alt="Image"/> Etiology and Pathogenesis of Diabetes
Type 1 Diabetes
More than 20 different regions of the human genome show some linkage with type 1 diabetes mellitus [31]. Many of these genes carry a risk, others protect.
The strongest linkage is seen for the major histo-compatibility complex, which is located on chromosome 6 (IDDM1 locus). The importance of some HLA class II genes (e.g., DR7, DR9, DQA1 0301, DQB1 0201) differs among ethnic groups [9], as may be true for HLA class I genes. The physiological role of HLA molecules is to present foreign and self antigens to T lymphocytes and to other cells involved in the initiation of insulitis. The region of the insulin genes on chromosome IIp15 (IDDM2 locus) may also be involved. The importance of other type 1 diabetes mellitus-associated gene loci remains open.
Even in monozygotic twins the concordance for diabetes is not more than 50%, which indicates the importance of nongenetic factors. Environmental factors have been mainly studied in laboratory animals. The spontaneous diabetic NOD mouse is the star model, where numerous modulations of the environment or immunomodulatory protocols have been reported to lower the incidence of diabetes mellitus [32]. The ease of this success in preventing diabetes in a mouse model means that the observations cannot be simply transferred to the human situation.
In humans some seasonal variations of incidence with peaks in winter and early spring have been reported [11,33], but they seem to be absent in HLADR 3-positive and very young children [51]. The introduction of cow-milk-based diets before 3 months of age has been accused as a diabetogenic factor, but the epidemiological data remain controversial [34]. A homology of bovine serum albumin and human islet proteins and of immunogenic epitopes on β casein Al which resemble β-cell epitopes (immunogenic mimicry) have been suggested to be responsible for the induction of insulitis. Prospective or controlled intervention studies comparing feeding with cow-milk proteins and breastfeeding will be needed to answer this question [34]. Nitrosamines, various toxins, and infection with rubella, German measles, mumps, coxsackievirus B1, Epstein-Barr virus, and cytomegalovirus have also been discussed as possible causes. With the exception of congenital rubella virus infection [35], definite evidence of a causal role remains to be established.
Type 1 diabetes mellitus is an insulin deficiency syndrome caused by β-cell destruction. This is the result of an immune-mediated disease which leads to chronic inflammation of the islets of Langerhans, called insulitis. Various types of mononuclear cells are involved. On the basis of animal experiments, two types of insulitis may be distinguished [36–38]:
• Benign Th-2 (T-heiper-2 cell) type insulitis is characterized by secretion of interleukin (IL)-4, IL-10, and IL-13 and absence of aggressive immune cells. Cellular infiltration is located in the periphery of the islets and little β-cell destruction is seen.
• Destructive Th-1 (T-helper-1 cell) type insulitis is characterized by secretion of interferon (IFN)-γ;, tumor necrosis factor (TNF)-α, and IL-2 and the presence of cytotoxic T cells and activated macrophages, which migrate into the islets and cause β-cell damage by induction of apoptosis or necrosis.
As a rule, insulitis is a chronic process which may begin in early childhood [39]. Its earliest sign seems to be the appearance of islet autoantibodies in blood, which may be detected many years before clinical diabetes can be diagnosed. Whether insulitis will proceed to clinical diabetes, and how rapidly this may occur, seems to depend on a variety of hitherto hypothetical immune modulatory factors. Th-2 cytokines suppress Th-1 cells and vice versa [40,41]. IF the Th-2/ Th-1 balance is shifted towards a Th-1 dominance, β-cell destruction will proceed until insulin release has dropped so low that blood glucose can no longer be regulated within the normal range, and clinical diabetes will become manifest [42] (Fig. 4.1).
Fig. 1.1a, b Development of type 1 diabetes mellitus. a Insulin secretion in relation to clinical signs. b Insulin secretion in relation to type of insulitis. (Adapted by permission from Martin and Kolb [43])
In recent-onset diabetes, histological analysis of the pancreas shows infiltration by mononuclear cells, mostly T lymphocytes and monocytes/macrophages. Insulin-producing β cells are preferentially attacked. Other lobules of the pancreas may contain either completely insulin-deficient small islets which consist of A, D, and PP cells (A cells secrete glucagon, D cells somatostatin, and PP cells pancreatic polypeptide) or apparently normal islets. Such normal islets may persist for several years after diagnosis and could explain the remission or “honeymoon” phase and different grades of severity of the disease.
B lymphocytes and islet cell autoantibodies are not essential for β-cell destruction [433]. In the early stages of insulitis, glucose metabolism and stimulated insulin secretion are normal. When stimulated, early insulin secretion drops in autoantibody-positive subjects to the 1st percentile of normal, this indicates a loss of more than 80% of the β cells and the manifestation of diabetes mellitus in the very near future [44].
Type 2 Diabetes
Genes and Determination Factors
Type 2 diabetes mellitus is a heterogeneous group of disorders that result from the combination of insulin resistance and impaired insulin secretion. Their etiology “may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance” [3]. A widely accepted pathogenetic model assumes that diabetes develops in carriers of susceptibility genes if they are exposed to determination factors. The idea of a genetic basis is supported by both twin studies and differences in prevalence between ethnic groups [45]. The genetic influence is stronger than in type 1 diabetes (Table 1.5). Multiple candidate genes have been nominated, including “thrifty genes” related to the metabolic syndrome [47,48], but the type 2 diabetes genes are not yet established. The mutations that have been found in MODY [49] play no role in ordinary type 2 diabetes.
Most determination factors are related to insulin resistance (Table 1.6). Some of these factors, such as age, are beyond our control, but most can be influenced.
