Human fetal islet transplantation in type 1 diabetics: comparison of immunological effects between multiple implantation regimens.

Previous studies have suggested that the multiple transplants might be equally metabolically efficient to a single regimen for human adult islets. The aim of this study was to compare immunological and metabolic parameters after each of the two regimens of human fetal islets (HFI). Group A single transplants (n = 9) had 180 +/- 20 x 1000 HFI equivalents (IEQs) implanted via a single intramuscular injection. In group B multiple transplants (n = 8) islets were implanted by three consecutive injections of 60 +/- 10 x 1000 IEQs at 7-day intervals. We analyzed the immunological parameters of CD4/CD8 T lymphocyte ratios; islet cell antibodies (ICAs) and insulin antibodies (IAs). We estimated insulin secreting capacity (ISC) as the metabolic parameter. We observed that the CD4+/CD8+ T-cell ratio increased, peaking on day 90, in similar fashion in both groups: day -1: A = 1.18 +/- 0.03 versus B = 1.19 +/- 0.04; on day 90: A = 1.79 +/- 0.09, versus B = 1.75 +/- 0.08 (P = NS) immediately before the decrease in C-peptide levels. Thereafter the ratios rapidly decreased without statistical differences. The levels of ICAs did not change. The levels of IAs, which were increased before transplant, then decreased without statistical differences between the groups. The values of ISC increased after transplant and then decreased similar to the T-cell ratio. Our results demonstrated that regimens of multiple and single HFIs did not show differences in the kinetics of the immunological response presumably mediating graft destruction. The CD4/CD8 ratio increased as the C-peptide level decreased, peaking on day 90 at the time of a decrease in C-peptide. These results may be useful for clinical studies of HFIs for type 1 diabetic patients.

Human fetal islet transplantation in type 1 diabetic patients: comparison of metabolic effects between single and multiple implantation regimens.

Previous studies suggest that multiple transplantations might be equally efficient to a single regimen for human adult islets. The aim of this study was to compare metabolic parameters after each of the two regimens of human fetal islet (HFI) transplantation in type 1 diabetics. In group A (single transplant, n = 9), 180 +/- 20 x 1000 HFI equivalents (IEQs) were implanted by a single IM injection; in group B (multiple transplants, n = 8) islets were implanted as three consecutive injections (60 +/- 10 x 1000 IEQs) at 7-day intervals. We analyzed the metabolic parameters on days -1, 30, 60, 90, 120, 150, and 180 after the procedure. Among the metabolic parameters, we evaluated insulin secretion capacity-ISC (C peptide, RIA), metabolic control (HbA1c, chromatography), and insulin daily dose IDD. We found that C peptide levels increased, peaking on day 90 (A: 0.38 +/- 0.15; B: 0.34 +/- 0.19 nmol/L, P = NS) and then rapidly decreasing without differences, the HbA1c levels and IDD decreased in the same manner without differences between the groups. Our results demonstrate that multiple and single islet transplant regimens are equally efficient to temporarily restore a significant ISC with improvement of metabolic and clinical parameters. The results imply that the two regimens have an equal clinical value.

[Human fetal pancreatic islet transplantation in insulin-dependent diabetics: possibilities of early detection of transplant destruction]. / Tranplantacija ostrvaca humanog fetalnog pankreasa u insulin-zavisnih dijabeticara: mogucnost rane detekcije destrukcije transplantata.

The factors determining the outcome of human fetal islet transplantation in patients with insulin-dependent diabetes mellitus (IDDM) remain unclarified. In this study we analysed the ratio between immunoregulatory lymphocyte subpopulations in order to search for a possible marker of the immune destruction of transplanted islets. Human fetal islets were isolated by collagenase digestion, cultured for 14 days at 37 degrees C, 5% CO2, and implanted under fascia of m. rectus abdominis in 7 IDDM patients (5 pancreata per patient). After transplantation we evaluated simultaneously the level of metabolic control through HbA1c values determined by chromatography, the capacity of insulin secretion through the C-peptide levels (determined by radioimmunoassay) before and 6 minutes after 1 mg glucagon i.v. stimulation, and the ratio between CD4+ and CD8+ lymphocytes determined by immunofluorescence using monoclonal antibodies. We found that metabolic control after transplantation was improved together with the decrease of the insulin daily dose, and the improvement was simultaneous to the increase of both basal and glucagon-stimulated C-peptide levels. Four months after transplantation we detected a remarkable decrease in the secretion capacity, accompanied by the necessity for an increase in daily insulin dose to maintain optimal metabolic control. However, the loss of islet function was preceded by the increase in CD4+/CD8+ ratio, thus reflecting the presumable accumulation of CD4+ inducer T-lymphocytes. When the islet secretion capacity was destroyed, we found a decrease in CD4+/CD8+ ratio, reflecting the recruitment of CD8+ effector cells.(ABSTRACT TRUNCATED AT 250 WORDS)

[Use of cyclosporin A for remission induction in newly-detected insulin-dependent diabetes]. / Primena ciklosporina A u indukciji remisije u novootkrivenom insulini-zavisnom dijabetesu.

