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J Am Soc Nephrol 18: 1619-1623, 2007
© 2007 American Society of Nephrology
doi: 10.1681/ASN.2007040522
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Nephrology beyond JASN

Metabolic Syndrome—What We Know and What We Don't Know

LPR6 Mutation in a Family with Early Coronary Disease and Metabolic Risk Factors. Science 315: 1278–1282, 2007

ManiAr. , RadhakrishnanJ. , WangH. , ManiAl. , ManiM.A. , Nelson-WilliamsC. , CarewK.S. , ManeS. , NajmabadiH. , WuD. and LiftonR.P.


Figure 1
Eberhard Ritz Feature Editor

What has been called the "metabolic syndrome" is one of the great challenges to health care. Even at present it has assumed catastrophic proportions, but it poses an even greater threat in the future (1). Almost a century ago, several authors had observed that risk factors such as obesity (particularly visceral obesity), prediabetes or diabetes, hypertension, hyperuricemia, hyperlipidemia, and others cluster (2–4), but the full impact of this phenomenon has been felt only recently with the onset of widespread caloric overnutrition and physical inactivity (5). Particularly threatening are obesity and metabolic syndrome in the young—a dire perspective for health and life expectancy in future generations (5). The "renaissance" of the metabolic syndrome began with G.M. Reaven's famous Banting lecture on insulin resistance as the basis of syndrome "X" (6). With questionable arguments (7), it has been assumed that insulin resistance is the pathophysiological basis underlying the metabolic syndrome. At any rate, this concept has generated enormous interest as reflected by no less than 19,277 publications on this subject quoted by PubMed.

Apart from their association with cardiovascular risk and the high incidence of hypertension, cardiac disease, and stroke, obesity and the metabolic syndrome predispose to kidney disease, either directly (8–10) or indirectly via increasing the prevalence of diabetes and hypertension. In the retrospective-prospective Kaiser Permanente study of Hsu et al. (8), the increased risk of end-stage renal disease (ESRD) persisted even after correction for the latter two confounders. The argument of a direct effect is further supported by the observation in the Framingham study that new-onset chronic kidney disease (CKD) is correlated to the body mass index (BMI) (11) and by a nationwide Swedish study documenting that ESRD is also correlated to BMI (12). The prevalence of the metabolic syndrome with its renal sequelae (13–15) is high in the US and in Western Europe, but renal sequelae are not restricted to the Western world (16,17). It is of interest that the critical BMI for the occurrence of ESRD is apparently less in Asians, ie, 22 kg/m2 (18), than in Caucasians, ie, 25 kg/m2 (19), which is in line with the well known lower BMI threshold for cardiovascular risk in Asians (20). Obesity, particularly visceral obesity, increases the risk and the magnitude of albuminuria (21,22) in nondiabetic and diabetic (23,24) patients. The hypothesis that obesity is causal is further supported by the observation that obesity accelerates the progression of primary renal disease (25,26) and that intentional weight loss reverses this trend (27).

Obesity with the features of the metabolic syndrome causes renal dysfunction (28). It increases glomerular filtration rate (GFR), renal blood flow (RBF), and filtration fraction (FF) in experimental and clinical observations (29–31), causes glomerulomegaly (32,33), and in extreme cases leads to focal-segmental glomerulosclerosis (34,35)—sufficient reasons for the nephrologist to be interested in the topic of obesity and metabolic syndrome.

The original idea behind the concept of the metabolic syndrome was to list a cluster of risk factors so as to capture in the present epidemic of obesity the individuals at highest cardiovascular risk deserving particularly intensive intervention. With this laudable intention in mind, the National Cholesterol Education Program (NCEP), the International Diabetes Federation (IDF), the World Health Organization (WHO), the European Group for the Study of Insulin Resistance, the American Association of Clinical Endocrinologists, and other groups established criteria for the diagnosis of this syndrome. The most widely used criteria (NCEP Adult Treatment Panel III) include waist circumference, triglycerides, HDL-cholesterol, blood pressure, and fasting glucose (36).

This catalog has been criticized for several reasons. On the one hand its predictive power is substantially lessened by the fact that continuous variables were dichotomized and correlated factors were included, which caused them to lose power as independent predictors, and on the other hand two highly predictive factors, age and smoking, were not included (9). Therefore it comes as no surprise that alternative predictors such as the Framingham score or microalbuminuria are more potent predictors in the general population (9) and in diabetics (37).

A more fundamental critique was raised by Kahn et al.38, who argued that the role of insulin resistance as the unifying concept was uncertain in the NCEP Adult Treatment Panel III catalog, that the selection of the criteria was arbitrary, and the medical value of the syndrome unclear. G.M. Reaven, who had launched the concept of a risk factor cluster related to insulin resistance, joined the discussion with an article entitled "The Metabolic Syndrome: Requiescat in Pace" (7).

