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-Cells of the Endocrine Pancreas: 35 Years of Research but the Enigma Remains

Novartis Institutes for BioMedical Research (J.G.), Cambridge, Massachusetts 02139; and Department of Cell Physiology and Metabolism (I.F., C.B.W.), University Medical Centre, 1211 Geneva 4, Switzerland

Correspondence: Address all correspondence and requests for reprints to: Jesper Gromada, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, Massachusetts 02139. E-mail: jesper.gromada{at}novartis.com

Glucagon, a hormone secreted from the -cells of the endocrine pancreas, is critical for blood glucose homeostasis. It is the major counterpart to insulin and is released during hypoglycemia to induce hepatic glucose output. The control of glucagon secretion is multifactorial and involves direct effects of nutrients on -cell stimulus-secretion coupling as well as paracrine regulation by insulin and zinc and other factors secreted from neighboring ß- and -cells within the islet of Langerhans. Glucagon secretion is also regulated by circulating hormones and the autonomic nervous system. In this review, we describe the components of the -cell stimulus secretion coupling and how nutrient metabolism in the -cell leads to changes in glucagon secretion. The islet cell composition and organization are described in different species and serve as a basis for understanding how the numerous paracrine, hormonal, and nervous signals fine-tune glucagon secretion under different physiological conditions. We also highlight the pathophysiology of the -cell and how hyperglucagonemia represents an important component of the metabolic abnormalities associated with diabetes mellitus. Therapeutic inhibition of glucagon action in patients with type 2 diabetes remains an exciting prospect.

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