Insulin action at a molecular level – 100 years of progress

Abstract

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.

Transcriptomic Regulation of Muscle Mitochondria and Calcium Signaling by Insulin/IGF-1 Receptors Depends on FoxO Transcription Factors

“…Numerous studies indicate that insulin action in muscle regulates a wide variety of physiological functions and controls transcripts of metabolism, autophagy, mitochondrial function, chromatin remodeling, and cytoskeletal maintenance (O'Brien and Granner, 1996;Rome et al, 2003;Batista et al, 2019;White and Kahn, 2021). The current study reveals that under normal physiological conditions (in the absence of systemic glucose or lipid abnormalities) loss of IR or IGF1R alone in muscle only mildly alter gene expression, consistent with the mild change in muscle mass from these animals (O'Neill et al, 2015).…”

Insulin at 100 years – is rebalancing its action key to fighting obesity-related disease?

“…The core anatomy of postreceptor signalling was elucidated over the next two decades ( White and Kahn, 2021 ; Haeusler et al, 2018 ). This was, for some time, commonly characterised as a bifurcating cascade leading to mitogenic signalling through the RAS/RAF/MEK/ERK pathway and predominantly metabolic signalling through phosphoinositide 3-kinase (PI3K).…”

“…For example, somatic mutations activating the PI3K signalling pathway are among the most common driver mutations in cancer and other growth disorders ( Madsen et al, 2018 ), and co-operation between RAS and PI3K signalling is well documented ( Castellano and Downward, 2011 ). Indeed, further signalling subpathways have been identified downstream of INSR, and a complex array of intra- and interpathway crosstalk and feedback has been identified ( White and Kahn, 2021 ; Accili et al, 1996 ). Further challenging notions of the linear insulin signalling pathway, some evidence suggests that receptor tyrosine kinases, far from being static cell surface receptors that solely initiate signalling cascades, can themselves form transcriptional complexes within the nucleus ( Goldfine and Smith, 1976 ; Hancock et al, 2019 ).…”

“100 Years of progress in understanding insulin, its mechanism of action, and its roles in disease and diabetes therapy”

“…Insulin was also the stimulus for many other key advances which changed the concepts of modern biology, including the following discoveries: prehormone and prehormone processing, insulin receptor and its regulation in disease, insulin receptor tyrosine kinase, and unraveling of the molecular mechanism of insulin action. The latter topic, including the roles of insulin receptor substrates and PI 3-kinase, is reviewed in detail in the article by White and Kahn [ 2 ], along with the important relationship between insulin and insulin-like growth factors reviewed in the article by LeRoith et al. [ 3 ].…”