Insulin: The Friend and the Foe in the Development of Type 2 Diabetes Mellitus

Abstract

Insulin, a hormone produced by pancreatic β-cells, has a primary function of maintaining glucose homeostasis. Deficiencies in β-cell insulin secretion result in the development of type 1 and type 2 diabetes, metabolic disorders characterized by high levels of blood glucose. Type 2 diabetes mellitus (T2DM) is characterized by the presence of peripheral insulin resistance in tissues such as skeletal muscle, adipose tissue and liver and develops when β-cells fail to compensate for the peripheral insulin resistance. Insulin resistance triggers a rise in insulin demand and leads to β-cell compensation by increasing both β-cell mass and insulin secretion and leads to the development of hyperinsulinemia. In a vicious cycle, hyperinsulinemia exacerbates the metabolic dysregulations that lead to β-cell failure and the development of T2DM. Insulin and IGF-1 signaling pathways play critical roles in maintaining the differentiated phenotype of β-cells. The autocrine actions of secreted insulin on β-cells is still controversial; work by us and others has shown positive and negative actions by insulin on β-cells. We discuss findings that support the concept of an autocrine action of secreted insulin on β-cells. The hypothesis of whether, during the development of T2DM, secreted insulin initially acts as a friend and contributes to β-cell compensation and then, at a later stage, becomes a foe and contributes to β-cell decompensation will be discussed.

Keywords: autocrine; compensation; decompensation and type 2 diabetes; hyperinsulinemia; insulin; pancreatic β-cell; β-cell mass.

Figure 1

Insulin and insulin-like growth factor (IGF)-1 receptors. There are six types of receptors: insulin receptor (IR)-A, IR-B, IGF-1R and hybrid receptors, IR-A/IR-B, IGF-1R/IR-A and IGF-1R/IR-B. Expression of IR-A and IR-B is tissue specific. In adult life, IR-B is predominantly expressed in insulin target tissues such as liver, muscle and adipose tissue. IR-A is predominantly expressed in fetal tissues, and its expression declines during adulthood. IR-A and IR-B receptors can form hybrid receptors with each other, or along with one half of the IGF-1R. These receptors, the IGF-1R and hybrids bind the three ligands, insulin, IGF-1 and IGF-2 with different affinities. This figure depicts the order of their affinities to the different ligands by the size of the ligand font. Smaller font indicates lower affinity, and bigger font, higher affinity.

Figure 2

β-Cell life and death in the development of the obesity-mediated type 2 diabetes mellitus (T2DM). A simplified representation of the possible events involved in β-cell health and disease during the life time of a β-cell. The essential roles of insulin and IGF-1 signaling pathways in β-cell function and mass are depicted and the deleterious effects of their dysregulation are described. We included hyperinsulinemia, a key culprit factor that is often overlooked, which we believe might contribute to the common defects in the insulin and IGF-1 signaling pathways at the periphery and in islet β-cells that lead to the development of T2DM.