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Metabolic syndrome in aging people: prevalence, risk assessment, need for treatment and prevention Torna agli editoriali

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 and lifestyle.

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 antiplatelet agents.
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 syndrome

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 11.
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 Sep;3(9):482-9. Review.
8: Cardona F, Morcillo S, Gonzalo-Marin M, Garrido-Sanchez L, Macias-Gonzalez
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 May;19(5):741-8.
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 Apr;8(1):16-22. Review.
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. Review.
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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