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Home / Resources / Clinical Gems / International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #49: Biosynthesis, secretion, and action of glucagon Part 3 of 4

International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #49: Biosynthesis, secretion, and action of glucagon Part 3 of 4

Control of glucagon release

There is considerable evidence that the control of glucagon secretion is multifactorial and involves direct effects of nutrients on α-cell stimulus-secretion coupling as well as paracrine regulation by insulin, somatostatin and, possibly, other mediators such as zinc, γ-amino-butyric acid (GABA) or glutamate [48,49]. Glucagon secretion is also regulated by circulating hormones and the autonomic nervous system [50,51]. Table 10.1 lists the factors and conditions demonstrated as stimulators of glucagon secretion. The main physiologic or pathophysiologic stimulators of glucagon release are hypo- glycemia (insulin-induced, associated with starvation or intense muscular exercise), hyperaminoacidemia (the rise in plasma glucagon levels after a balanced meal is probably due mainly to amino acid-induced glucagon release), stimulation of the adrenergic system (stress, exercise, and possibly hypoglycemia), and stimulation of the vagal system, which together with hormones like GIP and CCK-PZ probably participate in the mixed meal-induced glucagon rise.


The factors and conditions associated with inhibition of glucagon release are listed in Table 10.2. The main physiologic inhibitors of glucagon release are probably hyperglycemia and hyperinsulinemia (in a glucose-rich or carbohydrate-rich meal) and high circulating levels of FFA. It has been suggested that glucokinase may serve as a metabolic glucose sensor in pancreatic α cells, and hence constitute a mechanism for direct regulation of glucagon release by extracellular glucose. Intra-islet insulin, glucagon, and somatostatin release have been shown to be interrelated [52]. In such paracrine mechanisms, further data suggest that the oscillatory pattern of islet hormone release may be particularly important [53,54]. Using isolated perifused human islets, it has been shown that glucose generates coincident insulin and somatostatin pulses and clear antisynchronous glucagon pulses [55]. The periodicity of these pulses is 7 to 8 min. The fact that these pulses occur in isolated islets demonstrates that their origin is the islets themselves and independent of external metabolic, hormonal, or neuronal signals. The nature of the intra-islet signal(s) coordinating the secretion of the various endocrine cells of the islets of Langerhans is still the subject of intense investigation [56 – 61].

Some aspects of glucagon physiology and pathophysiology

Glucagon as a counterregulatory hormone

Numerous studies have shown that the liver is the main site at which moment-to-moment control of glucose homeostasis takes place and that in normal humans glucagon is the major glucose counterregulatory hormone. By antagonizing the suppressive effects of insulin on glucose production and by stimulating glucose production when appropriate, glucagon not only defends the organism against hypoglycemia, but also restores normoglycemia if hypoglycemia occurs. Perturbation of the mechanisms controlling hypoglycemia-induced glucagon     release in some diabetic patients markedly increases the risk of severe hypoglycemia in these subjects. Other hormones, such as epinephrine (acutely) and growth hormone and cortisol (more slowly), participate in the counterregulation of the effects of insulin, but careful clinical observations suggest that indeed glucagon is the first line of defense against hypoglycemia [62].

Glucagon in exercise

Glucagon levels increase progressively during prolonged exercise [63], during which blood glucose remains relatively constant thanks to a fine balance between muscle glucose uptake and liver glucose production. Although a rise in plasma glucagon does not appear to be essential for increased glucose production during exercise, the presence of glucagon does appear to be necessary.

Glucagon in stress

Hyperglucagonemia is a classic feature of stress [64]. It occurs mainly as a result of the β-adrenergic stimulation associated with stress and undoubtedly contributes to the hyperglycemia, which is a classical finding in this condition.

Glucagon in starvation

Starvation is accompanied by a decline in circulating insulin and a moderate rise in plasma glucagon [65]. The main effects of glucagon during starvation are at the liver, where it contributes to the maintenance of continuous liver glucose output (initially by stimulating glycogenolysis, and later by promoting gluconeogenesis) and the induction of ketogenesis. Whether glucagon contributes to the stimulation of adipose tissue lipolysis during starvation is still disputed.

Glucagon and adaptation to extrauterine life

A significant rise in plasma glucagon occurs soon after birth in all species investigated so far, which suggests that glucagon has a crucial role in neonatal glucose homeostasis [66]. Furthermore, an important role of glucagon in thermogenic regulation has been suggested.

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