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• Combining a systemic immune modulator (anti CD-3e) with antigen-specific (proinsulin peptide) Treg induction is more efficacious in reverting type 1 diabetes (JCI [2006] doi: 10.1172/JCI27191) Safe induction of autoantigen-specific long-term tolerance is the "holy grail" for the treatment of autoimmune diseases. In animal models of type 1 diabetes, oral or i.n. immunization with islet antigens induces Tregs that are capable of bystander suppression. However, such interventions are only effective early in the prediabetic phase. Here, we demonstrate that a novel combination treatment with anti-CD3e-specific antibody and i.n. proinsulin peptide can reverse recent-onset diabetes in 2 murine diabetes models with much higher efficacy than with monotherapy with anti-CD3 or antigen alone. In vivo, expansion of CD25⁺Foxp3⁺ and insulin-specific Tregs producing IL-10, TGF-a, and IL-4 was strongly enhanced. These cells could transfer dominant tolerance to immunocompetent recent-onset diabetic recipients and suppressed heterologous autoaggressive CD8 responses. Thus, combining a systemic immune modulator with antigen-specific Treg induction is more efficacious in reverting diabetes. Since Tregs act site-specifically, this strategy should also be expected to reduce the potential for systemic side effects.

DCCT intensively treated with insulin (ITT) fails significance in primary (time-to-initial-event) analysis of Cardiovascular Disease (CVD) in 11 year EDIC Follow-Up. (In a secondary analysis an ITT population intensively treated with insulin over about one-third the total observation period had fewer cardiovascular events than a conventionally treated ITT population) (NEJM[2005]353:2643-2653) Background Intensive diabetes therapy aimed at achieving near normoglycemia reduces the risk of microvascular and neurologic complications of type 1 diabetes. We studied whether the use of intensive therapy as compared with conventional therapy during the Diabetes Control and Complications Trial (DCCT) affected the long-term incidence of cardiovascular disease. Methods The DCCT randomly assigned 1441 patients with type 1 diabetes to intensive or conventional therapy, treating them for a mean of 6.5 years between 1983 and 1993. Ninety-three percent were subsequently followed until February 1, 2005, during the observational Epidemiology of Diabetes Interventions and Complications study. Cardiovascular disease (defined as nonfatal myocardial infarction, stroke, death from cardiovascular disease, confirmed angina, or the need for coronary-artery revascularization) was assessed with standardized measures and classified by an independent committee. Results During the mean 17 years of follow-up, 46 cardiovascular disease events occurred in 31 patients who had received intensive treatment in the DCCT, as compared with 98 events in 52 patients who had received conventional treatment. Intensive treatment reduced the risk of any cardiovascular disease event by 42 percent (95 percent confidence interval, 9 to 63 percent; P=0.02) and the risk of nonfatal myocardial infarction, stroke, or death from cardiovascular disease by 57 percent (95 percent confidence interval, 12 to 79 percent; P=0.02). The decrease in glycosylated hemoglobin values during the DCCT was significantly associated with most of the positive effects of intensive treatment on the risk of cardiovascular disease. Microalbuminuria and albuminuria were associated with a significant increase in the risk of cardiovascular disease, but differences between treatment groups remained significant (P<0.05) after adjusting for these factors. Conclusions Intensive diabetes therapy has long-term beneficial effects on the risk of cardiovascular disease in patients with type 1 diabetes.

• Insulin + N-alpha-Deoxycholyl-l-lysyl-methylester (Insulin/DCK) Formulation Can be Absorbed in the Intestine and is Biologically Efficacious (Diabetologia [2005]48:405-411) Aims/hypothesis  The development of an orally active insulin formulation will offer great advantages over conventional injectable insulin therapy in the treatment of patients with diabetes mellitus. Since insulin absorption in the intestine is restricted by the natural physiological characteristics of insulin, we developed a small synthetic compound, N-alpha-deoxycholyl-l-lysyl-methylester (DCK), as an insulin carrier to enhance oral delivery. Methods   Streptozotocin-induced diabetic rats orally received single doses of insulin (42 U/kg) or insulin/DCK formulation (10, 21, 30 and 42 U/kg) under fasting conditions. Blood glucose levels and plasma insulin concentrations were measured for 6 h following the administration of the agents. An OGTT was also performed immediately after the administration of the oral insulin/DCK formulation. Results  The administration of 21, 30 and 42 U/kg (based on insulin activity) of insulin/DCK formulation reduced plasma glucose levels by up to 33.0% (median; range 30.6–70.2%), 78.5% (39.4–86.8%) and 75.2% (67.0–87.4%), respectively, compared with baseline levels. Furthermore, plasma insulin concentrations were observed to rapidly increase. In the OGTT, the insulin/DCK formulation reduced the AUC_0–240 for glucose by 30.8% (22.3–54.9%) (p<0.01), and stabilized glycaemia for up to 4 h. Conclusions/interpretation  The results of this study demonstrate that the insulin/DCK formulation can be absorbed in the intestine and that it is biologically efficacious. We therefore suggest that this oral formulation could be used as an alternative to injectable insulin with enhanced clinical effects

