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PubMedDate not supplied

Effect of enalapril and losartan on the events that precede diabetic nephropathy in rats.

BACKGROUND: Mesangial cell proliferation, phenotype change, and increased transforming growth factor-beta (TGF-beta) precede mesangial expansion in diabetic rats. Experiments using mesangial cell culture have shown that angiotensin II increases TGF-beta production by these cells. The aim of the present study was to investigate the effect of enalapril and losartan on the events that precede diabetic nephropathy in rats. It was also analyzed if the determination of urinary TGF-beta could be a mean for the evaluation of therapeutic efficacy in this disease. METHODS: Eighty-two female Wistar rats were made diabetic by intravenous injection of streptozotocin diluted in citrate buffer, and citrate buffer alone was injected into the control group (N = 34). Ten days later, the right kidney was removed. Thirty diabetic rats were treated with enalapril, DMN + E, in drinking water (20 mg/L) and 24 with losartan, DMN + L (50 mg/L). Urinary TGF-beta was determined 90 days after STZ or buffer injection, the animals were killed, and the kidneys were removed for histological and immunohistochemical studies. RESULTS: The immunostaining for TGF-beta and fibronectin in the cortical tubulointerstitium and glomeruli was higher in untreated diabetic rats (p < 0.001). Treatment with enalapril or losartan reduced this increase. The urinary TGF-beta excretion (pg/mg urinary creatinine) was 48.6 +/- 5.9 in control animals, 603.9 +/- 80.41 in untreated diabetic rats, 279.3 +/- 47.0 in diabetic rats treated with enalapril, and 243.7 +/- 40.0 in rats treated with losartan. CONCLUSIONS: We concluded that enalapril or losartan treatment can modify events that precede diabetic nephropathy by reducing TGF-beta and fibronectin expression in glomeruli and tubulointerstitium as well as urinary TGF-beta content.

Albuminuria↗
PubMedDate not supplied

Soluble adhesion molecules in Finnish schoolchildren with signs of preclinical type 1 diabetes.

BACKGROUND: We measured the circulating concentrations of the soluble forms of intercellular adhesion molecule-1, ICAM-1 (sCD54) and L-selectin (sCD62L) in 104 non-diabetic Finnish schoolchildren testing positive for one or more diabetes-associated autoantibodies and in 104 autoantibody-negative children to elucidate the relationship between soluble adhesion molecules and humoral, genetic and metabolic markers of preclinical type 1 diabetes. METHODS: Specific enzyme-linked immunosorbent assays were used to analyse serum sICAM-1 and sL-selectin concentrations. RESULTS: The sICAM-1 and sL-selectin levels were comparable in the autoantibody-positive and control children, even when comparing children with multiple autoantibodies with those having one or no autoantibodies. The IA-2A titres in children testing positive for this autoantibody correlated with the sICAM-1 concentrations (rs=0.62, P=0.05), but otherwise no significant associations were seen between the autoantibody specificities and the concentrations of soluble adhesion molecules. Control children with HLA DQB1 genotypes conferring a low or decreased risk of type 1 diabetes had higher levels of sL-selectin than those with high or moderate risk genotypes (P=0.04). sL-selectin concentrations were significantly increased in the autoantibody-positive children with a first-phase insulin response (FPIR) below the 5th (n=11;P=0.026) or 10th percentiles (n=17;P=0.009) relative to the children with a normal FPIR. No associations were observed between sICAM-1 concentrations and DQB1 genotypes or FPIR. CONCLUSIONS: The data indicate that there are a few conspicuous signs of endothelial/leukocyte activation reflected in increased circulating levels of soluble adhesion molecules in schoolchildren who are positive for markers of preclinical type 1 diabetes. The correlation between sICAM-1 concentrations and IA-2A levels in the IA-2A-positive children suggests that the former may increase in late preclinical type 1 diabetes, as IA-2A are the last autoantibodies to appear in the prediabetic process. Increased sL-selectin concentrations in subjects with impaired beta-cell function may reflect an active destructive insulitis process.

Adolescent↗
PubMedDate not supplied

In vivo administration of the C16:0 fatty acid isoform of sulfatide increases pancreatic sulfatide and enhances glucose-stimulated insulin secretion in Zucker fatty (fa/fa) rats.

