Hypogonadism In Metabolic Syndrome: Cause Or . - JSciMed Central
CentralJournal of Endocrinology, Diabetes & ObesityReview ArticleSpecial Issue onLow T or True MaleHypogonadismHypogonadism in MetabolicSyndrome: Cause orConsequence? Lesson fromGenetic Hypogonadism andDisorders of Gender Identity*Corresponding authorAntonio Mancini, Department of Internal Medicine,Division of Endocrinology, Catholic University of the SacredHeart, Rome, Italy, Tel: 39-06-30154440 ; Fax: 39-0630157232 ; Email:Submitted: 30 March 2014Accepted: 28 May 2014Published: 30 May 2014ISSN: 2333-6692Antonio Mancini1*, Sebastiano Raimondo1, Chantal Di Segni1,Giovanni Gadotti1, Elena Giacchi2, Marcella Zollino3, GiovanniNeri3, Marco Bonomi4, Luca Persani4,5 and Alfredo Pontecorvi11Department of Internal Medicine, Division of Endocrinology, Catholic University ofthe Sacred Heart, Italy2Center for Study and Research on Natural Fertility Regulation, Catholic University ofthe Sacred Heart, Italy3Institute of Human Genetics, Catholic University of the Sacred Heart, Italy4Division of Endocrine and Metabolic Diseases & Lab. of Endocrine and MetabolicResearchOspedale San Luca, IRCCS Istituto Auxologico Italiano, Milan, Italy5Department of Clinical Sciences & Community Health, University of MilanCopyright 2014 Mancini et al.OPEN ACCESSKeywords Testosterone Insulin Insulin resistance Hypogonadism Klinefelter’s syndrome Gender identityAbstractHypogonadism is frequently associated with metabolic syndrome and testosteronelevels correlate with parameters which are part of the cluster defining the syndromeitself. Different studies suggest a positive role of testosterone replacement therapy,but different aspects (including the definition of hypogonadism, especially in agingmale, and the modality of treatment) still require confirmation. A model to explore therole of testosterone in influencing the beginning and course of the syndrome is earlyhypogonadism, due to genetic causes (both primary or secondary hypogonadism);moreover, few data are reported in transsexuals, despite the debate on biologicalbases of gender indentity, and the influence of pharmacological treatment beforeand after surgical sex reversal. We present here a review of literature and someparadigmatic cases, that seem to reinforce the concept of hypogonadism as a causativefactor of metabolic syndrome.ABBREVIATIONSMS: Metabolic Syndrome; T: Testosterone; KS: Klinfelter’sSyndrome; E2: Estradiol; SHBG: Steroid Hormone Binding Globin;hrGH: Human Recombinant Growth HormoneBACKGROUNDMetabolic syndrome (MS) is defined as a constellationof symptoms and organ involvement leading to augmentedcardiovascular risk and recognizing insulin resistance as a mainmechanism, even if small differences are present in differentclassifications [1-3]. Central obesity, hepatic steatosis andintracellular fat in muscle cells as well as lack of exercise andgenetic factors precipitate the development of insulin resistance.Hypogonadism is now recognized as a component of thesyndrome, due to the negative effects of hyperinsulinemia ontesticular function and confirmed by clinical and epidemiologicalobservations on the link between low levels of testosterone (T)and different components of MS [4-6], supported by studies inlate-onset hypogonadism, as recently reviewed [7].In vitro studies showed a stimulatory effect of insulin ontestosterone production in both rat- and mouse-Leydig cells[8,9], but Leydig cells may become insulin resistant as well asother cells in hyperinsulinemic states. Moreover, young insulinresistant men produced less testosterone when stimulatedwith human choriogonadotropin (hCG) compared with nonobese men [10]. Lower levels of testosterone, free-testosteroneand steroid hormone binding globin (SHBG) have been foundin both obese [11] and diabetic men [12,13]. Hyperinsulinemicstate inhibits the hepatic production of SHBG [14,26]; severalCite this article: Mancini A, Raimondo S, Di Segni C, Gadotti G, Giacchi E, et al. (2014) Hypogonadism in Metabolic Syndrome: Cause or Consequence? Lessonfrom Genetic Hypogonadism and Disorders of Gender Identity. J Endocrinol Diabetes Obes 2(2): 1040.
