Insulin-dependent Diabetes Mellitus Patient Research Articles

An automatic insulin infusion system based on LQG control technique

This paper makes an attempt to develop clinical simulation model of glucose–insulin interaction and to design an optimal controller to regulate the Blood Glucose (BG) level in Insulin–Dependent Diabetes Mellitus (IDDM) patients. For enhancing the quality of life of the patient, an automated insulin delivery system based on Linear Quadratic Gaussian (LQG) control algorithm is suggested, and to justify its efficacy a comparative analysis with conventional Proportional–Integral–Derivative (PID) control tuned using the Ziegler–Nichols method and optimal H∞ control based on solutions of Riccati equations is presented. For designing of the controller, a ninth–order linearised state–space model of the glucose–insulin interaction process of an IDDM patient has been used. The controller performances are assessed in terms of ability to track a normoglycaemic set point of 81 mg/dL (4.5 mmol/L) in the presence of Gaussian and stochastic noise.

Optimal H<SUB align="right">∞ insulin injection control for blood glucose regulation in IDDM patient using physiological model

This paper addresses the design of output feedback H∞ controller to deliver insulin via an implantable micro insulin dispenser for insulin-dependent diabetes mellitus (IDDM) patients. The theory of H-infinity optimal control has the feature of minimising the worst-case gain of an unknown disturbance input. When appropriately modified, the theory can be used to design a ‘switching’ controller that can be applied to insulin injection for blood glucose (BG) regulation in IDDM patient. The ‘switching’ controller is defined by a collection of basic insulin rates and a rule that switches the insulin rates from one value to another. The rule employed an estimation of BG from noisy measurements and the subsequent optimisation of a performance index that involves the solution of a ‘jump’ Riccati differential equation. With an appropriate IDDM patient model, simulation studies have shown that the controller could correct BG deviation using clinically acceptable insulin delivery rates to maintain normoglycaemia.

183 Isolation and partial characterization of a general hormone transporting blood protein complex

Using immobilized insulin, human blood serum insulin-binding proteins were isolated at physiological pH values and zinc concentrations. By means of enzyme-linked immunoassay, albumin (26.7 ± 1.75%), α-fetoprotein (2 ± 0.61%), transferin (10 ± 0.73%), retinol-binding protein (4 ± 0.75%), and immunoglobulin G (20.3 ± 0.95%) were identified in isolated protein complex from human blood serum. Gel filtration of isolated proteins on Sephadex G-75 has demonstrated formation of a supramolecular complex under pH 7.2 and zinc concentration of 1 mg/mL (Garipova et al., 2010). The possible existence of such complex is supported by the presence of lipocalin glycoproteins such as retinol-binding protein and transferrin in obtained proteins; lipocalins form the protein family, which is capable to form intermolecular complexes to ensure the delivery of hormones to target cells through their own cell receptors (Flower, 1996). It has been shown that the isolated protein complex, along with insulin, transports other hydrophilic hormones. By means of ELISA, protein hormones such as luteinizing (1 mU/mg), thyreotropic (0.03 mM/mg) hormones, and prolactin (0.5 mU/mg) were identified. In addition, the complex has included hydrophobic hormones: thyroxin (11.0 ± 0.5 nmol/mg), triiodothyronine (1.3 ± 0.06 nmol/mg), and testosterone (7.0 ± 0.03 nmol/mg). Based on these data, we have proposed an existence in human blood of a general transporting complex that is common for both hydrophobic and hydrophilic hormones. The core of this complex is formed by transporting proteins, including those relating to lipokalins. This complex transfers thyroxin, triiodothyronine, testosterone, thyroid-stimulating hormone, prolactin, and luteinizing hormone, as well as triglycerides and cholesterol to the tissues. The composition of insulin-binding protein complex was significantly changed in the insulin-dependent diabetes mellitus patient’s blood. Albumin and α-fetoprotein, which are present in a normal complex, are revealed only in trace amounts in samples isolated from the diabetic blood and are replaced by α1-acid glycoprotein, and possibly other unidentified proteins. Disturbance of hormone-transporting complex protein composition in the diabetic blood may be a reason of insulin delivery disruption. Perhaps, for the same reason, delivery to target cells of not only insulin, but also other members of the hormone-transporting complex, is disrupted in the diabetic blood.

