Lilly Lecture: Syndromes of Insulin Resistance: From Patient to Gene and Back Again

Abstract

The syndromes of insulin resistance are a group of clinically diverse disorders, and our understanding of their molecular pathogenesis has advanced in parallel with our understanding of the structure of the insulin receptor and the mechanism of insulin action. The most straightforward progress has related to defining the role of both anti-receptor antibodies and mutations in the insulin receptor gene in causing these disorders. Despite this progress, the cause of severe target cell resistance in patients without defects in the receptor locus remains unknown, and we are limited in our ability to relate specific molecular defects in insulin signalling to in vivo phenotypes, such as those relating to growth and development and function of adipose tissue and muscle. Answers to these questions may ultimately be explained by the existence of multiple species of insulin receptors expressed in different tissues, brought about by alternative splicing and receptor hybrids, and by divergent pathways of insulin signalling with different consequences for specific tissues. The possibility that the insulin receptor and GLUT4 may be candidate genes for inherited insulin resistance in NIDDM has been addressed with the aid of genetic screening techniques such as SSCP. Currently, the loci have not been implicated in studies in most patients. Transgenic methodologies will be powerful tools for pursuit of unanswered questions in the field of insulin resistance in coming years.

Nonalcoholic Fatty Liver Disease: Pathogenesis, Identification, Progression, and Management

“…2,31 These environmental factors contribute to lipid mobilization and lipolysis, the primary features in the development of IR. 32,33 Not only is IR common in those with hepatic steatosis, it also perpetuates the development of steatosis by inhibiting the secretion of triglycerides. 9 Normally, FFA are transported to the liver to be degraded in the mitochondria via a process known as mitochondrial betaoxidation.…”

Activity‐dependent regulation of alternative splicing patterns in the rat brain

“…This has various physiological consequences; it can create soluble instead of membrane-bound receptors (Baumbach et al, 1989;Eipper et al, 1992;Toksoz et al, 1992;Zhang et al, 1994;Hughes & Crispe, 1995;Tabiti et al, 1996), change the affinity towards ligands (Sugimoto et al, 1993;Xing et al, 1994;Suzuki et al, 1995), truncate proteins to produce inactive variants (Swaroop et al, 1992;van der Logt et al, 1992;Duncan et al, 1995;Sharma et al, 1995;Eissa et al, 1996) and change endocytotic pathways (Wang & Ross, 1995). In addition, inclusion or skipping of alternative exons can add or delete protein modules that change the affinity towards ligands (Chiquet et al, 1991;Danoff et al, 1991;Giros et al, 1991;Flier, 1992;Miki et al, 1992;Ogura et al, 1993;Ohsako et al, 1993; Correspondence: Dr Stefan Stamm, as above. E-mail: stamm@pop1.biochem.mpg.de Guiramand et al, 1995;Suzuki et al, 1995;Yan et al, 1995;Strohmaier et al, 1996), modulate enzymatic activity (O'Malley et al, 1995), create different hormones (Amara et al, 1982;Courty et al, 1995) and change properties of ion channels (Sommer et al, 1990;Kuhse et al, 1991).…”

Molecular dynamics of insulin/IGF‐I receptor transmembrane signaling

“…a single mutation in the insulin receptor $-subunit can be substantially more insulin resistant than expected from the loss of half the complement of functional insulin receptors. We and others therefore hypothesized that, in these patients' tissues, insulin hybrid receptors were being formed between wild-type and mutant a$ half-receptors, resulting in dysfunctional complexes Jacobs and Moxham, 1991;Flier, 1992;Frattali, et al, 1992b;O'Rahilly and Moller, 1992;Taylor et al, 1992). If hybrid receptor formation was random, as much as 75% of the cell surface receptors would be inactive.…”