Prophylactic insulin. Is it 'safe'?
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Animals↗
Biomedical subjects
K Josefsen
Publications and source records attributed to K Josefsen.
No risk of diabetes after insulin-shock treatment.
Prophylactic insulin treatment is effective in preventing diabetes in animal models of insulin-dependent diabetes mellitus (IDDM) but the safety of such preventive treatment in prediabetic human subjects remains unclear; insulin is a potential autoantigen that could accelerate beta-cell decompensation and onset of IDDM. We have investigated whether insulin treatment of non-diabetic subjects increases the risk of subsequent development of diabetes in a retrospective study of Danish patients who received insulin-shock treatment for psychiatric disorders. Mean age of the 481 patients at insulin-shock treatment was 32.6 (range 12.9-69.6) years. The patients received 59 (6-200) injections of 78 (16-261) IU bovine/porcine insulin. Hospital records provided an average of 22.0 (0.6-51.2) years' observation. During the observation time, IDDM developed in only 1 patient; 1.3 cases would be expected from Danish incidence data (p = 0.75). Similarly, there was no significant difference between the observed number of cases of non-insulin-dependent diabetes mellitus (NIDDM) and the number expected from Danish prevalence data (12 vs 10.2; p = 0.45). We collected blood samples from 27 of the patients. All but 2 (who had previously diagnosed NIDDM) had normal fasting blood glucose and plasma insulin concentrations, none had islet-cell antibodies, and only 2 had detectable insulin antibodies. Thus, the risk of diabetes was not increased by the use of many insulin injections in these non-diabetic subjects. We conclude that clinical trials on prevention of IDDM by prophylactic insulin treatment can be regarded as safe.
Adolescent↗
Interleukins increase surface ganglioside expression of pancreatic islet cells in vitro.
This experiment was conducted in order to investigate whether expression of gangliosides on islet cell surface in vitro is influenced by cytokines, especially interleukin 1. Islets from adult Lewis rats were incubated with different concentrations of recombinant-derived human cytokines. Following dispase treatment, the single cells were labeled with monoclonal antiganglioside antibodies A2B5 or R2D6, and conjugate. Both are directed against beta cells; A2B5 is recognized to bind specifically to pancreatic islet cells, while R2D6 is shown to bind no other pancreatic cells than beta cells. Surface labeling was evaluated in blind trials using a fluorescence microscope and a fluorescence-activated cell sorter (FACS). A2B5 staining demonstrated a significantly higher number of labeled cells after incubation with interleukin 1 alpha (14.9% +/- 2.8; p less than 0.005), interleukin 1 beta (23.2% +/- 4.2; p less than 0.0005) or TNF alpha (16.1% +/- 4.0; p = 0.005) compared to endotoxin controls (4.1% +/- 1.1). Interleukin 1 beta (9.5% +/- 1.5; p less than 0.005) showed a significantly increased number of R2D6-stained cells (control: 2.3% +/- 1.3). A similar but not significant effect was seen with interleukin 1 alpha and TNF alpha. Interleukin 6 had no effect on the antigen expression. The intensity of labeling was elevated among interleukin 1 beta-incubated cells compared to control samples. Thus, treatment of islets with different cytokines, especially interleukin 1 beta, increases surface antigen expression. We suggest that this mechanism of action in vitro may be of importance for the putative diabetogenic effect of interleukin 1.
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Beta-cell expression of 65-kDa heat-shock protein mRNA is function- and age-dependent.
This study examined the expression of mRNA coding for the 65-kDa heat-shock protein (HSP) in rat islet cells of different functional states and different ages. In addition, beta cells and non-beta cells purified by fluorescence-activated cell sorting were studied. Total RNA from islet cells and insulin-producing RINm5F cells was isolated and analyzed by Northern blotting using a cDNA probe coding for the human homologue to the mycobacterial 65-kDa HSP, after which blots were quantified by densitometric scanning. Isolated beta cells were found to express 65-kDa HSP mRNA. The expression was increased in Lewis islet cells exposed to heat shock or high glucose concentration, four- and three-fold, respectively (p < 0.01). In isolated beta cells cultured at high glucose concentration a doubling in the content of 65-kDa HSP mRNA was seen compared with islets cultured at low glucose concentration (p < 0.05). In islets from Lewis rats fasted for 24 h, the content of 65-kDa HSP mRNA was 42% lower than in islets isolated from normally fed Lewis rats (p < 0.01). Both in BB rats and Wistar Furth rats the content of 65-kDa HSP mRNA was found to be higher in the 30- and the 60-day-old rats compared with the neonatal animals (p < 0.01). The expression of 65-kDa HSP mRNA was increased in RINm5F cells following heat shock, while no induction was seen after stimulation with glucose, TPA or IBMX. It is concluded that the 65-kDa heat-shock protein belongs to the family of inducible functional antigens in beta cells, which strengthens the interest in 65-kDa HSP as an antigen possibly involved in the initiation of autoimmune beta-cell destruction.
Age Factors↗
Reduction of diabetes incidence in NOD mice by neonatal glucose treatment.
