Obstacles on the way to the clinical visualisation of beta cells: looking for the Aeneas of molecular imaging to navigate between Scylla and Charybdis.

For more than a decade, researchers have been trying to develop non-invasive imaging techniques for the in vivo measurement of viable pancreatic beta cells. However, in spite of intense research efforts, only one tracer for positron emission tomography (PET) imaging is currently under clinical evaluation. To many diabetologists it may remain unclear why the imaging world struggles to develop an effective method for non-invasive beta cell imaging (BCI), which could be useful for both research and clinical purposes. Here, we provide a concise overview of the obstacles and challenges encountered on the way to such BCI, in both native and transplanted islets. We discuss the major difficulties posed by the anatomical and cell biological features of pancreatic islets, as well as the chemical and physical limits of the main imaging modalities, with special focus on PET, SPECT and MRI. We conclude by indicating new avenues for future research in the field, based on several remarkable recent results.

Importance of ghrelin in hypothalamus-pituitary axis on growth hormone release during normal pregnancy in the rat.

Ghrelin is a hormone mainly produced in the stomach and its first discovered action was connected with regulating growth hormone secretion. It was found that ghrelin injection increases growth hormone release and that this action is dose-dependent. Ghrelin may influence growth hormone secretion both by central and peripheral action. Ghrelin acts via its receptors named growth hormone secretagogue receptors (GHSR). Ghrelin receptors were found in almost all tissues including the central nervous system. Besides influence on growth hormone secretion, ghrelin also regulates food intake and energy metabolism centrally as well as peripherally. In our study, active ghrelin and growth hormone levels in serum were measured. We also investigated gene expression of proghrelin, growth hormone releasing hormone (GHRH) and growth hormone receptor (GH-R) in the hypothalamus and the active form of ghrelin receptor (GHSR-1a) in hypothalamus and pituitary. Expression of growth hormone and growth hormone releasing hormone receptor (GHRH-R) in the pituitary were also measured. The results of our study indicate that active ghrelin and growth hormone levels in serum increased during pregnancy. Expression of ghrelin in hypothalamus and its receptor also increased in hypothalamus and pituitary during pregnancy. We also observed that growth hormone gene expression rose in pituitary, while its receptor mRNA level in hypothalamus decreased. Additionally, growth hormone expression in placenta decreased during pregnancy. Moreover, GHRH in hypothalamus and its receptor in pituitary showed reduced levels during pregnancy. Our results may indicate that ghrelin is a important factor influencing growth hormone release during pregnancy.

Ghrelin-producing epsilon cells in the developing and adult human pancreas.

AIMS/HYPOTHESIS: While the mechanisms of specification and the reciprocal relationships of the four types of endocrine cell (alpha, beta, delta and pancreatic polypeptide cells) within the human endocrine pancreas are well described in adults and during fetal development, ghrelin-immunoreactive cells (epsilon cells) remain poorly understood. METHODS: We studied epsilon cells in 24 human fetal pancreases between 11 and 39 weeks of development and in 32 pancreases from adult organ donors. RESULTS: We observed single epsilon cells scattered in primitive exocrine tissue from gestational week 13 in developing pancreas. Later in the developmental process, epsilon cells started to aggregate into clusters. From gestational week 21, epsilon cells were observed located around developing islets, forming an almost continuous layer at the peripheral rim of the islets. They remain localised on the mantle of the islets, although at different amounts, in the adult pancreas. Co-production of ghrelin with insulin, glucagon or somatostatin was not detected during fetal development. Co-production with pancreatic polypeptide was evident sporadically. Epsilon cells co-produced NK2 homeobox 2 and ISL LIM homeobox 1, but not NK6 homeobox 1 and paired box 6. A quantitative analysis was performed in the adult pancreas: there was an average of 1.17 + 1.17 epsilon cells per islet, the relative epsilon cell volume was 0.14 + 0.16% and the epsilon cell mass was 0.13 + 0.15 g. Neither sex nor age affected the epsilon cell mass, although there was a significant inverse correlation with BMI. CONCLUSIONS/INTERPRETATION: During fetal development epsilon cells show an ontogenetic and morphogenetic pattern that is distinct from that of alpha and beta cells.

Intrahepatic islet transplant in the mouse: functional and morphological characterization.

Although in a clinical setting islet transplantation is normally performed by percutaneous intrahepatic infusion, the kidney capsule has been the site of choice in nearly all the studies using mice. In the present study, we extensively characterized the mouse model of intraportally transplanted islets with the purpose to propose it as a model to study islet transplantation. C57BL/6 (n = 78) and BALB/C (n = 53) recipients were transplanted with 400 autologous islets alternatively through the portal vein (PV-Tx) or under the kidney capsule (KC-Tx). Glucose concentration during the first hour after syngeneic islet infusion was associated with subsequent long-term function confirming that early events have long-term effects on graft function. In both strains tested the probability to achieve islet function was significantly lower for PV-Tx than KC-Tx. Also in allogeneic models (C57BL/6 to BALB/C, n = 104; BALB/C to C57BL/6, n = 77) the probability to achieve primary function was significantly lower for PV-Tx than KC-Tx and the site of transplantation significantly affected the graft survival. Histological evaluation of livers showed the presence of features (embolism, thrombosis, focal areas of liver necrosis) that are absent in the kidney subcapsular site. Finally, significant differences in the outcome of PV-Tx were observed between the Th type 1 inflammatory-prone C57BL/6 mouse and the type 2 inflammatory-prone BALB/C mouse. Intraportal islet graft model has some features that are more similar to human clinical islet transplantation and should be used as a model to study not only engraftment but also mechanisms of immune suppression and immune tolerance.