Anna Giulia Cattaneo, M.D.
University of Insubria, DBSF, via J-H. Dunant, 3 - 21100 Varese.
The metabolic syndrome is an insulin-resistant state associated
with obesity and hypertension conditioning, if not adequately
managed, a substantial increment (more than twice) of the
cardiovascular disease hazard and mortality rate.
While it can be well established even in adolescents, its
prevalence shows an age-dependent increment, with a percentage
approaching 50% after the sixth decade of life. No differences
have been found between sexes.
The appearance of this syndrome late in life, the increment
of people reaching old age and even extreme aging, and the
spread of unhealthy lifestyles suggest the possibility of
a significant increment of the metabolic syndrome and its
associated pathologies in a near future. Complications can
be much more severe in aged people, in which the amount of
physical exercise necessary to grant an amelioration can be
hardly obtained, and the liver, the skeletal muscle and the
cardiovascular system channels can be seriously injured, independently
from syndrome itself. These same tissues represent the target
of potentially toxic substances acting in metabolic syndrome.
Free fatty acids, angiotensin II, insulin and a variety of
products of the adipose cells negatively affect insulin sensitivity,
glucose uptake and in general metabolic and energy processes
in hearth, liver and endothelia. A clear association exists
between increased RBC Na+-Li+ counter transport and a metabolic
syndrome of insulin resistance, hypertriglyceridemia, and
low plasma high-density lipoprotein (HDL) cholesterol, possibly
explaining the hypertensive fingerprints. The prothrombotic
state is another condition seriously aggravating both welfare
and health in aged people. Better pathogenesis knowledge,
leading to better early diagnosis, prevention and treatment,
seems to be highly desirable.
The diagnostic criteria have been stated by a number of medical
authorities: those dictated by the WHO are well representative
of other schedules, and are summarized as follows:
" Metabolic syndrome is confirmed in the presence of
insulin resistance (FBG?110 mg/dl), or impaired glucose tolerance,
or type 2 diabetes mellitus. This predominant feature must
be associated with at least two of these conditions: hypertension
(BP?140/90, not treated), BMI>30 and/or W/H>0.9 (M)
or 0.85 (F), plasma triglycerides?150 mg/dl, HDL cholesterol<35
(M) or <40 (F) mg/dl, albuminuria >20 mg/min.
The WHO group on diabetes definition, in accordance with the
American Association of Clinical Endocrinologists (AACE),
considers a primary, genetic trait for insulin resistance
as the necessary and dominant fingerprinting for the development
of metabolic syndrome. A complete list of candidate genes
for primary insulin resistance is hardly to found, and exceeding
the limits of this presentation. For that reason, only papers
published during the last two years on the argument are reported
here: for those eventually interested to this argument, a
wider bibliographic list is reported at the end of the Editorial.
" CAPN5 and 10: These genes codify for calpains, calcium-dependent
cysteine proteases involved in signal transduction. Products
of CAPN5 and CAPN10 are atypical calpains, lacking the calmodulin-like
domain characterizing other molecules of the same group. Variants
of CAPN5 and CAPN10 genes have been found associated with
metabolic syndrome or its component (insulin resistance, cardiovascular
risk, and type II diabetes). The encoding region of CAPN10,
associated to the type II diabetes, is located on the chromosome
2, within the NIDDM1 region (2q).
" PPARG: The protein encoded by this gene, the peroxisome
proliferators-activated receptor, is a regulator of adipocyte
differentiation. Splicing variants of the gene, located on
the chromosome 3, are associated to obesity and insulin resistance.
" ENPP1: The encoded protein may function to hydrolyze
nucleoside 5' triphosphates to their corresponding monophosphates
and may also hydrolyze diadenosine polyphosphates. The K121Q
allele of this gene is associated with features for metabolic
syndrome both in children and in adults. The gene is located
on chromosome 6.
" SERPINE1 (alias PAI-1): genotype 4G/4G has been found
associated with obesity and symptoms for future development
of metabolic syndrome in children. The gene encodes a peptidase
inhibitor, and is located on chromosome 7.
" URS2 and URS2R are genes encoding for urotensin 2 and
its receptor, and located on chromosome 1 and 17. A mutant
of each gene has been found associated to higher risk for
developing insulin resistance, impaired glucose tolerance
(IGT) and type II diabetes.
It could be easily deduced from these partial results that
a wide variety of functions seems to be affected by genetic
alterations potentially involved in insulin resistance development,
and genes are dispersed everywhere in the genome. Recently,
a locus on chromosome 15 (15q) has been found in association
with the metabolic syndrome. However, the same Authors observed
suggestive evidence of linkage on other chromosomes (1p, 3p,
3q, 6q, 7p, 19q, and 21q).