Nonparametric Identification of Glucose-Insulin Process in IDDM Patient with Multi-meal Disturbance

Modern close loop control for blood glucose level in a diabetic patient necessarily uses an explicit model of the process. A fixed parameter full order or reduced order model does not characterize the inter-patient and intra-patient parameter variability. This paper deals with a frequency domain nonparametric identification of the nonlinear glucose-insulin process in an insulin dependent diabetes mellitus patient that captures the process dynamics in presence of uncertainties and parameter variations. An online frequency domain kernel estimation method has been proposed that uses the input–output data from the 19th order first principle model of the patient in intravenous route. Volterra equations up to second order kernels with extended input vector for a Hammerstein model are solved online by adaptive recursive least square (ARLS) algorithm. The frequency domain kernels are estimated using the harmonic excitation input data sequence from the virtual patient model. A short filter memory length of M = 2 was found sufficient to yield acceptable accuracy with lesser computation time. The nonparametric models are useful for closed loop control, where the frequency domain kernels can be directly used as the transfer function. The validation results show good fit both in frequency and time domain responses with nominal patient as well as with parameter variations.

Diabetes mellitus modeling and short-term prediction based on blood glucose measurements

Insulin-Dependent Diabetes Mellitus (IDDM) is a chronic disease characterized by the inability of the pancreas to produce sufficient amounts of insulin. Daily compensation of the deficiency requires 4–6 insulin injections to be taken daily, the aim of this insulin therapy being to maintain normoglycemia – i.e., a blood glucose level between 4 and 7 mmol/l. To determine the quantity and timing of these injections, various different approaches are used. Currently, mostly qualitative and semi-quantitative models and reasoning are used to design such a therapy. Here, an attempt is made to show how system identification and control may be used to estimate predictive quantitative models to be used in design of optimal insulin regimens. The system was divided into three subsystems, the insulin subsystem, the glucose subsystem and the insulin–glucose interaction. The insulin subsystem aims to describe the absorption of injected insulin from the subcutaneous depots and the glucose subsystem the absorption of glucose from the gut following a meal. These subsystems were modeled using compartment models and proposed models found in the literature. Several black-box models and grey-box models describing the insulin/glucose interaction were developed and analyzed. These models were fitted to real data monitored by an IDDM patient. Many difficulties were encountered, typical of biomedical systems: Non-uniform and scarce sampling, time-varying dynamics and severe nonlinearities were some of the difficulties encountered during the modeling. None of the proposed models were able to describe the system accurately in all aspects during all conditions. However, all the linear models shared some dynamics. Based on the estimated models, short-term blood glucose predictors for up to two-hour-ahead blood glucose prediction were designed. Furthermore, we explored the issues that arise when applying prediction theory and control to short-term blood glucose prediction.

Nasotracheal intubation: an unusual cause of palatal perforation in an insulin dependent diabetes mellitus patient

A case of palatal perforation occurring in 7-year-old girl with IDDM due to nasotracheal intubation is reported. The child, who was not previously diagnosed of IDDM, was brought to hospital in comatose stage and was put on nasotracheal tube for maintaining respiration. This paper highlights the link between IDDM and palatal perforation communicating the nasal cavity due to naso-tracheal intubation.

Evidence for complement-dependent and -independent inhibition of insulin secretion from clonal beta-cells incubated in the presence of sera of newly diagnosed IDDM patients.

There are conflicting reports on the effect of serum from patients with insulin-dependent diabetes mellitus (IDDM) or normal human serum on beta-cell function and insulin secretion. Here, we report that the sera of newly diagnosed IDDM patients potently suppresses insulin secretion from a clonal rat pancreatic beta-cell line (BRIN-BD11), but do not alter cell viability. Indeed, the viability of the beta-cells was not significantly different between cells cultured in 10% (v/v) IDDM sera, normal human sera, or fetal calf serum after 24, 48 and 72 h. Alanine-stimulated insulin secretion from cells cultured for 24 h in (10% v/v) IDDM patient sera was reduced to 48% of that secreted from cells cultured in (10% v/v) normal human sera. After depletion of the complement components C1q and C3, the inhibition of insulin secretion induced by IDDM patient sera was significantly reversed (no significant difference was observed between cells cultured in complement-depleted IDDM patient sera and cells cultured in normal human sera or complement-depleted normal human sera). The concentration of glutamic acid decarboxylase (GAD) autoantibodies was markedly increased in the sera of six out of nine newly diagnosed IDDM patients in this study, whereas insulin auto-antibodies (IAA) were detected in the sera of three of the nine patients and islet-cell antibodies (ICA) in the sera of five of them. In addition, the concentration of soluble terminal complement complexes (SC5-9) was greater in some of the beta-cell culture media samples after 24 h incubation when the incubation medium was supplemented with IDDM patient sera than when supplementation was with normal human sera. We propose that the mechanism of sera-induced inhibition of insulin secretion from clonal beta-cells may involve complement- and cytokine-stimulated intracellular events that attenuate the metabolite-induced secretory process.

