**2. Why is there an increasing trend in the incidence of diabetes?**

In the past, most diabetics were known to have a genetic tendency towards the disease. However, that trend has rapidly given way in the past few decades to other causes, at least from a statistical perspective. These genetically-independent trends that explain the growth in the incidence of diabetes can be summarized as follows: (a) overall growth in population, (b) increased life expectancy resulting in a higher ratio of aged population more prone to diabetes, (c) increasing obesity trends, (d) unhealthy diets and (e) sedentary lifestyles.

in 5 of all undiagnosed cases of diabetes is in this region; 1 in 4 deaths due to diabetes occurred

**Figure 1.** According to international diabetes federation5th edition; 2012the number of diabetes increases to 371 mil‐ lion. North America & Caribean: More healthcare dollars were spent on diabetes in this region than any other; 1 in 10

Update of Type 1 Diabetes http://dx.doi.org/10.5772/55960 75

Type 1 diabetes develops slowly and progressive abnormalities in beta cell-function herald what appears to be a sudden development of hyperglycemia. Rising the hemoglobin A1c test (HbA1c) in the normal range[3], impaired fasting or glucose tolerance, as well as loss of first phase insulin secretion usually precede overt diabetes. The exact beta cell mass remaining at diagnosis is poorly defined and there are almost no studies of insulitis prior to diabetes onset [4]. For patients with long-term type 1 diabetes there is evidence of some beta cell function remaining (C-peptide secretion) though beta cell mass is usually decreased to less than 1% of normal [5]. At present methods to image/quantitate beta cell mass and insulitis are only beginning to be developed. In particular Positron Emission Tomography (PET) scanning utilizing a labeled amine (dihydrotetrabenazine) may provide the first method to image islet mass [6] and this is now being evaluated in man. A number of techniques are being evaluated

A large body of evidence indicates that the development of type 1 diabetes is determined by a balance between pathogenic and regulatory T lymphocytes [8]. A fundamental question is whether there is a primary autoantigen for initial T cell autoreactivity with subsequent

in this region [2]

adults in this region has diabetes.

**2.1. Pathogenesis**

to image insulitis [7].

In other words, diabetes has increasingly become a lifestyle-related disease as it afflicts young and old, in developed and developing nations, around the world. As the number of patients grows across the globe, there has never been a stronger and more urgent need for therapeutic measures that arrest the growth of the disease and alleviate its secondary manifestations.

Middle East & North Africa: 1 in 9 adults in this region have diabetes; More than half of people with diabetes in this region don't know they have it. Europe: 1 out of every 3 dollars spent on diabetes healthcare was spent in this region; 21.2 million people in this region have diabetes and don't know it. Western Pacific: 1 in 3 adults with diabetes lives in this region; 6 of the top 10 countries for diabetes prevalence are Pacific Islands. South & Central America: Only 5% of all healthcare dollars for diabetes were spent in this region; 1 in 11 adults in this region has diabetes. Africa: Over the next 20 years, the number of people with diabetes in the region will almost double; This region has the highest mortality rate due to diabetes. South East Asia: 1

**Figure 1.** According to international diabetes federation5th edition; 2012the number of diabetes increases to 371 mil‐ lion. North America & Caribean: More healthcare dollars were spent on diabetes in this region than any other; 1 in 10 adults in this region has diabetes.

in 5 of all undiagnosed cases of diabetes is in this region; 1 in 4 deaths due to diabetes occurred in this region [2]

#### **2.1. Pathogenesis**

Diabetes is one of the fastest growing diseases. Diabetes affects today an estimated 371 million people world-wide compared to 366 million by the end of 2011. Of course this includes 20 million to 40 million of patients with type 1 diabetes. While type 1 diabetes accounts for 5% to 20% of those with diabetes, it is associated with higher morbidity, mortality and health care cost than the more prevalent type 2 diabetes. Overall, 4.8 million people died and \$ 471 billion