Mancini et al. (2014)Email:Centralother mechanism have been hypothesized: direct inhibition oftesticular production by insulin and leptin, elevation of estrogenconcentrations and alterations in the secretion of gonadotropins[15-19]. It has been suggested that SHBG levels could be used asa specific marker of insulin resistance [20].Despite all the epidemiological findings on correlationbetween low T and metabolic deseases, Hypogonadism has alsobeen hypothesized to have a causative role in the development ofMS: low levels of T can predict future abdominal adiposity [21],insulin resistance, metabolic syndrome and type 2 diabetes [2134]. Testosterone influences the commitment of pluripotent stemcells and inhibits the development of preadipocytes; moreoverinsulin sensitivity of muscle cells is increased by augmentingmitochondrial capacity and fostering expression of oxidativephosphorylation genes [35]. A vicious circle has been thereforehypothesized [36-38], Testosterone is converted to 17-β-estradiol(E2) by the enzymatic activity of aromatase in adipose tissue.Thus, with higher adipocyte expression of aromatase comesa subsequent reduction of circulating testosterone. Fallingtestosterone promotes increasing adipocyte number and fatdeposition, which gradually leads to a further lowering effect ontestosterone levels. The excess of E2 inhibits the production ofGnRH and this explain why the physiological feedback cannotcompensate the T reduction in this situation; this is the so calledhypogonadal–obesity–adipocytokine hypothesis [30]Furthermore increased abdominal adiposity aggravatesoverall and Leydig cell insulin sensitivity and causes worsetesticular function.Also experimental models suggest that GnRH analog-inducedhypogonadotropic hypogonadism induce a dramatic increase invisceral adiposity [39]. This phenomenon could be of fundamentalrelevance in the population of prostatic carcinoma, who can haveincreased risk for MS due to age and pharmacological treatment[40], in fact complete T deprivation, as seen in androgendeprivation therapy (ADT), has adverse impact on risk factors forcardiovascular disease defining MS [41]This topic is also particularly relevant, when considering themorbidity and mortality related to hypogonadism. From crosssectional studies in healthy men, lower plasma total testosteronelevels seem to be associated with hyperinsulinemia, decreasedglucose tolerance, and a higher level of cardiovascular risk factors[42-43]. A relatively low blood concentration of testosterone inolder men might have adverse effects promoting atherosclerosisand explain the higher incidence of coronary heart disease inthe male [44]. Therefore, male hypogonadism can be associatedwith a metabolic syndrome as well as increased risk forcardiovascular disease, despite discrepant effects of testosteroneon cardiovascular system have been described [45,46].A possible link is related to oxidative stress, since reducedantioxidant defences have been demonstrated in acquired malehypogonadism and beneficial effects of testosterone replacementtherapy have been showed [47].To explore the role of Low Testosterone in determiningMetabolic Syndrome, an interesting model could be representedby hypogonadism on genetic basis, in which the effects of lowtestosterone are apparent in pubertal period (i.e. not influencingJ Endocrinol Diabetes Obes 2(2): 1040 (2014)sexual differentiation but the testicular function in followingperiods); moreover, the topic has been inadequately assessedin patients with alterations in gender identity. It has beenspeculated that in this patients an hypogonadism during sexualdifferentiation could have a causative role on the alteration ofgender identity.The question is really complex; in the first case for the rarityof syndromes, making difficult to perform longitudinal studies,both at the moment of the diagnosis and during testosteronereplacement therapy; in the second group, for the usualconfounding factor of steroid assumption, both before and aftersex reversal surgical procedure, but especially for the discussedinteraction between biological and psychological factors inpsychosexual differentiation process.PATIENTSCase 1A young 20-ys old male affected by hypogonadotropichypogonadism, with pubertal delay with small testes and lowgrade virilization. His kariotype was 46 XY, but a point mutationof codon 260 [Thyr 260 Met] in exon 2 of PROKR2 gene wasdiscovered in the proband and his father [48]. He had a III gradeobesity, coupled with hypogenitalism; the repeated GnRH testshowed an absent gonadotropin response; moreover, the testiswas scarcely responsive to hCG administration (basal 0.1, after72 h 1.03 ng/ml). In the investigation of the pituitary functiona GH deficiency was also observed (peak after GHRH plusarginine administration 3.04 ng/ml, less than the cut-off forobese subjects) [49]; in fact a virilization was observed with acombination of gonadotropin and hrGH administration.Case 2A 41-year-old man, already known by our genetics center for a45,X chromosome constitution and a normal male differentiation[50] came back with requests on his sexual and fertility potential.At the first observation (at 20 ys), high-resolution