The history and the definition of metabolic syndrome

The status like MetS was reported as early as in 1920s [1,2]. The word MetS itself was first used by Haller [3]. He mentioned about the risk of atherosclerosis associated with obesity, diabetes mellitus, hyperlipoproteinemia, hyperuricemia, and steatosis hepatis.

Reaven described that insulin resistance is the key factor of this phenomenon [4]. He proposed that insulin resistance is closely related to impaired glucose tolerance, hyperglycemia, hyperlipidemia and hypertension. He called this as “Syndrome X”. Then, Kaplan proposed the idea “Deadly quartet”, upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension [5].

WHO first made criteria for MetS in 1999 [6], consisting of obesity, hyperlipidemia, hypertension, hyperglycemia, insulin resistance and albuminuria [6]. Some other criteria have been published later, but it seems to be difficult to adapt the single criterion perfectly to all people, as there are genetic and environmental differences among people.

Metabolic syndrome and insulin resistance, hypertension

The criteria of MetS are still hotly debated [7,8], but insulin resistance is recognized as one of the key factors of MetS. The definitions of the American Association of Clinical Endocrinology (AACE) [9], WHO [6] and the European Group for the study of Insulin Resistance (EGIR) [10] focus on insulin resistance, whereas the widely used definitions such as, the National Cholesterol Education Program Adult Treatment Panel III criteria (NCEP-ATP III) [11], its modified version the American Heart Association / National Heart, Lung, and Blood Institute criteria (AHA/NHLBI) [12,13] and the International Diabetes Federation criteria (IDF) [14] rather focus on waist circumference. Nevertheless, as Reaven described, insulin resistance is related to pathogenesis of hyperglycemia, fatty acid dysregulation, and hypertension [4].

As for salt-sensitive hypertension, the relationship with MetS and insulin resistance has been pointed out. Uzu and colleagues have reported associations between the presence of MetS and salt-sensitive hypertension [15]. In essential hypertension, there are several reports that describe impaired insulin signaling [16-22]. McFarlane and Sechi showed direct correlation between plasma insulin levels and blood pressure in such patients [17,18]. Genetic background is thought to be important in both essential and salt-sensitive hypertension; it has been observed that offspring of hypertensive parents has abnormal glucose metabolism. As the relationship between hyperinsulinemia and hypertension is not seen in secondary hypertension, insulin resistance and hyperinsulinemia may not be consequences of hypertension [18,19].

In human the anti-natriuretic action of insulin is seen [23], which is supportive for the idea that hyperinsulinemia may contribute to the onset of hypertension via sodium retention in the kidney [24,25]. On the other hand insulin itself stimulates nitric oxide (NO) production, which relaxes the vascular tone through the phosphoinositide 3-kinase (PI3K) / Akt pathway [21,26], suggesting that hyperinsulinemia itself may not directly induce hypertension in the absence of insulin resistance [27]. However, in insulin resistance condition, it has been observed that the NO production stimulated by insulin is attenuated [28]. The resultant attenuated vasodilatation by insulin may underlie the onset of hypertension in insulin resistance condition.

In molecular aspects, there are some types of inherited hypertensions, e.g. Liddle’s syndrome [29] and pseudohypoaldosteronism type II or familial hyperkalemic hypertension (FHH) [30]. Although they never represent as common diseases, the investigations of the mechanism of these diseases have led to clarify novel signal transduction systems that may play important roles in the pathogenesis of MetS and hypertension. Liddle’s syndrome is due to mutation in epithelial Na channel (ENaC) in the distal tubule [31], whereas FHH is due to the abnormality in kinases (with-no-lysine [K] kinase; WNK 1~4) [32]. In addition to these distal nephron Na transport systems, however, the Na transport in proximal tubules may be also related to the pathogenesis of hypertension, as will be discussed below.

Insulin effect on renal proximal tubule and sodium transport

Insulin exerts its action on kidney, especially the whole nephron. As to proximal tubule, insulin accumulates in the proximal tubule [33]. In rabbit insulin binds to various segments of nephron [34], whereas insulin accumulates strongest in the proximal tubule of rat nephron [35]. Insulin is delivered to proximal tubule by two ways: by glomerular filtration and subsequent reabsorption from tubular cells, and by diffusion from peritubular capillaries and subsequent binding to insulin receptors [36].

