Insulin Resistance

^.Genetic Defect

Impaired glucose-induced insulin release (P-cell Dysfunction)

Hyperglycemia (NIDDM)

Figure 2 Schematic diagram of the glucose transporter translocation hypothesis. Insulin-responsive tissues, specifically adipose tissue and skeletal muscle, contain intracellular stores of glucose transporter proteins (GLUT). The binding of insulin and the subsequent increase in tyrosine kinase activity of the insulin receptor initiates a signaling cascade, which results in the tyrosine phosphorylation of insulin receptor substrates (IRS 1 -n), their binding to the enzyme phosphatidylinositol 3-kinase (PI 3-kinase), and the resultant activation of PI 3-kinase to produce phosphorylated phosphoinositides. This signaling cascade leads to the mobilization and insertion of stored glucose transporters into the plasma membrane, allowing for increased glucose influx into the cell in response to insulin.

insulin signals, defects in detecting/transducing the signal, a reduction in the total amount of glucose transporters, and/or inability of the transporters to properly dock with and incorporate into the plasma membrane. Of these, defects in insulin signaling and glucose transporter levels have been amply explored, and emerging evidence is being provided for defects in glucose transporter translocation. No studies have examined the mechanism of glucose transporter interaction with the plasma membrane in either humans or animals with diabetes. Finally, because the mechanism whereby the intracellular organelle detects the insulin signal is largely unknown, the possibility that this step is defective remains unexplored. A brief account of the status of glucose transporter levels, GLUT4 translocation, and defects in the insulin signaling pathway in diabetes is provided below. It is important to realize that, for the most part, these studies do not distinguish whether the defects found relate to the primary or secondary insulin resistance.

1. GLUT4 Expression

The levels of expression of the GLUT4 glucose transporter have been analyzed in a variety of animal models of type 2 diabetes and in tissue from individuals with type 2 diabetes (for review see 18,19). GLUT4 protein content is markedly diminished in adipose tissues of human and most animal models. It has been found that GLUT4 expression in adipocytes decreases as diabetes develops in older Zucker rats (18,19), and adipose cells taken from humans with type 2 diabetes also show a reduction in GLUT4 content (20). However, this change in GLUT4 levels is restricted to adipose tissue and is not seen in skeletal muscle of these animal models of type 2 diabetes as normal expression of GLUT4 is observed in muscle of db/db mice and Zucker rats (21-24). Muscle biopsies taken from individuals with type 2 diabetes also show normal skeletal muscle GLUT4 content (25). However, a small number of studies have examined the amount of GLUT4 protein on the plasma membrane of muscle from diabetic animals, and it was found to be abnormal (18,19). This may suggest that sorting of the transporter is a key factor in muscle, whereas net synthesis of the transporter is more pertinent in fat. Whether these changes cause the diabetic state or ensue from hyperglycemia, hyperinsulinemia, and/or hypertriglyceridemia remains to be established. In a study attempting to shed light on this question, brown adipose tissue was ablated in transgenic mice, resulting in a decrease in the total GLUT4 protein in adipocytes. This led to the development of diabetes, suggesting that a reduction in the level of GLUT4 could be causative in this disease (26). However, genetic knockout of the GLUT4 gene in muscle and fat did not create a phenotype of diabetes, although glucose intolerance was generated (27).

2. GLUT4 Translocation

In skeletal muscle of humans with type 2 diabetes, the plasma membrane does not show a reduction and in fact may show a small increase in the amount of GLUT4 transporters. Yet the stimulation of glucose uptake by insulin is totally blunted. Zierath et al. (28) showed that the membranes of these muscles display a diminished gain in glucose transporters in response to an insulin clamp. A similar observation was also made in two animal models of diabetes (24,29). Defective GLUT4 translocation is also seen in fat cells from these animals (30) and in fat cells from humans with type 2 diabetes (20). As a result, several explanations have been put forward to account for this reduced translocation of GLUT4 to the cell surface in skeletal muscle and adipocytes. These include topics that have been briefly mentioned, such as impaired translocation machinery and an inability of the transporters to functionally incorporate into the plasma membrane, in addition to the next topic to be discussed, an alteration in the signaling emerging from the insulin receptor.

3. Insulin Signaling

In animal models of type 2 diabetes and in humans with type 2 diabetes, there is considerable evidence for defects in the early stages of insulin action (3133). There is an approximately 50% decrease in insulin receptor phosphorylation and an 80% decrease in IRS-1 phosphorylation in liver and skeletal muscle of ob/ob mice (34). This was associated with a more than 90% decrease in insulin-stimulated PI 3-kinase activity associated with IRS-1 and no detectable stimulation of total PI 3-kinase activity. In addition, insulin-stimulated Akt kinase activity in skeletal muscle of the lean diabetic Goto-Kakizaki rat was reduced by 68% (35). Skeletal muscle isolated from individuals with type 2 diabetes also show defects at the level of the insulin receptor tyrosine kinase activity, IRS-1 expression and phosphorylation, and IRS-1-associated PI 3-kinase activity (36). A reduction in IRS-1 expression (by 70%) and IRS-1-associated PI 3-kinase activity has also been reported in adipose cells isolated from individuals with type 2 diabetes (20). Thus, in type 2 diabetes, there are defects at four early steps of insulin action. Whether there are also defects distal to the initial signaling events that contribute to impaired translocation of GLUT4 remains to be determined.

In addition to alterations in the level of expression or activation of the signaling molecules in type 2 diabetes, the isoform selectivity of signaling also changes. In adipose cells isolated from humans with type 2 diabetes, IRS-2 becomes the main docking protein for PI 3-kinase and Grb2 in response to insulin (20). This is not surprising because expression of IRS-2 increases, and this protein predominates as the main insulin receptor substrate in mice lacking IRS-1 (37,38). Importantly, mice genetically manipulated to lack IRS-1 do not develop diabetes (38), whereas mice lacking IRS-2 do (39).

In summary, changes in the levels of glucose transporter expression, defects in the insulin signaling pathway, and alterations in pattern of signaling molecules may all contribute to either or both primary and secondary insulin resistance in type 2 diabetes.

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