Pathophysiology of Diabetes Type 1

Type I diabetes mellitus, formerly referred to as juvenile-onset diabetes mellitus or insulin-dependent diabetes mellitus. This condition is known to occur at any age group, but the majority of affected individuals are diagnosed in their mid-teenage years.

This condition is characterized by a deficiency in the pancreatic hormone, called insulin. Insulin is particularly produced by a certain group of cells in the pancreas, called the beta cells. Experimental pathologic evidence amongst type I diabetics show that these beta cells are selectively affected and are eventually destroyed. This process is mediated by the body’s immune system. This initially causes derangements in insulin production. This may go unnoticed until eventually the pancreatic beta cells are fully destroyed causing ultimate failure of insulin secretion and production. Insulin normally functions to lower blood glucose levels after eating a meal. A deficiency of insulin causes excess glucose in the blood with serious potential complications, if left untreated. Because of this, type I diabetics are treated via insulin supplementation, delivered through a pump or via an injection. Prevention of this disease is still obscure since further research is needed to establish its exact pathogenesis.

The incidence of type I diabetes mellitus globally is highly variable. Research done by the World Health Organization showed a 350-fold difference among 100 studied populations. The highest reported incidence was seen in the Scandinavian countries, particularly in Finland, wherein 40 individuals are affected per 100,000 population. The lowest incidence is seen in China wherein <1 per 100,000 population was diagnosed. Due to these findings, environmental factors are hypothesized to play a role in the development of this disease.

According to the National Diabetes Statistics Report in 2014, an estimated 18,436 people younger than 20 years were newly diagnosed with type I diabetes annually. Compared with other ethnic groups, non-Hispanic white children and adolescents had the highest rates of new cases of this disease. What remains to be alarming is that data from large epidemiologic studies worldwide indicate that the incidence of Type I diabetes has been increasing by 2–5% worldwide.

Pathophysiologic Mechanisms

It is generally agreed that Type I diabetes develops as a result of synergistic effects of immunologic, genetic and environmental factors that ultimately destroy the pancreatic beta cells. Although no single environmental factor has been identified that is shown to cause this disease. We review the evidence behind all these mechanisms in an attempt to elucidate the pathophysiology of this disease.

Autoimmune Mechanism

The observation that in the majority of individuals, certain immunologic markers appear before this disease becomes clinically diagnosed points to a possible autoimmune mechanism in generating this disease.  Research data showed that a decline in the pancreatic beta cell mass with a resultant progressive impairment in insulin secretion. Although in the initial stages of the disease, a normal glucose tolerance may be maintained. The rate of decline differs for every patient. The overt clinical features of diabetes do not become evident until approximately 80% of the beta cells have been destroyed.

Pathological investigations show that pancreatic islet cells become infiltrated by lymphocytes, causing insulitis. As in any solid organ failure, once the inflammatory process subsides, the beta cells becomes atrophic and immunologic markers disappear. Research data on autoimmune processes in human and animal models of type I diabetes show evidence of islet cell autoantibodies, activated lymphocytes in the beta cells, lymph nodes surrounding the pancreas and systemic circulation. Protein stimulation of the beta cells causes proliferation of t-lymphocytes and cytokine release within the region of beta cell inflammation. The exact mechanism of beta cell destruction is not known, but this occurrence may be related to apoptosis, t-cell cytotoxicity and the formation of toxic metabolites after an inflammatory reaction.

Recently, therapeutic strategies are being investigated. Regenerative studies have been done in an attempt to replicate human beta cells. In addition, transplantation of pancreatic cells are being research at this time of writing.

Genetic Considerations

In the United States, if you have a first-degree relative with Type I diabetes mellitus, this puts you at a higher risk of acquiring Type I diabetes mellitus. To be precise, your risk is 1 in 20 compared to the general risk of 1 in 300. Concordance rate among monozygotic twins are also high at 30-50%, while dizygotic twins have a 6-10% concordance rate.

Genetic susceptibility testing for type I diabetes mellitus also involves multiple genes. Amongst the three classes of Human Leukocyte Antigen (HLA) genes, HLA II has the strongest association with Type I diabetes mellitus, with at least 17 loci contributing to the inherent susceptibility to this condition. For example, polymorphisms in the promoter region of insulin gene can account for at least 10% of the likelihood of acquiring type I diabetes. Most individuals with Type I diabetes have the HLA DR3 and/ or HLA DR4 haplotype. Hence, the risk of developing type I diabetes, increases ten fold in the relatives of the individuals with this disease. It is interesting to note that differences in risk are also dependent on which parent has the illness. Children of Type I diabetic mothers have only a 2% risk of developing this condition, whereas children of afflicted fathers have a higher risk at 7%. On the other hand, despite all these genetic associations, 85% of the newly diagnosed type I diabetics do not have any family history of this disease.

Environmental Factors

Numerous environmental factors have been proposed to trigger an immune event in genetically susceptible individuals. However, studying these factors have been challenging because the environmental trigger may have occurred years prior to developing a clinically overt disease. Environmental factors, which have been studied are viruses, namely Rubella, Coxsackie viruses, Cytomegalovirus and Rotavirus. Nutritional influences have also been studied, such as the effect of breastmilk, cow’s milk and bovine milk intake. These studies have been difficult to replicate and are inconclusive. Exposure to nitrosamine compounds can theoretically cause diabetes through the generation of free radicals. However, experimental studies on exposure and dietary intake remain elusive.

While significant advancements have been made in the care of type I diabetics, resulting in improved clinical outcomes and quality of life, further investigations are to be done to decipher its cellular and molecular pathophysiology ultimately leading to finding a cure for this disease.

References

• Atkinson, M. A. (2012). The Pathogenesis and Natural History of Type 1 Diabetes. Cold Spring Harbor Perspectives in Medicine,2(11).doi:10.1101/cshperspect.a007641
• Maahs, D. M., West, N. A., Lawrence, J. M., & Mayer-Davis, E. J. (2010). Chapter 1: Epidemiology of Type 1 Diabetes. Endocrinology and Metabolism Clinics of North America, 39(3), 481–497. http://doi.org/10.1016/j.ecl.2010.05.011
• National Diabetes Statistics Report, 2014 (pp. 1-11, Rep.). (2014). Atlanta, Georgia: Center for Disease Control and Prevention.
• Nokoff, N., &Rewers, M. (2013). Pathogenesis of type 1 diabetes: Lessons from natural history studies of high-risk individuals. Ann. N.Y. Acad. Sci. Annals of the New York Academy of Sciences,1281(1), 1-15. doi:10.1111/nyas.12021
• Rekittke, N. E., Ang, M., Rawat, D., Khatri, R., & Linn, T. (2016). Regenerative Therapy of Type 1 Diabetes Mellitus: From Pancreatic Islet Transplantation to Mesenchymal Stem Cells. Stem Cells International,2016, 1-22.doi:10.1155/2016/3764681
• Roep, B. O. (2003). The role of T-cells in the pathogenesis of Type 1 diabetes: From cause to cure. Diabetologia, 406, 305-321.doi:DOI 10.1007/s00125-003-1089-5
• Spollett, G. R. (2009). Diabetes in Finland: What Can Happen When a Country Takes Diabetes Seriously. Diabetes Spectrum,22(3), 188-190.doi:10.2337/diaspect.22.3.188