Insulin Resistance | PreDiabetes

Insulin Resistance and Hypoglycemia-Associated Autonomic Failure (HAAF) are conditions that can occur independently of diabetes but often associated with it.

Insulin resistance refers to a condition in which the body’s cells don’t respond properly to insulin, a hormone that helps regulate blood sugar levels. This can lead to higher levels of insulin in the blood, which can contribute to various health problems, including type 2 diabetes.

Hypoglycemia-associated autonomic failure (HAAF) is a condition in which repeated episodes of hypoglycemia (low blood sugar) lead to a blunted response of the body’s autonomic vasomotor system to subsequent episodes. This can result in an impaired ability to detect and respond to low blood sugar levels, putting affected individuals at risk for severe hypoglycemia. Which creates ambiguous, ubiquitous and confusing symptoms leading to the diagnosis of “Syndromes” or popular diagnosis du jours.

While these conditions can occur in people with diabetes, they can also occur in individuals without diabetes. Most people will never develop full diabetes blood markers, signs or symptoms. For example, insulin resistance can be seen in conditions such as polycystic ovary syndrome (PCOS) or obesity, while HAAF can occur in individuals who experience frequent episodes of hypoglycemia for other reasons, such as certain medications or rare medical conditions. It is curious that Metformin, a diabetes drug is helpful in lowering cholesterol,¹Gillani SW, Ghayedi N, Roosta P, Seddigh P, Nasiri O. Effect of Metformin on Lipid Profiles of Type 2 Diabetes Mellitus: A Meta-analysis of Randomized Controlled Trials. J Pharm Bioallied Sci. 2021 Jan-Mar;13(1):76-82.^,2Luo, F., Das, A., Chen, J. et al. Metformin in patients with and without diabetes: a paradigm shift in cardiovascular disease management. Cardiovasc Diabetol 18, 54 (2019).^,3Xu T, Brandmaier S, Messias AC et al. Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes. Diabetes Care 2015. doi: 10.2337/dc15-0658. ⁴Genuth S, Eastman R, Kahn R et al. Implications of the United Kingdom prospective diabetes study. Diabetes Care 2003;26(1):S28-32. ⁵Wulffele MG, Kooy A, De Zeeuw D et al. The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review. J Intern Med 2004;256(1):1–14. PCOS, ⁶Attia G M, Almouteri M M, Alnakhli F T (August 31, 2023) Role of Metformin in Polycystic Ovary Syndrome (PCOS)-Related Infertility. Cureus 15(8): e44493. doi:10.7759/cureus.44493^,7Johnson NP. Metformin use in women with polycystic ovary syndrome. Ann Transl Med. 2014 Jun;2(6):56.^,8Nestler JE, Metformin for the treatment of the polycystic ovary syndrome. N Engl J Med. 2008;358(1):47. ^,9Metformin Therapy for the Management of Infertility in Women with Polycystic Ovary Syndrome: Scientific Impact Paper No. 13. BJOG. 2017;124(12):e306. Epub 2017 Aug 23.^,10Barbieri RL. Metformin for the treatment of polycystic ovary syndrome. Obstet Gynecol. April 2003;101:785-93.^,11Morteza Taghavi S, Rokni H & Fatemi S 2011 Metformin decreases thyrotropin in overweight women with polycystic ovarian syndrome and hypothyroidism. Diabetes and Vascular Disease Research 8 47–48. and Hypothyroid,¹²Haroon S, Khan K, Maqsood M, et al. (February 11, 2021) Exploring the Effect of Metformin to Lower Thyroid-Stimulating Hormone in Euthyroid and Hypothyroid Type-2 Diabetic Patients. Cureus 13(2): e13283.^,13Pappa T, Alevizaki M. Metformin and thyroid: an update. Eur Thyroid J. 2013 Mar;2(1):22-8. doi: 10.1159/000346248. Epub 2013 Jan 19.^,14Karimifar M, Aminorroaya A, Amini M, Mirfendereski T, Iraj B, Feizi A, Norozi A. Effect of metformin on thyroid stimulating hormone and thyroid volume in patients with prediabetes: A randomized placebo-controlled clinical trial. J Res Med Sci. 2014 Nov;19(11):1019-26.^,15Isidro ML, Penín MA, Nemiña R & Cordido F 2007 Metformin reduces thyrotropin levels in obese, diabetic women with primary hypothyroidism on thyroxine replacement therapy. Endocrine 32 79–82.^,16Cappelli C, Rotondi M, Pirola I, Agosti B, Gandossi E, Valentini U, De Martino E, Cimino A, Chiovato L & Agabiti-Rosei E et al. 2009 TSH-lowering effect of metformin in type 2 diabetic patients: differences between euthyroid, untreated hypothyroid, and euthyroid on L-T4 therapy patients. Diabetes Care 32 1589–1590.^,17Morteza Taghavi S, Rokni H & Fatemi S 2011 Metformin decreases thyrotropin in overweight women with polycystic ovarian syndrome and hypothyroidism. Diabetes and Vascular Disease Research 8 47–48.

It’s important for individuals experiencing symptoms of insulin resistance or HAAF to consult with a healthcare professional for proper diagnosis and management. Treatment may involve lifestyle changes, medication, or other interventions aimed at improving insulin sensitivity and preventing episodes of hypoglycemia.

Clinical Pearl

• People with pre-diabetes or insulin resistance also can have low or normal blood sugars, if their high circulating insulin levels are further challenged by a prolonged period of fasting or dietary restriction, e.g. food allergy/sensitivities, Paleo, Keto, Vegan, Vegetarian, etc. 
• Red Blood Cell (RBC) agglutination (stuck together, shed oxygen) has been consistently associated with insulin resistance.
• Insulin Resistance deprives all parts of the body of glucose and oxygen. Both of which are delivered through the blood.

