Pathogenesis of type 1 diabetes

In Denmark 1 procent of the population develops type 1 diabetes. Type 1 diabetes is a complicated disease to study, as the decelopment of the disease depends on both genetic and environmental factors. We have primarily focused on environmental factors.
Signe Borch isolating liver cells from mice

The importance of cellular activity for the development of diabetes

Glucose stimulation increases the expression of beta cell antigens and is also responsible for increased incidence of type 1 diabetes. We therefore hypothesize that beta cell antigen activation of the immune system can be part of T1DM pathogenesis. 

A number of experiments carried out by both our and other groups support this activity hypothesis. Thus, conditions characterized by increased secretory demands for insulin, forcing the beta cells to increase the secretory activity, are associated with an increased incidence of type 1 diabetes. This applies, for example, to insulin resistance and high content of refined carbohydrates in the diet (as measured by the glycemic index). 

Likewise, almost all cases of Type 1 diabetes among pregnant women develop during the 3rd trimester of pregnancy. At this time of the pregnancy, the fetus is growing the most, forcing the maternal beta cells to secrete the most insulin. This observation does not mean, of course, that pregnancy is a risk factor for diabetes per se; the patients might well have developed diabetes at a later time in any case, leaving the pregnancy as a precipitating rather than causal factor for the disease development.

The role of gliadin

There is an intimate association between type 1 diabetes mellitus and coeliac disease, as both diseases are accompanied by a higher incidence of the other. Further, most patients acquire diabetes before the coeliac disease starts, while the opposite is only infrequently seen. Further, mice on gluten-free diet rarely acquires diabetes. 

Beta cell antigens

The main interest of the laboratory is the genetic regulation of the beta cell secretion, in particular during the development of type I diabetes, but also during physiological conditions. Glucose stimulation of beta cells increases expression of several beta cell genes. Since it has been suggested that beta cell activity is associated with an increased risk for the development of type 1 diabetes, we have characterized genes induced by glucose in MIN6 cells using subtraction cloning. 

We have identified a number of genes showing variable induction during glucose stimulation. First, several glycolytic pathway genes including enolase, triosephosphate isomerase, phosphoglycerate kinase, lactate dehydrogenase and aldolase are upregulated. We have also found that dynorphin is upregulated, although the function of the peptide in beta cells is not clear at the present.

The pancreatic beta-cell surface biomarker IC2

IC2 is a monoclonal autoantibody raised from a diabetic BB-rat in 1982. World-wide it is the only specific biomarker for the pancreatic beta-cell surface both in vitro and in vivo. Its potential application for noninvasive molecular imaging of the native and residual functional beta-cell mass in both healthy and diabetic patients is obvious and currently explored. 

Animal biodistribution with radioisotope-labeled fragments of IC2 have confirmed its pancreatic beta-cell specificity, and recombinant chimeric formats and proteolytic fragments of this rat IgM autoantibody have now been developed and is under investigation in vivo. A new nude mouse insulinoma model of human beta-cells is used as experimental model before clinical trials can be initiated in the benefit of diabetic research and patients. A search for the IC2-targeting autoantigen continues and point to the NKT-Type II cell targeting CD1d-sulfatid complex.

Dietary gluten

Several studies have documented that dietary modifications influence the development of type 1 diabetes (T1D). However, little is known about mechanisms by which diets modify T1D incidence. We investigated the effect of a gluten-free (GF) diet compared to a gluten-containing standard (STD) diet on selected T cell subsets, associated with regulatory functions as well as proinflammatory Th17 cells. 

Further, we have performed studies to test if wheat gluten, is able to induce differences in the cytokine pattern of Foxp3+ regulatory T cells (Tregs), as well as Foxp3- T cells. Collectively, our data indicate that dietary gluten influences the proportion of multiple regulatory T cell subsets as well as Th17 cells in mucosal lymphoid tissue while fewer differences were observed in non-mucosal lymphoid compartments. 

Further, STD diet modifies the cytokine pattern of both Foxp3- T cells and Foxp3+ Tregs towards a more inflammatory cytokine profile. This mechanism may contribute to the higher T1D incidence associated with gluten intake.

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