Mini‐review: Glucagon responses in type 1 diabetes – a matter of complexity

In recent years the role of altered alpha cell function and glucagon secretion in type 1 diabetes has attracted scientific attention. It is well established that glucagon responses to hypoglycemia are absent in type 1 diabetes, but more uncertain whether it is intact following other physiological and metabolic stimuli compared with nondiabetic individuals. The aim of this review is to (i) summarize current knowledge on glucagon responses during hypoglycemia in normal physiology and type 1 diabetes, and (ii) review human in vivo studies investigating glucagon responses after other stimuli in individuals with type 1 diabetes and nondiabetic individuals. Available data suggest that in type 1 diabetes the absence of glucagon secretion after hypoglycemia is irreversible. This is a scenario specific to hypoglycemia, since other stimuli, including administration of amino acids, insulin withdrawal, lipopolysaccharide exposure and exercise lead to substantial glucagon responses though attenuated compared to nondiabetic individuals in head‐to‐head studies. The derailed glucagon secretion is not confined to hypoglycemia as individuals with type 1 diabetes, as opposed to nondiabetic individuals display glucagon hypersecretion after meals, thereby potentially contributing to insulin resistance. The complexity of these phenomena may relate to activation of distinct regulatory pathways controlling glucagon secretion i.e., intra‐islet paracrine signaling, direct and autonomic nervous signaling.