Hepatalin

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Hepatalin is a hormone produced by the liver after feeding and plays a central role in the partitioning of the storage of nutrient energy by its action on glucose uptake and formation of glycogen in muscle. Hepatalin accounts for the majority of postprandial glucose uptake.

Hepatalin secretion from the liver is regulated by three signals: a hepatic parasympathetic-mediated signal, elevated hepatic glutathione (GSH), and pulses of insulin.[1]

Discovery[edit]

The discovery of hepatalin action was published in 1996[2] by a team led by W. Wayne Lautt from the University of Manitoba in Winnipeg, Manitoba, Canada.

The many roles of the hepatic nerves had been studied for years with Lautt proposing in 1979[3] that hepatic parasympathetic nerve dysfunction could result in type 2 diabetes.

The action of hepatalin was not seen until 1991 when an experiment was conducted to determine if insulin in the blood perfusing the brain could activate the nerves in the liver. It did not, but the response to an injection of a pulse of insulin either to the brain or systemically, was decreased by hepatic surgical denervation. Further studies showed that denervation of the liver reduced the response to insulin in the hindlimbs but had no effect on the liver.[2]

Naming and Identification[edit]

Early publications referred to hepatalin as HISS (hepatic insulin sensitizing substance) based on the observation that the response to the same dose of insulin was doubled after a meal.[4]

However, in March 2023, based on decades of research that showed that hepatalin was acting on different cell types through different regulatory mechanisms, a review of the relevant science[1] renamed HISS as "hepatalin."

Production[edit]

For hepatalin to be released from the liver, three simultaneous signals must be present.

Two of these are permissive feeding signals sent to the liver. Permissive means that these signals do not directly activate, but instead facilitate or allow some action. The first signal is a post-meal elevation in hepatic glutathione (GSH) levels (~50%).

The second signal is a hepatic parasympathetic-mediated[5] that releases acetylcholine to act on hepatic muscarinic receptors[6] resulting in activation of nitric oxide synthase and generation of nitric oxide in the liver.[7] Either signal alone is not sufficient to trigger hepatalin release.[5] The third required signal is a pulse of insulin.[8] The combination of these three signals triggers the release of a pulse of hepatalin from the liver.

Because hepatalin only appears during digestion, only in response to the three signals, is always seen in the presence of insulin, and because it is metabolized very quickly, the existence of hepatalin remained unknown for 100 years after insulin.

Hepatalin Action[edit]

The human body stores nutrient energy that it gets from meals by partitioning it between fats and glycogen. Hepatalin acts selectively on muscle, heart, and kidneys to store nutrient energy as glycogen. Hepatalin does not act on the liver or fat cells (adipocytes) or intestines. Insulin acts mainly on fat cells and the liver, storing fat in fat depots throughout the body, and glycogen and fat in the liver.

In a healthy state, the majority of glucose uptake is accounted for by hepatalin action in muscle. In response to an intravenous injection of insulin after a meal, hepatalin action accounted for approximately 55% of the glucose uptake (in rats[9]) and 66% (in humans[10]). The partitioning of the nutrient energy storage process in a healthy body is dependent on the ratio of insulin and hepatalin action.

If hepatalin action is decreased, glucose levels after a meal rise higher and for longer, and the pancreas must secrete much more insulin to manage the nutrient processing. Nutrient partitioning shifts from glycogen in muscle to lipids, with elevated blood and organ triglycerides resulting. If hepatalin action is reduced chronically, the metabolic consequences account for the predictable, chronological development of the dysfunctions known to be associated with the metabolic syndrome aka syndrome X.[11]

It has been proposed that hepatalin is the missing link in understanding and managing obesity, prediabetes, and type 2 diabetes.[1]

Hepatalin action decreases with age,[12] is worsened by a sugar supplemented diet.[13] Stress[14] and physical inactivity[15] and alcohol[16][17] reduce hepatalin secretion. In pregnancy, the role of hepatalin changes throughout the period of gestation. Hepatalin action predominates in the first trimester of gestation when uterine and fetal protein metabolism is required. Insulin action predominates in the third trimester when maternal and fetal fat stores are needed.[18]

Alcohol consumption during pregnancy results in dose-related suppression of hepatalin secretion in the adult offspring.[19]

Hepatalin can be acutely turned off and on by manipulation of the mechanisms (i.e., the three necessary signals) regulating hepatalin secretion.[5][9]

Media Coverage[edit]

Hepatalin's existence and discovery was published in the Winnipeg Free Press[20] and reprinted by the Toronto Star.[21] In the article, journalist Martin Cash writes:

"The existence and relevance of that hormone produced by the liver — Hepatic insulin-sensitizing substance (HISS), which SciMar is re-naming hepatalin — was discovered by Dr. Wayne Lautt, professor emeritus at the University of Manitoba’s department of pharmacology and therapeutics in 1996. Lautt’s lab raised $17.5 million in research grants over the years and in 2009 he and his son Mick founded SciMar to hone in on the research with the intent of making sure it will have an impact for the close to 500 million people around the world who live with type 2 diabetes or pre-diabetes."

