Autoimmune Type 1 Diabetes Mellitus

Halki Diabetes Remedy

New Treatment of Diabetes

Get Instant Access

Of the endocrine autoimmune diseases, autoimmune type 1 diabetes mellitus (hereafter referred to as type 1 diabetes) is the most extensively studied because of both disease prevalence and severity. In 2002, approximately 13 million people in the United States (6.3% of the population) suffered from diabetes, and approximately 5-10% of these cases were diagnosed as type 1 diabetes (15). Furthermore, in the year 2000, diabetes was the sixth leading cause of death listed on death certificates in the United States (15). Thus, despite supportive therapy, diabetes mellitus causes significant morbidity and mortality.

Type 1 diabetes is characterized by insulin deficiency secondary to progressive T-cell-mediated destruction of insulin-producing pancreatic p cells within the islets of Langerhans. Clinical therapy is supportive; blood glucose is controlled by insulin injections, diet, and exercise. Nevertheless, homeostatic maintenance of blood glucose through shifting physiologic conditions is clearly unrealistic, and long-term complications of chronic hyperglycemia, including retinopathy, peripheral neuropathy, stroke, cardiovascular disease, and nephropathy, frequently develop. Although tight glycemic control delays the development of chronic complications (16), the incidence of acute, life-threatening episodes of hypoglycemia is more than three times higher with this treatment (17).

The pathogenesis of type 1 diabetes has yet to be unequivocally identified. Genetic predisposition to the development of type 1diabetes is associated with multiple alleles both within and outside the major histocompatibility complex

(MHC) (reviewed in ref. 18). Penetrance, however, is variable, and may be associated with specific autoimmune-triggering events. A variety of environmental or random (stochastic) events may lead to the abrogation of immunologic tolerance to islet p cells. Viral infection has been associated with the development of type 1 diabetes through the process of molecular mimicry of islet antigens or bystander T-cell activation (19-21). Alternatively, antigenic similarities between islet cell antigens and antigens in cow's milk have been proposed to induce type 1 diabetes in genetically susceptible individuals (20). Loss of tolerance to islet p cells in genetically susceptible individuals likewise could occur through stochastic processes involving determinant spreading of cryptic epitopes (22).

Although there is a lack of consensus regarding autoimmune-triggering events, it is clear that autoimmunity toward islet p cells is T cell-mediated and, at least primarily, results from failure of peripheral tolerance mechanisms. A dual checkpoint peripheral tolerance failure model has been proposed to explain the pathogenesis of type 1 diabetes in genetically susceptible individuals (23). Progression through the first checkpoint suggested peripheral tolerance leads to autoreactive T-cell infiltration of pancreatic islets (a pathologic process known as insulitis), whereas progression to active destruction of islet p cells occurs after the second peripheral tolerance checkpoint. The dual checkpoint model may explain variable penetrance; a series of autoimmune-triggering events, whether stochastic or environmental, may lead to peripheral tolerance failure in genetically susceptible individuals. Therapeutic intervention at either of the peripheral tolerance regulatory checkpoints may prevent or halt the progression to type 1 diabetes. Ideally, patients with genetic susceptibility to type 1 diabetes could be identified in early infancy and the development of diabetes prevented. Unfortunately, early trials of preventive therapy have been unsuccessful (24). Moreover, in the majority of patients autoimmunity is developed at the time of clinical presentation, and thus therapeutic benefit must derive from reversal of active autoimmunity.

Hematopoietic stem cell transplantation may reverse autoimmunity in patients with type 1 diabetes. In mouse models of type 1 diabetes, autoimmunity can be adoptively transferred to nondiabetic hosts via allogeneic HSCT; conversely, allogeneic HSCT of healthy donor cells into diabetic recipients halts autoimmune disease progression (25). Likewise, transfer of type 1 diabetes from human donor to recipient was observed after a sibling HLA-identical bone marrow transplant (26). Genetic susceptibility to acquired immunity in type 1 diabetes thus appears to be expressed through immune cells, and defects inherent in hematopoietic cells can be corrected by allogeneic HSCT. Likewise, development of autoimmunity is dependent, to some extent, on environmental influences or stochastic events, and therefore autologous HSCT may restore self-tolerance by recapitulating hematopoiesis.

Was this article helpful?

0 0
Diabetes Sustenance

Diabetes Sustenance

Get All The Support And Guidance You Need To Be A Success At Dealing With Diabetes The Healthy Way. This Book Is One Of The Most Valuable Resources In The World When It Comes To Learning How Nutritional Supplements Can Control Sugar Levels.

Get My Free Ebook


Post a comment