The relative risk of type 2 in heavy smokers was 1.53, 95% CI: 1.14–2.05, while current smokers had relative risks of 0.17, 95% CI: 0.04–0.78 for type 1 diabetes (Diabetologia [2005] 47:1953-1956) Aims/hypothesis  We compared the association between smoking habits and later occurrence of type 2 diabetes on the one hand and between smoking and diabetes with autoimmunity on the other hand.Methods  We used data from a prospective study of 11-year cumulative incidence of diabetes in the Nord-Trøndelag Health Survey.Results  Confirming previous reports, heavy smoking (20 cigarettes per day) carried an increased relative risk (RR) of type 2 diabetes (n=738, RR=1.64, 95% CI: 1.12–2.39). In contrast, smoking reduced the risk of latent autoimmune diabetes in adults (LADA) and of traditional type 1 diabetes (LADA n= 81, RR=0.25, 95% CI: 0.11–0.60; type 1 diabetes, n=18, RR=0.17, 95% CI: 0.04–0.73).Conclusions/interpretations  The results indicate that nicotine influences autoimmune processes in human diabetes.

• Intranasal insulin may protect against type 1 diabetes (Diabetes Care[2004]27:2348-2355) OBJECTIVE—Mucosal administration of insulin retards development of autoimmune diabetes in the nonobese diabetic mouse model. We conducted a double-blind crossover study in humans at risk for type 1 diabetes to determine if intranasal insulin was safe, in particular did not accelerate ß-cell destruction, and could induce immune effects consistent with mucosal tolerance. RESEARCH DESIGN AND METHODS—A total of 38 individuals, median age 10.8 years, with antibodies to one or more pancreatic islet antigens (insulin, GAD65, or tyrosine phosphatase-like insulinoma antigen 2) were randomized to treatment with intranasal insulin (1.6 mg) or a carrier solution, daily for 10 days and then 2 days a week for 6 months, before crossover. The primary outcome was ß-cell function measured as first-phase insulin response (FPIR) to intravenous glucose at 0, 6, and 12 months and then yearly; the secondary outcome was immunity to islet antigens, measured monthly for 12 months. RESULTS—No local or systemic adverse effects were observed. Diabetes developed in 12 participants with negligible ß-cell function at entry after a median of 1.1 year. Of the remaining 26, the majority had antibodies to two or three islet antigens and FPIR greater than the first percentile at entry, as well as ß-cell function that generally remained stable over a median follow-up of 3.0 years. Intranasal insulin was associated with an increase in antibody and a decrease in T-cell responses to insulin. CONCLUSIONS—Results from this pilot study suggest that intranasal insulin does not accelerate loss of ß-cell function in individuals at risk for type 1 diabetes and induces immune changes consistent with mucosal tolerance to insulin. These findings justify a formal trial to determine if intranasal insulin is immunotherapeutic and retards progression to clinical diabetes. Abbreviations: Ab, antibody • DPT-1, Diabetes Prevention Trial–Type 1 • FPIR, first-phase insulin response • IA2, tyrosine phosphatase-like insulinoma antigen 2 • I/P, period 1 = I (insulin) and period 2 = P (placebo) • IQR, interquartile range • KLH, keyhole limpet hemocyanin • P/I, period 1 = P (placebo) and period 2 = I (insulin) • Th, T-helper

Doubts Surfacing about Edmonton Islet Transplantation Protocol (Science, [2004] 306:34-37)

• Islets Regenerate During Reversal of Type 1 Diabetes in NOD Mouse Model

DiaPep277 May Work Orally to Assist
Conversion of Helper to Suppressor Th2 Cells
in Models of Type 1 Diabetes

• A modified PDX-1 can differentiate human and tadpole hepatocytes into pancreatic exocrine and endocrine cells. (Current Biology [2003] 13: R96-R98) Making endocrine pancreas cells at will is one of the major goals of cellular based therapies for diabetes. The experimentally induced conversion of hepatocytes into pancreatic cells, using a modified version of the transcription factor PDX-1, may provide an alternative to stem cell approaches. Researchers have used an approach called transdifferentiation, which involves converting one type of cell to another (in this case, liver cells to pancreatic cells). "Other people have tried to convert cells with gene therapy, but a lot of times one single protein isn't enough. You need a combination of different factors," explains Marko Horb, lead author of the study and a postdoctoral research officer. Horb and his colleagues at the Centre for Regenerative Medicine at the University of Bath in England have engineered a modified version of a gene called PDX-1, which is necessary for fashioning the pancreas out of undifferentiated embryonic or stem cells. The idea was to introduce the modified PDX-1 into liver cells to see if they would produce pancreatic cells. When the PDX-1 gene was added to human liver cells in the laboratory, the cells acquired characteristics of pancreas cells and some even produced insulin. When added to tadpole liver cells, again, the PDX-1 seemed to produce all of the cell types usually found in a pancreas. This is somewhat different from stem cell research in that the tadpole cells were in the process of differentiating into pancreatic cells, though the cells were far from mature. The functionality of the what appeared to be constitutive insulin-producing cells was not evaluated.