New figures indicate that the number of people living with diabetes is expected to rise from 371 million in 2012 to 552 million by 2030, if no urgent action is taken. This equates to approx‐ imately three new cases every ten seconds or almost ten million per year. International diabetes federation also estimated that almost half of the people with diabetes are unaware that they

In some of the poorest regions in the world such as Africa, where infectious diseases have traditionally been the focus of health care systems, diabetes cases are expected to increase by 90% by 2030. At least 78% of people in Africa are undiagnosed and do not know they are living

**•** 80% of people with diabetes live in low and middle income countries.

**•** The greatest number of people with diabetes is between 40-59 years of age [2].

**2. Why is there an increasing trend in the incidence of diabetes?**

In the past, most diabetics were known to have a genetic tendency towards the disease. However, that trend has rapidly given way in the past few decades to other causes, at least from a statistical perspective. These genetically-independent trends that explain the growth in the incidence of diabetes can be summarized as follows: (a) overall growth in population, (b) increased life expectancy resulting in a higher ratio of aged population more prone to diabetes, (c) increasing obesity trends, (d) unhealthy diets and (e) sedentary lifestyles.

In other words, diabetes has increasingly become a lifestyle-related disease as it afflicts young and old, in developed and developing nations, around the world. As the number of patients grows across the globe, there has never been a stronger and more urgent need for therapeutic measures that arrest the growth of the disease and alleviate its secondary manifestations.

Middle East & North Africa: 1 in 9 adults in this region have diabetes; More than half of people with diabetes in this region don't know they have it. Europe: 1 out of every 3 dollars spent on diabetes healthcare was spent in this region; 21.2 million people in this region have diabetes and don't know it. Western Pacific: 1 in 3 adults with diabetes lives in this region; 6 of the top 10 countries for diabetes prevalence are Pacific Islands. South & Central America: Only 5% of all healthcare dollars for diabetes were spent in this region; 1 in 11 adults in this region has diabetes. Africa: Over the next 20 years, the number of people with diabetes in the region will almost double; This region has the highest mortality rate due to diabetes. South East Asia: 1

**•** 78,000 children develop type 1 diabetes every year

were spent due to diabetes in 2012 [1-2].

have diabetes [2].

74 Type 1 Diabetes

with diabetes (Figure 1):

Type 1 diabetes develops slowly and progressive abnormalities in beta cell-function herald what appears to be a sudden development of hyperglycemia. Rising the hemoglobin A1c test (HbA1c) in the normal range[3], impaired fasting or glucose tolerance, as well as loss of first phase insulin secretion usually precede overt diabetes. The exact beta cell mass remaining at diagnosis is poorly defined and there are almost no studies of insulitis prior to diabetes onset [4]. For patients with long-term type 1 diabetes there is evidence of some beta cell function remaining (C-peptide secretion) though beta cell mass is usually decreased to less than 1% of normal [5]. At present methods to image/quantitate beta cell mass and insulitis are only beginning to be developed. In particular Positron Emission Tomography (PET) scanning utilizing a labeled amine (dihydrotetrabenazine) may provide the first method to image islet mass [6] and this is now being evaluated in man. A number of techniques are being evaluated to image insulitis [7].

A large body of evidence indicates that the development of type 1 diabetes is determined by a balance between pathogenic and regulatory T lymphocytes [8]. A fundamental question is whether there is a primary autoantigen for initial T cell autoreactivity with subsequent recognition of multiple islet antigens. A number of investigators have addressed in the Non-Obese Diabetic (NOD) mouse (spontaneously develops type 1 diabetes) the importance of immune reactivity to insulin with the dramatic finding that eliminating immune responses to insulin blocks development of diabetes and insulitis, and importantly immune responses to downstream autoantigens such as the Islet specific molecule Glucose-6-phosphatase catalytic subunit-Related Protein( IGRP) [9]. Knocking out both insulin genes (mice in contrast to humans have two insulin genes) with introduction of a mutated insulin with alanine rather than tyrosine at position 16 of the insulin B chain prevents development of diabetes [10]. Recognition of this B-chain peptide of insulin by T lymphocytes depends upon a "nonstringent" T cell receptor with conservation of only the alpha chain sequence (Valpha and Jalpha) and not the N-region of the alpha chain, or the Beta chain [11].

