation of gut microbiota. Journal of Agricultural and Food Chemistry, 68(1), 33–47.
[11] https://drinkhrw.com/blog/sleep-deprivation-metabolic-syndrome-relationship/
[12] Park, Y.-M., Myers, M., & Vieira-Potter, V. J. (2014). Adipose tissue inflammation and metabolic dysfunction: Role of exercise. Missouri Medicine, 111(1), 65–72.
[13] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696539/
Ruderman, N., B., Carling, D., Prentki, M., & Cacicedo, J. M. (2013). AMPK, insulin resistance, and the metabolic syndrome. The Journal of Clinical Investigation, 123(7), 2764–2772.
[14] https://bmcsportsscimedrehabil.biomedcentral.com/track/pdf/10.1186/s13102-019-0119-7.pdf