Devasenan Devendra

Type 1 diabetes: recent developments

Type 1 diabetes is one of the most common chronic childhood illnesses, affecting 18 to 20 per 100 000 children a year in the United Kingdom.1 The American Diabetes Association committee recommends the term type 1A diabetes for immune mediated diabetes with its destruction of the islet β cells of the pancreas.2 Non-immune mediated diabetes with severe insulin deficiency is termed type 1B. In this review, we will use the term type 1 diabetes to refer to immune mediated type 1A diabetes. At present, the development of type 1 diabetes is a life sentence to a difficult therapeutic regimen that is only partially effective in preventing acute and chronic complications. We will concentrate here on recent advances in our understanding of the epidemiology, pathogenesis, prediction, and prevention of type 1 diabetes and new treatments for the disease. This review is based on information obtained from a recent Medline search with type 1 diabetes, pathogenesis, prediction, prevention, and treatment as key words. We also consulted summaries of the literature on type 1 diabetes (available with teaching slides at www.barbaradaviscenter.org/). Although most attention has focused on the increase in type 2 diabetes, a parallel rise in type 1 diabetes has occurred (1).1 Type 1 diabetes has always been known as a disease of childhood, but more recent epidemiological studies have indicated that the incidence is comparable in adults.3 The enormous international variation in incidence is now recognised. A child in Finland is almost 40 times more likely to develop type 1 diabetes than a child in Japan and almost 100 times more likely to get the disease than a child in the Zunyi region of China.1 The EURODIAB collaborative study, a registry involving 44 countries in Europe, indicates an annual rate of increase in incidence …

Evidence for a primary islet autoantigen (preproinsulin 1) for insulitis and diabetes in the nonobese diabetic mouse

It has been reported that an insulin 2 gene knockout, when bred onto nonobese diabetic (NOD) mice, accelerates diabetes. We produced insulin 1 gene knockout congenic NOD mice. In contrast to insulin 2, diabetes and insulitis were markedly reduced in insulin 1 knockout mice, with decreased and delayed diabetes in heterozygous females and no insulitis and diabetes in most homozygous female mice. Lack of insulitis was found for insulin 1 female homozygous knockout mice at 8, 12, and 37 weeks of age. Despite a lack of insulitis, insulin 1 homozygous knockout mice spontaneously expressed insulin autoantibodies. Administration of insulin peptide B:9-23 of both insulin 1 and 2 to NOD mice induced insulin autoantibodies. Insulin 1 is not the only lymphocytic target of NOD mice. Insulin 1 homozygous knockout islets, when transplanted into recently diabetic wild-type NOD mice, became infiltrated with lymphocytes and only transiently reversed diabetes. These observations indicate that loss of either insulin gene can influence progression to diabetes of NOD mice and suggest that the preproinsulin 1 gene is crucial for the spontaneous development of NOD insulitis and diabetes.

Early and Quantal (by Litter) Expression of Insulin Autoantibodies in the Nonobese Diabetic Mice Predict Early Diabetes Onset

Aiming to study the early stages of type 1 diabetes phenotype, before insulitis appears, we measured insulin autoantibodies (IAA) between 3 and 5 wk of age in the NOD mouse (early-IAA (E-IAA)). We report that IAA are found as early as at 3 wk of age, at weaning, and their expression is a quantal phenotype. Maternal autoantibody status influences this early phenotype, because animals of litters issued from IAA-positive ante partum mothers develop E-IAA with a significantly higher incidence than animals issued from IAA-negative mothers. These E-IAA represent synthesized rather than transplacental autoantibodies, as evidenced by higher levels in many offspring compared with maternal IAA, and negative as well as positive offspring in the same litters and it correlates with early diabetes onset, defining the first autoimmune window in diabetes pathogenesis. Therefore, autoimmune processes leading to type 1 diabetes initiate early in life, are influenced by maternal autoantibody status, and can be revealed by the presence of IAA. Our data suggest that the mechanisms responsible for the breakdown of self-tolerance are subjected not only to genetic predisposition, but also to the physiological status of the mother. Pathological progression to autoimmunity is marked by the presence of immunological windows relating early steps with final disease onset.

Immunotherapeutic approaches to prevent, ameliorate, and cure type 1 diabetes

Type 1A diabetes (T1D) is caused by autoimmune islet beta cell destruction precipitated by environmental triggers in genetically predisposed individuals. Islet beta cells produce insulin and are the primary target of this autoimmune disorder. Insulin, glutamic acid decarboxylase, and insulinoma associated-2 autoantibodies (IAA, GAD65, and IA-2) are the autoantibodies that have been associated most clearly with the development of T1D. Despite our current ability to predict T1D using genetic markers and detecting islet autoantibodies, we have yet to find a safe way to prevent the disease. However, there are more than 100 different therapies that prevent T1D in the nonobese diabetic (NOD) mouse model or the BioBreeding (BB) rats. This paper reviews a few select therapeutic approaches that have been or are being evaluated as possibilities for the prevention, amelioration, or cure of T1D.

Comparative study of oral versus subcutaneous B:9-23 insulin peptide in Balb/c mice as an experimental model for autoimmune diabetes.

Abstract: Insulin peptide B:9–23 (amino acids 9 to 23 of the B chain) can induce immune targeting of insulin and islets in normal Balb/c mice. The insulin autoantibodies induced react with insulin and not the immunizing peptide. Oral administration of insulin as well as subcutaneous insulin can sensitize to insulin.

Differential immune induction with subcutaneous versus oral administration of a diabetogenic insulin peptide in the NOD mouse.

Abstract: The B chain insulin peptide 9 to 23 (B:9–23) is a dominant T cell epitope of the NOD mouse. Given in oral form with multiple different vehicles, it did not alter expression of insulin autoantibodies in contrast to subcutaneous administration.