Impaired glucose-induced glucagon suppression after partial ...

cell secretion (34, 35). Consistent with such reasoning, previous studies in baboons and
minipigs have demonstrated a close inverse relationship between circulating insulin and
glucagon levels at a minute-by-minute basis (16, 17). Furthermore, selective destruction of
islet beta-cells in Göttingen minipigs has resulted in a loss of meal-induced glucagon
suppression and the development of overt hyperglycaemia (17). The present findings extend
these studies by showing that an inverse relationship between insulin and glucagon levels can
also be found at a systemic level, independent of the paracrine interaction of both hormones
within the individual islets. Thus, since the intra-islet relationship between alpha- and beta-
cells should not be affected by a hemi-pancreatectomy, the loss of glucose-induced
suppression of glucagon levels in the present experiments suggests that a general reduction in
systemic insulin levels may impair alpha-cell function as well. Of note, this effect was
apparent after both pancreatic head and tail resection. Such argumentation is also consistent
with previous studied by Robertson and colleagues showing elevated post-operative fasting
glucagon levels in healthy subjects who donated 50% of their pancreas for transplantation
(36). Taken together, these studies emphasize the importance of circulating insulin levels for
the maintenance of alpha-cell function and lend strong support to the postulate that the
hyperglucagonaemia in patients with type 2 diabetes develops as a consequence of the
reduction in beta-cell mass, rather than due to an independent, primary defect in alpha-cell
function. Such reasoning is also in line with the clinical finding that endogenous glucagon
levels often decline after exogenous insulin supplementation in patients with diabetes (37,
38). However, aside from these effects of systemic insulin, a direct paracrine interaction
between insulin and alpha-cells may still exist, as suggested by previous animal studies.
Arguably, the inverse relationship between beta- and alpha-cell secretion may also be
mediated by other secretory products of the beta-cell than just insulin. In this regard, a direct
inhibitory action of zinc on alpha-cell secretion has recently been postulated by some (39),
but not all groups (40). However, while such inhibitory actions of zinc may contribute to the
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