Symptoms of Insulin Resistance

• Autonomic Dysfunction (AD)S.¹⁸Julius, M. Valentini, and P. Palatini, “Overweight and hypertension: a 2-way street?” Hypertension, vol. 35, no. 3, pp. 807–813, 2000.^,19Alicia A. Thorp, Markus P. Schlaich, “Relevance of Sympathetic Nervous System Activation in Obesity and Metabolic Syndrome”, Journal of Diabetes Research, vol. 2015, Article ID 341583, 11 pages, 2015.  
  • Vasomotor Imbalance²⁰Alicia A. Thorp, Markus P. Schlaich, “Relevance of Sympathetic Nervous System Activation in Obesity and Metabolic Syndrome”, Journal of Diabetes Research, vol. 2015, Article ID 341583, 11 pages, 2015.^,21J. Fagius, “Sympathetic nerve activity in metabolic control some basic concepts,” Acta Physiologica Scandinavica, vol. 177, no. 3, pp. 337–343, 2003.
  • Poor Sampling of Hormones by Hypothalamus-Pituitary Axes (HPA, HPT, HPG, HPD, Blood glucose control)²²K. O’Dea, M. Esler, P. Leonard, J. R. Stockigt, and P. Nestel, “Noradrenaline turnover during under- and over-eating in normal weight subjects,” Metabolism, vol. 31, no. 9, pp. 896–899, 1982.^,23L. J. Aronne, R.Mackintosh, M. Rosenbaum, R. L. Leibel, and J. Hirsch, “Autonomic nervous system activity in weight gain and weight loss,” The American Journal of Physiology, vol. 269, no. 1, part 2, pp. R222–R225, 1995.^,24S.Welle, R. G. Schwartz, and M. Statt, “Reduced metabolic rate during 𝛽-adrenergic blockade in humans,”Metabolism: Clinical and Experimental, vol. 40, no. 6, pp. 619–622, 1991.^,25M. J. Lohse, “Molecular mechanisms of membrane receptor desensitization,” Biochimica et Biophysica Acta—Molecular Cell Research, vol. 1179, no. 2, pp. 171–188, 1993.^,26W. P. Hausdorff, M. G. Caron, and R. J. Lefkowitz, “Turning off the signal: desensitization of 𝛽-adrenergic receptor function,” The FASEB Journal, vol. 4, no. 11, pp. 2881–2889, 1990.^,27Alicia A. Thorp, Markus P. Schlaich, “Relevance of Sympathetic Nervous System Activation in Obesity and Metabolic Syndrome”, Journal of Diabetes Research, vol. 2015, Article ID 341583, 11 pages, 2015.^,28R. R. Townsend and S. Klein, “Lipolytic sensitivity and response to fasting in normotensive and hypertensive obese humans,” Metabolism: Clinical and Experimental, vol. 46, no. 9, pp. 1080–1084, 1997.^,29H. Lithell, T. Pollare, C. Berne, and B. Saltin, “Themetabolic and circulatory response to beta-blockade in hypertensive men is correlated tomuscle capillary density.,” Blood pressure, vol. 1, no. 1, pp. 20–26, 1992.^,30S. Rossner, C. L. Taylor, R. P. Byington, and C. D. Furberg, “Long term propranolol treatment and changes in body weight after myocardial infarction,” British Medical Journal, vol. 300, no. 6729, pp. 902–903, 1990. 
  • Adrenal Fatigue³¹Z. S. K. Lee, J. A. J. H. Critchley, B. Tomlinson et al., “Urinary epinephrine and norepinephrine interrelations with obesity, insulin, and the metabolic syndrome in Hong Kong Chinese,” Metabolism: Clinical and Experimental, vol. 50, no. 2, pp. 135–143, 2001.^,32N. E. Straznicky, E. A. Lambert, G. W. Lambert, K. Masuo, M. D. Esler, and P. J. Nestel, “Effects of dietary weight loss on sympathetic activity and cardiac risk factors associated with the metabolic syndrome,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 11, pp. 5998–6005, 2005.^,33N. E. Straznicky, N. Eikelis, E. A. Lambert, and M. D. Esler, “Mediators of sympathetic activation in metabolic syndrome obesity,” Current Hypertension Reports, vol. 10, no. 6, pp. 440–447, 2008.^,34G. Grassi, R. Dell’Oro, F. Quarti-Trevano et al., “Neuroadrenergic and reflex abnormalities in patients with metabolic syndrome,” Diabetologia, vol. 48, no. 7, pp. 1359–1365, 2005.^,35M. Schlaich, N. Straznicky, E. Lambert, and G. Lambert, “Metabolic syndrome: a sympathetic disease?” The Lancet Diabetes and Endocrinology, vol. 3, no. 2, pp. 148–157, 2015.^,36Alicia A. Thorp, Markus P. Schlaich, “Relevance of Sympathetic Nervous System Activation in Obesity and Metabolic Syndrome”, Journal of Diabetes Research, vol. 2015, Article ID 341583, 11 pages, 2015.
• Sleep Issues³⁷Córdoba J, Cabrera J, Lataif L, Penev P, Zee P, Blei AT. High prevalence of sleep disturbance in cirrhosis. Hepatology 1998; 27: 339-345^,38Franco RA, Ashwathnarayan R, Deshpandee A, Knox J, Daniel J, Eastwood D, Franco J, Saeian K. The high prevalence of restless legs syndrome symptoms in liver disease in an academic-based hepatology practice. J Clin Sleep Med 2008; 4: 45-49^,39Martino ME, Romero-Vives M, Fern ndez-Lorente J, De Vicente E, B rcena R, Gaztelu JM. Sleep electroencephalogram alterations disclose initial stage of encephalopathy. Methods Find Exp Clin Pharmacol 2002; 24 Suppl D: 119-122^,40Mostacci B, Ferlisi M, Baldi Antognini A, Sama C, Morelli C, Mondini S, Cirignotta F. Sleep disturbance and daytime sleepiness in patients with cirrhosis: a case control study. Neurol Sci 2008; 29: 237-240
  • Inability to stay asleep at night. (Sympathetic over-ride)⁴¹K. G. M. M. Alberti, P. Zimmet, and J. Shaw, “The metabolic syndrome—a new worldwide definition,” The Lancet, vol. 366, no. 9491, pp. 1059–1062, 2005.^,42E. S. Ford, “Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence,” Diabetes Care, vol. 28, no. 7, pp. 1769–1778, 2005.^,43S. Malik, N. D. Wong, S. S. Franklin et al., “Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults,” Circulation, vol. 110, no. 10, pp. 1245–1250, 2004.^,44J. M. Dekker,C.Girman, T. Rhodes et al., “Metabolic syndrome and 10-year cardiovascular disease risk in the Hoorn Study,” Circulation, vol. 112, no. 5, pp. 666–673, 2005.^,45Perciaccante A, Fiorentini A, Paris A, Serra P, Tubani L. Circadian rhythm of the autonomic nervous system in insulin resistant subjects with normoglycemia, impaired fasting glycemia, impaired glucose tolerance, type 2 diabetes mellitus. BMC Cardiovasc Disord. 2006 May 2;6:19^,46N. E. Straznicky, E. A. Lambert, G. W. Lambert, K. Masuo, M. D. Esler, and P. J. Nestel, “Effects of dietary weight loss on sympathetic activity and cardiac risk factors associated with the metabolic syndrome,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 11, pp. 5998–6005, 2005.^,47G. E. Alvarez, S. D. Beske, T. P. Ballard, and K. P. Davy, “Sympathetic neural activation in visceral obesity,” Circulation, vol. 106, no. 20, pp. 2533–2536, 2002.^,48N. E. Straznicky, N. Eikelis, E. A. Lambert, and M. D. Esler, “Mediators of sympathetic activation in metabolic syndrome obesity,” Current Hypertension Reports, vol. 10, no. 6, pp. 440–447, 2008.^,49G.Grassi, G. Seravalle, M. Colombo et al., “Body weight reduction, sympathetic nerve traffic, and arterial baroreflex in obese normotensive humans,” Circulation, vol. 97, no. 20, pp. 2037–2042, 1998.^,50C. L. Gentile, J. S. Orr, B. M. Davy, and K. P. Davy, “Modest weight gain is associated with sympathetic neural activation in nonobese humans,” The American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 292, no. 5, pp. R1834–R1838, 2007. 
  • Excess Daytime Sleepiness (body goes into Power-Saver Mode)⁵¹Peppard PE, Young T, Barnet JH, et al. Increased Prevalence of Sleep-Disordered Breathing in Adults. Am J Epidemiol 2013;177:1006-14.^,52McNicholas WT, Bonsigore MR; Management Committee of EU COST ACTION B26. Sleep apnoea as an independent risk factor for cardiovascular disease: current evidence, basic mechanisms and research priorities. Eur Respir J 2007;29:156-78.^,53Kent BD, McNicholas WT, Ryan S. Insulin resistance, glucose intolerance and diabetes mellitus in obstructive sleep apnoea. J Thorac Dis. 2015;7(8):1343-1357.^,54Maria R. Bonsignore, Cristina Esquinas, Antonia Barceló, Manuel Sanchez-de-la-Torre, Alessandra Paternó, Joaquin Duran-Cantolla, José M. Marín, Ferran Barbé. Metabolic syndrome, insulin resistance and sleepiness in real-life obstructive sleep apnoea. European Respiratory Journal May 2012, 39 (5) 1136-1143
• Thermogenesis (Sympathetic over-ride)
  • Also know as “Hot Flashes”.⁵⁵Alicia A. Thorp, Markus P. Schlaich, “Relevance of Sympathetic Nervous System Activation in Obesity and Metabolic Syndrome”, Journal of Diabetes Research, vol. 2015, Article ID 341583, 11 pages, 2015.^,56L. Landsberg, “Insulin-mediated sympathetic stimulation: role in the pathogenesis of obesity-related hypertension (or, how insulin affects blood pressure, and why),” Journal of Hypertension, vol. 19, no. 3, part 2, pp. 523–528, 2001.^,57L. J. Aronne, R.Mackintosh, M. Rosenbaum, R. L. Leibel, and J. Hirsch, “Autonomic nervous system activity in weight gain and weight loss,” The American Journal of Physiology, vol. 269, no. 1, part 2, pp. R222–R225, 1995.
• Hypoglycemic-Associated Autonomic Dysfunction (HAAF)
  • Patients with Insulin Resistance are likely to have impaired awareness of their hypoglycemia, termed Hypoglycemia Unawareness (HU).⁵⁸Cryer PE. Mechanisms of sympathoadrenal failure and hypoglycemia in diabetes. J Clin Invest. 2006 Jun;116(6):1470-3. doi: 10.1172/JCI28735.^,59Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure and its component syndromes in diabetes. Diabetes. 2005 Dec;54(12):3592-601. doi: 10.2337/diabetes.54.12.3592. PMID: 16306382.^,60Cryer PE. Diverse causes of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med. 2004 May 27;350(22):2272-9. doi: 10.1056/NEJMra031354. PMID: 15163777.  
  • Women are more prone to Hypoglycemic Unawareness.
  • The strongest risk factor for future hypoglycemia is the number of prior hypoglycemic events;
  • AD is common in Insulin Resistance / Metabolic Syndrome patients, and in those who suffer Iatrogenic Hypoglycemia⁶¹Chittineni C, Driver BE, Halverson M, et al. Incidence and Causes of Iatrogenic Hypoglycemia in the Emergency Department. West J Emerg Med. 2019;20(5):833-837. ^,62Allison MG, McCurdy MT. Alcoholic metabolic emergencies. Emerg Med Clin North Am. 2014;32(2):293–301.^,63Khanimov I, Shimonov M, Wainstein J, Leibovitz E. Hypoglycemia, Malnutrition and Body Composition. Adv Exp Med Biol. 2021;1307:71-84. doi: 10.1007/5584_2020_526. Erratum in: Adv Exp Med Biol. 2021;1307:577.^,64Cryer PE. Iatrogenic hypoglycemia as a cause of hypoglycemia-associated autonomic failure in IDDM. A vicious cycle. Diabetes. 1992 Mar;41(3):255-60. there is a hypoglycemia-associated autonomic failure (HAAF).⁶⁵Cryer PE. Hypoglycemia in diabetes: pathophysiological mechanisms and diurnal variation. Prog Brain Res. 2006;153:361–365 This is a result of decreased response of adrenaline and the SNS to hypoglycemia
• Hypoglycemic Unawareness (HU)
  • AD creates hypoglycemic unawareness, and therefore a vicious circle of worsening AD.⁶⁶Cryer PE. Diverse causes of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med. 2004;350(22):2272–2279.^,

• Blood sugar/glucose – High.
  • Mild, brief periods of low blood sugar are normal during the day, especially if meals are not eaten on a regular schedule. But prolonged hyperglycemia with some of the symptoms listed here, especially physical and mental fatigue, are not normal. 
  • Feeling agitated, jittery, moody, nauseated, or having a headache is common in Insulin Resistance, without immediate relief once food is eaten.
• Blood sugar / glucose – Low or Normal
  • Low Blood Sugar / Glucose
    • Occurs with Hypoglycemic Associated Autonomic Failure (HAAF) and/or Hypoglycemic Unawareness (HU).
  • Prolonged Period of Fasting or Dietary Restriction
    • People with pre-diabetes or insulin resistance also can have low or normal blood sugars, if their high circulating insulin levels are further challenged by a prolonged period of fasting or dietary restriction, e.g. food allergy/sensitivities, Paleo, Keto, Vegan, Vegetarian, etc.
• Bone Health
  • The higher the degree of insulin resistance, the greater the risk of osteoporosis.⁶⁷Ming Zhuo, Ze Chen, Mao-Lin Zhong, et.al., Association of insulin resistance with bone mineral density in a nationwide health check-up population in China, Bone, Volume 170, 2023, 116703, ISSN 8756-3282,^,68Gu, P., Pu, B., Xin, Q. et al. The metabolic score of insulin resistance is positively correlated with bone mineral density in postmenopausal patients with type 2 diabetes mellitus. Sci Rep 13, 8796 (2023).^,69Fu YH, Liu WJ, Lee CL, Wang JS. Associations of insulin resistance and insulin secretion with bone mineral density and osteoporosis in a general population. Front Endocrinol (Lausanne). 2022 Sep 20;13:971960.^,70Choo MS, Choi SR, Han JH, Lee SH, Shim YS (2017) Association of insulin resistance with near peak bone mass in the femur and lumbar spine of Korean adults aged 25-35: The Korean National Health and Nutrition Examination Survey 2008-2010. PLoS ONE 12(7): e0177311.^,71Nicola Napoli, Caterina Conte, Claudio Pedone, Elsa S Strotmeyer, Kamil E Barbour, Dennis M Black, Elizabeth J Samelson, Ann V Schwartz, Effect of Insulin Resistance on BMD and Fracture Risk in Older Adults, The Journal of Clinical Endocrinology & Metabolism, Volume 104, Issue 8, August 2019, Pages 3303–3310,^{, 72}Shieh, A., Greendale, G.A., Cauley, J.A. et al. Prediabetes and insulin resistance are associated with lower trabecular bone score (TBS): cross-sectional results from the Study of Women’s Health Across the Nation TBS Study. Osteoporos Int 33, 1365–1372 (2022).^,73Kathryn M. Thrailkill, Charles K. Lumpkin, Jr., R. Clay Bunn, Stephen F. Kemp, and John L. Fowlkes. Is insulin an anabolic agent in bone? Dissecting the diabetic bone for clues. American Journal of Physiology-Endocrinology and Metabolism 2005 289:5, E735-E745    

