Just over a century has passed for the reason that discovery of insulin, a time period during which the therapeutic powers of the hormone have broadened and refined. Insulin is an important treatment for type 1 diabetes and sometimes for type 2 diabetes, as well. Roughly 8.4 million Americans use insulin, in response to the American Diabetes Association.

100 years of research have greatly advanced medical and biochemical understanding of how insulin works and what happens when it’s lacking, however the reverse, how potentially fatal insulin hyper-responsiveness is prevented, has remained a persistent mystery.

In a latest study, published within the April 20, 2023 online edition of Cell Metabolism, a team of scientists on the University of California San Diego School of Medicine, with colleagues elsewhere, describe a key player within the defense mechanism that safeguards us against excessive insulin within the body.

Although insulin is one of the crucial essential hormones, whose insufficiency may end up in death, an excessive amount of insulin can be deadly.”

Michael Karin, PhD, Senior Study Creator, Distinguished Professor of Pharmacology and Pathology at UC San Diego School of Medicine

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

Hypoglycemia (low blood sugar) is a big reason behind death amongst individuals with diabetes.

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

That valve is a metabolic enzyme called fructose-1,6-bisphosphate phosphatase or FBP1, which acts to manage gluconeogenesis, a process during which the liver synthesizes glucose (the first source of energy utilized by cells and tissues) during sleep and secretes it to keep up regular supply of glucose within the bloodstream.

Some antidiabetic drugs, akin to metformin, inhibit gluconeogenesis but without apparent in poor health effect. Children born with a rare, genetic disorder during which they don’t produce sufficient FBP1 can even remain healthy and live long lives.

But in other cases, when the body is starved for glucose or carbohydrates, an FBP1 deficiency may end up in severe hypoglycemia. And not using a glucose infusion, convulsions, coma and possibly death can ensue.

Compounding and confounding the issue, FPB1 deficiency combined with glucose starvation produces antagonistic effects unrelated to gluconeogenesis, akin to an enlarged, fatty liver, mild liver damage and elevated blood lipids or fats.

To higher understand the roles of FBP1, researchers created a mouse model with liver specific FBP1 deficiency, accurately mimicking the human condition. Like FBP1-deficient children, the mice appeared normal and healthy until fasted, which quickly resulted within the severe hypoglycemia and the liver abnormalities and hyperlipidemia described above.

Gu and her colleagues discovered that FBP1 had multiple roles. Beyond playing a component within the conversion of fructose to glucose, FBP1 had a second non-enzymatic but critical function: It inhibited the protein kinase AKT, which is the first conduit of insulin activity.

“Principally, FBP1 keeps AKT in check and guards against insulin hyper-responsiveness, hypoglycemic shock and acute fatty liver disease,” said first writer Gu.

Working with Yahui Zhu, a vising scientist from Chongqing University in China and second writer of the study, Gu developed a peptide (a string of amino acids) derived from FBP1 that disrupted the association of FBP1 with AKT and one other protein that inactivates AKT.

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

Karin said the researchers would love to further develop E7 as a clinically useful alternative to insulin “because we’ve every reason to consider that it’s unlikely to cause insulin shock.”

Source:

University of California – San Diego

Journal reference:

Gu, L., et al. (2023). Fructose-1,6-bisphosphatase is a nonenzymatic safety valve that curtails AKT activation to stop insulin hyperresponsiveness. Cell Metabolism. doi.org/10.1016/j.cmet.2023.03.021.