**8. Concluding remarks**

316 Type 1 Diabetes – Complications, Pathogenesis, and Alternative Treatments

the inner mitochondrial membrane and develops in concert with mitochondrial and

Although type 1 diabetes is a T-cell–mediated autoimmune disease, until a few years ago relatively few studies have attempted to associate T-cell autoreactivity with disease progression, in comparison with efforts directed on monitoring autoantibodies, and those that have been performed were largely limited to CD4 T-cells (Roep, 2008). Currently, islet epitope-specific CD8 T cells are believed to have a pivotal role in the destruction process. Unfortunately, monitoring multiple epitope-specific CD8 T cell populations poses many technical problems. Recently, monitoring of CD8 T cells reactive to beta-cell-derived antigens has been performed using the combinatorial quantum dot technique, which has been validated using peripheral blood cells from recent-onset type 1 diabetic patients, their siblings, and control subjects (Velthuis et al., 2010). Moreover, during the progression of autoimmune diabetes, memory autoreactive regulatory CD8 T cells can be expanded that could effectively suppress the expansion of dominant and subdominant effectors (Khadra et al., 2010). Increasing evidence shows the significance of CD4 and CD8 regulatory T cells, expressing the marker CD25 or IL-2 receptor, in autoimmune disease models. On the contrary, very few study have dealt with the role of CD23 or low affinity IgE receptor. In 2004, given that abnormalities in redox balance clustered in type 1 diabetes families and the intracellular redox status seemed to modulate immune function, we aimed to investigate the relationship between oxidative stress and immunologic features. We measured oxidative markers, serum pro-inflammatory cytokines, soluble cytokine receptors, and subsets of peripheral blood lymphocytes (by varying combinations of CD4, CD8, CD23, and CD25) from type 1 patients, low-risk (i.e. without underlying islet autoimmunity) non-diabetic first-degree relatives of diabetic patients, and healthy subjects (Matteucci et al., 2004a). In these families, protein and lipid oxidation was confirmed from reduced sulfhydryl groups, increased advanced oxidation protein products, increased plasma and erythrocyte malondialdehyde. Relatives had decreased counts of monocytes, of cells coexpressing CD23 and CD25, and of CD25+ cells in peripheral blood. Patients with type 1 diabetes had similar defects and, in addition, showed decreased counts of peripheral CD4+CD8+ lymphocytes and increased serum levels of soluble receptors for IL-6 and IL-2. This was the first demonstration of leukocyte abnormalities in low-risk T1DM relatives, also presenting signs of oxidative stress. Moreover, our study reported first evidence that the oxidative stress observed in type 1 diabetes families was correlated to immunological hallmarks suggestive of different immunoregulatory mechanisms. A crucial question remained open: did the alteration in immune functions follow the altered intracellular redox status or vice versa? More recently, we have characterised CD26 expression of T cell subsets in patients with type 1 diabetes because 1) high expression of CD26 among CD8+ T cells has been suggested to be a marker of effective long-term memory T cell formation typical of acute resolved viral infections (Ibegbu et al., 2009), and 2) an increased risk of persistent viral infections, such as

hepatitis C (HCV), was reported among diabetic patients (Lonardo et al., 2009).

No significant difference was seen in percentages or absolute numbers of CD4+CD26+, CD4+CD26-, CD8+CD26+, and CD8+CD26- between type 1 diabetes and control people.

oxidative stress in diabetes (Frizzell et al., 2011).

**7. Immunological functions in type 1 diabetes families** 

Today, there is a great need to integrate molecular biology with whole organ physiology. Findings from molecular and cellular studies must be brought back to intact organ systems without loosing the physiological context (Königshoff et al., 2011). This is especially true in the field of metabolic diseases where the study of individual proteins and signalling pathways in detail may not be easily translated to the intact organism. Taken into account the enlarging list of phenotypic characteristics that might allow the early clinical identification of families possibly at risk for sporadic cases of type 1 diabetes, many questions await an answer. We suggest the two main (in our opinion) issues.

Fig. 4. Some of the potential mechanisms linking metabolic syndrome and T cell maintenance.