• Brain fogginess and inability to focus.
  • Brain requires oxygen and glucose to function efficiently. Insulin Resistance deprives the brain of the necessary oxygen and glucose.⁷⁴Cetinkalp S, Simsir IY, Ertek S. Insulin resistance in brain and possible therapeutic approaches. Curr Vasc Pharmacol. 2014;12(4):553-64.^,75Islam MR, Nyholt DR. Glucose-Related Traits and Risk of Migraine-A Potential Mechanism and Treatment Consideration. Genes (Basel). 2022 Apr 22;13(5):730.^,76Diamant M. Brain insulin signalling in the regulation of energy balance and peripheral metabolism. Ideggyogy Sz. 2007 Mar 30;60(3-4):97-108.^,77Williamson R, McNeilly A, Sutherland C. Insulin resistance in the brain: an old-age or new-age problem? Biochem Pharmacol. 2012 Sep 15;84(6):737-45.^,78Milstein JL, Ferris HA. The brain as an insulin-sensitive metabolic organ. Mol Metab. 2021 Oct;52:101234. doi: 10.1016/j.molmet.2021.101234. Epub 2021 Apr 15.^,79Ma L, Wang J, Li Y. Insulin resistance and cognitive dysfunction. Clin Chim Acta. 2015 Apr 15;444:18-23. doi: 10.1016/j.cca.2015.01.027.
  • Insulin resistance influences brain function by its action on cerebral glucose metabolism and on neurodegeneration.⁸⁰Femminella GD, Livingston NR, Raza S, et. al. Does insulin resistance influence neurodegeneration in non-diabetic Alzheimer’s subjects? Alzheimers Res Ther. 2021 Feb 17;13(1):47. doi: 10.1186/s13195-021-00784-w. PMID: 33597002; PMCID: PMC7890851.  
  • RBC agglutination slows blood flow to the muscles, nerves and all parts of the body. RBC agglutination causes RBCs to shed oxygen. Further depriving all of the body of oxygen and glucose.  
• Cardiovascular disease⁸¹Alicia A. Thorp, Markus P. Schlaich, “Relevance of Sympathetic Nervous System Activation in Obesity and Metabolic Syndrome”, Journal of Diabetes Research, vol. 2015, Article ID 341583, 11 pages, 2015.^,82Perciaccante A, Fiorentini A, Paris A, Serra P, Tubani L. Circadian rhythm of the autonomic nervous system in insulin resistant subjects with normoglycemia, impaired fasting glycemia, impaired glucose tolerance, type 2 diabetes mellitus. BMC Cardiovasc Disord. 2006 May 2;6:19^,83K. G. M. M. Alberti, P. Zimmet, and J. Shaw, “The metabolic syndrome—a new worldwide definition,” The Lancet, vol. 366, no. 9491, pp. 1059–1062, 2005.^,84Reaven G. The metabolic syndrome or the insulin resistance syndrome? different names, different concepts, and different goals. Endocrinol Metab Clin North Am. 2004;33(2):283-303.^,85Wilcox G. Insulin and insulin resistance. Clin Biochem Rev. 2005;26(2):19-39.  
  • RBC Agglutination causes RBCs to shed oxygen. Especially in turbulent areas, i.e. heart blood vessels. Free oxygen becomes destructive Reactive Oxygen Species (free-radicals) that damage interior of blood vessels. Cholesterol is used to spackle over the damaged areas.

• Depression.
  • Insulin resistance does not change with antidepressant treatment.⁸⁶Woo YS, Lim HK, Wang SM, Bahk WM. Clinical Evidence of Antidepressant Effects of Insulin and Anti-Hyperglycemic Agents and Implications for the Pathophysiology of Depression-A Literature Review. Int J Mol Sci. 2020 Sep 22;21(18):6969.^,87Fernandes BS, Salagre E, Enduru N, Grande I, Vieta E, Zhao Z. Insulin resistance in depression: A large meta-analysis of metabolic parameters and variation. Neurosci Biobehav Rev. 2022 Aug;139:104758. 
  • Insulin resistance is increased in depression during acute episodes.⁸⁸Watson KT, Simard JF, Henderson VW, Nutkiewicz L, Lamers F, Rasgon N, Penninx B. Association of Insulin Resistance With Depression Severity and Remission Status: Defining a Metabolic Endophenotype of Depression. JAMA Psychiatry. 2021 Apr 1;78(4):439-441.^,89Fernandes BS, Salagre E, Enduru N, Grande I, Vieta E, Zhao Z. Insulin resistance in depression: A large meta-analysis of metabolic parameters and variation. Neurosci Biobehav Rev. 2022 Aug;139:104758.^,90Reaven G. The metabolic syndrome or the insulin resistance syndrome? different names, different concepts, and different goals. Endocrinol Metab Clin North Am. 2004;33(2):283-303.^,91Wilcox G. Insulin and insulin resistance. Clin Biochem Rev. 2005;26(2):19-39.^,92Smith DJ. Insulin resistance and depression: difference in patient groups could have been explained by other factors. BMJ. 2005 Apr 23;330(7497):965; ^,93Singh MK, Leslie SM, Packer MM, Zaiko YV, Phillips OR, Weisman EF, Wall DM, Jo B, Rasgon N. Brain and behavioral correlates of insulin resistance in youth with depression and obesity. Horm Behav. 2019 Feb;108:73-83.^,94Okamura F, Tashiro A, Utumi A, Imai T, Suchi T, Tamura D, Sato Y, Suzuki S, Hongo M. Insulin resistance in patients with depression and its changes during the clinical course of depression: minimal model analysis. Metabolism. 2000 Oct;49(10):1255-60.    
  • When the brain is deprived of oxygen and glucose, brain function slows down, going into power saver mode creating the symptoms of “depression”. 
  • Brain requires oxygen and glucose to function efficiently. Insulin Resistance deprives the brain of the necessary oxygen and glucose.  
  • RBC agglutination slows blood flow to the brain. Further depriving the brain of oxygen and glucose.
• Dyslipidemia – Increased cholesterol and triglycerides.
  • High Cholesterol, LDL increase the stickiness of Red Blood Cells – RBC Agglutination.
  • Hypoxia (Low Oxygen):
    • High Cholesterol, LDL decreases the delivery and availability of oxygen to the tissues of the body.⁹⁵A. G. Marachev, Morphological Bases of Adaptation and Pathology of Human Lungs, Heart and Red Blood in the Far North Dissertation, Moscow, 1980.^,96A. G. Marachev, V. I. Sorokovoi, and A. V. Kornev, “Bioenergy of red blood cells in the inhabitants of the north,” Therapeutic archive, vol. 8, no. 3, pp. 407–415, 1982.^,97L. E. Panin, Energy Aspects of Adaptation, Medicine, Leningrad, 1978.^,98L. E. Panin, “Man in extreme conditions in the Arctic,” Bulletin of the Siberian Branch of the Russian Academy of Medical Sciences, vol. 30, no. 3, pp. 92–98, 2010.^,99N. W. Tietz and P. R. Finley, Сlinical Guide to Laboratory Tests, Philadelphia, 1983.^,100K. Kon, N. Maeda, M. Sekiya, T. Shiga, and T. Suda, “A method for studying oxygen diffusion barrier in erythrocytes: effects of haemoglobin content and membrane cholesterol,” The Journal of Physiology, vol. 309, no. 1, pp. 569–590, 1980.^,101A. Marachev, L. Solovenchyk, and A. Lapynsky, “Adaptive changes in lipid composition of membranes in the inhabitants of the north,” Arctic Medical Research, vol. 51, no. 2, pp. 98–102, 1992.^,102L. K. Dobrodeeva, A. V. Samodova, S. N. Balashova, K. O. Pashinskaya, “Intercellular Interactions in Peripheral Venous Blood in Practically Healthy Residents of High Latitudes”, BioMed Research International, vol. 2021, Article ID 7086108, 11 pages, 2021.  
  • RBC Agglutination causes RBCs to shed oxygen. Free oxygen becomes destructive Reactive Oxygen Species (free-radicals) that damage interior of blood vessels. Cholesterol is used to spackle over the damaged areas.
  • When Triglycerides are equal to or greater than Cholesterol suspect Diabetes.

• Exocrine Pancreas Insufficiency
  • The Pancreas is a doubled-entity organ, with both an exocrine (99% of the pancreas) and an endocrine (1% of the pancreas) component, reciprocally interacting in a composed system whose function is relevant for digestion, absorption, and homeostasis of nutrients. Thus, it is not surprising that disorders of the exocrine pancreas also affect the endocrine system and vice versa. It is well-known that patients with chronic pancreatitis develop a peculiar form of insulin resistance, caused by destruction and fibrotic injury of islet cells.¹⁰³Piciucchi M, Capurso G, Archibugi L, Delle Fave MM, Capasso M, Delle Fave G. Exocrine pancreatic insufficiency in diabetic patients: prevalence, mechanisms, and treatment. Int J Endocrinol. 2015;2015:595649.
  • Exocrine pancreatic insufficiency (EPI) stems from a deficiency of functional pancreatic enzymes with consequent maldigestion and malnutrition. EPI shares clinical symptoms and manifestations with other disorders and is a considerable burden to individuals affected.¹⁰⁴Barkin JA, Delk TB, Powell VJ. Symptoms, burden, and unmet needs of patients living with exocrine pancreatic insufficiency: a narrative review of the patient experience. BMC Gastroenterol. 2024 Mar 14;24(1):101.
  • Exocrine pancreatic insufficiency (EPI) is a disorder caused by the failure of the pancreas to deliver a minimum/threshold level of specific pancreatic digestive enzymes to the intestine, leading to the maldigestion of nutrients and macronutrients, resulting in their variable deficiencies. EPI is frequently under-diagnosed and, as a result, patients are often not treated appropriately.¹⁰⁵Lindkvist B. Diagnosis and treatment of pancreatic exocrine insufficiency. World J Gastroenterol. 2013 Nov 14;19(42):7258-66.^,106Whitcomb DC, Buchner AM, Forsmark CE. AGA Clinical Practice Update on the Epidemiology, Evaluation, and Management of Exocrine Pancreatic Insufficiency: Expert Review. Gastroenterology. 2023 Nov;165(5):1292-1301.^,
  • The exocrine pancreas is a functionally dangerous structure since it is exposed to digestion by its most aggressive enzymes (proteases, etc) despite self-protective measures such as the synthesis of some of these enzymes in the form of inactive zymogens (trypsinogen, etc.).¹⁰⁷Sánchez-Fayos Calabuig P, Martín Relloso MJ, González Guirado A, Porres Cubero JC. Enfermedad inflamatoria del páncreas por autoagresión enzimática: un modelo excepcional de crinofagia glandular [Inflammatory pancreatic disease due to enzyme autodigestion: an exceptional model of glandular crinophagy]. Gastroenterol Hepatol. 2007 Jun-Jul;30(6):343-50. Spanish. doi: 10.1157/13107569. PMID: 17662219.
  • Pancreatitis is the inflammation and autodigestion of the pancreas. Autodigestion describes a process whereby pancreatic enzymes destroy its own tissue leading to inflammation. The inflammation may be sudden (acute) or ongoing (chronic). Acute pancreatitis usually involves a single “attack,” after which the pancreas returns to normal. Severe acute pancreatitis can be life threatening. In chronic pancreatitis, permanent damage occurs to the pancreas and its function, often leading to fibrosis (scarring).¹⁰⁸Rodger A. Liddle. Chemical pancreatectomy: an unconventional approach to preventing autodigestion in pancreatitis. February 1, 2021. J Clin Invest. 2021;131(3):e146210.^,109Nagai H, Henrich H, Wünsch PH, Fischbach W, Mössner J. Role of pancreatic enzymes and their substrates in autodigestion of the pancreas. In vitro studies with isolated rat pancreatic acini. Gastroenterology. 1989 Mar;96(3):838-47.^,110H Nagai, H Henrich, P Wünsch, W Fischbach, J Mössner, Role of Pancreatic Enzymes and Their Substrates in Autodigestion of the Pancreas: In Vitro Studies With Isolated Rat Pancreatic Acini, Gastroenterology, Volume 96, Issue 2, Part 2, 1989, Pages 838-847,
  • It is well-known that patients with chronic pancreatitis develop a peculiar form of insulin resistance, caused by destruction and fibrotic injury of the islet cells.¹¹¹Piciucchi M, Capurso G, Archibugi L, Delle Fave MM, Capasso M, Delle Fave G. Exocrine pancreatic insufficiency in diabetic patients: prevalence, mechanisms, and treatment. Int J Endocrinol. 2015;2015:595649.^,112Struyvenberg MR, Martin CR, Freedman SD. Practical guide to exocrine pancreatic insufficiency – Breaking the myths. BMC Med. 2017 Feb 10;15(1):29.
  • Exocrine pancreatic insufficiency (EPI) is characterized by inadequate pancreatic enzyme delivery to the small intestine Exocrine pancreatic insufficiency (EPI) is characterized by inadequate pancreatic enzyme delivery to the small intestine, resulting in malabsorption. Clinical manifestations of EPI are often nonspecific and can lead to lack of timely recognition and diagnosis.¹¹³Perbtani Y, Forsmark CE. Update on the diagnosis and management of exocrine pancreatic insufficiency. F1000Res. 2019 Nov 26;8:F1000 Faculty Rev-1991.^,114Alkaade S, Vareedayah AA. A primer on exocrine pancreatic insufficiency, fat malabsorption, and fatty acid abnormalities. Am J Manag Care. 2017 Jul;23(12 Suppl):S203-S209.^,115Lv Y, Wei Q, Yuan X, Sun J, Zhang J, Qi L, Bao J, Su X, Li L. Two sides of the pancreas: Exocrine insufficiency is correlated with endocrine dysfunction in type 2 diabetes. Clin Chim Acta. 2021 Dec;523:81-86.
  • Myth: EPI occurs only with more than 90% loss of exocrine pancreatic function.
  • Expert opinion: EPI represents a graded response rather than a precise cut-off in pancreatic function and thus patients may benefit from early testing.¹¹⁶Struyvenberg, M.R., Martin, C.R. & Freedman, S.D. Practical guide to exocrine pancreatic insufficiency – Breaking the myths. BMC Med 15, 29 (2017).

