Insulin is a necessary treatment for type 1 diabetes and often for type 2 diabetes as well. About 8.4 million Americans use insulin, according to the American Diabetes Association.
In a new study published in the April 20, 2023 online edition of Cell Metabolism, a 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, insufficiency of which can lead to death, too much insulin can also be fatal,” said the study’s senior author Michael Currin, PhD, distinguished professor of pharmacology and pathology at the UC San Diego School of Medicine.
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One hundred years of research has greatly advanced the medical and biochemical understanding of how insulin works and what happens when it is lacking, but conversely, how to prevent fatal insulin hyper-responsiveness remains an ongoing mystery.
“While our bodies fine-tune insulin production, patients treated with insulin or drugs that stimulate insulin secretion often experience hypoglycemia, a condition that can lead to seizures, coma, and even death if unrecognized and untreated, which collectively defines the condition known as insulin resistance. Shock.”
Hypoglycemia (low blood sugar) is an important cause of death in people with diabetes.
In the new study, Karin, first author Lee Gu, PhD, a postdoctoral scholar in Karin’s lab, and colleagues described “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 acts to control gluconeogenesis, a process in which the liver synthesizes and secretes glucose (the primary source of energy used by cells and tissues) during sleep. Maintain a steady supply of glucose in the bloodstream.
Some antidiabetic drugs, such as metformin, inhibit gluconeogenesis but without apparent adverse effects. Babies born with rare, genetic disorders in which they don’t produce enough FBP1 can also stay healthy and live long lives.
But in other cases, when the body is starved for glucose or carbohydrates, FBP1 deficiency can lead to severe hypoglycemia. Without glucose infusion, convulsions, coma and possibly death can occur.
Compounding and confusing 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 fat.
To better understand the roles of FBP1, the researchers created a mouse model with liver-specific FBP1 deficiency, accurately mimicking the human condition. Like the FBP1-deficient littermates, the mice appeared normal and healthy until fasting, which immediately resulted in severe hypoglycemia and the liver abnormalities and hyperlipidemia described above.
Gu and his colleagues discovered that FBP1 had several roles. Besides playing a role in the conversion of fructose to glucose, FBP1 has a second non-enzymatic but important function: it inhibits the protein kinase AKT, which is the primary conduit of insulin activity.
“In general, FBP1 regulates AKT and protects against insulin hyper-responsiveness, hypoglycemic shock and acute fatty liver disease,” said first author Gu.
Working with Yahui Zhu, a leading scientist at Chongqing University in China and the study’s second author, Gu developed a peptide (a string of amino acids) derived from FBP1 that disrupted FBP1’s association with AKT and another protein that inactivates AKT.
“This peptide acts like an insulin mimetic, activating AKT,” Karin said. “When injected into mice rendered insulin resistant, a highly common pre-diabetic condition, due to long-term consumption of a high-fat diet, the peptide (alias E7) could reverse insulin resistance and restore normal glycemic control.”
Karin said researchers want to develop E7 as a clinically useful alternative to insulin “because we have every reason to believe that it is unlikely to cause insulin shock.”
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