Introduction Islet antigen-2 (IA-2, also known as islet cell antigen 512) and IA-2β, (also known as phogrin) are major autoantigens in type 1 diabetes. Autoantibodies against both proteins appear before the development of clinical diabetes, and
Jean-Claude Henquin, Myriam Nenquin, Andras Szollosi, Atsutaka Kubosaki, and Abner Louis Notkins
Elisabet Estil.les, Noèlia Téllez, Joan Soler, and Eduard Montanya
et al . 2004 , Nir et al . 2007 ). This may suggest that impaired β-cell replication could contribute to the reduction of β-cell mass in diabetes. Interleukin-1β (IL1B) is an important contributor to β-cell damage in type 1 diabetes ( Mandrup
Ghania Ramdani, Nadine Schall, Hema Kalyanaraman, Nisreen Wahwah, Sahar Moheize, Jenna J Lee, Robert L Sah, Alexander Pfeifer, Darren E Casteel, and Renate B Pilz
estrogen deficiency and type 1 diabetes, respectively ( Wimalawansa et al. 1996 , Wimalawansa 2000 , Jamal et al. 2004 , Nabhan & Rabie 2008 , Kalyanaraman et al. 2017 , 2018 b ). We have shown in vitro that PKG1 and 2 are both targets of
Rhonda D Prisby, Joshua M Swift, Susan A Bloomfield, Harry A Hogan, and Michael D Delp
reported in insulin-dependent type 1 diabetes mellitus differ from those reported in non-insulin-dependent type 2 diabetes. While the association between osteoporosis and type 1 diabetes is well established ( Silberberg 1986 , Forst et al . 1995 ), the
Andreas Börjesson and Carina Carlsson
islets treated with IL-1β. This may contribute to the elevated levels of proinsulin found both at the onset of type 1 diabetes as well as in type 2 diabetes. Table 1 Insulin and proinsulin content in islets cultured at different glucose
Janne Jensen, Elisabeth D Galsgaard, Allan E Karlsen, Ying C Lee, and Jens H Nielsen
Introduction The proinflammatory cytokines interleukin-1β (IL-1β), interferon-γ (IFN-γ) and tumour necrosis factor-α (TNF-α) are toxic to pancreatic β-cells and have been implicated in the pathogenesis of type 1 diabetes ( Eizirik
M G Cavallo, F Dotta, L Monetini, S Dionisi, M Previti, L Valente, A Toto, U Di Mario, and P Pozzilli
In the present study we have evaluated the expression of different beta-cell markers, islet molecules and autoantigens relevant in diabetes autoimmunity by a human insulinoma cell line (CM) in order to define its similarities with native beta cells and to discover whether it could be considered as a model for studies on immunological aspects of Type 1 diabetes.
First, the positivity of the CM cell line for known markers of neuroendocrine derivation was determined by means of immunocytochemical analysis using different anti-islet monoclonal antibodies including A2B5 and 3G5 reacting with islet gangliosides, and HISL19 binding to an islet glycoprotein. Secondly, the expression and characteristics of glutamic acid decarboxylase (GAD) and of GM2-1 ganglioside, both known to be islet autoantigens in diabetes autoimmunity and expressed by human native beta cells, were investigated in the CM cell line. The pattern of ganglioside expression in comparison to that of native beta cells was also evaluated. Thirdly, the binding of diabetic sera to CM cells reacting with islet cytoplasmic antigens (ICA) was studied by immunohistochemistry. The results of this study showed that beta cell markers identified by anti-islet monoclonal antibodies A2B5, 3G5 and HISL-19 are expressed by CM cells; similarly, islet molecules such as GAD and GM2-1 ganglioside are present and possess similar characteristics to those found in native beta cells; the pattern of expression of other gangliosides by CM cells is also identical to human pancreatic islets; beta cell autoantigen(s) reacting with antibodies present in islet cell antibodies (ICA) positive diabetic sera identified by ICA binding are also detectable in this insulinoma cell line.
We conclude that CM cells show close similarities to native beta cells with respect to the expression of neuroendocrine markers, relevant beta cell autoantigens in Type 1 diabetes (GAD, GM2-1, ICA antigen), and other gangliosides. Therefore, this insulinoma cell line may be considered as an ideal model for studies aimed at investigating autoimmune phenomena occurring in Type 1 diabetes.