Association of self-monitoring blood glucose profiles with glycosylated hemoglobin in patients with insulin-dependent diabetes

This chapter describes the association of self-monitoring blood glucose profiles, with glycosylated hemoglobin, in patients with insulin-dependent diabetes. Researchers have known for more than 20 years that glycosylated hemoglobin (Hb) is a marker for the glycemic control of individuals, with insulin-dependent diabetes mellitus (IDDM). Numerous studies have investigated this relationship and found that glycosylated hemoglobin generally reflects the average blood glucose (BG) levels of an IDDM patient over the past two months. However, the rapid development of home BG monitoring devices somewhat changes this conclusion. Contemporary memory meters store up to several hundred self-monitoring BG (SMBG) readings and can calculate various statistics, including the mean of these BG readings. High glycosylated hemoglobin is opposite to severe hypoglycemia (SH), as an extreme manifestation of IDDM, related to long-term complications. Contemporary memory meters store up to several hundred self-monitoring BG (SMBG) readings and can calculate various statistics, including the mean of these BG readings.

Evidence for enhanced rates of complement activation in serum from patients with newly diagnosed insulin-dependent diabetes mellitus exposed to rat islet cells and complement-dependent induction of islet cell apoptosis.

In this paper we report the concentration of terminal complement complexes (TCCs, SC5b-9, an index of complement activation) in newly diagnosed insulin-dependent diabetes mellitus (IDDM) patient serum and normal human serum. In the nine patients studied, levels of serum soluble TCCs were approximately 1.6-fold higher than in sera obtained from normal control individuals. On incubation of rat islet cells with diluted serum (10%, v/v, concentration), complement activation was increased at a significantly faster rate and the total TCC concentration was significantly higher in culture medium containing IDDM patient serum than in medium containing control serum. The concentration of anti-(glutamic acid decarboxylase) autoantibodies in newly diagnosed IDDM patient serum was on average 60-fold higher than in normal human control serum. IDDM patient serum (10%, v/v) induced apoptosis in islet cells, as determined by islet cell density changes and DNA fragmentation patterns. However, serum from IDDM patients was not able to induce apoptosis of the cells when complement components (C1q and C3) or antibodies were depleted. In addition, glutamine and the potent antioxidant 1-pyrrolidinecarbodithioic acid partially reversed cell death induced by IDDM patient serum in a concentration-dependent manner. The ATP concentration in islet cells incubated for 24 h in the presence of diluted IDDM patient serum was reduced to 4.4% of that observed in islet cells incubated in fetal calf serum or 7.3% of that observed in islet cells incubated in normal human serum. On the basis of these observations, we suggest that the pathway of IDDM patient serum-induced islet cell apoptosis may involve antibody-dependent complement activation, free radical generation and a precipitous fall in ATP levels.

Altered Peptide Ligands of Islet Autoantigen Imogen 38 Inhibit Antigen Specific T Cell Reactivity in Human Type-1 Diabetes

