Unveiling the Nonenzymatic Safety Valve that Regulates Insulin Response

Insulin is an essential hormone that regulates blood sugar levels in our body. It is produced by the pancreas and acts by stimulating glucose uptake in various tissues. However, in certain conditions, such as obesity or type 2 diabetes, insulin becomes less effective, leading to high blood sugar levels. Recent studies have shown that a protein called Fructose-1,6-bisphosphatase (FBPase) plays a critical role in regulating insulin sensitivity.

The Role of AKT in Insulin Response

Insulin signaling is a complex process that involves several proteins and pathways. AKT, also known as protein kinase B (PKB), is a key protein in this process. It is activated by insulin binding to its receptor on the surface of cells, which triggers a cascade of signaling events that ultimately lead to the activation of AKT. A PI3K-dependent method phosphorylates AKT at two particular locations, Thr308 and Ser473, to activate it.

Once activated, AKT plays a crucial role in regulating glucose metabolism. It promotes the translocation of glucose transporter 4 (GLUT4) to the cell surface, which allows for glucose uptake into cells, particularly in muscle and adipose tissue. AKT also inhibits the production of glucose by the liver, which helps to lower blood glucose levels.

However, in conditions such as obesity and insulin resistance, AKT becomes hyperactivated. This means that it is constantly turned on, even in the absence of insulin signaling. This leads to an over-response to insulin and can cause several metabolic disorders such as hyperglycemia, dyslipidemia, and hypertension.

Hyperglycemia, or high blood sugar, can lead to a variety of complications, such as nerve damage, kidney damage, and cardiovascular disease. Dyslipidemia, or abnormal levels of lipids in the blood, can increase the risk of atherosclerosis, which is the buildup of fatty deposits in the arteries. Hypertension, or high blood pressure, can increase the risk of heart disease, stroke, and other complications.

The Role of FBPase in Regulating Insulin Sensitivity

It is important to understand the role of enzymes in biochemical pathways and their potential for therapeutic intervention. Fructose-1,6-bisphosphatase (FBPase) is an enzyme that plays a critical role in the process of gluconeogenesis. Gluconeogenesis is the process by which glucose is synthesized from non-carbohydrate sources such as amino acids and fatty acids. FBPase catalyzes the hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate and inorganic phosphate. This reaction is a key regulatory step in gluconeogenesis, as it diverts the carbon flow away from glycolysis and towards glucose synthesis.

However, recent studies have shown that FBPase also plays a crucial role in regulating insulin sensitivity. Insulin is a hormone produced by the pancreas that regulates glucose homeostasis. It stimulates glucose uptake by various tissues, including the liver, muscle, and adipose tissue, through the activation of a cascade of signaling pathways. One of these pathways involves the activation of the protein AKT, which in turn stimulates glucose uptake in these tissues.

In conditions such as obesity and insulin resistance, AKT becomes hyperactivated, leading to an over-response to insulin. This hyperresponsiveness results in various metabolic disorders such as hyperglycemia, dyslipidemia, and hypertension. The recent study published in Nature Cell Metabolism has shed light on the role of FBPase in regulating AKT activation and preventing insulin hyperresponsiveness.

The study team discovered that FBPase engages directly with AKT and prevents it from activating. By inhibiting excessive glucose absorption, this condition reduces insulin hyperresponsiveness. Inhibiting the over-reaction to insulin and preserving insulin sensitivity, FBPase functions as a nonenzymatic safety valve. Our knowledge of the intricate mechanisms that control insulin signaling has been improved by the identification of this nonenzymatic function of FBPase.

Nonenzymatic Proteins as Future Drug Targets

The findings of this study have significant implications for the development of new therapies for metabolic disorders such as obesity and type 2 diabetes. By targeting FBPase, it may be possible to regulate insulin sensitivity and prevent the development of insulin resistance. The study provides new insights into the complex mechanisms that regulate insulin signaling and highlights the potential of nonenzymatic proteins as therapeutic targets.

Study DOI: 10.1016/j.cmet.2023.03.021

Engr. Dex Marco Tiu Guibelondo, BS Pharm, RPh, BS CpE

Editor-in-Chief, PharmaFEATURES