Journal of Endocrinology (1996) 150, 113–120
Jennifer Chen and Jenny E Gunton
Islet transplantation, a therapeutic option to treat type 1 diabetes, is not yet as successful as whole-pancreas transplantation as a treatment for diabetes. Mouse models are commonly used for islet research. However, it is clear disparities exist between islet transplantation outcomes in mice and humans. Given the shortage of transplant-grade islets, it is crucial that we further our understanding of factors that determine long-term islet survival and function post-transplantation. In turn, that may lead to new therapeutic targets and strategies that to improve transplant outcomes. Here, we summarise the current landscape in clinical transplantation, highlight underlying similarities and differences between mouse and human islets, and review interventions that are being considered to create a new pool of β-cells for clinical application.
H Gronbaek, B Nielsen, B Schrijvers, I Vogel, R Rasch, and A Flyvbjerg
It was recently discovered that the streptozotocin (STZ)-diabetic mouse model is characterised by GH hypersecretion in contrast to the STZ-diabetic rat, the former thus mimicking the changes in GH in human type 1 diabetes. Inhibition of circulating and renal IGF-I by long-acting somatostatin analogues reduces renal and glomerular growth and urinary albumin excretion in diabetic rats. The aim of the present study was to examine renal and glomerular growth in early experimental diabetes in mice along with changes in the GH/IGF-I axis following treatment with the somatostatin analogue octreotide. Balb/C(a) mice were randomised into non-diabetic controls, placebo-treated and octreotide-treated diabetic (50 microg/day) mice and examined 7 and 14 days after induction of diabetes. There was no effect of octreotide treatment on body weight, glycaemic control or food intake. However, octreotide treatment significantly inhibited renal and glomerular growth by the end of the study period when compared with placebo treatment. In addition, octreotide prevented an increase in kidney IGF-I by day 7. GH hypersecretion was observed in the diabetic groups but octreotide treatment reduced GH levels compared with placebo treatment by day 14. No significant differences in serum or kidney IGF-binding protein-3 levels were observed between placebo- and octreotide-treated diabetic mice. In conclusion, this new diabetic mouse model mimicking human type 1 diabetes is characterised by GH hypersecretion and the somatostatin analogue octreotide is able to prevent renal and glomerular growth, probably mediated through changes in circulating GH and local kidney IGF-I levels.
S. R. Crosby, C. D. Anderton, M. Westwood, J. M. P. Holly, S. C. Cwyfan Hughes, M. Gibson, C. A. Morrison, R. J. Young, and A. White
An immunoradiometric assay (IRMA) for the measurement of insulin-like growth factor-II (IGF-II) in human plasma has been developed, optimized and evaluated clinically in normal subjects and patients with disorders of the GH/IGF-I axis. Six monoclonal antibodies (MAbs) to recombinant human IGF-II (rhIGF-II) were produced, all of which had low cross-reactivity with rhIGF-I (< 0·01%) and insulin (< 0·01%). Compatibility of pairs of MAbs was tested in two-site IRMAs using three radioiodinated MAbs and three MAbs linked to Sephacryl S-300 (with separation of bound and free radiolabelled MAb by sucrose layering). Seven pairs of MAbs bound rhIGF-II and the combination of 125I-labelled W3D9 and W2H1 linked to solid phase was selected. The optimized assay had a completion time of 4 h, a minimum detection limit of 30 ng/ml (2·5 standard deviations from the zero standard) and detected a single peak of endogenous IGF-II in normal plasma which co-eluted with rhIGF-II after acid gel chromatography.
IGF-II was measured in formic acid/acetone extracts of plasma from 16 normal subjects (mean 685, range 516–1008 μg/l), four acromegalic patients (mean 637, range 553–700 μg/l), fourteen patients with type-1 diabetes (mean 635, range 247–753 μg/l), nine patients with uraemia (mean 423, range 78–850 μg/l), and three patients with Laron-type GH insensitivity (75, 35 and 36 μg/l). No significant fluctuations were detected between samples obtained hourly from 08.00 to 19.00 h in normal subjects.
Low levels of IGF-binding proteins (IGFBPs) remaining in plasma extracts may interfere with the measurement of IGF-II and give rise to falsely elevated IGF-II levels in radioimmunoassays or falsely suppressed levels in IRMAs. Such interference did not occur with the IRMA when used to measure IGF-II in extracts from normal subjects, acromegalic patients and patients with type-1 diabetes, and the addition of excess rhIGF-I in order to displace IGF-II from residual IGFBPs had no effect on IGF-II measurements in these samples. However, levels of IGF-II measured in extracts from patients with Laron-type GH insensitivity and patients with uraemia increased markedly after preincubation with excess rhIGF-I. The accurate measurement of IGF-II by IRMA in extracts from these subjects therefore requires the displacement of IGF-II from IGFBPs prior to assay. We conclude that, in contrast to radioimmunoassays, the two-site IRMA developed here provides a practical, rapid and specific method for the measurement of IGF-II in human plasma.
Journal of Endocrinology (1993) 137, 141–150