**6.3 IR in adipose tissue**

In DM2 patients with IR and low insulin levels, a greater lipolysis occurs in the adipocytes increasing the concentration of circulating FFA, particularly during the night; the capacity of insulin, in these cases, is being insufficient to maintain the FFA plasma levels within the normal range.

FFA, as already mentioned, contribute to elevate fasting glycemia through gluconeogenesis, which would be the main defect, and additionally reduce glucose uptake and oxidation in the muscle.

Increased FFA inhibits the activity of pyruvate dehydrogenase, an enzyme that participates in the final stage of glycolysis, thus slowing down glucose degradation and energy production by glucose metabolism.

The higher supply of long-chain FFA by the fatty acid-binding protein-2 (FABP-2) for their oxidation as a source of energy is another mechanism of competition with glucose.

Regulation of FFA metabolism is highly sensitive to insulin levels and is probably one of the first actions that are lost when insulinemia decreases and the individual is IR.

The metabolic pathways of IR in the liver, muscle and adipose tissue of DM2 patients is seen in **Figure 2**.

## **6.4 Cellular mechanisms**

In DM2 patients, IR is caused by alterations in the insulin receptor, and mainly postreceptor changes subsequent to insulin receptor binding. Disturbances at the receptor level would be caused by obesity of the patients and postreceptor ones would be more specific to DM2.

Normally, insulin action in relation to glucose uptake occurs by insulin binding to its receptor which is a tyrosine kinase that is activated by autophosphorylation on tyrosine, this being the first step. Subsequently, second messengers are produced, among others IRS and PI-3 K, which are also activated by phosphorylation on tyrosine; then, GLUT migrate from the intracellular space to the cell membrane to take up glucose from the blood stream through facilitated diffusion, which is a selective

**35**

participates.

**Figure 2.**

which is IR.

phosphorylation.

*Pathogenesis of Type 2 Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.83692*

translocation of a molecule against its gradient by transporters. As a last stage for ending the signal transmission, the receptor is inactivated by a dephosphorylating mechanism, a process in which protein-tyrosine phosphatase-1B (PTP-1B)

*Mechanism involved in insulin resistance in the liver, muscle and adipose tissue.*

In DM2, part of the IR is caused by a reduction of insulin binding to its receptors; however, defects in the protein substrates and in the enzymes, inside the cells, would be of greater importance, and they correspond to postreceptor defects. The abnormalities of the receptor do not explain the great IR of DM2 patients; therefore, postreceptor defects are considered to contribute in higher proportion to cause this disturbance. Numerous studies have demonstrated that insulin receptor binding in the various tissues of DM2 patients is decreased by 50% in obese subjects and by 20% in normal weight subjects. Besides, the autophosphorylation capacity of the receptor is 40% less than in nondiabetic individuals. The decrease in kinase activity of the receptor is a relatively specific damage of the diabetic state, which can be due to an intrinsic enzymatic defect of the receptor. In DM2, only a small fraction of the total receptors is capable of autophosphorylation under insulin stimulus; therefore, the activity of the receptors is reduced leading to lower action of the hormone,

In DM2 patients, there could exist deterioration in insulin-mediated IRS-1 phosphorylation when a proportion of these protein factors that phosphorylate on serine (not on tyrosine) are inactivated. Consequently, the insulin signal transmission is lower inside the cell [34], and glucose transport is reduced due to diminished PI-3 K activity. There is also a significant reduction in the number of glucose transporters available in the cell membrane, which would be due to a disorder in their distribution as they remain within an inactive intracellular pool, the final result being hyperglycemia. Increased FFA reduces glucose transport translocation through inhibition of PKCβ activity and lower GLUT

The β cell is in charge of responding to these higher demands caused by IR, increasing insulin synthesis in order to preserve normal levels of fasting and postprandial glycemias. In DM2, insulin is incapable of responding to the demands of IR; it is evident that the ability of the β cell for secreting insulin under the glucose

DM2 does not develop if there is no β cell dysfunction even if there exists IR.

stimulus for maintaining glycemic homeostasis is lost in DM2.

#### **Figure 2.**

*Type 2 Diabetes - From Pathophysiology to Modern Management*

**6.2 IR in the muscle**

prandial hyperglycemia.

**6.3 IR in adipose tissue**

plasma levels within the normal range.

uptake and oxidation in the muscle.

patients is seen in **Figure 2**.

