The Welcome Resurgence of the α-Cell: A Pro Glucagon Commentary

  1. R. Paul Robertson
  1. From the Pacific Northwest Diabetes Research Institute, Seattle,Washington.
  1. Corresponding author: R. Paul Robertson, rpr{at}pnri.org.

Of late an increasing number of publications about glucagon, a hormone that once enjoyed center stage with insulin but for several decades has been sitting in the wings, have appeared. The primary function of this islet α-cell product is to regulate hepatic glycogenolysis to supply increased endogenous glucose production. Clinically, this is a critical role. Release of this hormone is triggered by hypoglycemia, and it rescues patients with type 2 diabetes from hypoglycemia when too much insulin is used for glycemic control. Sadly, patients with type 1 diabetes do not have this luxury. In the absence of functional β-cells, the α-cell does not respond to hypoglycemia. The central relationship between these two cells is that the β-cell, by its own response to stop secreting insulin during hypoglycemia, provides an essential signal to the α-cell to release glucagon. This chain reaction only happens during hypoglycemia, so it takes both signals (hypoglycemia and an insulin decrement) to activate the α-cell. This phenomenon has been variably termed the intraislet insulin hypothesis (1) or the insulin switch-off signal (2).

A major stimulus for refocusing on glucagon has been an increasing number of intriguing studies from basic electrophysiological, biochemical, and animal physiology laboratories involving other regulators of α-cell function, including zinc, GABA, glutamate, somatostatin, ghrelin, and the autonomic nervous system (rev. in 3 …

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