Even polymorphism found in the mitochondrial genome (16189T>C)
is associated to the development of insulin resistance end
metabolic syndrome (Ann. N.Y.Acad:Sci., 2005, 1042, 1-18).
The complexity of the cumulative view is even enhanced when
a complete list of putative genes and mutations is considered,
but the interpretation of the phenotype remains unclear. The
large number of hypothesis formulated to explain the insulin
resistance in these individuals gives the impression of an
incomplete, poorly integrated framework. It is possible that
further studies, planned to test large numbers of genes in
selected cases, in which the syndrome at its beginning is
present in an incomplete form, with only insulin resistance
and moderate overweight, could help to a better understanding.
In fact, clinical and epidemiological studies have been done
focusing the attention on genes potentially involved in the
mechanism for development of the diseases complicating the
syndrome: hypertension, or diabetes, or cardiovascular risk,
and so on. This could be confounding.
However, on a clinical point of view, the importance to cure
and prevent at the best the metabolic syndrome derive from
complications associated to it, which can be dramatic. Insulin
resistance is not responsible in itself for the increased
morbidity and mortality in subjects affected by the syndrome;
on the contrary, when one or more of associated conditions
are present, they act by an additive pattern on the increased
risk of coronary hearth disease and its mortality rate.
Obesity, physical inactivity and aging play their role in
increasing the risk for developing atherogenic dyslipidemia,
hypertension, prothrombotic and proinflammatory state and
increased blood glucose levels, but these effects seems to
limited to subject presenting a basic insulin resistance.
Clinical strategies for control of metabolic syndrome cannot
act on genetic predisposition, or on aging process, but can
be directed against obesity and inactivity by modulating diet
1. A multiple step reduction of body weight based on diet
and exercise as been proposed as an efficient preventive and
therapeutic approach. Steps are on a yearly base: in this
time the goal is to loss 10 kg. The time of treatment will
be conditioned by the gravity of obesity degree, but the rate
of weight reduction should not be subordinated to the entity
of excess of body weight. A reduction of 10 Kg per year can
be easily reached by a caloric reduction of 300 Cal/day (or
100 Cal/day if exercise is associated).
2. When worsening of clinical conditions occurs despite a
well planned prevention schedule, or in subjects not easily
managed or presenting an advanced state of disease, it can
be necessary to add drugs. Suggested drugs to treat hypertension
are ACE inhibitors and angiotensin receptor blockers, atherogenic
dyslipidemia can be controlled with nicotinic and fibric acid,
and the prothrombotic status, for which anticoagulants are
considered be poorly appropriate to treat metabolic syndrome
seems to be adequately treated with low-dose aspirin or other
3. Open diabetes does not appear promptly, but the shift from
simple impaired glucose tolerance and open diabetes can be
easily checked by measuring at several months intervals both
glucose and insulin levels in blood. The progression from
normal state to type 2 diabetes is accompanied by the appearance
of an U-shaped curve of insulin secretion. Fasting plasma
insulin levels rise as fasting glucose levels climb into the
range of impaired glucose tolerance but then fall as diabetes
develops and worsens. The sign is present when fasting levels
are checked, but even with measures of postprandial or glucose-stimulated
glycaemia and insulinemia. This fact gives the time to start
an appropriate prevention of worsening, by acting on unhealthy
lifestyle. Diet and exercise have been documented to be much
more effective than drugs treatment. Failure to treat can
allow a cautious addition of metformin, the drug of choice.
Alphaglucosidase inhibitors and thiazolidinediones represent
possible options. It should be kept in mind the central role
played by insulin resistance in this syndrome, so different
from common diabetes: that is the reason for considering poorly
adequate, in the majority of cases, the use of sulfonylureas
and insulin, than can be used only when open diabetes occurs.
In any case, hyperglycaemia due to insulin resistance in metabolic
syndrome should not be confounded with common type II diabetes
mellitus. Differences are well documented by genetic (the
lack in metabolic syndrome of a locus responsible for the
genetic alterations associated to the disease, like the 2q
region, NIDDM1, in noninsulin-dependent diabetes mellitus)
and histological features. In diabetes, depots of amyloid
in the pancreatic islets are usually present. The amyloid
consists of beta-strands of aggregate amylin (IAPP gene),
a peptide formed by 37 amino acid whose amount round up 1%
of total insulin content in islets. Amyloid depots are only
found in patients affected by diabetes or some insulinomas,
never in insulin resistance associated to obesity, nor in
normal individuals. .