• Islet Neogenesis Associated Protein (INGAP) Peptide Now in Human Clinical Trials for Type 1 DM (Intellihealth, [2002] Jan 14) By Associated Press, 1/15/2002 NORFOLK, Va. - A substance that has cured diabetes in some laboratory animals is now being tested on people. The INGAP, or Islets Neogenesis Associated Protein, peptide encourages the growth of insulin-producing cells in the pancreas. The body needs insulin to process sugar, and diabetes results from the inability to make or use insulin. While the ultimate goal is to cure diabetes, INGAP has the potential to at least help diabetics manage their illness better, said Dr. Aaron I. Vinik, director of research at the Strelitz Diabetes Institutes at Eastern Virginia Medical School. ''It can change people's lives a huge amount if they don't have to take insulin anymore ... if they don't have to stick themselves seven to 10 times a day'' to test their blood-sugar level, Vinik said. The peptide derives from discoveries made by Vinik, professor of medicine, pathology and neurobiology at EVMS, and Dr. Lawrence Rosenberg, professor of surgery and medicine at McGill University in Montreal. Vinik and Rosenberg found that injecting INGAP in certain species of diabetic animals increased insulin levels and lowered glucose levels. Some animals were cured 39 days after they began the therapy and had normal blood-sugar levels even after stopping treatment for eight days, Vinik said. An estimated 16 million Americans, and 130 million people worldwide, have diabetes. The disease requires patients to prick their fingers to check blood-sugar levels several times a day and inject themselves with insulin or wear an abdominal insulin pump. It can cause nerve damage, blindness and kidney and heart failure. INGAP is a gene that encodes proteins that have the potential to produce cells capable of making the hormones necessary for keeping people's blood-sugar levels normal, Vinik said. INGAP gets directly at the ''biological ineptitude'' of the pancreas while other drugs treat the symptoms and complications of diabetes, he said. Vinik and Rosenberg identified the smaller, active portion of the INGAP protein, which was isolated and termed the INGAP Peptide. It can be synthesized in a test tube, Vinik said. In July, the researchers applied to the US Food and Drug Administration for permission to test the peptide on people. Approval was granted in September. The study will assess the safety and tolerability of injections of various daily dosages of INGAP Peptide in 62 people. Participants must be insulin-dependent diabetics between 18 and 65 who are relatively healthy. Three people began the injections in early December. More patients are needed for the trial being conducting by diabetes specialists at three study sites - the Texas Diabetes Institute at the University of Texas at San Antonio; the Diabetes Care Center at the University of North Carolina at Chapel Hill; and the MedStar Research Institute in Washington. The trial should be finished by summer, Vinik said. If INGAP proves safe and tolerable, additional clinical studies involving more people would be needed to study its effectiveness. The drug could be on the market within 10 years, said Scott Mohrland, vice president of the therapeutics division of GMP Companies Inc., a medical technology company in Fort Lauderdale, Fla., that has a licensing and funding agreement with EVMS.

• Treatment of newly diagnosed type 1 diabetes with DiaPep277 seems to preserve endogenous insulin production (Lancet [2001] 358: 1749) Background Type 1 diabetes results from autoimmune destruction of insulin-producing pancreatic ß cells. The 60 kDa heat-shock protein (hsp60) is one of the known target self antigens. An immunomodulatory peptide from hsp60, p277, arrested ß-cell destruction and maintained insulin production in newly diabetic NOD mice. We did a randomised, double-blind, phase II study of peptide treatment in patients with newly diagnosed (<6 months) type 1 diabetes. Methods 35 patients with type 1 diabetes and basal C-peptide concentrations above 0·1 nmol/L were assigned subcutaneous injections of 1 mg p277 and 40 mg mannitol in vegetable oil (DiaPep277; n=18) at entry, 1 month, and 6 months, or three placebo injections (mannitol in vehicle; placebo; n=17). The primary endpoint was glucagon-stimulated C-peptide production. Secondary endpoints were metabolic control and T-cell autoimmunity to hsp60 and to p277 (assayed by cytokine secretion). 31 patients completed 10 months of follow-up and were included in the intention-to-treat analysis. Findings At 10 months, mean C-peptide concentrations had fallen in the placebo group (n=16) but were maintained in the DiaPep277 group (n=15; 0·26 [SD 0·11] vs 0·93 [0·35] nmol/L; p=0·039). Need for exogenous insulin was higher in the placebo than in the DiaPep277 group (0·67 [0·33] vs 0·43 [0·17] U/kg; p=0·042). Haemoglobin A1c concentrations were low (around 7%) in both groups. T-cell reactivity to hsp60 and p277 in the DiaPep277 group showed an enhanced T-helper-2 cytokine phenotype. No adverse effects were noted. Interpretation Although this study was small, treatment of newly diagnosed type 1 diabetes with DiaPep277 seems to preserve endogenous insulin production, perhaps through induction of a shift from T-helper-1 to T-helper-2 cytokines produced by the autoimmune T cells.

