Tumor necrosis factor α (TNF-α) [86–88]
Adapted from [78]
It has been suggested that genetically determined insulin resistance of the muscle is the primary defect in the majority of type 2 diabetic individuals [74,94]. However, in cell culture, muscle cells from lean, non-diabetic, insulin-resistant subjects do not preserve their insulin resistance, suggesting that environmental factors may be of pivotal importance in the insulin sensitivity of muscle [95].
Fig. 1.2 Hypothetical insulin signaling pathways. Insulin signaling is initiated at the level of the insulin receptor. The insulin receptor tyrosine kinase activity leads to tyrosine phosphorylation of insulin receptor substrates (IRS1, IRS2, She). The phosphotyrosine residues of these proteins transfer the signal via SH2 domains and adapter molecules (Grb2, SOS, Syp) onto signal mediators like PI-3 kinase and the RAS complex. The PI-3 kinase pathway leads to translocation of glucose transporter 4 GLUT-4) and stimulation of glycogen synthesis; the RAS complex is a mediator for the activation of the MAP kinase, which is important for insulin-dependent cell growth and protein synthesis. (Adapted by permission from Holman and Kasuga [90] and from J. Eckel, personal communication)
PI 3-kinase. phosphatidylinositol 3-kinase; IRS, insulin receptor substrate; Shc, adaptor protein Shc; SH2, Src homology 2; PKB, protein kinase B; SOS. son-of-sevenless; Ras, small GTP-binding protein; Raf proteins, serine-threonine kinases with homology to PKC; MAP kinase, mitogen activated protein kinase; GSK3, glycogen synthase kinase 3; GRB2, growth factor receptor binding protein 2: Syp, SH2 domain-containing protein-tyrosine-phosphatase
Table 1.9 Effects of insulin on different tissues
| Effect | Tissue |
|---|---|
| Stimulation of membrane transport | |
| Glucose | Muscle, adipose tissue |
| Amino acids | Muscle, adipose tissue |
| Ions | Muscle, adipose tissue, liver |
| Stimulation of synthesis | |
| Glycogen | Muscle, adipose tissue |
| Protein | Muscle, adipose tissue, lactating mammary gland |
| Fatty acids | Liver, adipose tissue, lactating mammary gland |
| Triglycerides | Liver, adipose tissue, lactating mammary gland |
| Inhibition of | |
| Lipolysis | Adipose tissue |
| Proteolysis | Muscle, liver |
| Gluconeogenesis and glucose production | Liver |
| Cell proliferation and differentiation | Stem cells, preadlpocytes, fibroblastsDifferentiated cells? |
In the liver insulin suppresses gluconeogenesis and hepatic glucose release. Insulin resistance may unleash hepatic glucose output, which plays a role in fasting hyperglycemia.
In adipocytes insulin inhibits lipolysis and stimulates glucose uptake, lipid synthesis, and esterification of fatty acids. Therefore, insulin resistance results in elevated plasma free fatty acids (FFA), which in their turn contribute to insulin resistance, increased gluconeogenesis, hepatic glucose output, and very-low-density lipoprotein (VLDL) production.
The mechanism of the relationship between obesity and insulin resistance is still a matter of debate. FFA could play a major role [100]. High plasma FFA concentrations induce insulin resistance in muscle and liver [96]. The augmentation of adipose mass results in increased FFA release. Since visceral fat cells are metabolically more active and more sensitive to lipolytic stimuli, the increase of FFA is most pronounced in persons with visceral obesity. This is in line with the high diabetes rate in this type of obesity.
At the molecular level, the Randle mechanism, the inhibition of the glycogen synthase [96], the inhibition of the insulin signal cascade [97], or genomic effects which could be mediated through peroxisome proliferator-activated receptor (PPAR)-α have been discussed as possibly implicated in insulin resistance [98].
The Randle mechanism, also called the glucose-fatty acid cycle, postulates an inhibition of muscular glucose utilization by FFA [99]. Its relevance in humans is debated [92,100]. FFA are also important stimulators of hepatic gluconeogenesis and hepatic glucose output [101], which is unleashed in early impaired glucose tolerance [102]. This effect allows the enhanced hepatic glucose output to be explained without postulating genuine hepatic insulin resistance.
Another link between obesity and insulin resistance could be related to the hormonal activity of adipose tissue. Fat cells produce a variety of molecules with endocrine and paracrine activity. Some of them, including leptin, estrogens, IGF-I, FFA, and complement factors are released into the circulation. The cytokines TNF-α, interieukin-6, and angiotensinogen or angiotensin may act locally. Since metabolically active fat cells are located not only in adipose tissue but also inside the muscle, in close vicinity to myocytes, signals from these fat cells may have effects on adipocytes or muscle cells without being detectable in the circulation.
There is some evidence that signals released from fat cells are involved in insulin resistance. In laboratory animals the expression of TNF-α in adipocytes is linked to insulin resistance [86]. This cytokine stimulates phosphorylation of the serine residues of IRS-1, leading to reduced activity of the insulin receptor tyrosine kinase [88,103]. An inhibition of insulin signaling at the phosphatidylinositol 3-kinase (PI-3 kinase) level has been shown in human fat cells [88]. It could explain why TNF-α inhibits insulin-stimulated glucose transporter 4 (GLUT-4) expression and translocation [88,104,105] and may thereby impair glucose utilization. In obesity and type 2 diabetes, the expression of TNF-α and its receptors is increased in adipose and muscle tissue [86,104].
Physical activity has major effects on glucose and lipid metabolism. The sequence of metabolic changes during exercise can be summarized as follows: white muscle