• Intestinal bloating.
  • Maldigestion is a digestive disorder that occurs when the body doesn’t break down food into its components properly, resulting in nutrients being digested differently. This can happen when the pancreas doesn’t produce the enzymes needed for digestion, such as amylase, lipases, and proteases.  
  • People with EPI cannot properly digest the food they eat, which can result in uncomfortable symptoms like gas and bloating.¹¹⁷Alkaade S, Vareedayah AA. A primer on exocrine pancreatic insufficiency, fat malabsorption, and fatty acid abnormalities. Am J Manag Care. 2017 Jul;23(12 Suppl):S203-S209.
  • Fat maldigestion due to EPI can lead to gas, bloating, and stomach pain.¹¹⁸DiMagno EP, Go VL, Summerskill WH. Relations between pancreatic enzyme outputs and malabsorption in severe pancreatic insufficiency. N Engl J Med. 1973;288:813–5.
    • There is decreased bicarbonate output causing a lower intestinal pH, which precipitates bile salt acids and impairs micelle formation of fats [6, 7].¹¹⁹Ghaneh P, Neoptolemos JP. Exocrine pancreatic function following pancreatectomy. Ann N Y Acad Sci. 1999;880:308–18.^,120Guarner L, Rodríguez R, Guarner F, Malagelada JR. Fate of oral enzymes in pancreatic insufficiency. Gut. 1993;34:708–12.
    • Gas is one of the uncomfortable digestive problems that people with exocrine pancreatic insufficiency (EPI) experience. EPI is caused by a deficiency of pancreatic enzymes, which leads to maldigestion of macronutrients, especially fats. This can result in gas, bloating, and other digestive issues such as: Abdominal pain, Constipation, Diarrhea, Fatty stools, and Nausea.¹²¹Barkin JA, Delk TB, Powell VJ. Symptoms, burden, and unmet needs of patients living with exocrine pancreatic insufficiency: a narrative review of the patient experience. BMC Gastroenterol. 2024 Mar 14;24(1):101.
    • Fat maldigestion is compounded by decreased pancreatic secretion of lipase and colipase, further dampening hydrolysis of intraluminal fat.¹²²Struyvenberg MR, Martin CR, Freedman SD. Practical guide to exocrine pancreatic insufficiency – Breaking the myths. BMC Med. 2017 Feb 10;15(1):29.
    • Most intestinal gas is produced from food fermenting and putrefying due to inadequate production of digestive chemistry.
    • Insulin Resistance sufferers who eat carbohydrates suffer from gas, lots of it.
• Eye – Floaters, cataracts, declining vision¹²³Anan, F., Takayuki, M., Takahashi, N. et al. Diabetic retinopathy is associated with insulin resistance and cardiovascular autonomic dysfunction in type 2 diabetic patients. Hypertens Res 32, 299–305 (2009).^,124Parvanova A, Iliev I, Filipponi M, Dimitrov BD, Vedovato M, Tiengo A, Trevisan R, Remuzzi G, Ruggenenti P. Insulin resistance and proliferative retinopathy: a cross-sectional, case-control study in 115 patients with type 2 diabetes. J Clin Endocrinol Metab. 2004 Sep;89(9):4371-6.^,125Sinclair SH., Schwartz SS. Diabetic Retinopathy–An Underdiagnosed and Undertreated Inflammatory, Neuro-Vascular Complication of Diabetes. Frontiers in Endocrinology, 10, 2019 ISSN=1664-2392
  • retinal hemorrhages, floaters (soft exudates, hard exudates), Changes in blood vessels of the eyes (intraretinal microvascular abnormalities or venous beading)
  • Reversible cataracts¹²⁶Kiziltoprak H, Tekin K, Inanc M, Goker YS. Cataract in diabetes mellitus. World J Diabetes. 2019;10(3):140-153. doi:10.4239/wjd.v10.i3.140^,127Jin YY, Huang K, Zou CC, Liang L, Wang XM, Jin J. Reversible cataract as the presenting sign of diabetes mellitus: report of two cases and literature review. Iran J Pediatr. 2012;22(1):125-128.
  • Glaucoma – insulin resistance underpins the causality for intraocular pressure elevation and the consequent glaucomatous damages.¹²⁸Lee, JH., Kwon, YJ., Kim, S.J. et al. Metabolic syndrome as an independent risk factor for glaucoma: a nationally representative study. Diabetol Metab Syndr 15, 177 (2023).^,129Al Hussein Al Awamlh S, Wareham LK, Risner ML, Calkins DJ. Insulin Signaling as a Therapeutic Target in Glaucomatous Neurodegeneration. Int J Mol Sci. 2021 Apr 28;22(9):4672.^,130Dada T. Is Glaucoma a Neurodegeneration caused by Central Insulin Resistance: Diabetes Type 4? J Curr Glaucoma Pract. 2017 Sep-Dec;11(3):77-79.^,131Faiq, Muneeb A. Sengupta, Trina; Nath, Madhu; Velpandian, Thirumurthy; Saluja, Daman; Dada, Rima; Dada, Tanuj,; Chan, Kevin C.,. Ocular manifestations of central insulin resistance. Neural Regeneration Research 18(5):p 1139-1146, May 2023.

• Fatigue. Sometimes the fatigue is physical, but often it is mental.
  • Chronic fatigue syndrome (CFS), commonly known as Myalgic Encephalomyelitis (ME).¹³²Tomas C, Newton J. Metabolic abnormalities in chronic fatigue syndrome/myalgic encephalomyelitis: a mini-review. Biochem Soc Trans. 2018 Jun 19;46(3):547-553. 
  • CFS is associated with Insulin Resistance and Metabolic Syndrome,¹³³Germain A, Ruppert D, Levine SM, Hanson MR. Metabolic profiling of a myalgic encephalomyelitis/chronic fatigue syndrome discovery cohort reveals disturbances in fatty acid and lipid metabolism. Mol Biosyst. 2017 Jan 31;13(2):371-379. which further exacerbates fatigue.¹³⁴Maloney EM, Boneva RS, Lin JM, Reeves WC. Chronic fatigue syndrome is associated with metabolic syndrome: results from a case-control study in Georgia. Metabolism. 2010 Sep;59(9):1351-7.   
  • Increased energy strain may result from exertion-triggered tissue hypoxia, lead to systemic metabolic adaptation and compensation (Insulin Resistance).¹³⁵Fritschi C, Quinn L. Fatigue in patients with diabetes: a review. J Psychosom Res. 2010 Jul;69(1):33-41. doi: 10.1016/j.jpsychores.2010.01.021. 
  • Through various mechanisms, Insulin Resistance combined with Portal Hypertension are mediators of the key symptoms in ME/CFS and is a target for supportive intervention.¹³⁶Hoel F, Hoel A, Pettersen IK, Rekeland IG, Risa K, Alme K, Sørland K, Fosså A, Lien K, Herder I, Thürmer HL, Gotaas ME, Schäfer C, Berge RK, Sommerfelt K, Marti HP, Dahl O, Mella O, Fluge Ø, Tronstad KJ. A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome. JCI Insight. 2021 Aug 23;6(16):e149217.   
  • Muscles, nerves, brain, and all other parts of the body require oxygen and glucose to function efficiently. Insulin Resistance deprives all of them of the necessary oxygen and glucose. 
  • RBC agglutination slows blood flow to the muscles, nerves and all parts of the body. RBC agglutination causes RBCs to shed oxygen. Further depriving all of the body of oxygen and glucose.
• Fibromyalgia
  • Metabolic Syndrome or Insulin Resistance is associated with an increased risk of Fibromyalgia.¹³⁷Wolfe F, Smythe HA, Yunus MB, et al. The American College ofRheumatology 1990 criteria for the classification of fibromyalgia. Report of the multicenter criteria committee. Arthritis Rheum 1990;33:160–72.^,138Wolfe F, Clauw DJ, Fitzcharles MA, et al. 2016 Revisions to the 2010/ 2011 fibromyalgia diagnostic criteria. Semin Arthritis Rheum 2016; 46:319–29^,139Wolfe F, Smythe HA, Yunus MB, et al. The American College ofRheumatology 1990 criteria for the classification of fibromyalgia. Report of the multicenter criteria committee. Arthritis Rheum 1990;33:160–72.^,140Wolfe F, Clauw DJ, Fitzcharles MA, et al. 2016 Revisions to the 2010/ 2011 fibromyalgia diagnostic criteria. Semin Arthritis Rheum 2016; 46:319–29.^,141Tishler M, Smorodin T, Vazina-Amit M, Ramot Y, Koffler M, Fishel B. Fibromyalgia in diabetes mellitus. Rheumatol Int 2003;23:171–3.^,142Loevinger BL, Muller D, Alonso C, Coe CL. Metabolic syndrome in women with chronic pain. Metabolism 2007;56:87–93.^,143Mäntyselkä P, Miettola J, Niskanen L, Kumpusalo E. Glucose regulation and chronic pain at multiple sites. Rheumatology 2008;47:1235–8.^,144Lichtenstein A, Tiosano S, Comaneshter D, Amital H, Cohen AD, Amital D. Cross-sectional analysis of the associations between fibromyalgia and diabetes mellitus. Reumatologia 2018;56:275–8.
  • Fibromyalgia patients have a greater glycemic response to a glucose load than do healthy people.
  • The difference in the glycemic response is explained by Insulin Resistance and Metabolic Conditions.
• Fluid Retention
  • Failure of normal lymphatic function results in a build-up of interstitial fluid and can lead to the clinical manifestations such as lymphedema and ascites.¹⁴⁵Cardenas A, Bataller R, Arroyo V. Mechanisms of ascites formation. Clin Liver Dis 2000;4:447-465.^,146Harvey NL, Oliver G. Choose your fate: artery, vein or lymphatic vessel? Curr Opin Genet Dev 2004;14:499-505.^,147Oliver G, Alitalo K. The lymphatic vasculature: recent progress and paradigms. Annu Rev Cell Dev Biol 2005;21:457-483.^,148Tammela T, Alitalo K. Lymphangiogenesis: Molecular mechanisms and future promise. Cell 2010;140:460-476^,149Chung C, Iwakiri Y. The lymphatic vascular system in liver diseases: its role in ascites formation. Clin Mol Hepatol. 2013;19(2):99-104.  
  • This results in weight gain that is difficult to loose.
• Hypoglycemic Associated Autonomic Failure (HAAF)
  • Autonomic Dysfunction (AD) is common in Insulin Resistance / Metabolic Syndrome patients, and in those who suffer Iatrogenic Hypoglycemia¹⁵⁰Chittineni C, Driver BE, Halverson M, et al. Incidence and Causes of Iatrogenic Hypoglycemia in the Emergency Department. West J Emerg Med. 2019;20(5):833-837.^,151Allison MG, McCurdy MT. Alcoholic metabolic emergencies. Emerg Med Clin North Am. 2014;32(2):293–301.^,152Khanimov I, Shimonov M, Wainstein J, Leibovitz E. Hypoglycemia, Malnutrition and Body Composition. Adv Exp Med Biol. 2021;1307:71-84. doi: 10.1007/5584_2020_526. Erratum in: Adv Exp Med Biol. 2021;1307:577.^,153Cryer PE. Iatrogenic hypoglycemia as a cause of hypoglycemia-associated autonomic failure in IDDM. A vicious cycle. Diabetes. 1992 Mar;41(3):255-60. there is a hypoglycemia-associated autonomic failure (HAAF).¹⁵⁴Cryer PE. Hypoglycemia in diabetes: pathophysiological mechanisms and diurnal variation. Prog Brain Res. 2006;153:361–365 This is a result of decreased response of adrenaline and the SNS to hypoglycemia.¹⁵⁵Gaab J, Engert V, Heitz V, Schad T, Schürmeyer TH, Ehlert U. Associations between neuroendocrine responses to the Insulin Tolerance Test and patient characteristics in chronic fatigue syndrome. J Psychosom Res. 2004 Apr;56(4):419-24. doi: 10.1016/S0022-3999(03)00625-1. PMID: 15094026.  
  • Hypoglycemic Unawareness (HU)
    • Autonomic Dysfunction (AD) creates hypoglycemic unawareness, and therefore a vicious circle of worsening AD.¹⁵⁶Cryer PE. Diverse causes of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med. 2004;350(22):2272–2279.  
  • Symptoms of HAAF
    • sweating, hot flashes, (Thermogenesis)
    • palpitations, 
    • tremulousness, quivering, shakes;
    • anxiety, and hunger
• Hepatic Portal Hypertension
  • Insulin resistance (IR) is an important driver for the development of portal hypertension and nonalcoholic fatty liver. 
  • Hepatic Portal Hypertension is a multi-organ condition.