• Plasmid Vaccination with Insulin B Chain Prevents Autoimmune Diabetes in Nonobese Diabetic Mice. This effect is dependent upon IL-4 (The Journal of Immunology, [2001] 167: 2950-2955.)
  The insulin B (InsB) chain bears major type 1 diabetes-associated epitopes of significance for disease in humans and nonobese diabetic (NOD) mice. Somatic expression of InsB chain initiated early in life by plasmid inoculation resulted in substantial protection of female NOD mice against disease. This was associated with a T2 shift in spleen, expansion of IL-4-producing and, to a lesser extent, of IFN-gamma -secreting T cells in pancreatic lymph nodes, as well as intermolecular Th2 epitope spreading to glutamic acid decarboxylase determinants. A critical role of IL-4 for the Ag-specific protective effect triggered by plasmid administration was revealed in female IL-4^-/- NOD mice that developed diabetes and higher Th1 responses. Coadministration of IL-4-expressing plasmid or extension of the vaccination schedule corrected the unfavorable response of male NOD mice to DNA vaccination with InsB chain. Thus, plasmid-mediated expression of the InsB chain early in diabetes-prone mice has the potential to prevent transition to full-blown disease depending on the presence of IL-4.

• The natural killer T-cell ligand alpha-galactosylceramide prevents autoimmune diabetes in non-obese diabetic mice (Nature Medicine [2001] 7:1052-1056) Diabetes in non-obese diabetic (NOD) mice is mediated by pathogenic T-helper type 1 (Th1) cells that arise because of a deficiency in regulatory or suppressor T cells1, 2. V14–J15 natural killer T (NKT) cells recognize lipid antigens presented by the major histocompatibility complex class I-like protein CD1d (refs. 3,4). We have previously shown that in vivo activation of V14 NKT cells by -galactosylceramide (-GalCer) and CD1d potentiates Th2-mediated adaptive immune responses5, 6. Here we show that -GalCer prevents development of diabetes in wild-type but not CD1d-deficient NOD mice. Disease prevention correlated with the ability of -GalCer to suppress interferon- but not interleukin-4 production by NKT cells, to increase serum immunoglobulin E levels, and to promote the generation of islet autoantigen-specific Th2 cells. Because -GalCer recognition by NKT cells is conserved among mice and humans7, 8, these findings indicate that -GalCer might be useful for therapeutic intervention in human diseases characterized by Th1-mediated pathology such as Type 1 diabetes.

• ß-cell-directed autoimmunity can be reversed (J Clin Invest [2001] 108:63-72)

• Vigorous control of lipid levels and blood pressure is necessary in patients with type 1 diabetes (Diabetes [2001] 24:1053-1059)

• DNA vaccination is an effective strategy to prevent IDDM - IL-4 was also required for disease prevention (The Journal of Immunology[2001] 166: 2122-2132)

• Glucose-dependent insulin release achieved in non-beta cells (Science [2000] 290:1959-1962)

• Still More Participants Needed for Natiowide Study to Prevent Type 1 Diabetes(call 1-800-425-8361)

• Plasma ICA, GADAb, and PBMC reactivity to human fetal pancreatic proteins in transplant recipients is most consistent with reactivation of type 1 disease" (Transplantation [2000] 69(1):166-72)

• Once-Daily Glargine Insulin Approved for Injection (Lantus-tm) (24 April 2000, FDA Label)

• Initial reversal of insulin-dependent diabetes seen using islets generated in vitro from pancreatic stem cells (Nature Medicine [March 2000 Volume] 6 (Number 3): pp 278 - 282)

• FDA approves Animas Insulin Pump

• Long-Acting GLP-I agonist Exendin-4 Stimulates Both -Cell Replication and Neogenesis, Resulting in Increased beta-Cell Mass and Improved Glucose Tolerance in Diabetic Rats
  
• Glucagon-Like Peptide 1 and Exendin-4 Convert Pancreatic AR42J Cells Into Glucagon- and Insulin-Producing Cells
  

• New Sweetener (d-tagatose) Also Blunts Post-Prandial Hyperglycemia in UMd Study

• Orally administered amidated pectin insulin (PI) hydrogel beads sustain plasma concentrations of insulin in streptozotocin (STZ)- diabetic rats