So far it is known that insulin stimulates sodium reabsorption in the proximal tubule [23]. Insulin also stimulates volume absorption in rabbit proximal tubule, via basolateral side [37]. As proximal tubules reabsorb about seventy percents of total sodium filtered from glomeruli, the stimulation of proximal sodium reabsorption by insulin may well contribute to the increase of total fluid volume in the individual, leading to hypertension.

Gesek and Schoolwerth showed that in rat proximal tubule the activity of Na⁺-H⁺ exchanger type 3 (NHE3) is increased by insulin [38]. As NHE3 plays quite a significant role in the apical side of proximal sodium reabsorption, this effect of insulin is quite important. The cellular mechanism of insulin action was investigated by Lee- Kwon et al. [39,40] and Shiue et al. [41]. It is not still totally clarified but Akt seems to play a critical role in the PI3K mediated translocation of NHE3 into apical membranes of proximal tubular cells.

Ruiz et al. showed that insulin stimulates Na⁺-HCO₃ - cotransporter (NBCe1) in the basolateral side of proximal tubule [42]. Na⁺-K⁺- ATPase also plays a role in the Na⁺ reabsorption in the proximal tubule and is a target of insulin stimulation [43,44].

Difference of insulin signals between organs – tubules and adipose tissues

As described above, insulin has a significant effect on renal proximal tubule, but its mechanism is still under investigation. As for sodium transport we have examined the insulin signal transduction mechanism involving IRS1 and/or IRS2 [45]. In wild-type mice and IRS1-/- mice insulin significantly stimulated Na⁺-coupled HCO₃ - absorption but the stimulation was significantly attenuated in IRS2-/- mice. Moreover the Akt phosphorylation induced by insulin stimulation, which might mediate the effect of insulin on proximal absorption, was preserved in IRS1-/- mice but significantly reduced in IRS2-/- mice. In proximal tubule the tyrosine phosphorylation of IRS2 by insulin seems to be more prominent than that of IRS1, consistent with a major role of IRS2 in insulin-mediated transport stimulation in proximal tubule. Signaling defects specific to IRS1 are frequently showed in insulin resistance [46-49]. Our results suggest that the stimulation of proximal tubule transport by insulin may be preserved even in insulin resistance.

In fat tissue, which is one of the common tissues that insulin resistance arises, IRS1 seems to play a major role in the insulin signal transduction. Hotamisligil and colleagues first described that in mice adipose tissue TNF-α plays an important role in the development of insulin resistance [50]. TNF-α induces inflammation, leading to inhibition of IRS1/2 signal transduction pathways [51-53], and may inhibit the insulin signaling through the serine phosphorylation of IRS1 [54]. It is now established that IRS1 is phosphorylated at serine residues by various kinases [51]. These kinases seem to interfere with IRS1 functions, resulting in inhibition of insulin-receptor signaling and alteration in insulin action [55-57].

As described here, IRS2 signaling seems to be prominent in the proximal tubule, whereas IRS1 signaling seems to be major in adipose tissue. This difference in signaling pathways could explain the different responses to insulin between kidney and adipose tissue. Especially, even in insulin resistance, insulin signaling seems to be preserved in the proximal tubule, stimulating sodium and fluid reabsorption followed by hypertension. This may explain one of the important pathogenesis of hypertension under insulin resistance condition.

On the contrary in the glomeruli the insulin signal transduction seems to be reduced as in adipose tissue, as will be described in the next chapter.

Insulin effect in animal models: difference between glomeruli and tubules

Several rat models have been used to investigate the insulin effects in MetS condition and the mechanism of insulin resistance. One of the rat models is Otsuka Long-Evans Tokushima Fatty (OLETF) rat [58]. This rat has a defect in cholecystokinin -A (CCK-A) receptor [59], resulting in obesity due to overeating [60]. Compared to its counterpart control rat (Long-Evans Tokushima Otsuka rat; LETO rat), OLETF rat begins accelerated weight gain at 5 weeks of age, leading to about 40% excess of weight than LETO rat. Moreover, OLETF rat develops hyperglycemia and type II diabetes mellitus at about 18 weeks of age, resulting in insulin deficiency after 65 weeks of age [58].