• Hepatic Encephalopathy
  • Minimal Hepatic Encephalopathy effects areas of attention, alertness, response inhibition, and decision making functions¹⁵⁷Bajaj JS, Saeian K, Verber MD, Hischke D, Hoffmann RG, Franco J, Varma RR, Rao SM. Inhibitory control test is a simple method to diagnose minimal hepatic encephalopathy and predict development of overt hepatic encephalopathy. Am J Gastroenterol 2007; 102: 754-760^,158Ford JM, Gray M, Whitfield SL, Turken AU, Glover G, Faustman WO, Mathalon DH. Acquiring and inhibiting prepotent responses in schizophrenia: event-related brain potentials and functional magnetic resonance imaging. Arch Gen Psychiatry 2004; 61: 119-129^,159Schiff S, Vallesi A, Mapelli D, Orsato R, Pellegrini A, Umilt  C, Gatta A, Amodio P. Impairment of response inhibition precedes motor alteration in the early stage of liver cirrhosis: a behavioral and electrophysiological study. Metab Brain Dis 2005; 20: 381-392^,160Weissenborn K, Ennen JC, Schomerus H, Rückert N, Hecker H. Neuropsychological characterization of hepatic encephalopathy. J Hepatol 2001; 34: 768-773 and sleep disorders.¹⁶¹Córdoba J, Cabrera J, Lataif L, Penev P, Zee P, Blei AT. High prevalence of sleep disturbance in cirrhosis. Hepatology 1998; 27: 339-345^,162Franco RA, Ashwathnarayan R, Deshpandee A, Knox J, Daniel J, Eastwood D, Franco J, Saeian K. The high prevalence of restless legs syndrome symptoms in liver disease in an academic-based hepatology practice. J Clin Sleep Med 2008; 4: 45-49^,163Martino ME, Romero-Vives M, Fern ndez-Lorente J, De Vicente E, B rcena R, Gaztelu JM. Sleep electroencephalogram alterations disclose initial stage of encephalopathy. Methods Find Exp Clin Pharmacol 2002; 24 Suppl D: 119-122^,164Mostacci B, Ferlisi M, Baldi Antognini A, Sama C, Morelli C, Mondini S, Cirignotta F. Sleep disturbance and daytime sleepiness in patients with cirrhosis: a case control study. Neurol Sci 2008; 29: 237-240 Moreover, the brain fog and cognitive impairment results in the use of more healthcare resources focused on treating only the brain while ignoring the causative liver dysfunction.¹⁶⁵Rakoski MO, McCammon RJ, Piette JD, Iwashyna TJ, Marrero JA, Lok AS, Langa KM, Volk ML. Burden of cirrhosis on older Americans and their families: analysis of the health and retirement study. Hepatology 2012; 55: 184-191^,166Kappus MR, Bajaj JS. Covert hepatic encephalopathy: not as minimal as you might think. Clin Gastroenterol Hepatol 2012; 10: 1208-1219^,167Bajaj JS, Riggio O, Allampati S, Prakash R, Gioia S, Onori E, Piazza N, Noble NA, White MB, Mullen KD. Cognitive dysfunction is associated with poor socioeconomic status in patients with cirrhosis: an international multicenter study. Clin Gastroenterol Hepatol 2013; 11: 1511-1516^,168Bajaj JS, Hafeezullah M, Hoffmann RG, Varma RR, Franco J, Binion DG, Hammeke TA, Saeian K. Navigation skill impairment: Another dimension of the driving difficulties in minimal hepatic encephalopathy. Hepatology 2008; 47: 596-604^,169Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R. Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy. Hepatology 2007; 45: 549-559^,170Bajaj JS, Wade JB, Gibson DP, Heuman DM, Thacker LR, Sterling RK, Stravitz RT, Luketic V, Fuchs M, White MB, Bell DE, Gilles H, Morton K, Noble N, Puri P, Sanyal AJ. The multi-dimensional burden of cirrhosis and hepatic encephalopathy on patients and caregivers. Am J Gastroenterol 2011; 106: 1646-1653^,171Ridola L, Nardelli S, Gioia S, Riggio O. Quality of life in patients with minimal hepatic encephalopathy. World J Gastroenterol. 2018;24(48):5446-5453. doi:10.3748/wjg.v24.i48.5446  
  • Unfortunately, it is often under-diagnosed, likely related to the notion that highly specialized personnel concentrate all their efforts on the brain and Central Nervous System.¹⁷²Stinton LM, Jayakumar S. Minimal hepatic encephalopathy. Can J Gastroenterol. 2013;27(10):572-574.  
  • Internal Hemorrhoids: Esophageal varices/GERD,¹⁷³Marcos Pasarín, Juan G Abraldes, Eleonora Liguori, Beverley Kok and Vincenzo La Mura, Intrahepatic vascular changes in non-alcoholic fatty liver disease: Potential role of insulin-resistance and endothelial dysfunction, World Journal of Gastroenterology, 10.3748/wjg.v23.i37.6777, 23, 37, (6777-6787), (2017)^,174Delphine Degré, Thierry Gustot, Ariane Gerkens, Nathalie Boon, Jonas Schreiber, Antonia Lepida, Thomas Sersté, Pierre Deltenre, Jacques Devière, Eric Trépo and Christophe Moreno, Insulin resistance is associated with esophageal varices in alcoholic liver disease patients, European Journal of Gastroenterology & Hepatology, 10.1097/MEG.0000000000000627, 28, 7, (792-796), (2016).^,175Ying Li, Gao Yang, Jinwei Qiang, Songqi Cai and Hao Zhou, Incidence of insulin resistance and diabetes in patients with portosystemic shunts without liver dysfunction, Journal of International Medical Research, 10.1177/0300060516659392, 44, 5, (1040-1048), (2016). stomach varicies,¹⁷⁶Yamagami T, Tanaka O, Yoshimatsu R, et al. Value of embolisation of collateral veins from gastric varices before balloon-occluded retrograde transvenous obliteration. J Med Imaging Radiat Oncol. 2011;55:26–32.^,177Irani S, Kowdley KV, Kozarek RA. Gastric varices: an updated review of management. J Clin Gastroenterol. 2011;45:133–148.^,178Chikamori F, Kuniyoshi N, Kawashima T, et al. Gastric varices with gastrorenal shunt: combined therapy using transjugular retrograde obliteration and partial splenic embolization. AJR Am J Roentgenol. 2008;191:555–559. small intestine,¹⁷⁹Hashizume M, Kitano S, Sugimachi K, et al. Three-dimensional view of the vascular structure of the lower esophagus in clinical portal hypertension. Hepatology. 1988;8:1482–1487.^,180Nardone G, Budillon G. Treatment of duodenal varices by endoscopic sclerotherapy. Gastrointest Endosc. 1991;37:407–408.^,181Stephan G. Bleeding of duodenal varices in portal hypertension. Bruns Beitr Klin Chir. 1973 Aug;220(5):467–474.^,182Lebrec D, Benhamou JP. Ectopic varices in portal hypertension. Clin Gastroenterol. 1985 Jan;14(1):105–121.^,183Lim LG, Lee YM, Tan L, et al. Percutaneous paraumbilical embolization as an unconventional and successful treatment for bleeding jejunal varices. World J Gastroenterol. 2009 Aug 14;15(30):3823–3826. large intestine,¹⁸⁴Feldman Sr M, Smith VM, Warner CG. Varices of the colon. Report of three cases. JAMA. 1962;179:729–730.^,185Weingart J, Hochter W, Ottenjann R. Varices of the entire colon-an unusual cause of recurrent intestinal bleeding. Endoscopy. 1982;14(2):69–70.^,186Francois F, TadrosC,DiehlD. Pan-colonic varices and Idiopathicportal hypertension. J Gastrointestin, Liver Dis. 2007, Sep;16(3):325–328. diaphragm, umbilical,¹⁸⁷Jung SC, Lee W, Chung JW, et al. Unusual causes of varicose veins in the lower extremities: CT venographic and Doppler US findings. Radiographics. 2009 Mar-Apr;29(2):525–536.^,188Sano K, Shuin T, Takebayashi S, et al. A case of vesical varices as a complication of portal hypertension and manifested gross hematuria. J Urol. 1989 Feb;141(2):369–371.^,189Lugagne PM, Castaing D, Conort P. Portal hypertension: a rare cause of hematuria. Prog Urol. 1992 Apr;2(2):294–298.^,190Loganathan G, Shyamkumar NK, Kurian G, et al. Vesical varix in cirrhosis of liver. Indian J Gastroenterol. 2000 Oct-Dec;19(4):193–194. Uterine,¹⁹¹Gaspar Y, Detry O, de Leval J. Vesical varices in a patient with portal hypertension. N Engl J Med. 2001 Nov 15;345(20):1503–1504.^,192McHugh PP, Jeon H, Gedaly R, et al. Vaginal varices with massive hemorrhage in a patient with nonalcoholic steatohepatitis and portal hypertension: successful treatment with liver transplantation. Liver Transpl. 2008 Oct;14(10):1538–1540 Pelvic Congestion Syndrome,¹⁹³Williams PL, et al. Veins of the abdomen and pelvis: hepatic portal system. In: . Gray’s Anatomy. 38th ed. New York, NY: Churchill Livingstone; 1999:1602–1604.^,194Kies DD, Kim HS. Pelvic congestion syndrome: a review of current diagnostic and minimally invasive treatment modalities. Phlebology. 2012 Mar;27 Suppl 1:52-7.^,195Winer AG, Chakiryan NH, Mooney RP, Verges D, Ghanaat M, Allaei A, Robinson L, Zinn H, Lang EK. Secondary pelvic congestion syndrome: description and radiographic diagnosis. Can J Urol. 2014 Aug;21(4):7365-8. PMID: 25171280. gallbladder,¹⁹⁶Tarantino G, Citro V, Conca P, Riccio A, Tarantino M, Capone D, et al.: What are the implications of the spontaneous spleno-renal shunts in liver cirrhosis? BMC Gastroenterol. 2009; 9: 89.^,197Chawla Y, Dilawari JB, Katariya S. Gallbladder wall varices in portal vein thrombosis. AJR Am J Roentgenol. 1994 Mar;162(3):643–645.^,198Gabata T, Matsui O, Kadoya M, et al. Gallbladder varices: demonstration of direct communication to intrahepatic portal veins by color doppler sonography and CT during arterial portography. Abdom Imaging. 1997 Jan-Feb;22(1):82–84.^,199Sarin SK, Agarwal SR. Extrahepatic portal vein obstruction. Semin Liver Dis. 2002 Feb;22(1):43–58.^,200Shin SM, Kim S, Lee JW, et al. Biliary abnormalities associated with portal biliopathy: evaluation on MR cholangiography. AJR Am J Roentgenol. 2007 Apr;188(4):W 341–W 347. and spider/varicose veins in legs.²⁰¹Petren T. The veins of the extrahepatic biliary system and their pathologic anatomic significance. Vert Anat Ges. 1932;41:139–143.^,202Bosch J, Berzigotti A, Garcia-Pagan JC, Abraldes JG. The management of portal hypertension: rational basis, available treatments and future options. J Hepatol. 2008;48 Suppl 1:S68-92.  
  • External Hemorrhoids: Vaginal,²⁰³Jung SC, Lee W, Chung JW, et al. Unusual causes of varicose veins in the lower extremities: CT venographic and Doppler US findings. Radiographics. 2009 Mar-Apr;29(2):525–536.^,204McHugh PP, Jeon H, Gedaly R, et al. Vaginal varices with massive hemorrhage in a patient with nonalcoholic steatohepatitis and portal hypertension: successful treatment with liver transplantation. Liver Transpl. 2008 Oct;14(10):1538–1540 Rectal²⁰⁵Williams PL, et al. Veins of the abdomen and pelvis: hepatic portal system. In: . Gray’s Anatomy. 38th ed. New York, NY: Churchill Livingstone; 1999:1602–1604.^,206Caletti GC, Brocchi E, Ferrari A, et al. Value of endoscopic ultrasonography in the management of portal hypertension. Endoscopy. 1992;24(suppl 1):342–346.^,207Sharma M, Rameshbabu CS. Collateral pathways in portal hypertension. J Clin Exp Hepatol. 2012;2(4):338-352.^,208Sato T. Transabdominal color Doppler ultrasonography for the diagnosis of small intestinal and vesical varices in a patient successfully treated with percutaneous transhepatic obliteration. Clin J Gastroenterol. 2010;3(Number 4):214–218.^,209Hollinshead WH. The rectum and anal canal. In: . Anatomy for Surgeons. 2nd ed., vol. 2. Hoeber Medical Division, Harper & Row; 1971. 676–720.^,210Yachha SK, Dhiman RK, Gupta R, et al. Endosonographic evaluation of the rectum in children with extrahepatic portal venous obstruction. J Pediatr Gastroenterol Nutr. 1996 Nov;23(4):438–441.^,211Dhiman RK, Saraswat VA, Choudhuri G, et al. Endosonographic, endoscopic and histologic evaluation of alterations in the rectal venous system in patients with portal hypertension. Gastrointest Endosc. 1999 Feb;49(2):218–227. 