  C T Musabayane¹, O Munjeri², P Bwititi¹ and E E Osim¹

  ¹Department of Physiology, University of Zimbabwe, P O Box MP167, Mount Pleasant, Harare, Zimbabwe
  ²Department of Pharmacy, University of Zimbabwe, P O Box MP167, Mount Pleasant, Harare, Zimbabwe
   
  (Requests for offprints should be addressed to C T Musabayane)

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  Abstract

  We report successful oral administration of insulin entrapped in amidated pectin hydrogel beads (PI) in STZ-diabetic rats with a concomitant reduction in plasma glucose concentration. PI hydrogel beads were prepared by the gelation of humilin-(Isophane Human Insulin, Lilly, France SA) pectin solutions in the presence of calcium. Separate groups of STZ-diabetic rats were orally administered two PI beads (30 mg insulin) once or twice daily or three beads (46 mg) once daily for two weeks. Control non-diabetic and STZ-diabetic rats were orally administered pectin-hydrogel drug free beads. By comparison to control non-diabetic rats, untreated STZ-diabetic rats exhibited significantly low serum insulin concentration (0.32±0.03 ng.ml^-1, n=6 vs 2.60±0.44 ng.ml^-1, n=6) and elevated plasma glucose concentrations (25.84±1.44 mmol.L^-1 vs 10.72±0.52 mmol.L^{- 1}). Administration of two hydrogel beads twice daily (60 mg, active insulin) or three beads (46 mg) once a day to STZ-diabetic rats increased serum insulin levels (0.89±0.09 ng.ml^-1 and 1.85±0.26 ng.ml^-1, respectively) with a concomitant reduction in plasma glucose concentration (15.45±1.63 mmol.L^-1 and 10.56±0.26 mmol.L^-1, respectively). However, a single dose of PI beads (30 mg) did not affect serum insulin concentrations although plasma glucose levels (17.82±2.98 mmol.L^-1) were significantly reduced when compared with untreated STZ-diabetic rats. Pharmacokinetic parameters in STZ-diabetic rats show that orally administered insulin-loaded amidated pectin beads (30 mg) were more effective in sustaining serum insulin concentrations by comparison with sc insulin (30 mg). The data from this study suggest that this insulin loaded amidated pectin hydrogel bead formulation not only produces sustained release of insulin, but may also reduce plasma glucose concentration in diabetes mellitus.

  Journal of Endocrinology

• Insulin Gene Successfully Transfected into Diabetic Rats (!)

• IGF-1 Appears to Improve Control in Adolescent Diabetics Without Affecting Leptin Levels

• Insulinomimetic [L-783,281] found in Pseudomassaria fungi growing deep in the African rain forests near Kinsasha by investigators from Merck Research Laboratories can be given orally (but necessary clinical trials mean marketing is at least 3-4 years away)

• Ultralong-Acting Insulin (Glargine®) Safer and as Effective as NPH in Type 1 Diabetics

• Joslin Study Affirms Importance of the Parent-Teen Relationship in Affecting Outcomes

• The Basal-Bolus (Ultralente-Regular) Regimen of Insulin Administration is highly effective with carbohydrate counting in Type 1 Diabetes (according to Canadian investigators)

Monitoring

• Noninvasive monitoring now feasible also using ultrasound technology"(Nature Medicine [March 2000] Volume 6 Number 3 pp 347-350)

• Data suggest that persons with type 1 diabetes may not judge correctly when their BG level is too low to permit safe driving and may consider driving with a low BG level even when they are aware of the low level. Health care professionals should counsel their patients about the risk of driving with hypoglycemia and the importance of measuring BG level before driving. JAMA. 1999;282:750-754

• Watch-Like Device - Approved 9 May 2000 (!) - Will Check Blood Sugars Painlessly
  • No Needle Prick Needed for Experimental Home Diabetes Monitoring Check
  • 
    The device goes before an FDA Advisory Committee meeting on December 6th 1999. If approved the device could be on the market as early as April, 2000.
    
• FDA approves an implantable glucose electrode - the first link to closing the loop in the development of an artificial pancreas (an algorithm has been developed by University of Delaware Dr. Francis J. Doyle III and student Robert S. Parker who told reporters on 8 June 1999 that the model is designed to be a "computationally efficient algorithm" which could be stored on a computer chip and used in an implantable insulin pump. They added, "...we can get more aggressive control than even a healthy pancreas does." )
  
  
  
  
  
  
  