In conclusion, metabolic syndrome is an altered metabolic
condition determined by genetic bases, not to be confounded
with type II diabetes mellitus (MIDDM1), whose diagnosis and
prevention should be done early in life, even if clear morbidity
occurs after 60 years of age in the majority of cases. It
is a preventable disease, leading to even serious clinical
complications if not adequately treated. Prevention itself
is based on early and correct diagnosis, accurate follow-up
of worsening in insulin resistance and glucose tolerance,
and safe changes in lifestyle (mainly diet and exercise) that
are often curative even when a morbid state is present. Drug
treatments should be carefully done and avoided if not necessary.
Typical diseases follow a not well compensated state, and
main complications are linked to hypertension, poor mobility,
hyperglycaemia and even open diabetes, cardiovascular diseases
and prothrombotic state.
Choice of papers on the genetics of metabolic
1: Mesa JL, Loos RJ, Franks PW, Ong KK,
Luan J, O'Rahilly S, Wareham NJ,
Barroso I.; Diabetes. 2007 Mar;56(3):884-9.
2: Laclaustra M, Corella D, Ordovas JM.; Nutr Metab Cardiovasc
Dis. 2007 Feb;17(2):125-39. Epub 2007 Jan 30. Review.
3: Sharma AM, Staels B.; J Clan Endocrinol Metab. 2007 Feb;92(2):386-95.
Epub 2006 Dec 5. Review.
4: Antoine HJ, Pall M, Trader BC, Chen YD, Azziz R, Goodarzi
MO.; Fertil Steril. 2007 Apr;87(4):862-9. Epub 2006 Dec 4.
5: Taxi I, Milojkovic M, Sunder-Plassmann R, Lazarevic G,
Tasic NM, Stefanovic
V. ; Clin Chim Acta. 2007 Feb;377(1-2):237-42. Epub 2006 Oct
6: Lo JC, Zhao X, Scuteri A, Brockwell S, Sowers MR.; Am J
Med. 2006 Sep;119(9 Suppl 1):S69-78.
7: Pollex RL, Hegele RA.; Nat Clin Pract Cardiovasc Med. 2006
8: Cardona F, Morcillo S, Gonzalo-Marin M, Garrido-Sanchez
M, Tinahones FJ.; Clin Chem. 2006 Oct;52(10):1920-5. Epub
2006 Aug 17.
9: Berberoglu M, Evliyaoglu O, Adiyaman P, Ocal G, Ulukol
B, Simsek F, Siklar
Z, Torel A, Ozel D, Akar N.; J Pediatr Endocrinol Metab. 2006
10: Rubin D, Helwig U, Pfeuffer M, Schreiber S, Boeing H,
Fisher E, Pfeiffer A,
Freitag-Wolf S, Foelsch UR, Doering F, Schrezenmeir J.; J
Hum Genet. 2006;51(6):567-74. Epub 2006 May 24.
11: Broedl UC, Lehrke M, Fleischer-Brielmaier E, Tietz AB,
Nagel JM, Goke B,
Lohse P, Parhofer KG.; Cardiovasc Diabetol. 2006 May 15;5:11.
12: Sale MM, Woods J, Freedman BI.; Curr Hypertens Rep. 2006
13: Ong KL, Wong LY, Man YB, Leung RY, Song YQ, Lam KS, Cheung
BM.; Peptides. 2006 Jul;27(7):1659-67. Epub 2006 Apr 4.
14: Christensen MB, Lawlor DA, Gaunt TR, Howell WM, Davey
Smith G, Ebrahim S,
Day IN.; Diabetologia. 2006 Apr;49(4):673-7. Epub 2006 Feb
9. Erratum in: Diabetologia.2006 Nov;49(11):2815. Howell,
M W [corrected to Howell, W M].
15: Mackevics V, Heid IM, Wagner SA, Cip P, Doppelmayr H,
Lejnieks A, Gohlke H,
Ladurner G, Illig T, Iglseder B, Kronenberg F, Paulweber B.;
Eur J Hum Genet. 2006 Mar;14(3):349-56.
16: Shen YH, Zhang L, Gan Y, Wang X, Wang J, LeMaire SA, Coselli
JS, Wang XL.; J Biol Chem. 2006 Mar 24;281(12):7727-36. Epub
2006 Jan 17.
17: Li AC, Palinski W.; Annu Rev Pharmacol Toxicol. 2006;46:1-39.
18: Sookoian S, Garcia SI, Gianotti TF, Dieuzeide G, Gonzalez
CD, Pirola CJ.; Am J Hypertens. 2005 Oct;18(10):1271-5.
19: Bing C, Ambye L, Fenger M, Jorgensen T, Borch-Johnsen
K, Madsbad S,
Urhammer SA.; Diabet Med. 2005 Sep;22(9):1157-60.
20: Meirhaeghe A, Cottel D, Amouyel P, Dallongeville J.; Mol
Genet Metab. 2005 Sep-Oct;86(1-2):293-9. Epub 2005 Jun 22.
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