BACKGROUND: Sulfatide is present in the secretory granules of beta cells and has been shown, in vitro, to be involved in insulin processing and secretion. Of particular interest is one of the major sulfatide isoforms in the beta cells, the C16:0 fatty acid isoform, which has been shown to be involved in insulin crystal preservation in vitro. The aim of this study was to investigate the ability of C16:0 fatty acid isoform of sulfatide to affect insulin secretion and/or action and glycaemic control in the adipogenic 'prediabetic' Zucker rat. METHODS: The C16:0 sulfatide was administered to Zucker rats for 10 weeks, and fasting levels of plasma insulin and glucose were measured as well as levels after an intravenous (i.v.) glucose load. In addition, the sulfatide expression, examined by thin-layer chromatography-enzyme-linked immunosorbent assay and mass spectrometry, in the pancreas of C16:0 sulfatide-treated Zucker rats was compared to controls. RESULTS: The in vivo treatment of Zucker rats with C16:0 sulfatide resulted in significantly elevated glucose-stimulated insulin secretion (60-80% increase, p < 0.05), without significant changes in glucose tolerance. The treatment was associated with an ameliorated first-phase insulin response (3-4-fold, p = 0.009, 0.016) and a 60% increase of pancreatic sulfatide content (p = 0.001), possible by an uptake of C16:0 sulfatide. The fasting hyperinsulinaemia and blood glucose levels were unchanged. CONCLUSIONS: The treatment with C16:0 sulfatide elevates glucose-stimulated insulin secretion and enhances sulfatide content in the pancreas of Zucker rats.

Animals↗
PubMedDate not supplied

Programmed disorders of beta-cell development and function as one cause for type 2 diabetes? The GK rat paradigm.

Now that the reduction in beta-mass has been clearly established in humans with type 2 diabetes mellitus (T2DM) 1-4, the debate focuses on the possible mechanisms responsible for decreased beta-cell number and impaired beta-cell function and their multifactorial etiology. Appropriate inbred rodent models are essential tools for identification of genes and environmental factors that increase the risk of abnormal beta-cell function and of T2DM. The information available in the Goto-Kakizaki (GK) rat, one of the best characterized animal models of spontaneous T2DM, are reviewed in such a perspective. We propose that the defective beta-cell mass and function in the GK model reflect the complex interactions of three pathogenic players: (1) several independent loci containing genes causing impaired insulin secretion; (2) gestational metabolic impairment inducing a programming of endocrine pancreas (decreased beta-cell neogenesis) which is transmitted to the next generation; and (3) secondary (acquired) loss of beta-cell differentiation due to chronic exposure to hyperglycemia (glucotoxicity). An important message is that the 'heritable' determinants of T2DM are not simply dependant on genetic factors, but probably involve transgenerational epigenetic responses.

Adult↗
PubMedDate not supplied

Is insulin resistance caused by defects in insulin's target cells or by a stressed mind?

The importance of understanding insulin action is emphasized by the increasing prevalence of insulin resistance in various populations and by the fact that it plays an important pathophysiological role in many common disorders, for example, diabetes, obesity, hypertension and dyslipidemia. The primary factors responsible for the development of insulin resistance are so far unknown, although both genetic and environmental factors are involved. The genetic defects responsible for the common forms of insulin resistance, for example, in type 2 diabetes, are largely unidentified. Some studies from our group as well as by other investigators suggest that cellular insulin resistance is reversible and that it may be secondary to factors in the in vivo environment. These may include insulin-antagonistic action of hormones like catecholamines, glucocorticoids, sex steroids and adipokines as well as dysregulation of autonomic nervous activity and they could contribute to the early development of insulin resistance. Some of these factors can directly impair glucose uptake capacity and this might be due to alterations in key proteins involved in insulin's intracellular signaling pathways. This article briefly summarizes proposed mechanisms behind cellular and whole-body insulin resistance. In particular, we question the role of intrinsic defects in insulin's target cells as primary mechanisms in the development of insulin resistance in type 2 diabetes and we suggest that metabolic and neurohormonal factors instead are the main culprits.

Adipose Tissue↗
PubMed1994

Insulin-specific T cells are a predominant component of islet infiltrates in pre-diabetic NOD mice.

