**7.1 Hyperglucagonemia**

It has been found that in DM2 patients, fasting and postprandial glucagon levels are increased and directly correlated to the higher glucose production; such that in DM2 patients, hyperglucagonemia contributes to fasting hyperglycemia through hepatic gluconeogenesis. The bihormonal theory in DM2, insulin deficit and glucagon increase, was proposed in 1981 by Unger and is widely accepted today [35].

### **7.2 Diminished incretin effect**

It has been demonstrated that orally administered glucose induces greater insulin secretion than intravenously injected glucose; this is called the incretin effect.

Incretins are peptides secreted in the digestive tract that have a role in the regulation of glycemia. These are GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). These peptides, synthesized in the ileum and the jejunum, are released after oral glucose intake, stimulating endogenous insulin secretion and reducing glucagon secretion; also, they slow down gastric emptying and reduce appetite. GLP-1 is much more important, contributing with 90% to the total effect.

Decreased incretin effect is associated with the lower GLP-1 levels exhibited by DM2 patients in the postabsorptive state; GLP-1 deficit is related to lower insulin secretion, and consequently glucose production in the liver after meals is not inhibited either [36].

#### **7.3 Microbiota**

The digestive tract hosts a complex bacterial ecosystem of nearly 100 trillion microorganisms, with about 1000 species having multiple nutritional and metabolic functions. In DM2 patients, compared with nondiabetic subjects, a proportional increase of Gram-negative bacteria has been found, which would participate in the chronic inflammation state of this pathology [37].

Several mechanisms are proposed to explain the influence of gut microbiota (GM) on the onset of IR and DM2; the best founded mechanism postulated is the change in intestinal permeability with increase of endotoxemia.

It has been observed that since the beginning of the development of obesity and DM2, there exists an alteration in GM that is capable of inducing a disturbance in the intestinal barrier, causing the person to absorb more toxic substances. This metabolic endotoxemia, characterized by an increase in serum levels of lipopolysaccharides, contributes to the low-grade chronic inflammatory state that is associated to IR and to DM2 [38].

Lipopolysaccharides derived from the cell membrane of the Gram-negative bacteria of GM are known inflammation stimulators, which could be explained because they bind to Toll-like receptor 4 (TLR4) present in adipocytes, stimulating the production of proinflammatory cytokines, particularly TNFα and IL-6. These TLR4 favor NF-kβ activation, which regulates the synthesis of inflammatory molecules [39]; activation of TLR4 would cause an increase in the activity of the NF-kβ transcription factors of proinflammatory cytokines which prevent the interaction of insulin with its receptor, contributing to DM2 through lower insulin action.

#### **7.4 Increased renal glucose reabsorption**

It is presently accepted that alterations in the renal mechanisms of glucose regulation would be involved in the pathogenesis of DM2. In experimental studies, it has

**37**

genic disorders.

intracellular calcium.

lower effectiveness and higher cost.

however, they are still not exactly known.

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

been demonstrated that in DM2 there exists a poor adaptive response of the kidney,

Glucose reabsorption is mediated by sodium glucose-linked transporters (SGLT), a family of membrane transporters widely distributed throughout the body, of which SGLT1 and SGLT2 are expressed in the proximal convoluted tubule of the kidney. SGLT2 has a high capacity and reabsorbs 90% of the filtered glucose; this physiological mechanism is produced through a process of sodium/glucose active cotransport, such that when sodium is absorbed, an energy gradient is produced that permits the

In DM2 patients, a higher synthesis and absorption capacity of SLGT2 have been demonstrated, increasing maximal glucose transport from a glycemia of 180 mg/dl in healthy subjects to 240 mg/dl in DM2 patients. Thus, glucosuria begins at higher glycemic levels, originating a greater glucose reabsorption which contributes to maintaining the hyperglycemia. On the other side in DM2, increased renal gluconeogenesis has been found, resulting in higher glucose production and favoring

Considering all the above, in relation to the pathogenesis of DM2, DeFronzo [30] describes what he called the ominous octet, because the alterations exhibited by these patients are eight. These are in pancreatic β cells, less insulin secretion; IR in the liver with increase in gluconeogenesis; IR in muscular tissue with less glucose uptake; IR in adipose tissue with greater FFA production; in the gut, reduction in GLP-1 release with decreased incretin effect; hyperglucagonemia due to greater production in pancreatic α cells; in the kidney, increase in glucose reabsorption; and

In 2016, Schwartz [43] published that the alterations in DM2 patients are 11, thus adding to those mentioned above, gut microbiota, deregulation of the immune system, and increase of glucose uptake in the gut. The object of this description is to find similarities between the pathogenesis of DM2 and the pathogenesis of type 1 diabetes and in the future create a new β cell-centric classification of diabetes.

The present knowledge on the pathogenesis of DM2 has permitted the development of various drugs for the treatment of this type of diabetes, which act on the different disturbances presented by these patients to correct the multiple patho-

Sulfonylureas (SU), the first drugs used (1954), act on the β cells stimulating insulin secretion by closure of the ATP-sensitive K channels and elevation of

Later, in 1997, meglitinides appear they are insulin-secreting drugs with a shorter action than SU, which are employed as prandial regulators of glycemia. Their mechanism of action is similar to that of SU; they bind to specific receptors in the β cells, different from those of SU. Their use has been very limited due to their

Metformin, introduced in the USA in 1955, is an insulin-sensitizing drug belonging to the biguanide family, widely used as a monodrug or associated with other hypoglycemic drugs. Metformin reduces IR and fasting hyperglycemia by slowing down gluconeogenesis; it also increases glucose uptake by the muscle and favors glucose utilization by the gut. Several mechanisms of action have been postulated;

Another group of insulin-sensitizing drugs is constituted by thiazolidinediones (TZD), incorporated into the drug therapy in the year 2000 with the object

**8. Therapeutic implications of the pathogenesis of DM2**

through higher renal glucose reabsorption, favoring hyperglycemia [40].

entry of glucose into blood circulation independently of insulin [41].

even more the hyperglycemia of these patients [42].

in the brain, IR with a non-clarified effect.

