Impaired glucose-induced glucagon suppression after partial ...

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Discussion: Impaired glucagon suppression after glucose administration is a characteristic hallmark of type 2 diabetes (2, 4, 5). This has been held to be secondary to the loss of intra-islet insulin secretion in such patients (4, 14, 16, 17, 24). The present studies were designed to address the question, whether a 50% partial pancreatectomy would alter alpha-cell function in humans as well. We report that the glucose-induced decline in glucagon concentrations was lost after hemi-pancreatectomy. This impairment in alpha-cell function was closely related to the changes in insulin secretion, but appeared to be independent of the increases in glycaemia. Even though the maximum secretory capacity of the alpha-cells (e.g. in response to arginine or hypoglycaemia) has not been tested directly in this study, there was a tendency towards a reduction in fasting glucagon levels, consistent with the expected 50% reduction in alpha-cell mass. This is in line with previous studies by Seaquist and Robertson demonstrating an impaired glucagon response to i.v. arginine after hemi-pancreatectomy in humans (25). However, although the maximum glucagon responses seem to be primarily determined by the number of alpha-cells within the pancreas, the glucose-induced decline in glucagon concentrations is largely controlled by other factors. In this regard, macronutrients, and particularly glucose and amino acids, are important regulators (26, 27), but there is also good evidence that endocrine hormones, such as glucagon-like peptide 1 (GLP-1) (28), gastric inhibitory polypeptide (GIP) (12, 29), gastrin (30), and cholecystokinin (31), may play a role. In addition to these well established nutrient and endocrine factors, a number of studies have suggested a paracrine regulation of glucagon release (32). Thus, within the individual islets, the beta-cells are typically located in the core region, whereas the alpha-cells are predominantly located in the islet periphery. Since the blood flow within the islets is usually centripetally directed, reaching the beta-cell rich core first, and then traversing into the mantle region, the islet alpha-cells are being exposed to very high local insulin levels (33), and a number of in vitro studies have provided evidence for an inhibitory effect of insulin on alpha- 10
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 11
Page 1 and 2: J Clin Endocrin Metab. First publis
Page 3 and 4: Introduction: In health, glucose ho
Page 5 and 6: Materials and methods Study design
Page 7 and 8: assay (ELISA) from DAKOP Ltd., Camb
Page 9: However, after pancreatic head rese
Page 13 and 14: A number of previous studies in rat
Page 15 and 16: References: 1. Meier JJ, Butler PC
Page 17 and 18: 36. Robertson RP, Sutherland DE, Se
Page 19 and 20: Figure legends: Figure 1: Plasma co

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