Too much insulin can be just as dangerous as too little – ScienceDaily

One hundred years of research have advanced a great deal in the medical and biochemical understanding of how insulin works and what happens when it is lacking, but the opposite, how potentially fatal insulin hyperreactivity is prevented, remains a lingering mystery.

In a new study, published online in the April 20, 2023, issue of Cellular metabolismA team of scientists from the University of California San Diego School of Medicine, along with colleagues elsewhere, describe a key player in the defense mechanism that protects us against excess insulin in the body.

“Although insulin is one of the most essential hormones, the failure of which can lead to death, too much insulin can also be fatal,” said the study’s senior author, Michael Karin, PhD, Distinguished Professor of Pharmacology and Pathology at the School of Medicine. from UC San Diego.

“While our bodies finely tune insulin production, patients who are treated with insulin or medications that stimulate insulin secretion often experience hypoglycemia, a condition that if unrecognized and untreated can lead to seizures, coma, and even death.” death, which collectively define a condition called insulin shock.”

Hypoglycemia (low blood sugar) is a major cause of death among people with diabetes.

In the new study, Karin, first author Li Gu, PhD, a postdoctoral fellow in Karin’s lab, and colleagues describe “the body’s natural defense or safety valve” that reduces the risk of insulin shock.

That valve is a metabolic enzyme called fructose-1,6-bisphosphate phosphatase, or FBP1, which works to control gluconeogenesis, a process in which the liver synthesizes glucose (the main source of energy used by cells and tissues) during sleep. sleep and the secret to maintaining a constant supply of glucose in the bloodstream.

Some antidiabetic drugs, such as metformin, inhibit gluconeogenesis but without apparent deleterious effects. Children born with a rare genetic disorder in which they do not make enough FBP1 can also remain healthy and live long lives.

But in other cases, when the body lacks glucose or carbohydrates, a deficiency of FBP1 can lead to severe hypoglycemia. Without a glucose infusion, seizures, coma, and possibly death can occur.

To compound and confuse the problem, FPB1 deficiency combined with glucose starvation produces adverse effects unrelated to gluconeogenesis, such as enlarged fatty liver, mild liver damage, and elevated blood lipids or fats.

To better understand the functions of FBP1, the researchers created a liver-specific FBP1-deficient mouse model, precisely mimicking the human condition. Like the FBP1-deficient children, the mice appeared normal and healthy until fasted, which rapidly resulted in the severe hypoglycemia and liver abnormalities and hyperlipidemia described above.

Gu and his colleagues found that FBP1 had multiple functions. Beyond playing a role in the conversion of fructose to glucose, FBP1 had a second non-enzymatic but critical function: it inhibited the AKT protein kinase, which is the main channel of insulin activity.

“Basically, FBP1 keeps AKT in check and protects against insulin hyperreactivity, hypoglycemic shock, and acute fatty liver disease,” said first author Gu.

Working with Yahui Zhu, a visiting scientist at Chongqing University in China and second author of the study, Gu developed a peptide (a chain of amino acids) derived from FBP1 that disrupted the association of FBP1 with AKT and another protein that inactivates AKT.

“This peptide works as an insulin mimetic, activating AKT,” Karin said. “When injected into mice that have become resistant to insulin, a very common pre-diabetic condition, due to prolonged consumption of a high-fat diet, the peptide (nicknamed E7) can reverse insulin resistance and restore glycemic control. normal”.

Karin said the researchers would like to further develop E7 as a clinically useful alternative to insulin “because we have every reason to believe that it is unlikely to cause insulin shock.”

Co-authors include: 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.

Funding for this research came, in part, from the National Institutes of Health (grants R01DK120714, R01CA234128, R01DK133448, P01CA104838, R35CA197602, R01DK117551, R01DK125820, R01DK76906, P30DK060151, R01DK063151 98, R01DK125560 and R35GM122523), the Training for Graduates of UC San Diego Program in Cellular and Molecular Pharmacology (GM007752) and the National Science Foundation Graduate Research Scholarship (#DGE-1650112).