Insulin action at a molecular level - 100 years of progress.

The discovery of insulin 100 years ago and its application to the treatment of human disease in the years since have marked a major turning point in the history of medicine. The availability of purified insulin allowed for the establishment of its physiological role in the regulation of blood glucose and ketones, the determination of its amino acid sequence, and the solving of its structure. Over the last 50 years, the function of insulin has been applied into the discovery of the insulin receptor and its signaling cascade to reveal the role of impaired insulin signaling-or resistance-in the progression of type 2 diabetes. It has also become clear that insulin signaling can impact not only classical insulin-sensitive tissues, but all tissues of the body, and that in many of these tissues the insulin signaling cascade regulates unexpected physiological functions. Despite these remarkable advances, much remains to be learned about both insulin signaling and how to use this molecular knowledge to advance the treatment of type 2 diabetes and other insulin-resistant states.

A comprehensive account of insulin and LDL receptor activity over the years: A highlight on their signaling and functional role.

Insulin receptor (IR) was discovered in 1970. Shortcomings in IR transcribed signals were found pro-diabetic, which could also inter-relate obesity and atherosclerosis in a time-dependent manner. Low-density lipoprotein receptor (LDLR) was discovered in 1974. Later studies showed that insulin could modulate LDLR expression and activity. Repression of LDLR transcription in the absence or inactivity of insulin showed a direct cause of atherosclerosis. Leptin receptor (OB-R) was found in 1995 and its resistance became responsible for developing obesity. The three interlinked pathologies namely, diabetes, atherosclerosis, and obesity were later on marked as metabolic syndrome-X (MSX). In 2012, the IR-LDLR inter-association was identified. In 2019, the proficiency of signal transmission from this IR-LDLR receptor complex was reported. LDLR was found to mimic IR-generated signaling path when it remains bound to IR in IR-DLR interlocked state. This was the first time LDLR was found sending messages besides its LDL-clearing activity from blood vessels.

IL-4 and IL-13 Receptor Signaling From 4PS to Insulin Receptor Substrate 2: There and Back Again, a Historical View.

In this historical perspective, written in honor of Dr. William E. Paul, we describe the initial discovery of one of the dominant substrates for tyrosine phosphorylation stimulated by IL-4. We further describe how this "IL-4-induced phosphorylated substrate" (4PS) was characterized as a member of the insulin receptor substrate (IRS) family of large adaptor proteins that link IL-4 and insulin receptors to activation of the phosphatidyl-inositol 3' kinase pathway as well as other downstream signaling pathways. The relative contribution of the 4PS/IRS pathway to the early models of IL-4-induced proliferation and suppression of apoptosis are compared to our more recent understanding of the complex interplay between positive and negative regulatory pathways emanating from members of the IRS family that impact allergic responses.