Diabetes

Diabetes refers to a group of metabolic disorders that are characterized by increased plasma glucose concentrations and disturbances in lipid and protein metabolism (10). Differing in their aetiology, these disorders are the result from defects in insulin secretion, insulin action, or both.

Perhaps the earliest description of the disease was by the ancient Egyptians as early as 1550 BC.

However, the term “diabetes” which means “to run through” was apparently first used in the second century AD to describe the condition that causes increased urine output. Polyuria was later associated with the sweetness of the urine, as Indian physicians indicated in the 5-6^th centuries the urine’s honey-like taste, stickiness, and its ability to strongly attract ants. However, it was not until Thomas Willis had, in the 17^th century, replicated the observations made by his oriental colleagues regarding the sweet taste of the urine, that the diagnostic procedures started to improve greatly.

Today, according to the diagnostic criteria set by the World Health Organization (WHO), diabetes is assumed when fasting plasma glucose concentration is 7.0 mmol/l, or 11.1 mmol/l after the two-hour glucose load of 75g (11). Importantly, these criteria distinguish individuals with significantly increased risk of diabetic complications and premature death. In a clinical setting, observation of typical symptoms of diabetes, such as excessive thirst, polyuria and weight loss, with a random plasma glucose concentration 11.1 mmol/l may also lead to the diagnosis of diabetes.

2.1.1 Classification of diabetes

Rather than being one entity, a number of conditions with different underlying causes fall under the umbrella term of “diabetes”. The classification of diabetes is based on their aetiological differences. The two major categories of diabetes are type 1 and type 2 diabetes, with the latter being more dominant with respect to the number of affected individuals. These types of diabetes have previously been called “insulin-dependent diabetes mellitus” (IDDM) and “non-insulin-dependent diabetes mellitus” (NIDDM), respectively. The use of these terms is now discouraged, however, as they are based on the description of treatment rather than the pathogenesis. Type 1 diabetes is characterized by an autoimmune destruction of pancreatic islet -cell, while type 2 diabetes results from defects in insulin secretion and is accompanied with insulin resistance.

Although the great majority of patients with diabetes are classified as having either type 1 or type 2 diabetes, a host of other forms of diabetes also exist. Of these, latent autoimmune diabetes in adults (LADA) shares features with both type 1 and type 2 diabetes. Similarly to type 1 diabetes, LADA involves an autoimmune destruction of the -cells. However, it typically has slower rate of progression and later onset. Moreover, affected adults may retain some residual -cell function and may thus not require exogenous insulin at the time of diagnosis.

Idiopathic type 1 diabetes, more commonly observed among individuals of African and Asian origin, does not have evidence of autoimmunity. However, some of these patients have permanent insulinopenia and are prone to ketoacidosis.

Maturity onset diabetes of the young (MODY) is a condition that results from a genetic defect of -cell function. The disease is usually inherited in an autosomal dominant pattern.

Patients with MODY show impaired insulin secretion with minimal or no defect in insulin action. In gestational diabetes, hyperglycaemia of variable severity has its onset or first recognition in pregnancy. The condition may or may not be treated with insulin, and may persist postpartum.

2.1.2 Type 1 diabetes

Type 1 diabetes is a chronic autoimmune disease in which the destruction of insulin producing pancreatic -cells leads to insulin deficiency (12). Although the clinical signs of type 1 diabetes manifest only after a great majority of the -cell population have been lost, several silent immunological events take place prior to that. These events include production of islet autoantibodies (e.g., islet cell, glutamic acid decarboxylase, insulinoma-associated antigen-2, and zinc transporter 8 autoantibodies), and activation of self-reactive lymphocytes that eventually destroy the -cells (13). The onset of type 1 diabetes is typically prior to age 30, but can occur at any age. Although the precise progress to full-blown type 1 diabetes is not known, the disease is considered multifactorial. Type 1 diabetes occurs in genetically predisposed individuals after having encountered some poorly understood environmental risk factors. Putative environmental triggers include certain viruses, environmental toxins, and dietary factors such as early exposure to cow’s milk, or gluten (14). Substantial body of evidence suggests that vitamin D plays a protective role in type 1 diabetes. In the EURODIAB study, vitamin D supplementation in infancy significantly decreased the risk of type 1 diabetes (15). Similarly, in a Finnish study among 10,366 children, both regular and irregular vitamin D supplementation reduced the subsequent risk of type 1 diabetes (16).