The aim of this study was to investigate whether neonatal glucose treatment influences the incidence of diabetes in NOD mice. Thirty-nine NOD mice (19 males, 20 females) were treated with 8 g glucose/kg BW/day administered by subcutaneous injections twice a day for the first six days of life. Thirty-six untreated NOD mice (20 males, 16 females) served as a control group. In the glucose-treated group, 33% became diabetic compared with 58% in the control group (X2 = 5.3, p = 0.021). Among the glucose-treated males, 16% became diabetic compared with 50% of the untreated males (X2 = 5.5, p = 0.019), whereas 50% of the glucose-treated females became diabetic compared with 69% of the untreated females (X2 = 1.1, NS). We conclude that neonatal glucose treatment can reduce the diabetes incidence in NOD mice. These results could have implications for the prevention of type 1 diabetes mellitus in humans.
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Pancreatic islet-cell epitope recognized by an anti-sulphatide monoclonal antibody.
Insulin-dependent (Type 1) diabetes mellitus is recognized as an autoimmune disease and islet-cell antibody (ICA) is present in the majority of patients at diagnosis. ICA labels both beta and alpha cells and is believed to be directed against a glycolipid. In this study we examine the presence of sulphatide (3'-sulphogalactosylceramide) or closely related structures (sulpholactosylceramide and seminolipid) in islet cells by means of a monoclonal antibody, Sulph I. Histological examination of pancreatic tissue from Lewis and BB rats, and BALB/c and NOD mice showed a pronounced labelling of the islets of Langerhans with Sulph I. No staining of the exocrine pancreatic tissue, the heart, the liver, the adrenals, the thymus, the spleen or lymph nodes was seen, but staining of some tubular cells and glomerular cells in the kidney as well as of myelin in nerve cells was found. Cytological examination of isolated Lewis islet cells and their cell subpopulations, separated using a fluorescence-activated cell sorter (FACS), showed positive surface labelling of 97.3 +/- 2.2% (SD) of the beta cells and 84.4 +/- 3.0% of the non-beta cells. Thus, the epitope on the glycolipid sulphatide or closely related structures is--with the exception of neural and certain kidney tissue--specifically present in islet cells. Furthermore, the staining pattern of the antibody used, Sulph I, was equivalent to that of ICA.
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Prevention of diabetes mellitus in BB rats by neonatal stimulation of beta cells.
Antigen expression in type 1 (insulin-dependent) diabetes may depend on the functional state of beta cells. At birth, beta cells are immature, produce only a basal amount of insulin, and are unresponsive to glucose--but are sensitive to glucagon and arginine. beta cells of spontaneously diabetic BB rats were stimulated for the first 6 days after birth by glucose with glucagon or arginine to accelerate beta cell maturation, and possibly to induce antigen expression and tolerance. Over the first 200 days of life, only 23% of glucose and glucagon-treated BB rats, and 20% of glucose and arginine-treated BB rats developed diabetes, compared with 65% of untreated controls. This finding may explain the observation that children of mothers who have type 1 diabetes are three times less likely to develop the disease than children of fathers with type 1 diabetes. Earlier maturation of beta cells during the diabetic pregnancy may protect against diabetes in later life.
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Dependence of antigen expression on functional state of beta-cells.
Antigen expression corresponding to anti-islet cell surface monoclonal antibodies IC2 and A2B5 was studied. IC2 is a rat-rat hybridoma autoantibody produced from the BB rat; among islet cells, IC2 is beta-cell specific. A2B5 is an anti-ganglioside antibody described as labeling beta-cells. Islets of Langerhans from Lewis rats were isolated and cultured for 18 h in RPMI-1640 with five different glucose concentrations (2.2, 3.3, 5.5, 11.1, and 18.3 mM). In some experiments, islets were precultured for 2 or 3 days. After isolation of islet cells and antibody labeling, the percent of IC2+ beta-cells in the different groups increased from 33.3, 34.5, 40.9, and 57.2 to 58.6% (P less than 10(-6). For A2B5, the percent of labeled islet cells increased from 37.4, 41.8, 46.7, and 53.8 to 56.2% (P less than 10(-4). Thus, increasing glucose concentration leading to higher beta-cell activity implies an increase in antigen expression. Neither A2B5 nor IC2 reacts with insulin, as shown by absorption experiments and immune electron microscopy of binding sites. Electron microscopy of IC2-gold-labeled islet cells substantiated the beta-cell specificity of IC2. In conclusion, expression of the corresponding antigens to IC2 and A2B5 depends on the functional state of the beta-cells; because this has been shown to be an important factor in the development of insulin-dependent diabetes, our findings may be of potential pathogenetic interest.
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Sex-specific patterns of spleen recolonization in semiallogeneic "Sjögren-mice".
"Sjögren-mice" were produced by the transfer of two entire spleen equivalents of cells from parental strain mice to non-irradiated, adult F1 hybrids. The recipients developed an autoimmune exocrinopathy resembling primary Sjögren's syndrome. Since donor and host mice are haploidentical, no new antigens are introduced into the recipients. Donor cells may react against recipient antigens, eliciting a graft versus host (GVH) reaction. The origin of spleen cells was investigated by flow cytometry, using antibodies against murine MHC antigens. The results showed different colonization patterns: spleens of female recipients, grafted with cells from female donors, were almost completely colonized by donor type cells, whereas spleens of male recipients, grafted with either male or female cells, showed partial or complete colonization by donor type cells. The results suggest that the sex of both donor and host influences cellular reactions in lymphohaemopoietic chimeras.
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