A medical test designed around the science of hepatalin, which was described as a "new test can detect diabetes 10 years earlier than a diagnosis," was reported by Breakfast Television,[22] a Canadian news talk show.

References[edit]

  1. ^ a b c Lautt, W. Wayne (2023). "Hepatalin: the missing link in prediabetes, obesity, and type 2 diabetes". Canadian Journal of Physiology and Pharmacology. 101 (3): 117–135. doi:10.1139/cjpp-2022-0332. ISSN 0008-4212. PMID 36716439. S2CID 256415448.
  2. ^ a b Xie, H.; Lautt, W. W. (1996-05-01). "Insulin resistance of skeletal muscle produced by hepatic parasympathetic interruption". American Journal of Physiology. Endocrinology and Metabolism. 270 (5): E858–E863. doi:10.1152/ajpendo.1996.270.5.E858. ISSN 0193-1849. PMID 8967475.
  3. ^ Lautt, W. Wayne (1979-12-01). "Autonomic neural control of liver glycogen metabolism". Medical Hypotheses. 5 (12): 1287–1296. doi:10.1016/0306-9877(79)90096-3. ISSN 0306-9877. PMID 231734.
  4. ^ Lautt, W.W. (1998). Haussinger, D.; Jungermann, K. (eds.). "State of the Art 1997: Hepatic parasympathetic nerves and glucose metabolism". Liver and Nervous System. Falk Symposium (103). Kluwer Academic Publishers, UK: 1–14.
  5. ^ a b c Lautt, W. Wayne; Schafer, Joshua; Macedo, M. Paula; Legare, Dallas J. (2011). "Bethanechol and N -acetylcysteine mimic feeding signals and reverse insulin resistance in fasted and sucrose-induced diabetic rats". Canadian Journal of Physiology and Pharmacology. 89 (2): 135–142. doi:10.1139/Y11-001. ISSN 0008-4212. PMID 21326345.
  6. ^ Xie, Hongsheng; Lautt, W. Wayne (1995). "Induction of insulin resistance by cholinergic blockade with atropine in the cat". Journal of Autonomic Pharmacology. 15 (5): 361–369. doi:10.1111/j.1474-8673.1995.tb00402.x. ISSN 0144-1795. PMID 8744976.
  7. ^ Guarino, Maria P.; Correia, Nina C.; Lautt, W. Wayne; Macedo, M. Paula (2004). "Insulin sensitivity is mediated by the activation of the ACh/NO/cGMP pathway in rat liver". American Journal of Physiology. Gastrointestinal and Liver Physiology. 287 (3): G527–G532. doi:10.1152/ajpgi.00085.2004. ISSN 0193-1857. PMID 15331351. S2CID 6383761.
  8. ^ Reid, Maria A.G; Latour, Martin G; Legare, Dallas J; Rong, Na; Lautt, W Wayne (2002-08-01). "Comparison of the rapid insulin sensitivity test (RIST), the insulin tolerance test (ITT), and the hyperinsulinemic euglycemic clamp (HIEC) to measure insulin action in rats". Canadian Journal of Physiology and Pharmacology. 80 (8): 811–818. doi:10.1139/y02-102. ISSN 0008-4212. PMID 12269792.
  9. ^ a b Lautt, W. W.; Macedo, M. P.; Sadri, P.; Takayama, S.; Duarte Ramos, F.; Legare, D. J. (2001-07-01). "Hepatic parasympathetic (HISS) control of insulin sensitivity determined by feeding and fasting". American Journal of Physiology. Gastrointestinal and Liver Physiology. 281 (1): G29–G36. doi:10.1152/ajpgi.2001.281.1.G29. ISSN 0193-1857. PMID 11408252. S2CID 14651937.
  10. ^ Patarrão, Rita S.; Lautt, W. Wayne; Afonso, Ricardo A.; Ribeiro, Rogério T.; Guarino, Maria P.; Fernandes, Ana B.; Boavida, José M.; Macedo, M. Paula (2008). "Meal-induced insulin sensitization and its parasympathetic regulation in humans". Canadian Journal of Physiology and Pharmacology. 86 (12): 880–888. doi:10.1139/Y08-080. ISSN 0008-4212. PMID 19088809.
