Adapted from [120]
Frequently the manifestation of type 1 diabetes seems to be precipitated by coincident diseases that increase the insulin requirement, such as infections, pregnancy, hyperthyroidism, glucocorticoid treatment, or severe somatic stress (myocardial infarction, major surgery, etc,).
In about two-thirds of subjects a remission will follow the initiation of therapy. The required insulin dose decreases and metabolism stabilizes due to some recovery of insulin and C-peptide secretion together with improved insulin sensitivity. The remission period can be prolonged by experimental immunomodulatory therapy [123]. However, sooner or later the individual will become C-peptide-negative. After some weeks or months, remission is usually followed by a relapse and the development of irreversible clinical diabetes, which under unfavorable conditions may proceed to end-stage diabetes with chronic complications.
If diabetes mellitus is suspected, the diagnosis should immediately be checked by laboratory tests. If the diagnosis is confirmed, it is advisable to start therapy and normalize the metabolism promptly, because this seems to improve the chances of inducing a remission [124].
Treated type 1 diabetes mellitus is not associated with hypertension, lipid disorders, or obesity. However, this does not rule out their existence at diagnosis or that they may develop later. The further course of the disease is determined by the lability of the metabolism, problems of insulin substitution, glucose monitoring, hypoglycemia, and hyperglycemia. The quality of metabolic control is the main determinant of the prognosis.
Type 2 Diabetes
In the majority of cases the disease begins as a metabolic syndrome. In this early stage most symptoms are reversible. Progression to clinical diabetes is not inevitable. The progress of the blood glucose disorder from impaired fasting glucose or impaired glucose tolerance to overt diabetes may take years. Even when diagnostic criteria are reached, hyperglycemia may not cause the classical symptoms, and glucosuria may be minimal or lacking due to an elevated renal threshold. Other symptoms will often be misinterpreted as a normal attribute of aging. Thus, it may take a couple of years until diabetes is diagnosed.
In contrast to type 1 diabetes mellitus, glucose metabolism in type 2 diabetes mellitus is usually fairly stable. However, treatment is usually more difficult than in type 1 diabetes because it requires life-style changes. The disorder tends to increasing severity, and over the years it becomes more and more difficult to achieve near-normal metabolic control [125]. As in the case of type 1 diabetes, the prognosis of type 2 diabetes depends on the quality of metabolic control. However, in addition to glucose metabolism, the other components of the metabolic syndrome such as obesity, hypertension, and dyslipoproteinemia, and life style are equally important.
The chronic complications of diabetes - mainly microangiopathy, neuropathy, and macroangiopathy - are major problems, because they determine the prognosis and quality of life of the patients. Although the details of their pathogenesis are not fully understood, there is no doubt that the diabetic condition is the major cause. Epidemiological studies have shown that their incidence increases with poor metabolic control [126–132] and can be reduced by lowering HbA1c[127,130,131,133]; however, the beneficial effect of strict metabolic control on macroangiopathy is rarely significant [127,130,133–135]. Many proposals have been put forward to explain “diabetes the risk factor,” which forms a network of potentially pathogenetic mechanisms. Recent articles have covered specific topics and the reader is referred to these publications [136–145]. It is not the aim of this short introduction to add another review.
In addition to insulin deficiency/hyperglycemia. other pathogenic factors such as adverse life style, hypertension, lipid disorders, proteinuria, unfavorable hemorrheology, and activated hemostasis are also involved. These will be mentioned in the context of the various clinical manifestations.
The following section outlines the role of hyperglycemia in the pathogenetic network leading to microangiopathy [146–149].
Introduction to the Pathogenesis of Microangiopathy
Hyperglycemia has three important effects that are to some extent interdependent: nonenzymatic glycation, activation of the polyol pathway, and generation of reactive oxygen species (ROS).
The formation of early glycation endproducts (Schiff base and Amadori products) is reversible, but glycated long-lived molecules like DNA and matrix/basement membrane proteins may undergo irreversible cross-linking and other not yet fully understood complex reactions to form advanced glycation endproducts (AGE).
This process leads to considerable changes in their three-dimensional structure and function. Glycated LDL (low-density lipoproteins) are more atherogenic than nonglycated LDL The charge of matrix proteins may be altered, leading to increased permeability, and basement membrane proteins may become resistant to degradation andincrease in thickness and stiffness. AGE may impair the relaxation of vessels by quenching nitric oxide [150]. Moreover, they favor coagulation and thrombosis and initiate atherosclerosis by stimulating macrophages to express AGE receptors (RAGE) and to release cytokines such as TNF-α. IL-1. and IGF.
The activation of the polyol pathway leads to the accumulation of sorbitol, which is followed by myoinositol depletion and inactivation of Na+-K+-ATPase channels. In addition, the production of fructose and sorbitol, which contribute to the formation of AGE, is increased.
There is much evidence that both advanced glycation endproducts (AGE) and high glucose are able to induce the generation of ROS in various types of vascular cells and that this process plays an important role in the initiation of vascular complications in diabetes. In addition to the autoxidation of glucose, three different mechanisms of ROS production are presently under debate:
1. Activation of a membrane-bound, macrophage-like NADH-oxidase. Activation of NADH-oxidase in endothelial cells and smooth muscle cells has been reported in subjects with hypertension and hypercholesterolemia.