**2. Natural history of DM2**

DM2 is a progressive disease that develops in stages. Its natural history probably begins 10–20 years before its clinical onset, as a preclinical period with IR [4**].**

Hyperinsulinemia is initially capable of maintaining normal fasting and postprandial glycemias. This stage would be associated with increased levels of free fatty acids (FFA) in the obese IR patient.

Subsequently, and before DM2 manifests, IR is maintained, but the secretory capacity of the β cell begins to decline and glycemias rise, reaching abnormality levels for fasting glycemia and glucose intolerance, which are prediabetes stages. In these periods, chronic hyperglycemia is an important factor in the perpetuation of damage to the pancreatic β cells; as it increases and IR is maintained, glycemic levels progressively increase until finally clinical diabetes is established.

The stages of the pathogenesis of DM2 are shown in **Figure 1**.

The insulin secretory defects observed in DM2 contribute to IR. During the evolution of DM2, the IR state is maintained, and the insulin secretory capacity gradually decreases, arriving at an insulin hyposecretion in which it will be necessary, in some cases, to start insulin therapy.

Hyperglycemia in DM2 not only represents the biochemical manifestation of the disease, but it is rather, in itself, a permanent factor responsible for maintaining the diabetic state.

We will now refer to the multiple factors involved in the genesis of DM2.

**Figure 1.** *Stages in pathogenesis of type 2 diabetes.*
