A physiologic and pharmacological basis for implementation of incretin hormones in the treatment of type 2 diabetes mellitus

Abstract

Progressive deterioration of β-cell function is a hallmark of type 2 diabetes mellitus (DM). Together with increasing insulin resistance in peripheral tissues (in both the liver and the skeletal muscle), the inability of pancreatic insulin secretion to manage fasting and postprandial glucose levels results in hyperglycemia. Currently available oral antidiabetes agents improve glycemic parameters, but no single drug addresses the numerous pathophysiologic defects known to contribute to hyperglycemia in patients with type 2 DM. Dysregulation in the incretin system is another component of the pathophysiologic processes that lead to DM. Agents used to correct defects in the incretin system, such as glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors, offer the potential to restore glucose-dependent insulin secretion and improve β-cell function. Glucagon-like peptide 1 receptor agonists also promote weight loss and provide beneficial effects on cardiovascular risk factors. A new approach that promotes the selection of pharmacotherapy for the treatment of patients with DM, with the goal of slowing or reversing the natural history of the disease, may be in order. Clinicians can select agents to address specific pathophysiologic defects to improve glycemia, with the hope of preventing the development of complications.

FIGURE 1.

Natural history of type 2 diabetes mellitus. The 3 core pathophysiologic defects likely responsible for the progressive nature of the disease and deterioration in glycemic control, insulin resistance, insulin deficiency, and impaired incretin effect are highlighted, showing their relative function and course. IFG = impaired fasting glucose; IGT = impaired glucose tolerance. From Am J Med, with permission from Elsevier.

FIGURE 2.

Pathogenesis of type 2 diabetes mellitus. The role of environmental and genetic factors on insulin secretion and insulin resistance. FFAs = free fatty acids; MODY = maturity-onset diabetes of the young. From the American Diabetes Association, with permission.

FIGURE 3.

Actions of glucagon-like peptide 1 (GLP-1) in peripheral tissues. The GLP-1 acts directly on the endocrine pancreas, heart, stomach, and brain, whereas actions on liver and muscle are indirect. GI = gastrointestinal. From Cell Metab, with permission from Elsevier.