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

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 pathogenic disorders.

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 intracellular calcium.

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 lower effectiveness and higher cost.

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; however, they are still not exactly known.

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

#### *Type 2 Diabetes - From Pathophysiology to Modern Management*

#### **Figure 3.**

*Pathogenic alterations of type 2 diabetes and pharmacotherapy.*

of reducing IR, especially in adipose tissue. They act by binding to the PPAR-Ύ nuclear receptors, also known as glitazone receptors. Their use is restricted and has been questioned because of their adverse effects, among others, heart failure and possible vesical cancer.

In 2005, GLP-1 receptor agonists (GLP-1 RA) were incorporated. These are drugs that improve the diminished incretin effect of DM2 patients. They are resistant to the action of dipeptidyl peptidase-4 (DPP-4) enzyme which degrades native GLP-1 in 1–2 minutes. Through an action similar to GLP-1, they stimulate insulin secretion. GLP-1 RA are injectable and very expensive, and, in addition to their hypoglycemic action, they have other effects as mentioned above.

One year later DPP-4 inhibitors (DPP-4i) appeared, which are at present extensively used. DPP-4i also act restoring the diminished incretin effect; they inhibit the rapid degradation of GLP-1 by the enzyme and indirectly favor insulin secretion.

The most recently incorporated group of hypoglycemic drugs (2013) are the SGLT2 inhibitors that partially block renal glucose reabsorption which is increased in DM2 patients. Their effect is to lower glycemia by causing glucosuria independently of insulin. Several of these drugs are available, and other benefits have been described for them, the most important being a lower risk of cardiovascular disease [45].

**Figure 3** shows, together with the main pathogenic alterations of DM2, the corresponding hypoglycemic drugs employed in the usual clinical practice [44].

We hope that in the near future, even better new drugs will be developed that will be able to stop the natural evolution of DM2, slowing down the destruction of the β cell mass and thus reducing the important public health problem of this pathology.
