Objectives In men, androgen deprivation contributes to the development of metabolic syndrome and type 2 diabetes (T2D). In women, androgen excess predisposes to insulin resistance and T2D. There is a bidirectional modulation of glucose homeostasis by androgen in males and females that we analyze in this review. Methods We review the literature in both rodents and humans on the role of androgens and the androgen receptor (AR) in the control of glucose and energy metabolism in health, obesity and T2D. Results Sex-specific activation of AR in the hypothalamus, skeletal muscle, liver, adipose tissue and pancreatic islet β cells accounts for maintenance or disruption in energy metabolism and glucose homeostasis. Conclusion We argue that AR is a target to prevent androgen-related metabolic disorders.

Although men with testosterone deficiency are at increased risk of type 2 diabetes (T2D), previous studies have ignored the role of testosterone and the androgen receptor (AR) in pancreatic β–cells. We show that male mice lacking AR in β-cells (βARKO) exhibit decreased glucose-stimulated insulin secretion (GSIS) leading to glucose intolerance. The AR agonist dihydrotestosterone (DHT) enhances GSIS in cultured male islets, an effect that is abolished in βARKO−/y islets and human islets treated with an AR antagonist. In β-cells, DHT-activated AR is predominantly extranuclear and enhances GSIS by increasing islet cAMP and activating the protein kinase A. In mouse and human islets, the insulinotropic effect of DHT depends on activation of the glucagon like peptide-1 (GLP-1) receptor and accordingly, DHT amplifies the incretin effect of GLP-1. This study identifies AR as a novel receptor that enhances β-cell function, a finding with implications for prevention of T2D in aging men.

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