Metabolic and hormonal studies of Type 1 (insulin-dependent) diabetic patients after successful pancreas and kidney transplantation

Long-term normalization of glucose metabolism is necessary to prevent or ameliorate diabetic complications. Although pancreatic grafting is able to restore normal blood glucose and glycated haemoglobin, the degree of normalization of the deranged diabetic metabolism after pancreas transplantation is still questionable. Consequently glucose, insulin, C-peptide, glucagon, and pancreatic polypeptide responses to oral glucose and i.v. arginine were measured in 36 Type 1 (insulin-dependent) diabetic recipients of pancreas and kidney allografts and compared to ten healthy control subjects. Despite normal HbA1 (7.2±0.2%; normal <8%) glucose disposal was normal only in 44% and impaired in 56% of the graft recipients. Normalization of glucose tolerance was achieved at the expense of hyperinsulinaemia in 52% of the subjects. C-peptide and glucagon were normal, while pancreatic polypeptide was significantly higher in the graft recipients. Intravenous glucose tolerance (n=21) was normal in 67% and borderline in 23%. Biphasic insulin release was seen in patients with normal glucose tolerance. Glucose tolerance did not deteriorate up to 7 years post-transplant. In addition, stress hormone release (cortisol, growth hormone, prolactin, glucagon, catecholamines) to insulin-induced hypoglycaemia was examined in 20 graft recipients and compared to eight healthy subjects. Reduced blood glucose decline indicates insulin resistance, but glucose recovery was normal, despite markedly reduced catecholamine and glucagon release. These data demonstrate the effectiveness of pancreatic grafting in normalizing glucose metabolism, although hyperinsulinaemia and deranged counterregulatory hormone response are observed frequently

Somatostatin and dopamine receptors as targets for medical treatment of Cushing's Syndrome

Somatostatin (SS) and dopamine (DA) receptors are widely expressed in neuroendocrine tumours that cause Cushing's Syndrome (CS). Increasing knowledge of specific subtype expression within these tumours and the ability to target these receptor subtypes with high-affinity compounds, has driven the search for new SS- or DA-based medical therapies for the various forms of CS. In Cushing's disease, corticotroph adenomas mainly express dopamine receptor subtype 2 (D2) and somatostatin receptor subtype 5 (sst5), whereas sst2is expressed at lower levels. Activation of these receptors can inhibit ACTH-release in primary cultured corticotroph adenomas and compounds that target either sst5(pasireotide, or SOM230) or D2(cabergoline) have shown significant efficacy in subsets of patients in recent clinical studies. Combination therapy, either by administration of both types of compounds separately or by treatment with novel somatostatin-dopamine chimeric molecules (e.g. BIM-23A760), appears to be a promising approach in this respect. In selected cases of Ectopic ACTH-producing Syndrome (EAS), the sst2-preferring compound octreotide is able to reduce cortisol levels effectively. A recent study showed that D2receptors are also significantly expressed in the majority of EAS and that cabergoline may decrease cortisol levels in subsets of these patients. In both normal adrenal tissue as well as in adrenal adenomas and carcinomas that cause CS, sst and DA receptor expression has been demonstrated. Although selected cases of adrenal CS may benefit from sst or DA-targeted treatment, its total contribution to the treatment of these patients is likely to be low as surgery is effective in most cases

The intrapituitary stimulatory effect of lipopolysaccharide on ACTH secretion is mediated by paracrine-acting IL-6

During infection/inflammation bacterial lipopolysaccharide (LPS) activates the immune system and thus enhances the level of circulating cytokines. These circulating cytokines induce adaptive processes within the endocrine system and in particular stimulate the HPA axis to increase the level of anti-inflammatory acting glucocorticoids in the circulation. We have shown recently that LPS stimulates intrapituitary IL-6 production in folliculostellate cells via specific receptors and the p38a mitogen-activated protein kinase/nuclear factor- kappa B pathway. To test the Physiological relevance of these findings, we studied whether LPS could enhance ACTH secretion via paracrine-acting intrapituitary IL-6. Lipopolysaccharide stimulated IL-6 secretion both in monolayer and aggregate mouse pituitary cell cultures, but only in aggregates, ACTH secretion was significantly enhanced by LPS. Other hormones, such as GH or PRL, were less stimulated by LPS. My4, an antibody that blocks the interaction of LPS with the LPS receptor CD14, suppressed both LPS-induced IL-6 and ACTH secretion in aggregate cultures. A neutralizing anti-body against mouse IL-6 also inhibited LPS-induced ACTH secretion in aggregates. In mouse pituitary fragments, LPS-induced ACTH secretion was blocked by My4 and IL-6 antibodies, identically to re-aggregate cell cultures. LPS-induced ACTH secretion, mediated by intrapituitary IL-6, may represent a pituitary-specific mechanism that stimulates the HPA axis during infection/inflammatio