In a brand-new study, published in the April 20, 2023, online edition of the journal Cell Metabolism, a team of researchers at the University of California San Diego (UCSD) School of Medicine, with colleagues in other places, describe an essential player in the defense system that safeguards us against extreme insulin in the body.
” Although insulin is one of the most important hormones, whose insufficiency can lead to death, excessive insulin can also be deadly,” said senior research study author Michael Karin, PhD, Distinguished Professor of Pharmacology and Pathology at UCSD School of Medicine.
” While our body carefully tunes insulin production, clients who are treated with insulin or drugs that promote insulin secretion typically experience hypoglycemia, a condition that if gone without treatment and unacknowledged can lead to seizures, coma, and even death, which collectively specify a condition called insulin shock.”
Hypoglycemia (low blood sugar level) is a considerable cause of death among individuals with diabetes.
In the new study, Karin, very first author Li Gu, PhD, a postdoctoral scholar in Karins lab, and coworkers explain “the bodys natural defense or security valve” that reduces the threat of insulin shock.
That valve is a metabolic enzyme called fructose-1,6- bisphosphate phosphatase or FBP1, which acts to manage gluconeogenesis, a process in which the liver manufactures glucose (the main source of energy used by tissues and cells) throughout sleep and secretes it to preserve consistent supply of glucose in the blood stream.
Some antidiabetic drugs, such as metformin, hinder gluconeogenesis but without apparent ill effect. Children born with a rare, congenital disease in which they do not produce sufficient FBP1 can likewise remain live and healthy long lives.
However in other cases, when the body is starved for glucose or carbohydrates, an FBP1 deficiency can lead to severe hypoglycemia. Without a glucose infusion, convulsions, coma and perhaps death can take place.
Compounding and puzzling the issue, FPB1 shortage combined with glucose starvation produces negative effects unrelated to gluconeogenesis, such as an enlarged, fatty liver, mild liver damage and elevated blood lipids or fats.
To better understand the functions of FBP1, researchers produced a mouse model with liver specific FBP1 deficiency, accurately mimicking the human condition. Like FBP1-deficient children, the mice appeared healthy and normal until fasted, which quickly resulted in the extreme hypoglycemia and the liver abnormalities and hyperlipidemia described above.
Gu and her coworkers found that FBP1 had numerous roles. Beyond playing a part in the conversion of fructose to glucose, FBP1 had a second non-enzymatic but vital function: It prevented the protein kinase AKT, which is the primary avenue of insulin activity.
” Basically, FBP1 keeps AKT in check and defend against insulin hyper-responsiveness, hypoglycemic shock and severe fatty liver disease,” said first author Gu.
Working with Yahui Zhu, a vising scientist from Chongqing University in China and 2nd author of the research study, Gu established a peptide (a string of amino acids) derived from FBP1 that disrupted the association of FBP1 with AKT and another protein that suspends AKT.
” This peptide works like an insulin mimetic, triggering AKT,” stated Karin. “When injected into mice that have been rendered insulin resistant, a highly typical pre-diabetic condition, due to prolonged usage of high-fat diet, the peptide (nicknamed E7) can reverse insulin resistance and bring back regular glycemic control.”
Karin stated the researchers wish to further develop E7 as a medically useful alternative to insulin “because we have every reason to think that it is not likely to trigger insulin shock.”
Referral: “Fructose-1,6- bisphosphatase is a nonenzymatic security valve that reduces AKT activation to prevent insulin hyperresponsiveness” byAuthor links open overlay panelLi Gu 1 11, Yahui Zhu 2 11, Kosuke Watari 1, Maiya Lee 1, Junlai Liu 1, Sofia Perez 1, Melinda Thai 1, Joshua E. Mayfield 3, Bichen Zhang 4, Karina Cunha e Rocha 4, Fuming Li 5 6 7, Laura C. Kim 5 6, Alexander C. Jones 3, Igor H. Wierzbicki 3, Xiao Liu 4 8, Alexandra C. Newton 3, Tatiana Kisseleva 8, Jun Hee Lee 9, Wei Ying 4, David J. Gonzalez 3 10, Alan R. Saltiel 4, M. Celeste Simon 5 6, Michael Karin, 20 April 2023, Cell Metabolism.DOI: 10.1016/ j.cmet.2023.03.021.
Co-authors consist of: Kosuke Watari, Maiya Lee, Junlai Liu, Sofia Perez, Melinda Thai, Joshua E. Mayfield, Bichen Zhang, Karina Cunha e Rocha, Alexander C. Jones, Igor H. Wierzbicki, Xiao Liu, Alexandra C. Newton, Tatiana Kisseleva, Wei Ying, David J. Gonzalez and Alan R. Saltiel, all at UC San Diego; Fuming Li, University of Pennsylvania and Fudan University, China; Laura C. Kim and M. Celeste Simon, University of Pennsylvania; Jun Hee Lee, University of Michigan.
Financing for this research came, in part, from the National Institutes of Health (grants R01DK120714, R01CA234128, R01DK133448, P01CA104838, R35CA197602, R01DK117551, R01DK125820, R01DK76906, P30DK063491, R21HD107516, R01DK125560, r00dk115998 and r35gm122523), the UC San Diego Graduate Training Program in Cellular and Molecular Pharmacology (GM007752) and the National Science Foundation Graduate Research Fellowship (#DGE -1650112).
Disclosure: Michael Karin and Alan Saltiel are founders and stockholders in Elgia Pharmaceuticals. Karin has received research assistance from Merck and Janssen Pharmaceuticals.
Researchers determined a metabolic enzyme called fructose-1,6- bisphosphate phosphatase (FBP1) that acts as a natural defense against insulin shock. The scientists discovered that FBP1 inhibits the protein kinase AKT, preventing insulin hyper-responsiveness and related complications. They developed a peptide obtained from FBP1, called E7, which can reverse insulin resistance and bring back normal glycemic control in mice. Insulin is a vital treatment for type 1 diabetes and frequently for type 2 diabetes. Approximately 8.4 million Americans utilize insulin, according to the American Diabetes Association.
Scientist recognized a metabolic enzyme called fructose-1,6- bisphosphate phosphatase (FBP1) that acts as a natural defense against insulin shock. They established a peptide derived from FBP1, called E7, which can reverse insulin resistance and bring back typical glycemic control in mice.
Researchers identify a key gamer that helps avoid “insulin shock” and might cause a healing alternative to the hormone used by millions of individuals with diabetes.
Simply over a century has actually passed because the discovery of insulin, a period throughout which the restorative powers of the hormonal agent have actually broadened and improved. Insulin is a vital treatment for type 1 diabetes and often for type 2 diabetes, too. Approximately 8.4 million Americans use insulin, according to the American Diabetes Association.
One a century of research have considerably advanced medical and biochemical understanding of how insulin works and what happens when it is lacking, but the reverse, how possibly fatal insulin hyper-responsiveness is prevented, has stayed a persistent mystery.