Type 1 diabetes, insulin-dependent diabetes mellitus (IDDM) results from autoimmune T cell-dependent destruction of insulin producing β-cells in the pancreatic islets of Langerhans. T cells from recent-onset IDDM patients specifically proliferate to β cell membrane Ag enriched fractions, containing the mitochondrial 38kD islet antigen (Imogen). Recently, we identified a peptide epitope (Imogen p55-70) that is recognized by a 38kD-specific, Th1 clone from an IDDM patient. In animal models of autoimmune diseases, altered self peptide ligands (APL) have been used effectively in peptide-based immune prevention or therapy. No such APL, however, have been reported so far that can modulate autoreactive T-cell responses in IDDM. Here, we have designed APL of p55-70. These APL efficiently downregulatein vitroactivation of the 38kD-specific Th1 clone induced by either p55-70 or by native β cell autoantigens. Self peptide reactive T-cell proliferation could be inhibited only when APL and the self peptide were present on the same APC. Unrelated peptides with equal HLA-DR binding affinity were not effective, excluding simple MHC competition as the mechanism for T-cell modulation. APL triggered upregulation of CD69 and CD25 expression, but not T-cell proliferation, TCR down-modulation or T-cell anergy. Thus, the p55-70 APL inhibit β cell autoantigen-induced activation of an Imogen-reactive T-cell clone derived from an IDDM patient, by acting as partial TCR agonists that inhibit TCR down-modulation.

Cloned T Cells from a Recent Onset IDDM Patient Reactive with Insulin B-chain

Insulin-dependent diabetes mellitus (IDDM) results from selective auto-immune destruction of insulin producing β-cells. T-cell reactivity and auto-antibodies to several islet proteins such as insulin, GAD and IA-2 are associated with IDDM in mice and men. In NOD mice, the majority of T cells from insulitis specifically recognize the insulin B-chain peptide amino acid 9-22, in contrast to the periphery where the precursor frequency is much lower. It is important to note that these cells are diabetogenic. Surprisingly, the same insulin B-chain region contains epitopes recognized by protective T cells. In fact, autoimmune diabetes in NOD mice could be prevented by prophylactic treatment with this immunodominant T-cell epitope. In humans, however, no immunodominant regions of insulin have yet been defined. We have isolated and characterized a human insulin-specific T-cell clone that was derived from peripheral blood of a newly diagnosed IDDM patient. This patient displayed weakly positive primary T-cell responses to insulin. The peptide recognized by the clone was mapped to the insulin B chain (B:11-27). Functionally, the human insulin-specific CD4+T cells displayed a Th1/0 like cytokine profile and were restricted by HLA-DR. The previously proposed alternative superantigen-like binding of insulin-B chain peptide outside of the peptide binding groove of HLA-DR could not be confirmed, since T-cell recognition was inhibited in competition experiments of insulin-B chain peptide with HLA-DR16 binding influenza peptide HA307-319. Our results indicate that human clonal T cells isolated from a recent onset IDDM patient recognize an epitope overlapping with the insulin B-chain region that is immunodominant and potentially therapeutic in NOD mice. This observation may be useful in studying the role of insulin-specific T cells in IDDM, and may eventually help to establish peptide-based immunotherapies in IDDM.

Effect of adjustment of maternal serum ?-fetoprotein levels in insulin-dependent diabetes mellitus

Our objective was to determine the effect of the 20% upward adjustment of maternal serum alphafetoprotein (MSAFP) in patients with insulin-dependent diabetes mellitus (IDDM) on the number of patients that would be classified at increased risk for pregnancy complicated by either Down syndrome (DS) or neural tube defect (NTD). We retrospectively evaluated a database containing 63,110 patients who underwent multiple serum marker screening between 14 and 22 weeks gestation; 620 patients with IDDM had measurements of MSAFP of which 479 also had measurements of beta-HCG, allowing calculation of DS risk. Increased NTD risk was defined as MSAFP >2.5 MOM while increased DS risk was defined as a calculated risk > or =1/270. One IDDM patient delivered an infant with a NTD; it was not detected on serum screening. No infants were born with DS. Of the 620 patients with MSAFP determinations, 9 had values >2.5 MOM before adjustment. After upward adjustment, 7 additional patients were identified. Sixteen patients were identified at increased risk for DS before and after adjustment. Our data suggest that the 20% upward adjustment of MSAFP increases by 78%, the number of patients who would require further evaluation for NTD's. Although we were able to identify 620 women with IDDM who underwent serum screening for NTD, the low prevalence of NTD's did not allow us to demonstrate an increased detection rate. The effect of upward adjustment of MSAFP on the number of patients categorized at increased DS risk appears to be minimal.