Our group investigated whether the effect of insulin on the proximal tubule of OLETF rats is preserved or not [61]. We also investigated the adipose function under insulin resistant condition in these rats. The stimulation of glucose uptake into adipocytes by insulin was severely impaired in OLETF rats compared to LETO rats, indicating that OLETF rats develop insulin resistance in adipose tissue. In sharp contrast, the stimulation of NBCe1 by insulin was comparable in both rats. In OLETF rats Akt phosphorylation by insulin was preserved in renal cortex tissue but severely reduced in adipocytes. These results suggest that in general obese condition, such as MetS and/or insulin resistance, hyperinsulinemia may contribute to the emergence of hypertension by facilitating renal Na absorption.

In glomeruli the signal transduction pathway by insulin seems to be differently affected from that of proximal tubules, rather as is in adipose tissue. King and colleagues have recently clarified that the responses to insulin in rat models of diabetes and obesity – Zucker lean rats and control SD rats - are different between glomeruli and tubules [62]. In the glomeruli insulin-induced phosphorylation of IRS1, Akt, endothelial nitric oxide synthase (eNOS), and glycogen synthase kinase 3a (GSK3a) were all inhibited in glomeruli but not in the tubules. The defect in glomerular insulin signaling was similar to that in all other vascular tissues when exposed to insulin resistance and diabetes [63,64]. On the other hand, renal tubules seemed to be selectively protected from developing insulin resistance. This conclusion seems to be consistent with the preserved insulin action on proximal tubule in OLETF rats [61].

One of the organ dysfunction elicited by MetS should be diabetic nephropathy (DN) [65]. The pathogenesis of DN is still under investigation. As to type I diabetes, the presence of insulin resistance seems to be necessary for the onset of DN [66]. Coward and colleagues have shown that the glomerular podocyte plays the key function in insulin signal pathway [67]. They created two types of mice model with podocyte-specific insulin receptor knockout and showed that insulin rapidly and directly signal to the podocyte, and directly and specifically reorganize the actin cytoskeleton of podocytes. It has been known that the main damaged cell type in human DN is podocytes with foot widening [68,69]. Other group showed that the similar knockout mice (podocyte insulin-receptor knockout) developed albuminuria and had histological changes characteristic to DN, e.g. loss of podocyte morphology, and even podocyte apoptosis [70]. As podocyte loss is an important feature of DN that occurs in the relatively early stage and is a good predictor of disease progression [69,71], investigations of the insulin effect on podocyte may help develop the new strategy for prevention and treatment of DN.

Does improvement of insulin resistance ameliorate kidney function?

The relation between MetS and kidney function has been vigorously investigated. Several studies suggest that the improvement of lifestyle and use of drugs may ameliorate kidney function. For example, exendin-4, one of the anti-diabetic drug glucagon-like peptide-1 analogues has been suggested to ameliorate diabetic nephropathy [72]. Other anti-diabetic drug, peroxisome proliferator- activated receptors gamma (PPAR-γ) agonist, was proved to ameliorate mesangial expansion, improve GFR, and reduce albuminuria [73-75]. As for life style it has been shown that in MetS subjects exercise induced improvement in renal function [76]. However, there has been no clear evidence showing direct relation between kidney function and insulin resistance. Further investigations will be required to solve this issue.

MetS is the main life-threatening disorder in developed and some developing countries. It is also a menace to kidney probably due to concomitant insulin resistance and following diabetes and hypertension. The criterion of MetS is still not completely established but insulin resistance is certainly a key factor of MetS.

In insulin resistance condition, the signal transduction pathway of insulin is impaired in most organs and tissues. However, the situation may be different in proximal tubule. In proximal tubules the insulin signaling pathway is probably preserved and, hence, hyperinsulinemia may stimulate proximal transport. The resultant sodium retention, together with the impaired vasodilatation by insulin, may induce hypertension. In contrast, glomerulus may develop insulin resistance like other vascular system. In particular, podocytes seems to be mainly affected by insulin resistance, responsible for the histological change characteristic to DN. Figure 1 summarizes the potential effects of MetS on insulin signaling in the kidney.

Figure 1: Effects of MetS on insulin signaling in the kidney. In the glomerulus insulin resistance induced by and/or concomitant with MetS leads to the impairment of insulin signaling in the glomerulus. This leads to diabetic nephropathy probably due to podocyte injury. In contrast in the proximal tubule insulin signaling is preserved, and hyperinsulinemia triggers increment of proximal reabsorption and hypertension.

To prevent kidney impairment by insulin resistance, two different approaches may be required; for proximal tubules it is necessary to prevent the excessive stimulation of reabsorption by insulin, whereas for glomerulus the prevention of podocyte injury may require the improvement of insulin signaling.