Certainly the concept of metabolic syndrome may be useful in raising public awareness of the obesity issue and for filtering out those obese patients with the most adverse metabolic profile and in greatest need of intervention—but as a scientific instrument it is a blunt sword.

What this discussion illustrates is that the topic is the incomplete understanding of the pathogenesis. The latter is underscored by a completely unexpected observation linking the features of the metabolic syndrome to a pathway that even the most intellectually enterprising investigators had not thought of. The observation goes back to a unique Iranian family that was an extreme outlier kindred with an extraordinary prevalence of coronary artery disease despite no history of smoking and despite normal body weight. Of the 58 family members, the 28 individuals affected with autosomal early coronary artery disease had hyperlipidemia, hypertension, and diabetes, as well as osteoporosis causing low-impact hip fractures in some individuals. In the affected individuals the mean LDL cholesterol concentration was 176 mg/dl, the mean fasting triglycerides 240 mg/dl, the mean BP 175/103 mmHg, and late type-2 diabetes was present in 77%. Astonishingly, HDL cholesterol was normal. Almost all individuals fulfilled the NCEP Adult Treatment Panel III criteria of the metabolic syndrome (36). The pattern of inheritance suggested a highly penetrant autosomal dominant trait.

A genome-wide analysis of linkage assessing all single nucleotide polymorphisms (SNP) demonstrated linkage to a segment of chromosome 12p. The relevant interval contained only 6 genes, among which is LRP6 (LDL receptor-related protein), a protein in the Wnt signaling pathway. This candidate gained plausibility from the observation that mice deficient in its paralog LRP5 are characterized by hypercholesterolemia and impaired glucose tolerance on a high-fat diet (39) and on a specific genetic background (apoE–/–) (40). In addition, in humans LRP5 determines bone mass, loss-of-function mutations causing low bone mass, and gain-of-function mutations causing high bone mass (41).

Sequencing of LRP6 showed a missense mutation (R611C) in an epidermal growth factor (EGF)-like domain preserved from Xenopus to humans—obviously of substantial functional significance. Carriers of this mutation had higher triglycerides, blood pressure, fasting blood glucose, and prevalence of diabetes. In vitro studies in a cell line showed that the mutant LRP6 reduced Wnt signaling.

A brief comment: What is the Wnt pathway? Two decades ago a proto-oncogene of virally-induced mouse mammary tumors (int-1) and a homologous gene coding for segment polarity of Drosophila during larval development (wingless; wild-type) were identified (42). The term Wnt reflects the two founder observations. This phylogenetically old class of related cysteine-rich glycoproteins is involved in vertebrates and invertebrates in a highly conserved signaling cascade. Wnts bind frizzled (Fz) proteins, transmembrane receptors that cooperate with transmembrane molecules of the above-mentioned LRP family, LRP5 and LRP6 in vertebrates. It has been suspected but not proven that Wnt, frizzled, and LRP form a trimolecular complex (43). A secreted antagonist named Dickkopf (Dkk) inhibits Wnt signaling by directly binding to LRP5 and LRP6 (44). Wnt signaling and LRP6, among others (45), is not only involved in development and organogenesis but is necessary in adult life as well. To the nephrologist it is of interest that the Wnt pathway is involved in branching of epithelial tubules (46), including renal tubules (47,48), and its components are expressed by tubular cells in proteinuric nephropathies (49) and play an important role in the genesis of polycystic kidney diseases (50).

Why is the observation of Mani et al. (51) so interesting and important? It is not because this is a common defect; indeed, the authors were unable to find a comparable mutation in a sample of 400 unrelated subjects with coronary heart disease. But the discovery that disturbance of the Wnt signaling pathway reproduces facets of coronary heart disease and the metabolic syndrome may well provide novel targets for intervention in more common varieties of metabolic syndrome. The metabolic syndrome certainly is not a monogenic disease and it is likely that many genetic determinants, apparently also the Wnt pathway, are involved in its genesis.

Not least of all, the finding of Mani et al. (51) illustrates how incomplete our current knowledge of the metabolic syndrome is, justifying the warning against rash extrapolations (7,38).


   Footnotes
 
Address correspondence to: Prof. Eberhard Ritz, Department Internal Medicine, Divisionof Nephrology, Bergheimer Strasse 56a, D-69115 Heidelberg, Germany. Phone: +49-0-6221-601705 or +49-0-6221-189976; Fax: +49-0-6221-603302; E-mail: Prof.E.Ritz{at}t-online.de


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