Effect of adjustment of maternal serum α‐fetoprotein levels in insulin‐dependent diabetes mellitus

Our objective was to determine the effect of the 20% upward adjustment of maternal serum alphafetoprotein (MSAFP) in patients with insulin-dependent diabetes mellitus (IDDM) on the number of patients that would be classified at increased risk for pregnancy complicated by either Down syndrome (DS) or neural tube defect (NTD). We retrospectively evaluated a database containing 63,110 patients who underwent multiple serum marker screening between 14 and 22 weeks gestation; 620 patients with IDDM had measurements of MSAFP of which 479 also had measurements of β-HCG, allowing calculation of DS risk. Increased NTD risk was defined as MSAFP >2.5 MOM while increased DS risk was defined as a calculated risk ≥1/270. One IDDM patient delivered an infant with a NTD; it was not detected on serum screening. No infants were born with DS. Of the 620 patients with MSAFP determinations, 9 had values >2.5 MOM before adjustment. After upward adjustment, 7 additional patients were identified. Sixteen patients were identified at increased risk for DS before and after adjustment. Our data suggest that the 20% upward adjustment of MSAFP increases by 78%, the number of patients who would require further evaluation for NTD's. Although we were able to identify 620 women with IDDM who underwent serum screening for NTD, the low prevalence of NTD's did not allow us to demonstrate an increased detection rate. The effect of upward adjustment of MSAFP on the number of patients categorized at increased DS risk appears to be minimal. Am. J. Med. Genet. 75:176–178, 1998. © 1998 Wiley-Liss, Inc.

Screening of the TAP1 gene by denaturing gradient gel electrophoresis in insulin-dependent diabetes mellitus: detection and comparison of new polymorphisms between patients and controls.

New protective or disease-associated polymorphisms in the TAP1 gene were sought in insulin-dependent diabetes mellitus (IDDM) patients with the use of denaturing gradient gel electrophoresis (DGGE) screening of genomic DNA. The TAP1 gene is located in the human leukocyte antigen (HLA) class II region of the genome and encodes components of a peptide transporter essential for antigen presentation by HLA class I molecules. Fragments of TAP1 corresponding to the 5' promoter, each of the 11 exons (with portions of adjacent intronic regions) and the 3' flanking region were amplified by the polymerase chain reaction and then subjected to DGGE. DNA fragments of TAP1 yielded DGGE bands with patterns whose frequencies differed between IDDM patients and controls. Specific DGGE band patterns with fragments corresponding to the promoter, exons or introns 3, 6, 7, 8, 9 or 10 of TAP1 were detected exclusively in either patients or controls. Sequencing of TAP1 fragments encompassing exon 7 gave rise to a DGGE band pattern exclusively observed in an IDDM patient and sequencing revealed a previously unidentified polymorphisms at codon 518 (GTC-->ATC, Val-->Ile). Another unique polymorphism uncovered by DGGE revealed by sequencing a polymorphism in intron 2 in a diabetic patient. The genotypes of additional HLA class II matched patients and controls were determined with regard to five exonic and one intronic TAP1 polymorphism. A 10 base pair intronic insertion in intron 9 was exclusively identified in controls and missing from patients (P = 0.017). Further large population-based studies may reveal whether these newly identified at risk or protective TAP1 variants confer markers of statistical risk in diverse population groups.

The identification of CD4+ T cell epitopes with dedicated synthetic peptide libraries.

For a large number of T cell-mediated immunopathologies, the disease-related antigens are not yet identified. Identification of T cell epitopes is of crucial importance for the development of immune-intervention strategies. We show that CD4+ T cell epitopes can be defined by using a new system for synthesis and screening of synthetic peptide libraries. These libraries are designed to bind to the HLA class II restriction molecule of the CD4+ T cell clone of interest. The screening is based on three selection rounds using partial release of 14-mer peptides from synthesis beads and subsequent sequencing of the remaining peptide attached to the bead. With this approach, two peptides were identified that stimulate the beta cell-reactive CD4+ T cell clone 1c10, which was isolated from a newly diagnosed insulin-dependent diabetes mellitus patient. After performing amino acid-substitution studies and protein database searches, a Haemophilus influenzae TonB-derived peptide was identified that stimulates clone 1c10. The relevance of this finding for the pathogenesis of insulin-dependent diabetes mellitus is currently under investigation. We conclude that this system is capable of determining epitopes for (autoreactive) CD4+ T cell clones with previously unknown peptide specificity. This offers the possibility to define (auto)antigens by searching protein databases and/or to induce tolerance by using the peptide sequences identified. In addition the peptides might be used as leads to develop T cell receptor antagonists or anergy-inducing compounds.