Numerous investigation have demonstrated that T cells are involved in destruction of beta cells in the NOD mouse, a widely studied model of type I diabetes. In this report we describe a series of islet-specific T cell lines established from islet-infiltrating lymphocytes obtained from individual pre-diabetic NOD mice as well as a large panel of clones derived from these lines. Proliferation assays indicated that these nominally islet-specific lines responded vigorously to porcine insulin. Furthermore, of 40 islet-specific clones derived from lines established from 12-week-old mice, 22 (55%) responded to insulin. A similar analysis of islet-specific clones established from 7-week-old mice indicated that 2 of 14 (14%) were insulin specific. These findings demonstrate that insulin-specific T cells can comprise a major portion of the spontaneously arising T cell response to islets in NOD mice.

Animals↗
PubMed2005

Evidence for an enhanced adhesion of DC to fibronectin and a role of CCL19 and CCL21 in the accumulation of DC around the pre-diabetic islets in NOD mice.

The non-obese diabetic (NOD) mouse is a widely used animal model for the study of human diabetes. The lymphocytic (peri-)insulitis is preceded by an early accumulation of dendritic cells (DC) around the islets of Langerhans. This DC accumulation is thought to derive from an influx of monocytes attracted by pro-inflammatory chemokines. Besides chemokines, extracellular matrix (ECM) proteins play an important role in the accumulation of leukocytes in tissues. We studied the expression of the chemokines CCL2, CCL5, CXCL10, CCL19 and CCL21 over time in pancreases of NOD and control mice by ELISA on pancreas lysates as well as by immunohistochemistry. In addition, we studied the adhesive capacity of bone marrow-derived DC (BMDC) to ECM components. DC in the NOD pancreas accumulated at sites with an intense expression of fibronectin. In vitro, NOD BMDC showed increased fibronectin adhesion and increased VLA-5 expression. At the time of early DC accumulation (<10 wk), the lymphoid tissue-related chemokines CCL19 and CCL21 were increased. Our findings support the view that the early accumulation of DC around the NOD islets is not the consequence of an enhanced attraction of precursors and immature DC by pro-inflammatory chemokines. It rather might be the consequence of an aberrantly enhanced adhesion and retention of NOD DC.

Animals↗
PubMed1995

Islet phosphoinositide hydrolysis and insulin secretory responses from prediabetic fa/fa ZDF rats.

The sequence of events that culminate in the development of diabetes in the fa/fa Zucker diabetic fatty (ZDF) rat is unclear. In the present series of experiments islets from 5 week old prediabetic fa/fa male rats were isolated and their phosphoinositide (PI) hydrolysis and insulin secretory responses compared to those obtained from lean nondiabetic age- and weight-matched control rats. Peak first and second phase insulin secretory responses to 20mM glucose averaged 77 +/- 10 (mean +/- SE, n = 7) and 491 +/- 47 pg/islet/min from lean, nondiabetic control islets. The comparable responses from fa/fa prediabetic rat islets were significantly greater, 264 +/- 51 and 810 +/- 78 pg/islet/min. In a parallel fashion 3H-inositol efflux and inositol phosphate responses from prediabetic rat islets were also greater than comparable control responses. These findings demonstrate that significant increases in the phospholipase C-mediated hydrolysis of islet PI pools and insulin release in response to hyperglycemic stimulation can be detected prior to the emergence of diabetes in the fa/fa ZDF rat. These early changes in beta cell responsiveness to glucose may contribute to the hyperinsulinemia and subsequent insulin resistance characteristic of this animal model of non-insulin dependent diabetes mellitus.

Animals↗
PubMed1999

Increased sensitivity of prediabetic nonobese diabetic mouse to the behavioral effects of IL-1.

The nonobese diabetic (NOD) mouse is a model of spontaneous insulin-dependent diabetes mellitus (IDDM) or type I diabetes. In humans, and in animal models of IDDM, the progression of the disease is modulated by various environmental factors, particularly infectious agents. Interleukin-1 (IL-1) plays a pivotal role in the development of IDDM, and modulation of its synthesis may be a mechanism by which environmental modulation of disease progression occurs. Since various alterations at the level of the gene, number, and sensitivity of IL-1 receptors have been described in different animal models of autoimmune disease, we investigated, in the prediabetic NOD mouse, the presence of IL-1 receptors and their functional behavioral characteristics. Here we present evidence that prediabetic NOD mice exhibit a normal distribution and density of functional brain IL-1 receptors, but are more sensitive to the behavioral effects of IL-1 than the control ICR strain.

