Type 2 diabetes mellitus is a progressive disease characterized by multiple abnormalities, including insulin resistance, declines in β-cell function, and defects in α-cell function.
There are pathophysiologic abnormalities, which typically manifest before T2DM is diagnosed and continue throughout the disease process.
5 Skeletal tissue insulin resistance, a contributor to hyperglycemia, is evident in early stages of the disease. Insulin resistance has been attributed to impaired binding of insulin to its cellular receptors and to post-binding defects, contributing to impaired glucose transport. These defects also include diminished glucose phosphorylation, impaired glycogen synthase activity, insulin signal transduction abnormalities, and decreased insulin tyrosine kinase activity.
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Early in the course of T2DM, the pancreatic β cells compensate for peripheral insulin resistance by secreting more insulin. This progressive augmentation of insulin secretion by β cells eventually leads to an inability of these cells to compensate for insulin resistance. It has been estimated that as much as 80% of β cells have lost their insulin secretory function by the time of diabetes mellitus diagnosis.
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The array of metabolic abnormalities contributing to the pathogenesis of T2DM—extending beyond insulin resistance and β-cell dysfunction—has been referred to as the “Ominous Octet” (
Figure).
7 For example, patients' adipocytes demonstrate accelerated lipolysis, the kidneys increase glucose uptake
and reabsorption, and the brain exhibits impaired insulin function.
7 Patients with T2DM also have inappropriately elevated levels of glucagons, which are produced by pancreatic α cells. As a result, the liver releases excessive amounts of glucose, further contributing to hyperglycemia.
The diagnosis of T2DM is established with several hyperglycemic parameters (ie, FPG, ≥126 mg/dL; random glucose, >200 mg/dL; and HbA
1c, >6.5%).
8 Although available medications can lower levels of FPG, postprandial plasma glucose (PPG), and HbA
1c, several of these agents are associated with risks of hypoglycemia and weight gain.
8 Therefore, a need exists for exploration and implementation of newer treatments, which, on a physiologic basis, improve defects of β-cell and α-cell function, and, on a clinical basis, improve glycemic control without adverse effects.