is the metabolic syndrome, which was first described in 1967 [50] (Table 1.7). Its multifactorial etiology is not yet fully understood [52]. The metabolic syndrome precedes and accompanies overt diabetes. Its components also constitute risk factors for vascular complications. This explains why many subjects already show angiopathies at the time of diagnosis of diabetes mellitus. For this reason, it is reasonable to expand the concept of type 2 diabetes to the early disorders of the preclinical phase, which traditionally have been neglected.
Obesity is closely related to physical inactivity. Both physical inactivity and obesity are associated with type 2 diabetes [53–56]. The relationship is most pronounced in the visceral (android, truncal, abdominal central) type of obesity [57–59]. This type of obesity is in its turn related to aging [60] and to physical inactivity [61]. Increasing abdominal adipose tissue mass and weight gain are predictors of impaired glucose tolerance, dyslipoproteinemia, hypertension, and hyperuricemia [55]. Weight reduction predicts improvement of these risk factors [62] and of life expectancy [63]. This direct relationship indicates that obesity and physical activity are causal determininants rather than being accidentally associated with these disorders.
Table 1.6 Determination factors of type 2 diabetes mellitus
| Family history of diabetes mellitus Age Metabolic syndrome Physical inactivity Western life style Diabetogenic drugs Endocrinopathies and pregnancy |
The importance of life style has been shown in longitudinal studies on, for example. Indians who emigrated to South Africa [64], and Japanese people who emigrated to North America [65], where they developed not only obesity but also diabetes. Thus, a genetic predisposition to diabetes may be revealed only under the influence of a diabetogenic life style. This concept has been confirmed in other populations [66,67] and by intervention studies (see p. 19). It has also been suggested that fetal malnutrition may predispose to the metabolic syndrome [68–71], but this hypothesis has been challenged [72,73].
Insulin Sensitivity
In the majority of type 2 diabetic individuals insulin resistance seems to be a very early or indeed the primary metabolic disorder [74–76]. In the general population insulin sensitivity varies over a wide range. The variation between members of a family is smaller than that between families [91], indicating a genetic determination.
The mechanisms of insulin resistance most likely involve polygenic defects [76] (Table 1.8), which cannot be discussed in this chapter. However, insulin resistance may also be acquired [77]. Some factors that enhance insulin resistance are identical with determination factors of type 2 diabetes (Table 1.6).
The biochemistry of insulin resistance has been extensively studied. Insulin acts through binding to a specific receptor which is composed of two extracellular insulin-binding α-subunits (135 kDa) and two cytoplasmic β-subunits (95 kDa) that carry a tyrosine kinase domain. Insulin binding initiates a conformational change which results in the activation of a tyrosine kinase. Important substrates of this kinase are the receptor itself and the insulin receptor substrates IRS-1 to IRS-4. Processes which are not completely understood connect the hormone to different signaling cascades which trigger either metabolic or mitogenic stimulation (Fig. 1.2).
The effects of insulin are cell-specific (Table 1.9). Insulin stimulates glucose uptake and glycogen synthesis in muscle. Insulin resistance of the muscle may precede impaired glucose tolerance. It usually begins with an impairment of nonoxidative glucose metabolism; later, oxidative glucose metabolism is also involved [91–93]. These defects may contribute to postprandial hyperglycemia.
Table 1.7 The metabolic syndrome originally [50] and today
| 1969 | 2000 |
|---|---|
| Obesity | aObesity, abdominal typeaInsulin resistance |
| Hyperinsulinemia | Hyperinsulinemia |
| Impaired glucose tolerance | aImpaired glucose tolerance, type 2 diabetes Dyslipoproteinemia |
| Hypertriglyceridemia | aHypertriglyceridemiaaLow-HDL cholesterol Small, dense LDL |
| Hyperlipidacidemia | Hyperlipidacidemia |
| Abnormal adipose tissue metabolism | HypertensionActivated hemostasisPlatelet activationLowPAI-1 Low thromboplastinHyperfibrinogenemiaHyperuricemiaHyperandrogenemia in womenaAlbuminuria |
a WHO criteria [51]
HDL, High-density lipoprotein; LDL, low-density lipoprotein; PAI-1, plasminogen activator inhibitor-1
Table 1.8 Causes and candidate genes of primary insulin resistance
| Insulin receptor Insulin binding site (α-subunit) Tyrosine kinase activity (β-subunit) |
| Insulin receptor substrate IRS-1 (polymorphism) [79,80] |
| Glucose utilization CLUT-4 (decreased expression and/or translocation) [81] Glycogen synthase? Hexokinase II? |
|
Others
Rad [82]
Glucagon receptor [83]
Fatty acid binding protein (FABP) [84]
β3-Adrenergic receptor [
|