  11. ^ Lautt, W.W.; Ming, Z. (2010). Preedy, V.R.; Srirajaskanthan, R.; Lakshman, R.; Watson, R.R. (eds.). "Use of an antioxidant cocktail for insulin resistance associated with age and a high sugar diet: a hepatic mechanism". Nutrition, Diet Therapy, and the Liver. Taylor and Francis, CRC Press: Chapter 21, pp.319-333.
  12. ^ Lautt, W. Wayne; Ming, Zhi; Legare, Dallas J. (2010). "Attenuation of age- and sucrose-induced insulin resistance and syndrome X by a synergistic antioxidant cocktail: the AMIS syndrome and HISS hypothesisThis article is one of a selection of papers published in a Special Issue on Oxidative Stress in Health and Disease". Canadian Journal of Physiology and Pharmacology. 88 (3): 313–323. doi:10.1139/Y09-130. ISSN 0008-4212. PMC 3160976. PMID 20393596.
  13. ^ Ribeiro, R. T.; Lautt, W. W.; Legare, D. J.; Macedo, M. P. (2005-05-01). "Insulin resistance induced by sucrose feeding in rats is due to an impairment of the hepatic parasympathetic nerves". Diabetologia. 48 (5): 976–983. doi:10.1007/s00125-005-1714-6. ISSN 1432-0428. PMC 2925889. PMID 15830187.
  14. ^ Seredycz, Larissa I.; Ming, Zhi; Lautt, W. Wayne (2006). "Acute hemorrhage causes hepatic insulin sensitizing substance (HISS)-dependent insulin resistance". Canadian Journal of Physiology and Pharmacology. 84 (11): 1145–1151. doi:10.1139/y06-064. ISSN 0008-4212. PMID 17218979.
  15. ^ Chowdhury, Kawshik K.; Legare, Dallas J.; Lautt, W. Wayne (2011-01-01). "Insulin sensitization by voluntary exercise in aging rats is mediated through hepatic insulin sensitizing substance (HISS)". Experimental Gerontology. 46 (1): 73–80. doi:10.1016/j.exger.2010.10.006. ISSN 0531-5565. PMID 20955773. S2CID 21915881.
  16. ^ Lautt, W. Wayne; Legare, Dallas J.; Reid, Maria A.G.; Sadri, Parissa; Ting, Justin W.; Prieditis, Heather (2005). "Alcohol Suppresses Meal-Induced Insulin Sensitization". Metabolic Syndrome and Related Disorders. 3 (1): 51–59. doi:10.1089/met.2005.3.51. ISSN 1540-4196. PMID 18370710.
  17. ^ Ting, Justin W.; Lautt, W. Wayne (2006-08-01). "The effect of acute, chronic, and prenatal ethanol exposure on insulin sensitivity". Pharmacology & Therapeutics. 111 (2): 346–373. doi:10.1016/j.pharmthera.2005.10.004. ISSN 0163-7258. PMID 16310255.
  18. ^ Lovat, Nicole E.J.; Legare, Dallas J.; Gieni, Randall S.; Lautt, W. Wayne (2020). "Gestational postprandial insulin sensitivity in the Sprague Dawley rat: the putative role of hepatic insulin sensitizing substance in glucose partitioning in pregnancy". Canadian Journal of Physiology and Pharmacology. 98 (8): 541–547. doi:10.1139/cjpp-2019-0575. ISSN 0008-4212. PMID 32453968. S2CID 218910200.
  19. ^ Sadri, Parissa; Legare, Dallas J; Takayama, Shinichiro; Lautt, W Wayne (2005-04-01). "Increased incidence of hepatic insulin-sensitizing substance (HISS)-dependent insulin resistance in female rats prenatally exposed to ethanol". Canadian Journal of Physiology and Pharmacology. 83 (4): 383–387. doi:10.1139/y05-023. ISSN 0008-4212. PMID 15877113.
  20. ^ Updates, Martin Cash Posted: Last Modified: | (2021-07-27). "Jul 2021: Developing a new way to diagnose, treat diabetes". Winnipeg Free Press. Retrieved 2023-07-10.
  21. ^ "Developing a new way to diagnose, treat diabetes". thestar.com. 2021-07-27. Retrieved 2023-07-10.
  22. ^ "This new test can detect diabetes 10 years earlier than a diagnosis – Breakfast Television". Retrieved 2023-07-10.
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