Molecular mechanisms of insulin resistance in glucagon-producing alpha cells

Abstract

Type II diabetes mellitus is a chronic disease, affecting more than 150 million people worldwide. Type II diabetes mellitus is characterized by insulin resistance of peripheral tissues (liver, muscle and fat), β-cell dysfunction, as well as by the elevation in the concentration of glucagon in plasma. Considering that insulin inhibits glucagon secretion and gene transcription, the hyperglucagonemia and hyperinsulinemia in type II diabetes mellitus suggests that there is insulin resistance also in the glucagon-producing pancreatic α-cells. Hyperglucagonemia contributes to hepatic glucose production and to elevated glucose levels in type II diabetes mellitus. However, the molecular mechanisms of insulin resistance at pancreatic islet α-cells are unknown. In the present work the effect of molecules, implicated in conferring insulin resistance in some other tissues, was investigated on the regulation of glucagon gene transcription by insulin at the level of the pancreatic islet α-cell. Insulin inhibition of glucagon gene transcription in the glucagon-producing α-cell InR1G9 provided a suitable model for this study. The results of this work indicate that elevated levels of insulin or the proinflammatory cytokine interleukin 1-beta are able to reverse the insulin-induced inhibition of glucagon gene transcription. Functional studies with a constitutively active form of protein kinase B showed that protein kinase B still inhibited glucagon gene transcription after a chronic insulin treatment; together with a markedly reduced phosphorylation of PKB, this demonstrates that targets upstream of PKB within the insulin signaling pathway are affected by chronic insulin treatment. Indeed, it was found that chronic insulin treatment blocked insulin signaling at the level of the activation of the insulin receptor and at the level of the insulin receptor substrate 1. After chronic insulin treatment, the activity and expression of the insulin receptor and of the insulin receptor substrate 1 were reduced. Downregulation of the receptor was found to be a reversible, time-dependent process. In addition, further results suggested that the downregulation was due to an enhanced degradation. Degradation of the insulin receptor was neither mediated through proteasomal nor β-arrestin-associated degradation mechanisms. Instead, insulin receptor downregulation appears to be mediated through lysosomal degradation. Taken together the results of the present study suggest that elevated insulin and interleukin 1-beta levels lead to the development of an insulin resistant state at the level of the pancreatic islet α-cells in type II diabetes mellitus.