Impaired glucose-induced glucagon suppression after partial ...

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intra-islet inhibition of glucagon release, they are less likely to play a role for the impaired glucose-induced suppression of glucagon secretion observed after hemipancreatectomy in this study, where the paracrine regulation of hormone secretion within the individual islets was not specifically altered. Moreover, even though the observed relationships between insulin and glucagon levels suggest a direct interaction between both islet hormones, other pancreatic hormones might have contributed as well. In particular, somatostatin has been previously shown to act both as a paracrine and endocrine regulator of alpha-cell secretion (41, 42). It is therefore possible that the reduction in delta-cell mass and secretion induced by the hemipancreatectomy has contributed to the observed impairment in glucose-induced glucagon suppression. Alternatively, one might argue that the lack of glucagon suppression might have been secondary to the partial removal of the duodenum leading to impaired glucose-induced GLP-1 secretion. Unfortunately, incretin levels were not determined in this study. However, since alterations in glucagon secretion were found after both pancreaticoduodenectomy and after pancreatic tail resection (where the duodenum is not affected at all), such explanation appears less likely. Although a tendency towards a loss of glucose-induced glucagon suppression was detectable in all groups of patients studied, the reduction in fasting glucagon levels was more pronounced in patients undergoing surgery for the removal of benign adenomas, extrapancreatic tumours or pancreatic cancer than in patients with chronic pancreatitis. Most likely this is due to the fact that in patients with chronic pancreatits the secretion of both insulin and glucagon was already markedly abnormal prior to surgery, meaning that the additional alterations induced by the hemipancreatectomy were less apparent than in the other patient groups (43). Consistent with this, the pre-operative insulin levels and glucagon levels were lowest in patients with chronic pancreatitis (18). 12
A number of previous studies in rats and mice have suggested that functional alterations in islet secretion are only detectable after reductions in beta-cell mass in the range of ~80-90% (44, 45), whereas less extensive pancreatic resections can be tolerated without measurable disturbances in circulating islet hormone concentrations (46). These reports are contrasted by larger animal studies, where alterations in both insulin and glucagon secretion occurred already after an ~50% beta-cell loss (15, 17, 47). Furthermore, studies in individuals with impaired fasting glucose, who typically already exhibit defects in insulin secretion (48), have revealed an ~50% deficit in beta-cell mass even before the full onset of type 2 diabetes (49). The present studies showing marked alterations in both insulin and glucagon secretion after hemipancreatectomy are therefore consistent with these previous studies and re-emphasize the importance of beta-cell mass for the maintenance of glucose homoeostasis. There has been some debate regarding the distribution of islet alpha- and beta-cells within the pancreas. Indeed, in different studies in humans and in animal models, the majority of alpha- and beta-cells were found in the pancreatic tail, whereas Pancreatic Polypeptide secreting cells were predominantly shown in the pancreatic head and the uncinate process (50- 54). In the present studies fasting glucagon concentrations were almost unchanged after pancreatic head resection, but substantially lowered after removal of the pancreatic tail. This may suggest a predominance of alpha-cells in the pancreatic tail compared to the head and body regions. However, since the maximum glucagon responses have not been tested directly, this study does not allow for valid conclusions in this regard. The present and our previous study (18) have also shown significant improvements in glycaemia within the first 90 min after the oral glucose load, which is surprising in light of the concomitant reduction in insulin secretion. This may on the one hand be due to an improvement insulin sensitivity induced by the removal of the abnormal pancreatic tissue. On the other hand it seems possible that the transient reduction in glycaemia immediately after glucose ingestion was caused by a delay in gastric emptying secondary to the surgical trauma. 13
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 and 10: However, after pancreatic head rese
Page 11: cell secretion (34, 35). Consistent
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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