• Disc Bulges: 96% of disc bulges seen on MRI images are Epidural Varices.²¹²Al Khalloufi K, Laiyemo AO. Management of rectal varices in portal hypertension. World J Hepatol. 2015;7(30):2992-2998. doi:10.4254/wjh.v7.i30.2992^,213LaBan MM, Ay-Ming W, Shetty A, Sessa GR and Taylor RS. Varicosities of the paravertebral plexus of veins associated with nocturnal spinal pain as imaged by magnetic resonance venography. Am J. Phys. Med. Rehabil. 1999 78 (1): 72 – 76.^,214MM Laban, AM Wang, AN Shetty, RS. Taylor. Varicosities of the paravertebral plexus of veins associated with nocturnal spinal pain as imaged by magnetic resonance venography – A brief report. Am J Physical Medicine & Rehabilitation 78(1):72-6 · January 1999^,215Gauthier G, Wildi E. Porto-systemic encephalo-myelopathy. Rev Neurol (Paris). 1975 May;131(5):319-38.
• Cauda Equina Syndrome (CES) by means of direct mechanical compression or congested flow-induced ischemia.²¹⁶Nardone R, Buratti T, Oliviero A, Lochmann A, Tezzon F. Corticospinal involvement in patients with a portosystemic shunt due to liver cirrhosis: a MEP study. J Neurol. 2006 Jan;253(1):81-5. Epub 2005 Aug 4.^,217AlTahan HA, Amer RR, Madani AA, Bakhsh EA. An unusual cause of cauda equina syndrome: lumbar epidural venous engorgement. Am J Case Rep. 2018; 19: 694–698.^,218Carvalho DZ, Hughes JD, Liebo GB, et al. Venous congestive myelopathy due to chronic inferior vena cava thrombosis treated with endovascular stenting: case report and review of the literature. J Vasc Interv Neurol. 2015; 8(1): 49–53.^,219Go MR, Baril DT, Leers SA, Chaer RA. Acute cauda equina syndrome secondary to iliocaval thrombosis successfully treated with thrombolysis and pharmacomechanical thrombectomy. J Endovasc Ther. 2009; 16(2): 233–237.^,220Mohit AA, Fisher DJ, Matthews DC, et al. Inferior vena cava thrombosis causing acute cauda equina syndrome. Case report. J Neurosurg. 2006; 104(1 Suppl): 46–49. 
• Brain and Spinal Cord Myelopathy causing changes in the central nervous system blood flow and neural degeneration.²²¹Lee JH, Song WJ, Kang KC. Myelopathy-mimicking symptoms of epidural venous engorgement and syringomyelia due to inferior vena cava stenosis at the thoracolumbar junction in a patient with Budd-Chiari syndrome. J Neurosurg Spine. 2015; 23(4): 467–470.^,222Tazawa K, Shimojima Y, Okano T, Yazaki M, Takei Y, Shimojo H, Kobayashi K, Saheki T, Ikeda S. An autopsy case with adult onset type II citrullinemia showing myelopathy. J Neurol Sci. 2007 Feb 15;253(1-2):77-80. Epub 2007 Jan 2.^,223Panicker J, Sinha S, Taly AB, Ravishankar S, Arunodaya GR. Hepatic myelopathy: a rare complication following extrahepatic portal vein occlusion and lienorenal shunt. Neurol India. 2006 Sep;54(3):298-300.^,224Gauthier G, Wildi E. Porto-systemic encephalo-myelopathy. Rev Neurol (Paris). 1975 May;131(5):319-38.  
• Hypertension – Increased blood pressure.
  • It is a fact that most people with hypertension have too much insulin and are Insulin Resistant. It is often possible to show a direct relationship between insulin resistance and blood pressure: as insulin levels elevate, so does blood pressure. A close relationship exists among insulin resistance, glucose alterations, and arterial hypertension.  
  • ²²⁵Antoniotti V, Amore M, Caputo M, Fania C, Mancioppi V, Casoli G, Tini S, Antonioli A, Aimaretti G, Rabbone I, Bellone S, Prodam F. Glucose Alterations, Insulin Resistance, Arterial Hypertension, and Renin are Strictly Associated in Pediatric Obesity. J Endocr Soc. 2023 Jun 26;7(8):bvad088.^,226Miroshnik NIu, Chamontin B, Brillac T, Salvador M, Amar J. Arterial’naia gipertenziia i insulinorezistentnost’ [Arterial hypertension and insulin resistance]. Lik Sprava. 1995 Sep-Dec;(9-12):44-7. Russian. PMID: 8983788.^,227Landsberg L. Insulin resistance and hypertension. Clin Exp Hypertens. 1999 Jul-Aug;21(5-6):885-94. doi: 10.3109/10641969909061017. PMID: 10423110.
  • Insulin resistance and reactive hyperinsulinemia occur not only in patients with obesity, impaired glucose tolerance or non-insulin-dependent (Type 2) diabetes mellitus, but also in many non-obese, non-diabetic individuals with early stages of Portal Hypertension.²²⁸Weidmann P, Müller-Wieland D, de Courten M, Krone W. Insulinresistenz und arterielle Hypertonie [Insulin resistance and arterial hypertension]. Herz. 1995 Feb;20(1):16-32. German. PMID: 7713473.
  • Essential arterial hypertension is an insulin-resistant state.²²⁹Ferrannini E, Buzzigoli G, Bonadonna R, Giorico MA, Oleggini M, Graziadei L, Pedrinelli R, Brandi L, Bevilacqua S. Insulin resistance in essential hypertension. N Engl J Med. 1987 Aug 6;317(6):350-7.
  • Common mechanisms, for instance, involve upregulation of the renin-angiotensin-aldosterone system, oxidative stress, inflammation, and activation of the immune system, have a role in the association between insulin resistance and arterial hypertension.²³⁰Sinha S, Haque M. Insulin Resistance Is Cheerfully Hitched with Hypertension. Life (Basel). 2022 Apr 10;12(4):564.
  • Insulin resistance causes reduced vascularization of the skeletal muscles which on the background of insulin resistance leads to enhanced development of hypertension with subsequent hypertrophy of the vascular wall and left ventricle and to the development of arteriosclerosis.²³¹Hrnciarová M, Hrnciar J, Jakubíková K. Inzulínová rezistencia a artériová hypertenzia [Insulin resistance and arterial hypertension]. Vnitr Lek. 1995 Feb;41(2):111-6. Slovak. PMID: 7725634.
• Reduced Muscle Vascularization
  • The skeletal muscle is one of the main targets of insulin and its action is central for the maintenance of glucose homeostasis.²³²Thiebaud D, Jacot E, Defronzo RA, Maeder E, Jequier E, Felber J-P. The effect of graded doses of insulin on total glucose uptake, glucose oxidation, and glucose storage in man. Diabetes. 1982;31:957–963.
  • The skeletal muscle vasculature behaves in an extremely flexible manner.²³³Saltin B, Radegran G, Koskolou M, Roach R. Skeletal muscle blood flow in humans and its regulation during exercise. Acta Physiol Scand. 1998;162:421–436.^,234Klitzman B, Damon D, Gorczynski R, Duling B. Augmented tissue oxygen supply during striated muscle contraction in the hamster. Relative contributions of capillary recruitment, functional dilation, and reduced tissue PO2. Circ Res. 1982;51:711–721.
  • Skeletal muscle microvascular (capillary) blood flow plays an important role in glucose metabolism by increasing the delivery of glucose and insulin to the myocytes. This process is impaired in insulin-resistant individuals.²³⁵Abdul-Ghani MA, DeFronzo RA. Pathogenesis of insulin resistance in skeletal muscle. J Biomed Biotechnol. 2010;2010:476279.^,236Sylow L, Tokarz VL, Richter EA, Klip A. The many actions of insulin in skeletal muscle, the paramount tissue determining glycemia. Cell Metab. 2021 Apr 6;33(4):758-780.^,237Carmichael, L., Keske, M.A., Betik, A.C. et al. Is vascular insulin resistance an early step in diet-induced whole-body insulin resistance?. Nutr. Diabetes 12, 31 (2022).
  • Obesity, insulin resistance and ageing are all associated with impaired microvascular responses to insulin in skeletal muscle.²³⁸Keske MA, Premilovac D, Bradley EA, Dwyer RM, Richards SM, Rattigan S. Muscle microvascular blood flow responses in insulin resistance and ageing. J Physiol. 2016 Apr 15;594(8):2223-31.
  • Insulin resistance causes reduced vascularization of the skeletal muscles.²³⁹Hrnciarová M, Hrnciar J, Jakubíková K. Inzulínová rezistencia a artériová hypertenzia [Insulin resistance and arterial hypertension]. Vnitr Lek. 1995 Feb;41(2):111-6. Slovak. PMID: 7725634.
  • Multiple Chemical Sensitivities (MCS)
    • Multiple Chemical Sensitivity (MCS) individuals are more Insulin Resistant and those with MCS and Functional Somatic Disorders (FSD)²⁴⁰Dantoft TM, Nordin S, Andersson L, Petersen MW, Skovbjerg S, Jørgensen T. Multiple chemical sensitivity described in the Danish general population: Cohort characteristics and the importance of screening for functional somatic syndrome comorbidity-The DanFunD study. PLoS One. 2021 Feb 24;16(2):e0246461. have an impaired glucose metabolism.²⁴¹Bjerregaard AA, Petersen MW, Gormsen LK, Skovbjerg S, Jørgensen NR, Linneberg A, Cedeño-Laurent JG, Jørgensen T, Dantoft TM. Insulin Resistance Is Associated with Multiple Chemical Sensitivity in a Danish Population-Based Study-DanFunD. Int J Environ Res Public Health. 2021 Nov 30;18(23):12654. 