First question: may insulin-resistance be the common denominator of the observed familial peculiarities? And therefore, second question: could an early correction of one/some of

The Enlarging List of Phenotypic Characteristics That

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these common clinical abnormalities modify the natural history of the disease and thence its epidemiology? The data above summarised suggest to consider also alternative ways beyond the traditional immuno-based interventions so far extensively investigated in the field of type 1 diabetes. There is increasing attention to the role of metabolic syndrome and immune responses as well as to the relation between the immune and neuroendocrine systems (Figure 4). The adipocyte-derived proinflammatory hormone leptin can affect the survival and proliferation of autoreactive CD4 T cells (Matarese et al., 2008; Galgani et al., 2010). Immune and neuroendocrine systems have bidirectional communications (Kelley et al., 2007; Berczi et al., 2009). Growth hormone and ghrelin are expressed in immune cells, which in turn bear receptors for these hormones (Hattori, 2009). Leptin, ghrelin, insulin-like growth factor 1, insulin-like growth factor binding protein 3, and cytokines regulate both thymopoiesis and maintenance of T cells. Therefore, elucidation of metabolic syndrome, T cell metabolism, hormones, and microbiota may lead to new insights into the maintenance of proper immune responses (Hsu & Mountz, 2010).

At the present state of knowledge and given the current diabetes epidemic, it would seem reasonable that proper, more realistic, public health interventions (by general and family practitioners) are designed that address general issues such as feeding, lifestyle, overweight, 'borderline' blood pressure, impaired fasting glucose, etc. These health interventions, beyond the conventional boundaries that have for so long limited the visual field, might have a favourable cost-benefit ratio.

#### **9. References**


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**16** 

 *Cyprus* 

**Altering Trends in the Epidemiology of Type 1 Diabetes Mellitus in Children and Adolescents** 

Diabetes mellitus is a group of metabolic diseases characterised by chronic hyperglycemia resulting from defects in insulin secretion and/or insulin action, or both [1]. The history of diabetes dates back to 1550 BC as the polyuric states were described in an Egyptian papyrus, where treatment was given with a four day decoction of bones, wheat, grain, grit and earth. The term diabetes was coined by Aretaeus of Cappadocia in the 2nd century AD for conditions causing increased urine output. The sweet taste of diabetic urine was noted in the 5th century AD by Indian physicians and in 1776, Matthew Dobson confirmed that diabetic serum and urine contained sugar. The revolution in the history of Diabetes was the discovery of insulin by Banting, Best and colleagues in 1922 (http://wwunix.oit.umass.edu

Type 1 diabetes mellitus (T1DM) is one of the most common endocrine metabolic disorders in children and adolescence worldwide with serious acute and chronic complications. It has been proven that T1DM represents the ending result of an autoimmune destruction of the pancreatic islet beta cells in genetically susceptible individuals exposed to certain but still unclear environmental factors. The precise cause of T1DM is not known. However, multiple genetic and environmental risk factors seem to play an important role in the genesis of the disease. The genetic background is complex and difficult to be explained by the involvement of HLA gene region alone. On the other hand viral and nutritional factors changing continuously from country to country, may contribute to the etiology of T1DM. There is no doubt that monitoring temporal trends and incidence of T1DM contribute to the international effort to determine the exact pathogenesis of the disease and it is of critical public health importance. All these temporal trends in the incidence of T1DM have provided significant clues for understanding the disease, most likely reflecting environmental changes more than genetic changes and detecting the factors that implicated

In this chapter we review the changing trends in the epidemiology of T1DM and we present

The prevalence of T1DM greatly varies between different countries, within countries, and between different ethnic populations. The global variation of the incidence of T1DM is

data on the rising incidence of T1DM in Greek Cypriot population.

**1. Introduction** 

in this increase.

/~abhu000/diabetes/index.html).

**2. Incidence-changing trends** 

Elisavet Efstathiou and Nicos Skordis

*Makarios Hospital, Nicosia* 

*Paediatric Endocrine Unit, Department of Paediatrics,* 