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

*Type 2 Diabetes - From Pathophysiology to Modern Management*

It has been found that in DM2 patients, fasting and postprandial glucagon levels are increased and directly correlated to the higher glucose production; such that in DM2 patients, hyperglucagonemia contributes to fasting hyperglycemia through hepatic gluconeogenesis. The bihormonal theory in DM2, insulin deficit and glucagon increase, was proposed in 1981 by Unger and is widely accepted today [35].

It has been demonstrated that orally administered glucose induces greater insulin secretion than intravenously injected glucose; this is called the incretin effect. Incretins are peptides secreted in the digestive tract that have a role in the regulation of glycemia. These are GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). These peptides, synthesized in the ileum and the jejunum, are released after oral glucose intake, stimulating endogenous insulin secretion and reducing glucagon secretion; also, they slow down gastric emptying and reduce appetite. GLP-1 is much more important, contributing with 90% to the total effect.

Decreased incretin effect is associated with the lower GLP-1 levels exhibited by DM2 patients in the postabsorptive state; GLP-1 deficit is related to lower insulin secretion, and consequently glucose production in the liver after meals is not inhibited either [36].

The digestive tract hosts a complex bacterial ecosystem of nearly 100 trillion microorganisms, with about 1000 species having multiple nutritional and metabolic functions. In DM2 patients, compared with nondiabetic subjects, a proportional increase of Gram-negative bacteria has been found, which would participate

Several mechanisms are proposed to explain the influence of gut microbiota (GM) on the onset of IR and DM2; the best founded mechanism postulated is the

It has been observed that since the beginning of the development of obesity and DM2, there exists an alteration in GM that is capable of inducing a disturbance in the intestinal barrier, causing the person to absorb more toxic substances. This metabolic endotoxemia, characterized by an increase in serum levels of lipopolysaccharides, contributes to the low-grade chronic inflammatory state that is associated

Lipopolysaccharides derived from the cell membrane of the Gram-negative bacteria of GM are known inflammation stimulators, which could be explained because they bind to Toll-like receptor 4 (TLR4) present in adipocytes, stimulating the production of proinflammatory cytokines, particularly TNFα and IL-6. These TLR4 favor NF-kβ activation, which regulates the synthesis of inflammatory molecules [39]; activation of TLR4 would cause an increase in the activity of the NF-kβ transcription factors of proinflammatory cytokines which prevent the interaction of insulin with its receptor, contributing to DM2 through lower insulin action.

It is presently accepted that alterations in the renal mechanisms of glucose regulation would be involved in the pathogenesis of DM2. In experimental studies, it has

in the chronic inflammation state of this pathology [37].

change in intestinal permeability with increase of endotoxemia.

**7. Other pathogenic alterations of DM2**

**7.1 Hyperglucagonemia**

**7.2 Diminished incretin effect**

**7.3 Microbiota**

to IR and to DM2 [38].

**7.4 Increased renal glucose reabsorption**

**36**

been demonstrated that in DM2 there exists a poor adaptive response of the kidney, through higher renal glucose reabsorption, favoring hyperglycemia [40].

Glucose reabsorption is mediated by sodium glucose-linked transporters (SGLT), a family of membrane transporters widely distributed throughout the body, of which SGLT1 and SGLT2 are expressed in the proximal convoluted tubule of the kidney. SGLT2 has a high capacity and reabsorbs 90% of the filtered glucose; this physiological mechanism is produced through a process of sodium/glucose active cotransport, such that when sodium is absorbed, an energy gradient is produced that permits the entry of glucose into blood circulation independently of insulin [41].

In DM2 patients, a higher synthesis and absorption capacity of SLGT2 have been demonstrated, increasing maximal glucose transport from a glycemia of 180 mg/dl in healthy subjects to 240 mg/dl in DM2 patients. Thus, glucosuria begins at higher glycemic levels, originating a greater glucose reabsorption which contributes to maintaining the hyperglycemia. On the other side in DM2, increased renal gluconeogenesis has been found, resulting in higher glucose production and favoring even more the hyperglycemia of these patients [42].

Considering all the above, in relation to the pathogenesis of DM2, DeFronzo [30] describes what he called the ominous octet, because the alterations exhibited by these patients are eight. These are in pancreatic β cells, less insulin secretion; IR in the liver with increase in gluconeogenesis; IR in muscular tissue with less glucose uptake; IR in adipose tissue with greater FFA production; in the gut, reduction in GLP-1 release with decreased incretin effect; hyperglucagonemia due to greater production in pancreatic α cells; in the kidney, increase in glucose reabsorption; and in the brain, IR with a non-clarified effect.

In 2016, Schwartz [43] published that the alterations in DM2 patients are 11, thus adding to those mentioned above, gut microbiota, deregulation of the immune system, and increase of glucose uptake in the gut. The object of this description is to find similarities between the pathogenesis of DM2 and the pathogenesis of type 1 diabetes and in the future create a new β cell-centric classification of diabetes.