• Nerve Pain – Blood / Nerve Reciprocity
  • Peripheral neuropathy is associated with Insulin Resistance independent of Metabolic Syndrome.²⁴²Stino AM, Smith AG. Peripheral neuropathy in prediabetes and the metabolic syndrome. J Diabetes Investig. 2017 Sep;8(5):646-655. doi: 10.1111/jdi.12650. Epub 2017 May 3. PMID: 28267267; PMCID: PMC5583955.^,243Han L, Ji L, Chang J, Wen J, Zhao W, Shi H, Zhou L, Li Y, Hu R, Hu J, Lu B. Peripheral neuropathy is associated with insulin resistance independent of metabolic syndrome. Diabetol Metab Syndr. 2015 Mar 3;7:14. doi: 10.1186/s13098-015-0010-y. PMID: 25774226; PMCID: PMC4359792.^,244Singh A, Chauhan A, Goyal P, Kaur J, Ramesh P. Insulin resistance as a predictor of sensory neuropathy in prediabetes. Indian J Med Spec 2019;10:95-8^,245Leow MKS, Wyckoff J Under-recognised paradox of neuropathy from rapid glycaemic control Postgraduate Medical Journal 2005;81:103-107.  
  • Neurons are very needy little things, requiring oxygen and glucose to function. 
  • Unlike some other cell types in your body, they cannot survive long without oxygen and glucose.²⁴⁶A.V. Hill, Physical Nature of the Nerve Impulse. Nature 131, 233 The more active the nerve cell is, the more oxygen and glucose it needs.  
  • Nerves and all other parts of the body require oxygen and glucose to function efficiently. Insulin Resistance deprives all of them of the necessary oxygen and glucose.²⁴⁷Jukka Mäkitie, Heikki Teräväinen. Peripheral nerve injury and recovery after temporary ischemia. H. Acta Neuropathol (1977) 37: 55. 
  • All nerves depend wholly upon the arterial system for their oxygen and glucose and the quality of their function, such as sensation, signal transmission and motion.
  • A loss of blood flow results in nerve cell deterioration and ultimately in nerve death starting within minutes. A deteriorating nerve send pain signals to the brain.
  • RBC agglutination slows blood flow to the nerves and all parts of the body. 

• Nonalcoholic Fatty Liver (NAFL)
  • Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic (Liver) component of the Metabolic Syndrome and Insulin Resistance.²⁴⁸Vanni E, Bugianesi E, Kotronen A, De Minicis S, Yki-Järvinen H, Svegliati-Baroni G. From the metabolic syndrome to NAFLD or vice versa? Dig Liver Dis. 2010 May;42(5):320-30.^,249Bugianesi E, Moscatiello S, Ciaravella MF, Marchesini G. Insulin resistance in nonalcoholic fatty liver disease. Curr Pharm Des. 2010 Jun;16(17):1941-51.^,250Kitade H, Chen G, Ni Y, Ota T. Nonalcoholic Fatty Liver Disease and Insulin Resistance: New Insights and Potential New Treatments. Nutrients. 2017 Apr 14;9(4):387.^,251Kristina M. Utzschneider, Steven E. Kahn, The Role of Insulin Resistance in Nonalcoholic Fatty Liver Disease, The Journal of Clinical Endocrinology & Metabolism, Volume 91, Issue 12, 1 December 2006, Pages 4753–4761,^,252Khan, R.S., Bril, F., Cusi, K. and Newsome, P.N. (2019), Modulation of Insulin Resistance in Nonalcoholic Fatty Liver Disease. Hepatology, 70: 711-724. 
  • The features of NAFLD are similar to those of metabolic disorders such as obesity, inflammation, insulin resistance, and type 2 diabetes.²⁵³Marchesini G., Brizi M., Morselli-Labate A.M., Bianchi G., Bugianesi E., McCullough A.J., Forlani G., Melchionda N. Association of nonalcoholic fatty liver disease with insulin resistance. Am. J. Med. 1999;107:450–455.^,254Haas J.T., Francque S., Staels B. Pathophysiology and mechanisms of nonalcoholic fatty liver disease. Annu. Rev. Physiol. 2016;78:181–205.^,255Loomba R., Abraham M., Unalp A., Wilson L., Lavine J., Doo E., Bass N.M. Nonalcoholic steatohepatitis clinical research network. Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology. 2012;56:943–951. 
  • A condition marked by elevated liver enzymes, abnormally high levels of fat in the liver, and enlargement of the organ, the severity of nonalcoholic fatty liver disease increases with obesity,²⁵⁶K. G. M. M. Alberti, R. H. Eckel, S. M. Grundy et al., “Harmonizing the metabolic syndrome: a joint interim statement of the international diabetes federation task force on epidemiology and prevention; national heart, lung, and blood institute; American heart association; world heart federation; international atherosclerosis society; and international association for the study of obesity,” Circulation, vol. 120, no. 16, pp. 1640–1645, 2009.^,257Y. Matsuzawa, “Pathophysiology and molecular mechanisms of visceral fat syndrome: the Japanese experience,” Diabetes/ Metabolism Reviews, vol. 13, no. 1, pp. 3–13, 1997. and abdominal fat and may develop as a result of Insulin Resistance.
• Obstructive Sleep Apnea
  • Insulin Resistance has been reported in patients with obstructive sleep apnea.²⁵⁸A. Witkowski, A. Prejbisz, E. Florczak et al., “Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patientswith resistant hypertension and sleep apnea,” Hypertension, vol. 58, no. 4, pp. 559–565, 2011
  • Obstructive sleep apnea, Insulin Resistance and sympathetic over-activity occur simultaneously.²⁵⁹Egan BM. Renal sympathetic denervation: a novel intervention for resistant hypertension, insulin resistance, and sleep apnea. Hypertension. 2011;58(4):542-543.^,260A. Witkowski, A. Prejbisz, E. Florczak et al., “Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patientswith resistant hypertension and sleep apnea,” Hypertension, vol. 58, no. 4, pp. 559–565, 2011^,261Vgontzas AN, Papanicolaou DA, Bixler EO, Hopper K, Lotsikas A, Lin HM, Kales A, Chrousos GP. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J Clin Endocrinol Metab. 2000 Mar;85(3):1151-8. doi: 10.1210/jcem.85.3.6484. PMID: 10720054.
  • Obstructive sleep apnoea (OSA) is a clinical syndrome characterized by repeated episodes of pharyngeal obstruction during sleep that lead to intermittent hypoxia (IH), sleep fragmentation and excessive daytime sleepiness.²⁶²Peppard PE, Young T, Barnet JH, et al. Increased Prevalence of Sleep-Disordered Breathing in Adults. Am J Epidemiol 2013;177:1006-14.^,263McNicholas WT, Bonsigore MR; Management Committee of EU COST ACTION B26. Sleep apnoea as an independent risk factor for cardiovascular disease: current evidence, basic mechanisms and research priorities. Eur Respir J 2007;29:156-78.^,264Kent BD, McNicholas WT, Ryan S. Insulin resistance, glucose intolerance and diabetes mellitus in obstructive sleep apnoea. J Thorac Dis. 2015;7(8):1343-1357.
  • Sleep apnea is a breathing disorder in which you stop breathing for very short periods of time while sleeping. 
  • Red Blood Cell (RBCs) become sticky with Insulin Resistance. RBCs deliver 98.5% of oxygen to the tissues of the body. 
  • Movement during daily activities prevents clumping of RBCs.
  • Lack of movement during sleep allows RBCs to stick together causing oxygen release far away from the tissues that need it. 
  • Oxygen deprivation triggers alarm signals causing a person to wake and move. Temporarily dispersing RBCs from each other and allowing diminished oxygen delivery.