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Pathogenesis

• TNF-alpha plays an important role in the initiation of T1D in the NOD mouse by regulating the activation of islet-specific pancreatic lymph node T cells (Proc. Natl. Acad. Sci. USA, [2005] 10.1073/pnas.0508122102) TNF-alpha has been linked to the development of type 1 diabetes (T1D). We previously reported that neonatal treatment of nonobese diabetic (NOD) mice with TNF-alphaaccelerated the onset of T1D, whereas TNF-alpha blockade in the same time period resulted in a complete absence of diabetes. The mechanisms by which TNF-alpha modulates development of T1D in NOD mice remain unclear. Here we tested the effects of TNF-alpha on the maturation of dendritic cells (DCs) in the NOD mouse. We found that neonatal treatment with TNF-alpha caused an increase in expression of maturation markers on CD11c⁺CD11b⁺ DC subpopulations, whereas treatment with anti-TNF-alpha resulted in a decrease in expression of maturation markers in the CD11c⁺CD11b⁺ subset. Moreover, neonatal treatment with TNF-alpha resulted in skewed development of a CD8alpha⁺CD11b^-CD11c⁺ DC subset such that TNF-alpha decreases the CD8alpha⁺CD11c⁺ DC subset, increases the CD11c⁺CD11b⁺ subset, and causes an increase in the expression of CD40 and CD54 on mature DCs capable of inducing immunity. Anti-TNF-alpha-treated mice had an increase in the CD8alpha⁺CD11c⁺ DCs. Notably, adoptively transferred naïve CD4⁺ T cells from BDC2.5 T cell receptor transgenic mice proliferated in the pancreatic lymph nodes in TNF-alpha-treated NOD mice but not in anti-TNF-alpha-treated mice. Finally, we show that anti-TNF-alpha-treated mice showed immunological tolerance to islet cell proteins. We conclude that TNF-alpha plays an important role in the initiation of T1D in the NOD mouse by regulating the maturation of DCs and, thus, the activation of islet-specific pancreatic lymph node T cells.

• Zonulin-induced loss in small intestinal barrier function is involved in the pathogenesis of type 1 diabetes in the BB diabetic-prone animal model (PNAS [2005]102:2916-2921) Increased intestinal permeability has been observed in numerous human autoimmune diseases, including type-1 diabetes (T1D) and its' animal model, the BB-wor diabetic prone rat. We have recently described zonulin, a protein that regulates intercellular tight junctions. The objective of this study was to establish whether zonulin-dependent increased intestinal permeability plays a role in the pathogenesis of T1D. In the BB diabetic-prone rat model of T1D, intestinal intraluminal zonulin levels were elevated 35-fold compared to control BB diabetic-resistant rats. Zonulin up-regulation was coincident with decreased small intestinal transepithelial electrical resistance, and was followed by the production of autoantibodies against pancreatic beta cells, which preceded the onset of clinically evident T1D by ~25 days. In those diabetic prone rats that did not progress to diabetes, both intraluminal zonulin and transepithelial electrical resistance were similar to those detected in diabetic-resistant animal controls. Blockade of the zonulin receptor reduced the cumulative incidence of T1D by 70%, despite the persistence of intraluminal zonulin up-regulation. Moreover, treatment responders did not seroconvert to islet cell antibodies. Combined together, these findings suggest that the zonulin-induced loss in small intestinal barrier function is involved in the pathogenesis of T1D in the BB diabetic-prone animal model.

• IgG4-subclass of glutamic acid decarboxylase antibody is more frequent in latent autoimmune diabetes in adults than in type 1 diabetes (Diabetologia [2005] 47:1984-1989) Aims/hypothesis  Glutamic acid decarboxylase autoantibodies (GADA) are the most frequent beta-cell-specific autoantibodies in type 1 diabetes and in latent autoimmune diabetes in adults (LADA). The autoimmune attack on pancreatic islet cells is associated with a T helper 1 cell (T_h1) response, mainly represented by IgG₁-subclass in humans. It has been proposed that the presence of IgG₄ may be associated with a T_h2 response. The aim of our study was to compare the GADA IgG-subclass distribution between adult patients with type 1 diabetes and LADA. Methods  Patients with type 1 diabetes (n=45) and patients with LADA (n=60) were included. Radioimmunoprecipitation assay with IgG-subclass specific Sepharose (IgG₁, IgG₂, IgG₃ and IgG₄) was used to precipitate the antibody/antigen-complex. Results  We only detected IgG₄-subclass of GADA in subjects with LADA (26.7%; p<0.001). IgG₁ was the most common GADA-subclass in both groups, however IgG₁ as the solely expressed subclass was more common among type 1 diabetic patients (77.8%; p<0.05). The rank order of the frequencies of IgG-subclasses in type 1 diabetes was IgG₁>IgG₃>IgG₂>IgG₄ and in LADA patients IgG₁>IgG₄>IgG₂>IgG₃. Conclusions/interpretation  The difference in GADA IgG-subclasses could indicate a different immune response, possibly an altered balance between T_h1 and T_h2 cytokine profile in pancreatic islets. This difference could contribute to the slower rate of beta cell destruction in LADA patients, as reflected by a higher C-peptide level at clinical onset.

