Impaired glucose-induced glucagon suppression after partial ...

Introduction:
In health, glucose homoeostasis is tightly regulated by the interplay of insulin and glucagon
secretion from pancreatic islets (1). Thus, under conditions of prolonged fasting, glucagon
levels rise, enhancing hepatic glycogenolysis and gluconeogenesis, whereas oral or
intravenous glucose administration typically results in a decline in glucagon levels (2, 3).
Furthermore, a brisk increase in glucagon secretion in response to falling blood glucose
concentrations provides a safeguard against the development of hypoglycaemia (2, 3).
Alterations in glucagon secretion are frequently found in patients with type 2 diabetes (4).
Thus, an insufficient suppression of glucagon levels after oral glucose or meal ingestion is
thought to contribute significantly to the excessive hepatic glucose production in type 2
diabetic patients (2, 5-7). Such abnormalities in glucagon secretion have been reported not
only in patients with overt diabetes, but even in pre-diabetic subjects, such as individuals with
impaired glucose tolerance (IGT) (8). However, the aetiology of these defects in glucagon
secretion is less clear, and two different explanations have been expounded. 1) The lack of
glucose-induced suppression of glucagon levels in type 2 diabetes could represent a primary,
possibly genetically determined, defect in alpha-cell function, independent of other metabolic
abnormalities in such patients (9, 10). Such argumentation would imply that defects in
glucagon secretion predispose subjects to developing type 2 diabetes (11). Against this, we
and others have failed to detect any defects in alpha-cell function in individuals at high risk
for developing type 2 diabetes, such as first-degree relatives (12, 13). 2) Alternatively, the
lack of glucose-induced suppression of glucagon levels in patients with type 2 diabetes may
be secondary to the deficit in beta-cell mass and the overall reduction in insulin secretion in
such patients (14-16). In line with this hypothesis, a selective 50% reduction in beta-cell mass
induced by the beta cytotoxin, alloxan, led to the development of both fasting and
postprandial hyperglucagonaemia in Göttingen minipigs (17). Several experiments have
suggested a close interaction of alpha- and beta-cells at the individual islet level (14-16).
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