Advertisement
IRS2 takes center stage in the development of type 2 diabetes
Matthew J. Brady
Department of Medicine, Committee on Molecular Metabolism and Nutrition, University of Chicago, Chicago, Illinois, USA.
Address correspondence to: Matthew J. Brady, University of Chicago, Department of Medicine, MC 1027, 5841 S. Maryland Avenue, Chicago, Illinois 60637, USA. Phone: (773) 702-2346; Fax: (773) 834-0486; E-mail: mbrady@medicine.bsd.uchicago.edu.
Find articles by Brady, M. in: JCI | PubMed | Google Scholar
Published October 1, 2004 - More info
J Clin Invest. 2004;114(7):886–888. https://doi.org/10.1172/JCI23108.
© 2004 The American Society for Clinical Investigation
Diabetes mellitus is characterized by an inability of the body to efficiently utilize circulating nutrients. Normally, in response to elevation of plasma glucose, insulin is secreted by β cells in the islets of Langerhans and promotes energy uptake, metabolism, and storage. Type 2 diabetes is preceded by the development of insulin resistance in target tissues (1), but the molecular causes of its initiation and progression remain unclear. Obesity is the predominant risk factor for the onset of insulin resistance, although other genetic and environmental factors also contribute (2). Islets initially compensate for the loss of insulin sensitivity by expanding β cell mass and insulin secretory capacity, but over time, they cannot continue to meet the chronic stress of increased insulin demand. The loss of β cells and reduction in circulating insulin levels occur despite continuing peripheral insulin resistance, resulting in chronic hyperglycemia. However, the underlying molecular links among the cascade of obesity, insulin resistance, islet compensation, eventual β cell failure, and onset of frank diabetes remain unidentified.
-
IRS2 mediates insulin signaling in responsive cells
Insulin signals by binding to a specific tyrosine kinase receptor expressed in target cells, which results in the increased phosphorylation of a number of substrate proteins and activation of complex second messenger cascades that regulate glucose and lipid metabolism (3). Insulin receptor substrate (IRS) proteins are a family of molecules that are directly phosphorylated by the insulin receptor (Figure 1), which leads to the recruitment and activation of additional signaling proteins (4). The crucial role of IRS proteins in insulin action has been demonstrated using transgenic knockout mouse models (5). Ablation of Irs1 resulted in growth retardation and insulin resistance, but not overt diabetes due to increased β cell mass (6–8). In contrast, Irs2–/– mice displayed many of the hallmarks of type 2 diabetes in human subjects: peripheral insulin resistance coupled with a lack of compensatory β cell expansion, resulting in hyperglycemia, diabetes, and premature death (9, 10). These results demonstrated a crucial role for IRS2 in insulin sensitivity in liver and skeletal muscle, as well as β cell proliferation.
Figure 1Role of IRS2 in insulin signaling. Insulin binds to its receptor in target cells, leading to the activation of an intrinsic tyrosine kinase located in the β subunit. The resulting autophosphorylation (P) of the insulin receptor on tyrosine (Tyr) residues increases the association of various signaling molecules, including IRS2. Insulin receptor directly phosphorylates IRS2 on multiple tyrosine residues, which, in turn, initiates a variety of second messenger cascades. Recent work has demonstrated a critical role for IRS2 in the maintenance of peripheral insulin sensitivity, central leptin sensitivity, and proper β cell development in the islets of Langerhans (11, 12). Thus, IRS2 plays a central role in preserving insulin action in multiple cell types, while reduction of IRS expression and/or function may be a fundamental cause of the development of insulin resistance, obesity, β cell failure, and type 2 diabetes. S_S, disulphide bond.
However, due to the systemic knockout of Irs2 in these animals, the relative contribution of reduced IRS2 levels in various cell types to the development of diabetes remained unclear. In this issue of the JCI, Lin et al. (11) and Kubota et al. (12) independently generated a novel transgenic mouse model by crossing a floxed Irs2 mouse with a mouse expressing Cre recombinase under the control of the rat insulin promoter. Thus, the floxed Irs2 would only be excised from the genomic DNA in cell types that also expressed Cre, resulting in a tissue-specific knockout of Irs2. In the offspring of these mice, Cre expression was, as expected, highest in the insulin-producing β cells, but it also was present in several regions of the brain including the hypothalamus. The mice exhibited targeted disruption of Irs2, with levels reduced by greater than 90% in islets and 30–50% in the hypothalamus but no change in skeletal muscle, liver, or adipose tissue. Despite the restricted reduction in Irs2, these mice exhibited many of the same phenotypic changes seen in the global Irs2–/– mice: central leptin resistance, peripheral insulin resistance, obesity, glucose intolerance, β cell failure, and hyperglycemia. Of particular interest, partial reduction of hypothalamic Irs2 affected peripheral insulin sensitivity independently of reduced Irs2 levels in liver, muscle, or fat. Perhaps most unexpectedly, Lin et al. also reported the spontaneous reversal of diabetes in their transgenic mice upon aging due to β cell regeneration and subsequent compensation for the persistent peripheral insulin resistance.
Copyright © 2024 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)