It has been postulated that some of the recent-onset insulin-dependent diabetics, after the initial use of insulin therapy, might develop the "honey moon period", i.e., a spontaneous remission of the disease, defined as the state of normal metabolic control maintained without insulin therapy. However, it has also been shown that spontaneous remission appears only in 5% of the patients treated with conventional insulin therapy and lasts, most frequently, not more than a few weeks. Different therapeutic regimens of immunosuppression and immunomodulation have been used worldwide in order to induce the remission, based on the findings that an autoimmune process underlies the pathogenesis of this type of diabetes. In this study, we have shown the results of the follow-up analysis of the effects of the treatment with cyclosporin A in 21 recent-onset insulin-dependent diabetics. In 15 of those patients insulin treatment was applied as bi-daily doses of monocomponent insulin preparations, and in 6 of them intensified insulin therapy with human insulin was used. In the first group, the remission was achieved in 46.66% and in the second group in 66.66%, which is a significantly higher incidence than in control groups treated only with insulin, without cyclosporin. Moreover, the duration of remission was longer in the patients treated with cyclosporin. The analysis of the residual beta cell secretory capacity has shown that C-peptide levels (taken as a marker for insulin secretion) were slightly higher in patients with the spontaneous remission than in those with the cyclosporin-induced remission both in basal conditions and after stimulation with 1 mg of glucagon. In the patients with cyclosporin A-induced remission we found an improved basal C-peptide secretion and, even more, we detected a significant improvement in beta cell response to the glucagon stimulation. The analysis of the first-phase insulin secretory response (the insulin response to rapidly injected glucose during the intravenous glucose tolerance test) which has been shown to be impaired very early during the development of diabetes, has demonstrated the lack of its recovery both in the spontaneous and in cyclosporin A-induced remissions. The analysis of the molar insulin/C-peptide ratio has detected the impairments of this ratio which remains decreased both in spontaneous and cyclosporin-induced remissions.

Androgen levels during sequential insulin euglycemic clamp studies in patients with polycystic ovary disease.

It is postulated that insulin may play a role in the regulation of ovarian androgen production. In order to test the possible interrelation between serum insulin levels and androgen production, sequential euglycemic insulin clamp (Mode 9:1 on Biostator, insulin infusion rate: 0.1; 0.2 and 0.4 U/kg b. wt/h, each rate for 90 min, BC = 80 mg/dl) was done in 6 patients with polycystic ovary disease and normal glucose tolerance. Insulin, C-Peptide, testosterone and dehydroepiandrosterone-sulphate were measured in 0, 70, 80, 90, 160, 170, 180, 250, 260 and 270 min. Significant suppression of C-Peptide levels were achieved (0 min vs 270 min = 0.81 + 0.25 vs 0.15 + 0.20 nmol/l; P less than 0.05). Basal insulin as well as the mean plateau for each insulin infusion rate were as follows: 28 + 9; 248 + 119; 427 + 69 and 524 + 77 microU/l. There was significant testosterone increase at the end of insulin infusion (0 vs 270 min = 4.8 + 1.2 vs 8.1 + 1.7 nmol/l; P less than 0.05). There were no significant changes in dehydroepiandrosterone-sulphate levels during clamp studies (0 vs 270 min = 1055 + 133 vs 913 + 114 ng/ml; P greater than 0.05). It is concluded that acute insulin infusion under the condition of sequential euglycemic clamp could increase androgen production in the ovaries of patients with PCO.

Prolactin and growth hormone response in induced hypoglycaemia in obese patients.

Obesity represents a metabolic abnormality which brings a disordered hormone response during functional pituitary tests. Twenty obese patients were investigated and growth hormone and prolactin response during the insulin tolerance test were determined and the result was compared to an adequate control group consisting of 10 healthy nonobese patients. Two types of prolactin response were obtained--one normal and one decreased, unlike the growth hormone response which was constantly decreased. The authors discuss the hypothesis according to which the defect of endocrine hypothalamus might be an etiological factor of obesity.