1.4.1 Definition
The importance of insulin becomes particularly evident under pathophysiological con-ditions—namely in diabetes mellitus. The chronic hyperglycaemia of subjects suffering from this disease is the result of a combination of genetically determined and acquired defects leading to secretory deficiency of β-cells as well as insulin insensitivity of the target tissues. Diabetes mellitus constitutes a heterogenous group of disorders that share the common feature of chronically increased levels of blood glucose. According to the current criteria of the World Health Organization (WHO) diabetes mellitus is diagnosed if the plasma glucose concentration exceeds 11.1 mM 2 h after a defined (75 g) oral glucose load or is higher than 7 mM in the fasting state.
Based on etiological criteria diabetes is classified into type 1, type 2, gestational and
‘other types’ of diabetes. In the case of type 1 it has been established that this disease originates from an absolute lack of insulin release due to an autoimmune reaction that
1 Introduction
leads to β-cell lysis and islet destruction. Because of the more or less complete absence of nutrient induced insulin secretion, diseased subjects rely on regular injections of the hormone in order to survive. Type 1 diabetes accounts for∼5% of all diabetic cases.
Type 2 diabetes (T2D) is very heterogeneous in itself and is characterized by various combinations of defective insulin release and insulin resistance. The chronic hyper-glycaemia in T2D causes many secondary complications primarily of the micro- and macrovascular system. This leads to a significantly reduced life expectancy and quality of life due to coronary heart diseases, renal failure, stroke, blindness and lower extremity amputations as a result of vascular and nerve damage. T2D accounts for up to 95% of all newly diagnosed diabetes cases and approximately 6% of the European population and more than 170 million people worldwide are afflicted by the disease. Due to its rising prevalence in developed and even more in developing countries it poses an ever greater public health problem (Pickup and Williams,2003).
1.4.2 Etiology of type 2 diabetes
The etiology of T2D is only insufficiently understood but it is considered to be a heterogenous syndrome that usually appears in middle age and is exacerbated by obesity.
Both genetic and environmental factors contribute to a variable extent to the develop-ment of the disease. The genetic background of some rare monogenetic types of T2D like maturity-onset diabetes of the young (MODY) is known but the vast majority of T2D forms is considered to be polygenic (Rhodes,2005).
For a long time the view prevailed, that desensitization of insulin target tissues, i.e.
mainly liver and musculature, is the predominant cause of diabetes. A lack of insulin responsiveness would decrease the amount of glucose cleared from the blood and thus increase the demand onβ-cells to secrete the peptide hormone. This stress would sooner or later lead to β-cell failure. However, there is growing evidence that the decreased secretory capacity ofβ-cells might be the primary genetic factor leading to T2D. In several studies it has been demonstrated that both first degree relatives and monozygotic twins of T2D patients show impaired insulin secretion but normal insulin sensitivity if matched for obesity. This impairment presents itself as prominent reduction of first but also second phase GSIS (Vaag et al.,1995;van Haeften et al.,1998;Gerich,2002).
Furthermore, overt obesity is almost always connected to insulin resistance but only a small fraction of obese individuals develops diabetes (Gerich,2002). This evidence suggests that in most cases β-cells are able to cope with the increased secretory demand by increasing their insulin output. T2D only develops when a genetically determined propensity to β-cell dysfunction is challenged by the increased demand of insulin secretion caused by insulin resistance. This leads to insufficient insulin secretion in relation to the prevailing hyperglycaemia (Cerasi,1995;Gerich,1998,2000;Chiasson and Rabasa-Lhoret, 2004). The reduced capacity to secrete appropriate amounts of insulin is thought to result both from a reduction inβ-cell mass (Rhodes,2005) and from impaired secretory function of singleβ-cells (Kahn,2001).
In contrast to the notion of inheritedβ-cell dysfunction it is frequently stated that the defect is secondary to the toxic effects of the prevailing hyperglycaemia and increased level of circulating fatty acids (hyperlipedemia) in T2D (Prentki et al.,2002). However, in an extensive clinical study it has been shown that even aggressive control of plasma glucose levels does not prevent the deterioration ofβ-cell function (UKPDS,1998).
Many possible lesions would decrease or abolishβ-cell responsiveness to glucose but the primary mechanism of stimulus-secretion coupling in these cells remains largely intact: The closing of ATP-dependent K+-channels and the subsequent depolarization leading to influx of Ca2+ via L-type Ca2+-channels seems to be functional in T2D (Ashcroft and Gribble, 1999). Accordingly, the putative impairment is most likely due to KATP-channel independent mechanisms—for instance being caused by defective glucose metabolism or being attributable to impaired secretory machinery function.
Indeed, a recent finding suggests that the protease calpain-10 (Ma et al., 2001)—
encoded by the only unequivocally identified susceptibility-gene for T2D (Horikawa et al.,2000)—is involved in Ca2+-sensing of theβ-cell secretory apparatus (Marshall et al.,2005). Furthermore, a single nucleotide polymorphism (SNP) in the syntaxin-1 gene has been shown to be frequent in human T2D as well (Tsunoda et al.,2001).
This raises the interesting possibility that similarly as has recently been discussed for schizophrenia (Mirnics et al.,2000;Wong et al.,2004) alterations in the expression of genes coding for exocytotic proteins might be also involved in T2D.
1 Introduction