When should ACE Inhibitors be given to normotensive patients with IDDM

See page 1787 Recent clinical trials have shown that angiotensinconverting-enzyme (ACE) inhibitors have beneficial effects on progression of nephtropathy in patients with insulindependent diabetes mellitus (IDDM). In today’s Lancet the EUCLID trial, the largest of its kind to date, reports that an ACE inhibitor significantly reduced urinary albumin excretion (UAE) rate in normotensive IDDM patients. These studies have led to questions that include which IDDM patient should receive an ACE inhibitor and when an ACE inhibitor should be given. The indication for starting ACE inhibitors is clear if the patient also has raised blood pressure. But in normotensive patients what would be a rational approach? Several epidemiology studies published more than a decade ago showed that 30-40% of IDDM patients developed clinical evidence of diabetic nephropathy. Although the prevalence of diabetic nephropathy has been decreasing during the past 3 decades because of improving diabetic care, diabetic nephropathy still represents the leading cause of dialysis in the western world. Fortunately recent studies have yielded encouraging results, and an integrated strategy now can be developed to prevent progression of diabetic nephropathy. Since not every IDDM patient will develop severe diabetic nephropathy, ideally preventive measures such as ACE inhibitors should be given only to those IDDM patients who are at risk of developing overt nephropathy. But reliable and practical ways of identifying those normotensive patients with such high risk before the onset of nephropathy are not yet available. The alternative is to identify those normotensive IDDM patients who are at a very early stage of diabetic nephropathy and are likely to develop advanced nephropathy. UAE has emerged as the best marker and the most practical method for detection of early diabetic nephropathy, and the occurrence of persistent microalbuminuria predicts later development of renal failure in IDDM patients. 1

Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria

Summary Background Renal disease in people with insulin-dependent diabetes (IDDM) continues to pose a major health threat. Inhibitors of angiotensin-converting enzyme (ACE) slow the decline of renal function in advanced renal disease, but their effects at earlier stages are unclear, and the degree of albuminuria at which treatment should start is not known. Methods We carried out a randomised, double-blind, placebo-controlled trial of the ACE inhibitor lisinopril in 530 men and women with IDDM aged 20–59 years with normoalbuminuria or microalbuminuria. Patients were recruited from 18 European centres, and were not on medication for hypertension. Resting blood pressure at entry was at least 75 and no more than 90 mm hg diastolic, and no more than 155 mm hg systolic. Urinary albumin excretion rate (AER) was centrally assessed by means of two overnight urine collections at baseline, 6, 12, 18, and 24 months. Findings There were no differences in baseline characteristics by treatment group; mean AER was 8.0 μg/min in both groups; and prevalence of microalbuminuria was 13% and 17% in the placebo and lisinopril groups, respectively. On intention-to-treat analysis at 2 years, AER was 2.2 μg/min lower in the lisinopril than in the placebo group, a percentage difference of 18.8% (95% CI 2·0–32·7, p=0·03), adjusted for baseline AER and centre, absolute difference 2.2 μg/min. In people with normoalbuminuria, the treatment difference was 1·0 μg/min (12·7% [−2·9 to 26·0], p=0·1). In those with microalbuminuria, however, the treatment difference was 34.2 μg/min (49·7% [−14·5 to 77·9], p=0·1; for interaction, p=0·04). For patients who completed 24 months on the trial, the final treatment difference in AER was 38·5 μg/min in those with microalbuminuria at baseline (p=0·001), and 0·23 μg/min in those with normoalbuminuria at baseline (p=0·6). There was no treatment difference in hypoglycaemic events or in metabolic control as assessed by glycated haemoglobin. Interpretation Lisinopril slows the progression of renal disease in normotensive IDDM patients with little or no albuminuria, though greatest effect was in those with microalbuminuria (AER ≥20 μg/min). Our results show that lisinopril does not increase the risk of hypoglycaemic events in IDDM.