**6.4 Cellular mechanisms**

would be more specific to DM2.

and energy production by glucose metabolism.

is reduced.

glucose.

is IR.

through the metabolites of the Krebs cycle, serve as a substrate for gluconeogenesis. In the liver, at least two types of alterations have been found: the already mentioned increase in hepatic gluconeogenesis and an incapacity both of insulin and of glycemia to inhibit glucose production. In individuals with IR, the hepatic glucose cycle is increased due to a higher activity of glucose-6-phosphatase that dephosphorylates glucose-6-phosphate, which once dephosphorylated cannot be metabolized in the

Glucose utilization by the skeletal muscle is mainly mediated by insulin and reaches about 5 g/hour in the postabsorptive state. In DM2 patients, this process is severely disrupted, glucose uptake is decreased, and the amount of stored glycogen

Glycogenesis is approximately 60% lower due to a lower activity of the muscle glycogen synthase (GS) [33]. In the IR state, insulin is incapable of stimulating muscle GS; there is excess glucose in the postabsorptive state, but it is not deposited in the form of glycogen, such that this genetic defect directly contributes to post-

In DM2 patients with IR and low insulin levels, a greater lipolysis occurs in the adipocytes increasing the concentration of circulating FFA, particularly during the night; the capacity of insulin, in these cases, is being insufficient to maintain the FFA

FFA, as already mentioned, contribute to elevate fasting glycemia through gluconeogenesis, which would be the main defect, and additionally reduce glucose

Increased FFA inhibits the activity of pyruvate dehydrogenase, an enzyme that participates in the final stage of glycolysis, thus slowing down glucose degradation

The higher supply of long-chain FFA by the fatty acid-binding protein-2 (FABP-2) for their oxidation as a source of energy is another mechanism of competition with

Regulation of FFA metabolism is highly sensitive to insulin levels and is probably one of the first actions that are lost when insulinemia decreases and the individual

The metabolic pathways of IR in the liver, muscle and adipose tissue of DM2

In DM2 patients, IR is caused by alterations in the insulin receptor, and mainly postreceptor changes subsequent to insulin receptor binding. Disturbances at the receptor level would be caused by obesity of the patients and postreceptor ones

Normally, insulin action in relation to glucose uptake occurs by insulin binding to its receptor which is a tyrosine kinase that is activated by autophosphorylation on tyrosine, this being the first step. Subsequently, second messengers are produced, among others IRS and PI-3 K, which are also activated by phosphorylation on tyrosine; then, GLUT migrate from the intracellular space to the cell membrane to take up glucose from the blood stream through facilitated diffusion, which is a selective

glycolysis such that glucose enters the circulation favoring hyperglycemia.

**34**

*Mechanism involved in insulin resistance in the liver, muscle and adipose tissue.*

translocation of a molecule against its gradient by transporters. As a last stage for ending the signal transmission, the receptor is inactivated by a dephosphorylating mechanism, a process in which protein-tyrosine phosphatase-1B (PTP-1B) participates.

In DM2, part of the IR is caused by a reduction of insulin binding to its receptors; however, defects in the protein substrates and in the enzymes, inside the cells, would be of greater importance, and they correspond to postreceptor defects. The abnormalities of the receptor do not explain the great IR of DM2 patients; therefore, postreceptor defects are considered to contribute in higher proportion to cause this disturbance.

Numerous studies have demonstrated that insulin receptor binding in the various tissues of DM2 patients is decreased by 50% in obese subjects and by 20% in normal weight subjects. Besides, the autophosphorylation capacity of the receptor is 40% less than in nondiabetic individuals. The decrease in kinase activity of the receptor is a relatively specific damage of the diabetic state, which can be due to an intrinsic enzymatic defect of the receptor. In DM2, only a small fraction of the total receptors is capable of autophosphorylation under insulin stimulus; therefore, the activity of the receptors is reduced leading to lower action of the hormone, which is IR.

In DM2 patients, there could exist deterioration in insulin-mediated IRS-1 phosphorylation when a proportion of these protein factors that phosphorylate on serine (not on tyrosine) are inactivated. Consequently, the insulin signal transmission is lower inside the cell [34], and glucose transport is reduced due to diminished PI-3 K activity. There is also a significant reduction in the number of glucose transporters available in the cell membrane, which would be due to a disorder in their distribution as they remain within an inactive intracellular pool, the final result being hyperglycemia. Increased FFA reduces glucose transport translocation through inhibition of PKCβ activity and lower GLUT phosphorylation.

The β cell is in charge of responding to these higher demands caused by IR, increasing insulin synthesis in order to preserve normal levels of fasting and postprandial glycemias. In DM2, insulin is incapable of responding to the demands of IR; it is evident that the ability of the β cell for secreting insulin under the glucose stimulus for maintaining glycemic homeostasis is lost in DM2.

DM2 does not develop if there is no β cell dysfunction even if there exists IR.