• Polycystic Ovarian Syndrome
  • Insulin Resistance causes Polycystic Ovary Syndrome (PCOS).²⁶⁵Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989;38:1165–1174.^,266Chang RJ, Nakamura RM, Judd HL, Kaplan SA. Insulin resistance in nonobese patients with polycystic ovarian disease. J Clin Endocrinol Metab. 1983;57:356–359.^,267M. P. Schlaich, N. Straznicky, M. Grima et al., “Renal denervation: a potential new treatment modality for polycystic ovary syndrome?” Journal of Hypertension, vol. 29, no. 5, pp. 991–996, 2011.^,268Ehrmann DA, Sturis J, Byrne MM, Karrison T, Rosenfield RL, Polonsky KS. Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus. J Clin Invest. 1995;96:520–527.^,269Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care. 1999;22:141–146.
  • Insulin Resistance causes a shift in androgens (male type hormones) in women, and is strongly correlated with preceding PCOS.²⁷⁰Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab. 1999;84:165–169.^,271Welt CK, Arason G, Gudmundsson JA, et al. . Defining constant versus variable phenotypic features of women with polycystic ovary syndrome using different ethnic groups and populations. J Clin Endocrinol Metab. 2006;91:4361–4368.^,272Marshall JC, Dunaif A. Should all women with PCOS be treated for insulin resistance?. Fertil Steril. 2012;97(1):18-22. doi:10.1016/j.fertnstert.2011.11.036^,273Cindy T. Pau, Candace Keefe, Jessica Duran, Corrine K. Welt, Metformin Improves Glucose Effectiveness, Not Insulin Sensitivity: Predicting Treatment Response in Women With Polycystic Ovary Syndrome in an Open-Label, Interventional Study, The Journal of Clinical Endocrinology & Metabolism, Volume 99, Issue 5, 1 May 2014, Pages 1870–1878
  • The action of metformin in PCOS primarily affects glucose levels and reduces the conversion of estrogen into testosterone.²⁷⁴Cindy T. Pau, Candace Keefe, Jessica Duran, Corrine K. Welt, Metformin Improves Glucose Effectiveness, Not Insulin Sensitivity: Predicting Treatment Response in Women With Polycystic Ovary Syndrome in an Open-Label, Interventional Study, The Journal of Clinical Endocrinology & Metabolism, Volume 99, Issue 5, 1 May 2014, Pages 1870–1878^,275Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17α activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med. 1996;335:617–623.^,276Cindy T. Pau, Candace Keefe, Jessica Duran, Corrine K. Welt, Metformin Improves Glucose Effectiveness, Not Insulin Sensitivity: Predicting Treatment Response in Women With Polycystic Ovary Syndrome in an Open-Label, Interventional Study, The Journal of Clinical Endocrinology & Metabolism, Volume 99, Issue 5, 1 May 2014, Pages 1870–1878

• Sleepiness during the day. (Power-Saver Mode)
  • Daytime sleepiness in OSA individuals is a reflection of an overall propensity to sleep²⁷⁷Roure N, Gomez S,Mediano O, et al. Daytime sleepiness and polysomnography in obstructive sleep apnea patients. Sleep Med 2008 May 13^,278Gottlieb DJ, O’Connor GT, Wil JB. Genome-wide association of sleep and circadian phenotypes. BMC Med Genet 2007;8(Suppl 1):59. with diminished ventilatory response during nocturnal sleep, hence increased hypoxemia, and the associated hypercapnia.  
  • Insulin Resistance is connected with circadian misalignment and elevations of blood pressure.²⁷⁹Bass J, Takahashi JS. Circadian integration of metabolism and energetics. Science. 2010 Dec 3; 330(6009):1349–54.^,280Mesarwi O, Polak J, Jun J, Polotsky VY. Sleep disorders and the development of insulin resistance and obesity. Endocrinol Metab Clin North Am. 2013 Sep;42(3):617-34. Excessive sleep is associated with Insulin Resistance,²⁸¹Vgontzas AN, Papanicolaou DA, Bixler EO, Hopper K, Lotsikas A, Lin HM, Kales A, Chrousos GP. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J Clin Endocrinol Metab. 2000 Mar;85(3):1151-8. doi: 10.1210/jcem.85.3.6484. PMID: 10720054 and metabolic dysfunction.²⁸²Buxton OM, Marcelli E. Short and long sleep are positively associated with obesity, diabetes, hypertension, and cardiovascular disease among adults in the United States. Soc Sci Med. 2010 Sep; 71(5):1027–36.^,283Cappuccio FP, D’Elia L, Strazzullo P, Miller MA. Quantity and quality of sleep and incidence of type 2 diabetes: a systematic review and meta-analysis. Diabetes Care. 2010 Feb; 33(2):414–20. 
  • Many people with Insulin Resistance get sleepy immediately after eating a meal exceeding their Carbohydrate Tolerance. Body is going into power-saver mode like your electronic device.
  • Fatigue after meals, craving sugar after meals, must have dessert: 
  • Cut back on carbs until you are no longer sleepy after meals and/or do not crave sugar after eating.

• Thyroid / Hypothyroid
  • Hypothyroidism and Metabolic Syndrome (MetS) are associated with Insulin Resistance.²⁸⁴Hussein, M.A., Fawzi, M., Ibrahim, A. et al. Thyroid dysfunction and insulin resistance in patients with nonalcoholic fatty liver disease. Egypt J Intern Med 30, 97–102 (2018).^,285Jain, Amit & Dholariya, Sagar & Masroor, Mirza & Lali, P & Chandra, Lal & Dhanwal, Dinesh. (2020). Association of Anti-TPO Antibodies with Insulin Resistance in Patients of Hypothyroidism with Metabolic Syndrome: A Cross-sectional Study. Journal of Clinical & Diagnostic Research . Oct2020, Vol. 14 Issue 10, p9-13. 5p.
  • Everything the body does is defensive in nature.
  • Supply vs. Demand
    • Thyroid Hormones stimulate the metabolic rate. 
    • Insulin Resistance slows the metabolic rate. 
    • Thyroid will slow production of thyroid hormones to compensate for insulin resistance.

• Thyroid Antibodies
  • Thyroid TPO Antibodies and TAA Antibodies are increased in those with Insulin Resistance.²⁸⁶Zhao H, Zhang Y, Ye J, Wei H, Huang Z, Ning X, Fu X. A Comparative Study on Insulin Secretion, Insulin Resistance and Thyroid Function in Patients with Polycystic Ovary Syndrome with and without Hashimoto’s Thyroiditis. Diabetes Metab Syndr Obes. 2021;14:1817-1821^,287Gabriela Brenta, “Why Can Insulin Resistance Be a Natural Consequence of Thyroid Dysfunction?”, Journal of Thyroid Research, vol. 2011, Article ID 152850, 9 pages, 2011. https://doi.org/10.4061/2011/152850^,288Hussein, M.A., Fawzi, M., Ibrahim, A. et al. Thyroid dysfunction and insulin resistance in patients with nonalcoholic fatty liver disease. Egypt J Intern Med 30, 97–102 (2018). https://doi.org/10.4103/ejim.ejim_3_18^,289Jain, Amit & Dholariya, Sagar & Masroor, Mirza & Lali, P & Chandra, Lal & Dhanwal, Dinesh. (2020). Association of Anti-TPO Antibodies with Insulin Resistance in Patients of Hypothyroidism with Metabolic Syndrome: A Cross-sectional Study. Journal of Clinical & Diagnostic Research . Oct2020, Vol. 14 Issue 10, p9-13. 5p.^,290Varım, Ceyhun et al. “Insulin resistance in the patients with euthyroid Hashimoto thyroiditis.” Biomedical Research-tokyo 28 (2017): 1543-1547. 
• Weight Gain
  • Insulin resistance is the primary defect leading to Increased sympathetic activity and weight gain.²⁹¹S. Julius, M. Valentini, and P. Palatini, “Overweight and hypertension: a 2-way street?” Hypertension, vol. 35, no. 3, pp. 807–813, 2000.^,292Alicia A. Thorp, Markus P. Schlaich, “Relevance of Sympathetic Nervous System Activation in Obesity and Metabolic Syndrome”, Journal of Diabetes Research, vol. 2015, Article ID 341583, 11 pages, 2015. 
  • The fat in Insulin Resistance is generally stored around the midsection in both males and females.   
  • Chronic sympathetic activity is an adaptive physiological response²⁹³K. O’Dea, M. Esler, P. Leonard, J. R. Stockigt, and P. Nestel, “Noradrenaline turnover during under- and over-eating in normal weight subjects,” Metabolism, vol. 31, no. 9, pp. 896–899, 1982.^,294L. J. Aronne, R.Mackintosh, M. Rosenbaum, R. L. Leibel, and J. Hirsch, “Autonomic nervous system activity in weight gain and weight loss,” The American Journal of Physiology, vol. 269, no. 1, part 2, pp. R222–R225, 1995.^,295S.Welle, R. G. Schwartz, and M. Statt, “Reduced metabolic rate during 𝛽-adrenergic blockade in humans,”Metabolism: Clinical and Experimental, vol. 40, no. 6, pp. 619–622, 1991. used to stimulate thermogenesis and stabilize body weight during periods of overeating.²⁹⁶L. Landsberg, “Insulin-mediated sympathetic stimulation: role in the pathogenesis of obesity-related hypertension (or, how insulin affects blood pressure, and why),” Journal of Hypertension, vol. 19, no. 3, part 2, pp. 523–528, 2001.  
  • Modest weight gain is associated with an increase in sympathetic nerve activity and decrease in parasympathetic activity.²⁹⁷L. J. Aronne, R.Mackintosh, M. Rosenbaum, R. L. Leibel, and J. Hirsch, “Autonomic nervous system activity in weight gain and weight loss,” The American Journal of Physiology, vol. 269, no. 1, part 2, pp. R222–R225, 1995. 

Fatty Liver Conditions

• What Is Fatty Liver?
• Best Fatty Liver Support
• Best Lab Tests for Fatty Liver
• Portal Hypertension
• Non-Alcholic Fatty Liver
• Insulin Resistance | PreDiabetes

Related Keywords:

• Insulin resistance symptoms
• Insulin resistance diet
• Insulin resistance treatment
• Metabolic syndrome diagnosis
• Syndrome X causes
• Hypoglycemic associated autonomic failure management

Top Competitor Sites with URLs:

Website: healthline.com

Website: mayoclinic.org

Website: webmd.com

Suggested Sites for Outreach and Backlinks:

American Diabetes Association

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Harvard Health Publishing

References

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  Gillani SW, Ghayedi N, Roosta P, Seddigh P, Nasiri O. Effect of Metformin on Lipid Profiles of Type 2 Diabetes Mellitus: A Meta-analysis of Randomized Controlled Trials. J Pharm Bioallied Sci. 2021 Jan-Mar;13(1):76-82.
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  Luo, F., Das, A., Chen, J. et al. Metformin in patients with and without diabetes: a paradigm shift in cardiovascular disease management. Cardiovasc Diabetol 18, 54 (2019).
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  Xu T, Brandmaier S, Messias AC et al. Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes. Diabetes Care 2015. doi: 10.2337/dc15-0658.
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  Genuth S, Eastman R, Kahn R et al. Implications of the United Kingdom prospective diabetes study. Diabetes Care 2003;26(1):S28-32.
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