A simulation model of the cost of the incidence of IDDM in Spain

This study estimates the direct health care costs of the incidence of insulin-dependent diabetes mellitus (IDDM) in Spain. A discrete event simulation model was developed to approximate the natural history of a cohort of newly diagnosed patients in a given year and used to calculate the average costs which would accumulate during the lifetime of the group of patients. The model takes into account both the underlying costs of control and maintenance of the disease plus the additional costs of long-term complications that are likely to develop as the disease progresses. The model is based on national and international epidemiological and demographic information combined with local cost data. The number of newly diagnosed cases of IDDM each year, based on Spanish epidemiological data, was calculated to be approximately 1791 cases in 1994. The baseline results from the model indicate that the average life expectancy of an IDDM patient is approximately 59.6 years with an average lifetime cost of 12.7 million pesetas per individual (1994 undiscounted values), 5.1 million pesetas per individual when discounted at a rate of 6% and 8060 million pesetas for the entire newly diagnosed cohort discounted at a rate of 6%. Sensitivity analysis was undertaken in order to observe the effect on the result of changes in the values of key variables.

Immune reactivity of diabetes-associated human monoclonal autoantibodies defines multiple epitopes and detects two domain boundaries in glutamate decarboxylase.

Autoreactive islet cell Abs (ICA) accompany the pathogenic destruction of pancreatic beta cells in insulin-dependent diabetes mellitus (IDDM). Human monoclonal ICA (MICA 1-6), previously derived from a DR1/DR7-positive newly diagnosed diabetic patient, recognized the islet cell autoantigen glutamate decarboxylase 65 (GAD65) and defined two distinct conformational (MICA 1/3 and MICA 4/6) and one linear (MICA 2) autoimmune epitopes in this molecule. We have isolated 4 new ICA-reactive B cell lines, one from a DR4/DR11-positive newly diagnosed IDDM patient (MICA 7) and three from a DR3 homozygous patient with both IDDM and Graves' disease (MICA 8-10). Like MICA 1-6, MICA 7-10 are specific for GAD65, suggesting that GAD65-reactive B cells dominate the ICA response in IDDM. Comparative analysis of MICA 1-6 and MICA 7-10, using GAD65 mutants and blocking experiments, showed that MICA 7-10 define three novel conformational autoimmune epitopes in GAD65. Further structural analysis of the MICA 1-10 epitopes revealed two distinct and one overlapping region of epitope clusters. Thus, the C-terminal region, defined by amino acids 450 to 570, harbors the conformational MICA1/3 and MICA 7 epitopes as well as the linear epitope of MICA 2 (amino acids 506-531). The MICA 4/6 and MICA 10 epitopes are located in the middle region of the molecule defined by amino acids 245 to 449, whereas the N-terminal region contributes only to the MICA 8/9 epitopes (encompassed in amino acids 39-585). MICA 1-6, 7, and 8-10, derived from three IDDM patients of different HLA haplotypes, define six different epitopes in GAD65 and represent tools to determine the spectrum, possible HLA association, and temporal order of epitope recognition in IDDM.

Cloning and Characterization of Islet Cell Antigen-related Protein-tyrosine Phosphatase (PTP), a Novel Receptor-like PTP and Autoantigen in Insulin-dependent Diabetes

Cloning of the cDNA encoding a novel human protein- tyrosine phosphatase (PTP) called islet cell antigen-related PTP (IAR) predicts a receptor-like molecule with an extracellular domain of 614 amino acids containing a hydrophobic signal peptide, one potential N-glycosylation site, and an RGDS peptide which is a possible adhesive recognition sequence. The 376-amino acid intracellular region contains a single catalytic domain. Recombinant IAR polypeptide has phosphatase activity. Northern blot analysis shows tissue-specific expression of two IAR transcripts of 5.5 and 3. 7 kilobases, which are most abundant in brain and pancreas. The IAR PTP is homologous in its intracellular region to IA-2, a putative PTP that is an insulin-dependent diabetes mellitus (IDDM) autoantigen. IAR is also reactive with IDDM patient sera. IAR and IA-2 may distinguish different populations of IDDM autoantibodies since they identify overlapping but nonidentical sets of IDDM patients. Thus IAR is likely to be an islet cell antigen useful in the preclinical screening of individuals for risk of IDDM.