Animals↗
PubMed2002

During the early prediabetic period in NOD mice, the pathogenic CD8(+) T-cell population comprises multiple antigenic specificities.

In the NOD mouse model of type 1 diabetes, major histocompatibilitycomplex (MHC) class I-restricted CD8(+) T cells are essential for disease development. However, the extent of diversity of their antigenic specificities during early pathogenesis remains unclear. An insulin-derived peptide was recently identified as the epitope for the NOD-derived diabetogenic T-cell clone G9C8. To explore the possibility that the early pathogenic CD8(+) T-cell population comprises additional antigenic specificities, we employed the T-cell clones AI4 and NY8.3, both of which are pathogenic and represent specificities present in early insulitic lesions. The clones responded to distinct fractions of chromatographically separated class I MHC-bound peptides purified from NOD-derived NIT-1 beta cells, and neither clone recognized the insulin-derived peptide. NIT-1 cells represent an unlimited peptide source that will allow for the future isolation and sequencing of the novel multiple epitopes targeted early in the autoimmune response by pathogenic CD8(+) T cells.

Animals↗
PubMed1994

Sera from patients with IDDM and healthy individuals have antibodies to ICA69 on western blots but do not immunoprecipitate liquid phase antigen.

ICA69 is a recently cloned pancreatic islet protein proposed as a potential target of autoimmunity in insulin dependent diabetes mellitus (IDDM). The aim of our study was to verify the relevance of ICA69 antibodies as markers of the disease. We measured antibodies to ICA69 in sera from newly-diagnosed IDDM patients, in age- and sex-matched normal controls, and in sera prior to the onset of IDDM (pre-IDDM). Human islet ICA69 was cloned and inserted into a bacterial expression vector and an in vitro transcription vector. Binding to affinity purified recombinant ICA69 on Western blots was found in 33/48 (68%) sera from newly-diagnosed IDDM patients and in 36/56 (64%) controls. No differences in band intensity were found between IDDM and controls. Using immunoprecipitation of 35S methionine labelled in vitro translated ICA69, none of 53 sera from newly diagnosed IDDM patients, 0 of 57 control sera and 1 of 24 pre-IDDM sera had detectable antibodies. We conclude that solid-phase assays are inappropriate for measurement of ICA69 antibodies as specific markers of IDDM and that antibodies to ICA69 are not detected by a liquid-phase immunoprecipitation assay. These data support neither a role for ICA69 as a relevant autoantigen in IDDM, nor a role for the measurement of antibodies to ICA69 in the prediction of IDDM.

Adolescent↗
PubMed1994

HLA-DQB1 genotypes and islet cell antibodies in the identification of siblings at risk for insulin-dependent diabetes (IDDM) in Finland. Childhood Diabetes in Finland (DiMe) Study Group.

The risk of progression to IDDM can be evaluated by diabetes-related autoantibodies such as cytoplasmic islet cell antibodies (ICA) or genetic determinants as markers. In this prospective study we wanted to estimate the predictive value of the combination of these markers in siblings of diabetic children. A sample of 770 siblings was observed from the time of diagnosis in the index case for a median period of 5.8 years (range 0.01-7.3 years) for development of ICA and insulin autoantibodies (IAA) and progression to clinical diabetes. The most important susceptibility and protection associated DQB1 alleles were defined by four sequence-specific oligonucleotide probes. DNA samples were available from 89 originally non-diabetic ICA positive siblings of whom 28 presented with IDDM during the study period, as well 100 randomly chosen ICA negative control siblings. More than half (11/28; 55%) of the siblings who had the high risk DQB1 genotypes progressed to clinical IDDM compared to 6/37 (16%) of those who had protective/neutral genotypes (P = 0.006). Of all genotyped secondary cases, 36% (n = 33) had a genotype associated with the highest risk (DQB1*0302/0201), whereas 27% had genotypes without any susceptibility alleles (P values < 0.0001 and = 0.0002, respectively, compared with ICA negative siblings). The results demonstrate the feasibility of the combination of genetic and immunological markers in the prediction of the risk for IDDM within families.

Adolescent↗
PubMed1995

Insulin-secretory-granule specific T cell clones in human IDDM.