Within the Multinational Project for Childhood Diabetes (DIAMOND), the WHO has studied the worldwide incidence of type 1 diabetes (17). In this study, considerable differences in the incidences of type 1 diabetes between countries have been observed. While the highest incidence rates have been observed among European and North American populations, those of the Asian populations are fairly low. Interestingly, of the 57 countries studied during the period 1990–

1999, the highest incidence figures were observed in Finland. Compared to countries like Venezuela and China with a yearly incidence of 0.1/100,000, Finland stood far apart with its 40.9 cases per 100,000 inhabitants every year.

In the same study, a global increasing trend in the incidence of type 1 diabetes was observed.

Worldwide, the mean annual increase during the 10 year period was 2.8%, while the respective figure for Finland was 4.2%. In a Finnish study, Harjutsalo et al. also reported an increase in the incidence of type 1 diabetes (18). Between years 1980 and 2005 the annual incidence was observed to increase from 31.4/100,000 to 64.2/100,000. The increase was particularly large among the children aged 0–4 years. This substantial increase in the diabetes incidence during

such a short time period cannot be explained by alterations in genetic susceptibility alone.

Indeed, various environmental factors are likely to contribute to this increase.

2.1.3 Metabolic syndrome

The metabolic syndrome is a cluster of factors that have been associated with an increased risk of cardiovascular events and type 2 diabetes. These risk factors include abdominal obesity, increased blood pressure, low high-density lipoprotein concentration, and increased fasting glucose and triglyceride concentrations (19).

Reaven introduced the term Syndrome X in 1988 when addressing the relationships between insulin resistance and compensatory hyperinsulinaemia in many patients with impaired glucose tolerance or type 2 diabetes (20). Although compensatory hyperinsulinaemia may prevent the development of distinct hyperglycaemia, individuals with insulin resistance are at heightened risk of glucose intolerance combined with detrimental changes in lipid metabolism and blood pressure (20, 21).

The WHO was the first to give a formal definition for the metabolic syndrome in 1998 (22).

To qualify for the metabolic syndrome, an individual must have either insulin resistance, type 2 diabetes, or impaired fasting glucose together with any two of the following criteria:

hypertension, elevated triglyceride concentrations, low HDL concentrations microalbuminuria or abdominal or overall obesity.

Since the publication of the WHO criteria, a number of other criteria for the metabolic syndrome have been issued. In 2001, the Adult Treatment Panel III (ATP III) published their criteria for the metabolic syndrome (23). As opposed to the WHO, ATP III did not require one essential criterion for the metabolic syndrome, but determined five criteria of equal importance:

abdominal obesity, hypertension, low HDL concentration, high triglyceride concentration and glucose intolerance. The metabolic syndrome was assumed when at least three of these five criteria were fulfilled.

The International Diabetes Federation proposed their criteria for the metabolic syndrome in 2005 (24). Similarly to ATP III, they used five criteria but emphasized the importance of the abdominal obesity which had to be accompanied with any two of the remaining criteria. In 2009, a number of organizations published a joint statement with “harmonized” criteria for the metabolic syndrome, and once again removed adiposity from the centre of the syndrome to being just one of the five components (19).

Despite extensive research conducted around the metabolic syndrome, the concept of the syndrome remains controversial. According to some views patients should not be labelled with the metabolic syndrome diagnosis but rather all cardiovascular disease (CVD) risk factors should be individually and aggressively treated (25). Indeed, the WHO has stated that the metabolic syndrome should not be a clinical diagnosis but instead it should be viewed as a pre-morbid condition (26).

Traditionally, the metabolic syndrome has been associated with type 2 diabetes. However, clustering of the same risk factors is also evident among patients with type 1 diabetes. Among the FinnDiane population, the overall prevalence of the metabolic syndrome in men and women was 38% and 40%, respectively (27). Importantly, beyond the traditional risk factors, the

metabolic syndrome has been shown to be an independent risk factor for cardiovascular events in type 1 diabetes (28).