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 fiber metabolism dominates during the first few minutes of exercise. During endurance exercise red fibers dominate. Their aerobic glycolysis is increased and all endogenous and exogenous substrates are oxidized. Muscle and liver glycogen is mobilized and used up. Glucose uptake may increase up to 20-fold. Serum insulin decreases, indicating enhanced insulin sensitivity. After about 10 minutes' exercise, oxidation of FFA becomes more important and may increase to up to 50-fold of the basal level. Finally, energy metabolism is fueled mainly by FFA and β-hydroxybutyrate/acetoacetate. After strenuous exercise (e.g., marathon), plasma FFA may stay elevated and glucose uptake may remain reduced for several hours (“post-exercise insulin resistance”). A paradoxical increase in blood glucose is seen after short-term exhaustive exercise, which is the result of stress hormone release [106,107].
Increased insulin sensitivity during exercise is due to increased muscular blood flow with greater insulin delivery to muscle, opening of closed capillaries, which enhances the surface area for glucose uptake, and translocation of glucose transporters, mainly GLUT-4 [108]. Physical training stimulates GLUT-4 synthesis [109]. Enhanced insulin sensitivity vanishes in periods of physical inactivity. This occurs as early as after a few days of strict bed rest.
Clinical experience shows that in poorly controlled diabetic individuals insulin sensitivity is decreased. It improves when metabolic control is restored