Therapeutic Targets for the Prevention of Type 1 Diabetes Mellitus

Abstract

The pathogenesis of type 1 diabetes is multifactorial, involving genetic susceptibility, autoimmune mechanisms, and environmental factors. This article will focus on two main strategies for altering the underlying disease process in type 1 diabetes. The first strategy is to identify individuals at risk for the development of diabetes and to halt the immune process before it leads to overt clinical disease, Promising in vitro and animal studies with nicotinamide, parenteral insulin, and oral insulin led to large clinical prevention studies, such as the European Nicotinamide Diabetes Intervention Trial and the Diabetes Prevention Trial (DPT-1). These studies failed to show that nicotinamide and insulin prevented the disease in at risk relatives of patients with type 1 diabetes and left many questions unanswered. The second strategy focuses on intervention shortly after diagnosis in order to arrest the destruction of beta cells and to preserve residual beta-cell function as long as possible. Cyclosporin was an effective immunosuppressive but was rejected as a potential treatment for type 1 diabetes because of its renal toxicity. Recently, more attention has been focused on an anti-CD3 antibody, on DiaPep277, and on glutamic acid decarboxylase (GAD). Animal studies and small short-term human trials with these compounds have suggested that they may be effective interventions in patients recently diagnosed with type 1 diabetes.

Prevention of type 1 diabetes mellitus using a novel vaccine

“…A modified hsp65 oligopeptide (p277 DiaPep) was used successfully in the treatment of NOD mice. In a small human study in which the p277 was administered, better C-peptide levels and lower insulin requirements were achieved compared with the placebo group [Singh and Palmer, 2005].…”

“…These regulatory T cells are mainly CD4þ, Thelper (Th) cells, but other types of T cells, such as natural killer T cells (NKT) and CD8þ cells, also have regulatory functions. The CD4 þ CD25 þ FoxP3 þ T cells are able to shift the immune response either to a cellular (Th1) or humoral (Th2) path [Raz et al 2005;Singh and Palmer, 2005;Winter and Schatz, 2003;Wilson et al 1998]. The invariant NKT (iNKT) cells are one of the most potent immune regulators, thus these cells are widely studied in the pathogenesis of several diseases like T1DM, multiple sclerosis, and asthma, etc.…”

“…External triggers, such as virus infection, toxins or cow's milk, may initiate the autoimmune response in a genetically predisposed individual. There are several candidates for these initiating antigens, such as GADA, IA2-A, a heat shock protein (Hsp277), GAD65, a recently described zinc transporter (Znt8), and insulin and/or proinsulin [Vaziri-Sani et al 2010;Wenzlau et al 2009;Agardh et al 2005;Singh and Palmer, 2005;Wong, 2005;Petrovsky et al 2003;Winter and Schatz, 2003;Wilson and Buckingham, 2001;Fuchtenbusch et al 1998]. It is possible that there are more trigger antigens, but probably they differ from patient to patient.…”

“…The presentation of auto-antigens to the T cells at a high level, without costimulation, can lead to the inactivation of the autoreactive T cells, which can be used as a means of prevention. There many possible antigens, such as milk protein and bovine serum albumin, which show molecular mimicry with the surface proteins of the b-cells, Hsp, GAD65, and insulin [Singh and Palmer, 2005;Wong, 2005;Petrovsky et al 2003].…”

Effects of Camel’s Milk as a Vehicle for Insulin on Glycaemic Control and Lipid Profile in Type 1 Diabetics

“…Prevention and early treatment is important because diabetes interrupts normal developments in children and carries the threat of severe complication in more active period of life (Singh and Palmer, 2005) Its primary treatment is insulin injection replacement, however at present neither entire physiological insulin replacement could be achieved in clinical practice nor could metabolic disturbances be normalized. Insulin therapy is still the best treatment, however, among certain social groups needle phobia, cost and routine treatment forces these patients to adopt alternative treatments in the context of traditional ethno-medical practices.…”