• Beta cell MHC class I is a late requirement for diabetes (PNAS [2003] 10.1073) Type 1 diabetes occurs as a result of an autoimmune attack on the insulin-producing beta cells. Although CD8 T cells have been implicated both early and late in this process, the requirement for direct interaction between these cells and MHC class I on the beta cells has not been demonstrated. By using nonobese diabetic mice lacking beta cell class I expression, we show that both initiation and progression of insulitis proceeds unperturbed. However, without beta cell class I expression, the vast majority of these mice do not develop hyperglycemia. These findings demonstrate that a direct interaction between CD8 T cells and beta cells is not required for initiation or early disease progression. The requirement for class I on beta cells is a relatively late checkpoint in the development of diabetes.

• GAD65-reactive T cells are activated in patients with autoimmune type 1a diabetes (J Clin Invest [2002] 109:895-903) Insulin-dependent type 1 diabetes is an autoimmune disease mediated by T lymphocytes recognizing pancreatic islet cell antigens. Glutamic acid decarboxylase 65 (GAD65) appears to be an important autoantigen in the disease. However, T cells from both patients with type 1 diabetes and healthy subjects vigorously proliferate in response to GAD65 stimulation ex vivo, leading us to postulate that the critical event in the onset of human diabetes is the activation of autoreactive T cells. Thus, we investigated whether GAD65-reactive T cells in patients with diabetes functioned as previously activated memory T cells, no longer requiring a second, costimulatory signal for clonal expansion. We found that in patients with new-onset type 1 diabetes, GAD65-reactive T cells were strikingly less dependent on CD28 and B7-1 costimulation to enter into cell cycle and proliferate than were equivalent cells derived from healthy controls. We hypothesize that these autoreactive T cells have been activated in vivo and have differentiated into memory cells, suggesting a pathogenic role in type 1 diabetes. In addition, we observed different effects with selective blockade of either B7-1 or B7-2 molecules; B7-1 appears to deliver a negative signal by engaging CTLA-4, while B7-2 engagement of CD28 upregulates T cell proliferation and cytokine secretion

• B chain peptide 15-23 bound to K^d shows excellent T cell stimulation and the induction of CD8 cytotoxic T cells. (Proc. Natl. Acad. Sci. USA [2002] 99:5551-5556) The recognition of MHC-peptide complexes by T cells is governed by structural considerations that are determined by the sequences of the individual components and their interaction with each other. We have studied the function of a highly diabetogenic CD8 T cell clone that is specific for insulin B15-23:H-2K^d. We have then related this to modeled MHC-peptide structures. The native peptide binds poorly to H-2K^d, because of the small glycine residue at peptide position p9 that is incapable of productive interactions with the hydrophobic residues of pocket F. In addition, electrostatic repulsions between the peptide glutamate residue at position 7 and 152D of the MHC molecule heavy chain contribute to the poor binding. However, B chain peptide 15-23 bound to K^d shows excellent T cell stimulation and the induction of CD8 cytotoxic T cells. Peptide substitution has also shown that p6G is likely to be a T cell antigen receptor interaction site. Our studies have shown that the predictions seen in the models correlate closely with the observed effects in functional assays and provide insight into how this peptide, which would not be predicted to stimulate these cells on H-2K^d binding studies alone, could activate such highly pathogenic T cells.

• Viral RNA "Mimic" (Poly IC) and Insulin Self-Peptide (B9-23) Induce and Accelerate Type 1 Diabetes in Mouse Model (Proc. Natl. Acad. Sci. USA [2002] 99:5539-5544) Polyinosinic-polycytidylic acid (PolyIC), a "mimic" of double-stranded viral RNA, can induce diabetes when administered to rats with RT1^u, and immunization of normal H-2^d mice (e.g., BALB/c) with insulin B:9-23 peptide (but not H-2^b) results in the rapid induction of insulin autoantibodies. Because a mouse model of PolyIC/antigen-induced diabetes is lacking, we sought to produce insulitis and diabetes with either PolyIC and/or B:9-23 peptide immunization. Simultaneous administration of PolyIC and B:9-23 peptide to BALB/c mice (but with neither alone) induced insulitis. CD4 T lymphocytes predominated within islets, and the mice did not progress to hyperglycemia. Islets with transgene-induced expression of the costimulatory B7-1 molecule have enhanced diabetes susceptibility. Diabetes was frequently induced in B7-1 transgenic mice with H-2^d in contrast to H-2^b mice after PolyIC administration. Disease induction was accelerated by adding B:9-23 immunization to PolyIC. These studies demonstrate that "normal" mice have autoreactive T lymphocytes able to rapidly target islets and insulin given appropriate MHC alleles and that a peripherally administered insulin peptide (an altered peptide ligand of which is in clinical trials) can enhance specific anti-islet autoimmunity. These first PolyIC/insulin-induced murine models should provide an important tool to study the pathogenesis of type 1 diabetes with experimental autoimmune diabetes.

