In Vivo Mutagenesis of the Insulin Receptor

Abstract

Mice bearing targeted gene mutations that affect insulin receptor (Insr) function have contributed important new information on the pathogenesis of type 2 diabetes. Whereas complete Insr ablation is lethal, conditional mutagenesis in selected tissues has more limited consequences on metabolism. Studies of mice with tissue-specific ablation of Insr have indicated that both canonical (e.g. muscle and adipose tissue) and noncanonical (e.g. liver, pancreatic ␤-cells, and brain) insulin target tissues can contribute to insulin resistance, albeit in a pathogenically distinct fashion. Furthermore, experimental crosses of Insr mutants with mice carrying mutations that affect insulin action at more distal steps of the insulin signaling cascade have begun to unravel the genetics of type 2 diabetes. These studies are consistent with an oligogenic inheritance, in which synergistic interactions among few alleles may account for the genetic susceptibility to diabetes. In addition to mutant alleles conferring an increased risk of diabetes, these studies have uncovered mutations that protect against insulin resistance, thus providing proof-ofprinciple for the notion that certain alleles may confer resistance to diabetes.Diabetes is a growing threat to public health worldwide (1). Type 1 diabetes is caused by autoimmune destruction of pancreatic ␤-cells (2), whereas type 2 diabetes results from insulin resistance and impaired ␤-cell function (3). Insulin resistance is found in the main insulin target tissues (muscle, adipose cells, liver) of patients with overt diabetes. However, this is a consequence of chronic hyperinsulinemia and glucotoxicity (4). The question of whether insulin resistance represents a generalized impairment of insulin action or is initially restricted to specific organs has remained unclear, as has its relationship to impaired ␤-cell function. Although insulin receptor (Insr) 1 defects are uncommon as a cause of diabetes (5), this gene remains an attractive target for in vivo studies of insulin resistance, as it has been shown to be the master switch of the metabolic (6, 7) and growth-promoting actions (8, 9) of insulin. Insulin Receptor Gene Knock-outMice homozygous for null Insr alleles are born at term with slight growth retardation (9) but rapidly develop metabolic abnormalities, followed by diabetic ketoacidosis and death (6, 7). The marked difference between this phenotype and that of humans lacking INSR (5) has been reviewed elsewhere (10). Conditional Insr AblationThe lethal phenotype of Insr knock-out mice precludes a detailed analysis of Insr function in different tissues in adult mice. This problem has been circumvented by generating conditional knockouts using the Cre/loxP binary system (11) or combined haploinsufficient and dominant-negative mutations (Table I). Insulin Action in Skeletal Muscle andInsulin Resistance The cornerstone of current theories on the pathogenesis of type 2 diabetes is that skeletal muscle, the main site of insulin-dependent glucose disposal, is intrinsically unable to ...

Genes encoding longevity: from model organisms to humans

“…In contrast, complete disruption of the IR gene leads to insulin resistance, diabetes and shortened lifespan (Okamoto & Accili, 2003). Likewise, tissue-specific IR knockout mouse models develop obesity, insulin resistance and impaired glucose regulation, with the exception of fat-specific IR knockout mice (FIRKO) (Okamoto & Accili, 2003). These mice have reduced fat mass, are protected against age-related obesity and live longer than their littermates.…”

“…Furthermore, mice mutated for the IGF-1 receptor hint at a direct role for reduced IGF-1 signalling in mammalian longevity: Igf1r +/-females, but not males, exhibit a long-lived phenotype (Holzenberger et al ., 2003). In contrast, complete disruption of the IR gene leads to insulin resistance, diabetes and shortened lifespan (Okamoto & Accili, 2003). Likewise, tissue-specific IR knockout mouse models develop obesity, insulin resistance and impaired glucose regulation, with the exception of fat-specific IR knockout mice (FIRKO) (Okamoto & Accili, 2003).…”

Expression of the skeletal muscle dystrophin–dystroglycan complex and syntrophin-nitric oxide synthase complex is severely affected in the type 2 diabetic Goto–Kakizaki rat

“…skeletal muscle and adipose tissue, and non-canonical insulin targets, e.g. liver, pancreas and brain tissues, may contribute in distinctly different ways to clinical insulin resistance (Okamoto and Accili, 2003). The insulin receptor represents a tyrosine kinase, whereby insulin binding to the a-subunits causes the b-subunits to autophosphorylate, thus activating the catalytic activity of the receptor complex.…”

Systematic review: association of polycystic ovary syndrome with metabolic syndrome and non-alcoholic fatty liver disease

“…For example, knockout of INSR in white adipose tissue protects mice against obesity, whereas its elimination in brown adipose lead to the development of b-cell failure (see 101 for detailed analysis). By using microsatellite markers, analysis of linkage and familybased association, it was concluded that the INSR gene marker D19S884, which is located 1 cM telometric to the INSR gene, is significantly associated with PCOS (v 2 = 11.85; P < 0.0006).…”