T cell clones reactive to beta-cell antigens prepared from different species were established in order to identify putative pathogenic T cells in human IDDM. We were able to generate T cell clones from patients, but not from controls, reactive specifically to the insulin secretory enriched fraction (ISG) of a rat insulinoma RIN cell line. This finding is suggestive of an in vivo priming by the antigen(s). To examine the relevance of these T cell clones in the pathogenesis of IDDM, we studied their cytokine profile. T cell clones from the newly onset patients had a Th1 cytokine profile, while those from the prediabetic patient were of the Th2 subtype. This segregation suggests that RIN-ISG contains antigen(s) involved in the pathogenesis of this disease, since IDDM is considered a cell-mediated or Th1 disease. Since two of these clones also responded to a hamster insulinoma cell line HIT, at least two antigens in RIN-ISG could be defined by this panel of T cell clones. Examination of CDR3 sequences confirmed the clonality of the dual-reactive T cell clones. The finding of HIT-reactive cells in IDDM patients may be useful in efforts to identify prediabetic patients for immune intervention. Dual reactivity may provide a better prognosis than single reactivity. In contrast to T cell clones reactive to insulinomas, T cell clones reactive to normal human ISG were not found after over 200 clones were screened. In addition, RIN-ISG specific clones did not respond to either normal human or rat ISG, suggesting that IDDM antigens are below detectable levels in normal beta cells.

Amino Acid Sequence↗
PubMed1996

Cyclosporine delays but does not prevent clinical onset in glucose intolerant pre-type 1 diabetic children.

We conducted a pilot study of immunosuppression with low dose cyclosporine in first degree relatives of diabetic patients with immunologic and metabolic criteria for preclinical diabetes: islet cell antibodies (ICA) > or = 20 Juvenile Diabetes Foundation (JDF) units, first phase insulin response < 10th percentile and impaired glucose tolerance. Cyclosporine was given at an initial dose of 7.5 mg/kg*d and tapered after the end of the first year. Six cyclosporine-treated relatives were compared to nine historical controls followed at the same or at different centres. All untreated patients developed diabetes within 12 months (5.9 +/- 1.1 months). Four of the cyclosporine-treated subjects developed diabetes at 5, 24, 24 and 47 months while the other two are non diabetic 47 and 57 months after entry into the trial (time to diabetes > 34 +/- 8 months, P < 0.001 vs the control group; Mann-Whitney test). First phase insulin response increased to normal values in two patients. These results suggest that reversible functional impairment, in association with beta-cell destruction, contributes to the failure of insulin secretion in preclinical type 1 diabetes.

Adolescent↗
PubMed1997

Regulation of autoimmune diabetes by interleukin 3-dependent bone marrow-derived cells in NOD mice.

Interleukin-3 (IL-3), a multilineage colony stimulating factor, has been shown to augment alloreactive bone marrow-derived suppressor cell activity in vivo and in vitro. The present study examined the effect of IL-3 on autoimmune-mediated diabetes in NOD mice. Administration of IL-3 twice weekly starting at 2-4 weeks of age delayed the onset and reduced the overall incidence of diabetes. Bone marrow cells obtained from IL-3-treated NOD mice protected NOD mice from cyclophosphamide-induced diabetes but failed to prevent adoptively transferred diabetes. In vitro culture of bone marrow cells in medium containing IL-3 produced a Thy-1+CD3epsilonloCD4-CD8-CD25- immature T cell clone which prevented cyclophosphamide-induced diabetes. The cloned cells also effectively delayed the development of diabetes induced by transfer of T cells in adult thymectomized, irradiated, bone marrow-reconstituted NOD mice. These results suggest that IL-3 is capable of regulating extrathymic T cell development from the bone marrow and that these cells mediate strong immunoregulatory function.

Adoptive Transfer↗
PubMed1997

Identification of a novel type 1 diabetes-specific epitope by screening phage libraries with sera from pre-diabetic patients.

We used random peptide libraries displayed on phage to search for ligands to insulin dependent diabetes mellitus-related antibodies and were able to identify several candidate disease-related peptides. One of them, clone 92, showed a significant difference in the frequency of reactivity with the sera of patients and normal controls. Human immunoglobulins immunopurified on phage 92 specifically stained the islets on human pancreatic sections. When injected into rabbits, the selected peptide elicited antibodies that also stained human and rat pancreatic sections, with a pattern similar to that observed with immunoglobulins purified from the sera of patients. No reactivity was observed in other tissues. Our results indicate that the peptide identified in this work mimics a novel, diabetes-related self-antigen.

Animals↗