• _ß2-microglobulin is a type 1 susceptibility gene (Proc. Natl. Acad. Sci. USA, [2001] 98: 11533-11538) Type 1 diabetes in both humans and nonobese diabetic (NOD) mice results from T-cell-mediated autoimmune destruction of insulin-producing pancreatic ß cells. Linkage studies have shown that type 1 diabetes in NOD mice is a polygenic disease involving more than 15 chromosomal susceptibility regions. Despite extensive investigation, the identification of individual susceptibility genes either within or outside the major histocompatibility complex region has proven problematic because of the limitations of linkage analysis. In this paper, we provide evidence implicating a single diabetes susceptibility gene, which lies outside the major histocompatibility complex region. Using allelic reconstitution by transgenic rescue, we show that NOD mice expressing the _ß2 microglobulin (_ß2M)^a allele develop diabetes, whereas NOD mice expressing a murine _ß2M^b or human allele are protected. The murine _ß2M^a allele differs from the ß₂M^b allele only at a single amino acid. Mechanistic studies indicate that the absence of the NOD _ß2M^a isoform on nonhematopoietic cells inhibits the development or activation of diabetogenic T cells.

• Excess diabetic mortality, evident in all age groups, is most pronounced in young people with type1 (BMJ [2001] 322:1389-1393)

• IL-12 locally produced by islet-infiltrating cells plays a critical role in the development of type 1 diabetes (J Autoimmunity [2001]16:97-104)

• hCMV may be involved in the loss of T cell tolerance to autoantigen GAD65 by a mechanism of molecular mimicry leading to autoimmunity.Proc. Natl. Acad. Sci. USA, [2001] 98, Issue 7, 3988-3991

• pDNA vaccination is an effective strategy to prevent IDDM. - IL-4 was also required for disease prevention (The Journal of Immunology[2001] 166: 2122-2132)

• The MHC class II molecule of the non-obese diabetic (NOD) mice, I-Ag7, is associated with susceptibility to autoimmune diabetes. I-Ag7 molecules manifested normal intracellular trafficking and lifespan, and a small but clearly detectable fraction of I-Ag7 in the cells formed SDS- resistant compact dimers. The binding of an antigenic reference peptide to I-Ag7 was stable and was accompanied by compact dimer formation. Analysis of the binding specificity of I-Ag7 revealed a peptide binding motif of nine amino acids with a degenerate position at P1 and three conserved anchor positions: P4, P6 and P9. An allele-specific preference for negatively charged residues was found at P9, apparently due to the presence of the rare Ser residue at position 57 of the I-Ag7 beta chain. (International Immunology [1997] 9:43-51)

• Some patients with idiopathic type 1 diabetes have a nonautoimmune, fulminant disorder characterized by the absence of insulitis and of diabetes-related antibodies, a remarkably abrupt onset, and high serum pancreatic enzyme concentrations. (N Engl J Med 2000;342:301-7.)

• Blocking interaction between CD44, hyaluronic acid prevents type 1 diabetes in NOD mice

• Coronary Disease in Type 1's Correlates with Depression, NOT Glucose. Lower Extremity Arterial Disease, however, Does Correlate with Blood Glucose in Type 1's

• Genetic Abnormality in Diabetic Mice May Answer Why Autoimmune Disease Are More Common in Women

• Children and young adults with insulin dependent diabetes continue to be at increased risk for death from diabetic ketoacidosis

• The Human ENSA Gene That Encodes alpha-Endosulfine, a Regulator of beta-Cell KATP Channels, has been localized to an area of Chromosome 14 with IDDM susceptibility (IDDM11)

• Insulin Peptide Identified As Autoantigen In Diabetic Mouse -More than 88% of the CD-8 ["killer"]T cells infiltrating the pancreatic islets of 4-week-old NOD mice recognized tetramers containing the insulin B chain 15-23 peptide, according to this report. "The sequence of this peptide is identical to a corresponding region in the human insulin B chain, and it is also in a region identified as autoantigenic for CD-4 T cells."

• IL-13 can be added to the list of cytokines capable of downregulating immunoinflammatory diabetogenic pathways in NOD mice, and further support the concept that IL-4–related anti-inflammatory cytokines might have a role in the prevention of type 1 diabetes. Diabetes 48:1522–1528, 1999

• In identical twins discordant for type 1 diabetes the diabetic siblings appeared to have lower frequencies of CD4^-CD8^- V-alpha24JalphaQ⁺ T cells and to secrete NO interleukin-4

• Interleukin-4 appears to prevent insulitis and the development of Type 1 diabetes in the NOD mouse model

• The "64kd Antigen" -Glutamic Acid Decarboxylase - may be the key focus of attack in Type 1 Diabetes in that blocking antibodies and knockout protects against disease in the very comparable NOD mouse model

• The Kidney is probably as important as the Liver in Gluconeogenesis and Counter-regulation

[click here for a nice review of acute phase reactants in the inflammatory response]

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