**3. Genetic factors**

this question.

**3.1. MHC genes**

with susceptibility [18].

A mutation of the Forkhead bOX Protein 3 (FOXP3 gene, a transcription factor that controls the development of regulatory T cells is a cause of neonatal diabetes [12]. The syndrome is termed IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome. As reflected in the name, children with disorder suffer from overwhelming autoimmunity and usually die as infants. Of note bone marrow transplantation can reverse disease. IPEX syndrome is rare, as is neonatal diabetes. In the differential diagnosis of neonatal diabetes it must be recognized that half of children developing permanent neonatal diabetes have a mutation of the Kir6.2 molecule of the sulfonylurea receptor. These children with their non-

Update of Type 1 Diabetes http://dx.doi.org/10.5772/55960 77

Though more common than IPEX syndrome, the Autoimmune Polyendocrine Syndrome Type 1 (APS-1) syndrome is also rare. It results from a mutation of the "autoimmune regulator" AIRE gene, another transcription factor [13]. Approximately 15% of patients with this syn‐ drome develop autoimmune diabetes. The leading hypothesis as to etiology (e.g. Addison's disease, mucocutaneous candidiasis, and hypoparathyroidism) is that AIRE controls expres‐ sion of autoantigens and negative selection of autoreactive T lymphocytes within the thymus. A very recent dramatic discovery is the demonstration that essentially 100% of patients with Autoimmune Polyendocrine Syndrome type 1 (APS-1) have autoantibodies reacting with interferon alpha and other interferons. Such autoantibodies are extremely rare and essentially not found in patients with type 1 diabetes or Addison's disease outside of the syndrome.

Patients with type 1 diabetes and their relatives are at risk for development of thyroid autoimmunity, celiac disease, Addison's disease, pernicious anemia and a series of other autoimmune disorders [14]. Approximately 1/20 patients with type 1 diabetes have celiac disease by biopsy though the majority have no symptoms [15]. These asymptomatic individ‐ uals are usually detected with screening for transglutaminase autoantibodies. The level of transglutaminase autoantibodies relates to the probability of a positive biopsy and it is important for clinicians to know the threshold for likely positive biopsy for the assay they employ [16]. There remains controversy as to whether asymptomatic celiac disease when detected should be treated with a gluten free diet and large clinical trials are needed to address

Type 1 diabetes has become one of the most intensively studied polygenic disorders. There are MHC as well as non-MHC genes or loci candidate to contribute in the genetic susceptibility to type 1 diabetes pathogenesis. According to the recent version of the National Center for Biotechnology Information (NCBI) map viewer these genes are located on all human chromo‐ somes [17] (Figure 3). The strongest associations with both susceptibility and protection from type 1 diabetes are HLA DR and DQ molecules. For instance DQB1\*0602 alleles are associated with dominant protection and DR3-DQ2 molecules (DQB1\*0201) and DR4-DQ8 (DQB1\*0302)

autoimmune form of diabetes can be treated with oral sulfonylurea therapy.

As in other immune diseases both genetic factors as well as environmental factors contribute in the pathogenesis of the disease (Figure 2). Environmental factors exert their effects ones genetic susceptibility factors already exist.

**Figure 2.** A schematic figure shows how environmental factors trigger TYPE 1 DIABETES onset in genetically suscepti‐ ble persons which ends to the process of β-cell-specific autoimmunity processes which lead to the destruction of pan‐ creatic β-cell. As antigen presenting cell is triggered by auto antigens it releases intiinfalmatory cytokines eg IL-1 that signals T-helper 1 class to activate B-cell and T cell in order to release autoantibodies to attach pancreatic β-cell.
