Too much insulin can be deadly as too little: Study

Insulin is a critical treatment for type 1 diabetes and, in many cases, type 2 diabetes as well. According to the American Diabetes Association, approximately 8.4 million Americans use insulin. A team of scientists from the University of California San Diego School of Medicine, along with colleagues from other institutions, describe a key player in the defence mechanism that protects us from excessive insulin in the body in a new study published in the online edition of Cell Metabolism on April 20, 2023.

“Although insulin is one of the most essential hormones, whose insufficiency can result in death, too much insulin can also be deadly,” said senior study author Michael Karin, PhD, Distinguished Professor of Pharmacology and Pathology at UC San Diego School of Medicine. A century of research has greatly advanced medical and biochemical understanding of how insulin works and what happens when it is deficient, but how potentially fatal insulin hyperresponsiveness is prevented has remained a persistent mystery.

“While our body finely tunes insulin production, patients who are treated with insulin or drugs that stimulate insulin secretion often experience hypoglycemia, a condition that if gone unrecognized and untreated can result in seizures, coma and even death, which collectively define a condition called insulin shock.”

Hypoglycemia (low blood sugar) is a leading cause of death among diabetics. Karin, Li Gu, PhD, a postdoctoral scholar in Karin’s lab, and colleagues describe “the body’s natural defence or safety valve” that reduces the risk of insulin shock in the new study. That valve is a metabolic enzyme known as fructose-1,6-bisphosphate phosphatase, or FBP1, which regulates gluconeogenesis, a process in which the liver synthesises and secretes glucose (the primary source of energy used by cells and tissues) during sleep to maintain a steady supply of glucose in the bloodstream.

Some diabetes medications, such as metformin, inhibit gluconeogenesis without apparent adverse effects. Children born with a rare genetic disorder that causes them to produce insufficient FBP1 can also be healthy and live a long life. When the body is starved for glucose or carbohydrates, an FBP1 deficiency can cause severe hypoglycemia. Convulsions, coma, and possibly death can occur in the absence of a glucose infusion. FPB1 deficiency, when combined with glucose deprivation, causes adverse effects unrelated to gluconeogenesis, such as an enlarged, fatty liver, mild liver damage, and elevated blood lipids or fats.

To better understand FBP1’s roles, researchers created a mouse model with liver-specific FBP1 deficiency that closely resembled the human condition. The mice, like FBP1-deficient children, appeared normal and healthy until fasted, when they developed the severe hypoglycemia, liver abnormalities, and hyperlipidemia described above. Gu and her colleagues discovered that FBP1 performed multiple functions. FBP1 not only played a role in the conversion of fructose to glucose, but it also inhibited the protein kinase AKT, which is the primary conduit of insulin activity.

“FBP1 basically keeps AKT in check and protects against insulin hyper-responsiveness, hypoglycemic shock, and acute fatty liver disease,” explained first author Gu.

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

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

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.”