analysis ofprometaphase chromosomes revealed additional euchromaticmaterial on a 15-p chromosome, and in situ hybridizationwith Y-specific probe pDP105 gave positive signal on 15p11.2,suggesting at (Yp; 15p) translocation. This case was re-examinedat clinical, genetic, hormonal, and metabolic level. The newFluorescence in situ hybridization analyses on metaphasechromosomes showed that the derivative chromosome 15 wascharacterized as der (15) (Ypter-- q11.21::15p11.2-- qter) [51].Hypergonadotropinemic hypotestosteronemia was diagnosed,coupled with azoospermia; he had a I grade obesity with androidcharacteristic.Case 3A 40ys old was hospitalized for liver disease of unknown originand arterial hypertension. Hypergonadotropic hypogonadismwas present, together a clinical metabolic syndrome. Geneticstudies showed mosaicism 47,XXY(17)/46,XX(83). Metformintherapy was started with good clinical and metabolic response.Case 4A 30 ys old male, with classical Klinefelter’s Syndrome (KS)phenotype, was hospitalized for osteopenia and multinodular2/7
Mancini et al. (2014)Email:Centralgoiter; kariotype confirmed the diagnosis; he showed alsopsychological characteristics of mental retardation. On requestof his wife, he gave consent to heterologous insemination andis actually father of 4 children. He is under replacement therapywith enantate testosterone with good response at clinical leveland no complications.Case 5A 32-ys old men, with a surgical sex reversal from female tomale at the age of 26 ys (in two times, first bilateral mastectomyand then hysteroannesiectomy, followed by the complication ofan ileal volvolus) came to our observation for the monitoring ofreplacement therapy, due to some problems, such as headache.At this time he had good testosterone levels, with excess ofaromatization (T 4.48 ng/ml and E2 60 pg/ml). He performedintense physical activity and had a normal body weight withgood presence of lean body mass. No familiar history for diabetesmellitus was present.Case 6A 31-ys old woman, with a surgical sex reversal from maleto female (in two times, at the age of 26 and 28), came to ourobservation for the suspicion of a pituitary adenoma. She couldnot perform estrogen replacement therapy due to a venousthrombosis in inferior leg but had been treated with cyproteroneacetate. Repeated MRI showed pituitary hyperplasia, withoutevidence of focal lesions: PRL levels were normal both as basallevels (14 ng/ml) and in dynamic studies (peak after TRH 200ug iv 112.2 ng/ml). She had grade I obesity and underwentmetabolic evaluation in our center.The Table 1 shows the glycemic and insulinemic values afterstandard oral glucose tolerance test (75 g) showing in all casesan elevated peak insulin response, with normal glucose values; amarked insulin-resistance was present in case 3.DISCUSSION AND CONCLUSIONNo statistic conclusion can be drawn from this presentationand it is not our aim to do so, but to strengthen the hypothesisthat long-term hypogonadism, even if mild, can contribute to thedevelopment of MS.Epidemiological observations suggest a relationship betweenhypogonadism and cardiovascular diseases. Recent studieshave shown that men with Coronary Artery Disease (CAD) havesignificantly lower concentrations of bioavailable testosteronethan men with normal angiograms [52]. The prevalence ofTable 1: Metabolic parameters in our patients.Glucose adism89152Case 4Klinefelter’s syndrome8490174Case 6M to F transsexualCase 1Case 2Case 3Case 545 X, maleMosaic KlinefelterF to M transsexual897181J Endocrinol Diabetes Obes 2(2): 1040 (2014)195136hypogonadism in a population of men with CAD is about twice thatobserved in the general population [53]. Hypotestosteronemiais associated with an atherogenic lipid profile (elevated lowdensity lipoproteins and triglycerides, decreased high-densitylipoprotein), high fibrinogen with a hypercoagulable state, anincrease in insulin resistance and hyperinsulinemia, and highersystolic and diastolic blood pressure [54]. Experimental data alsoreinforce the concept of a positive effect of exogenous testosteroneadministration. In an animal model, castration increased aorticatheroma formation, and testosterone replacement amelioratedthis effect [55]. In addition, testosterone has direct vasoactiveproperties, which directly affect the vascular smooth muscle, notmediated by the nuclear androgen receptor, in that the effect istoo rapid and is not reduced by flutamide, a nuclear androgenreceptor blocker [56-58]. When testosterone is instilled intothe left coronary artery, vasodilatation ensues and coronaryflow increases [59]. More importantly, acute administrationof intravenous testosterone improves exercise tolerance andreduces the angina threshold in men with CAD [60,61]. Thesepositive effects seem to be related to the nongenomic action oftestosterone on vascular smooth muscle cells [62,63]. Oxidativestress can underlie the above-mentioned clinical conditions. Asdemonstrated by statistical metaanalysis, low testosteronemiaand androgen deficiency were associated with an increased riskof developing a metabolic syndrome over time [64]. However,the pathophysiological details of these changes in atherosclerosis[65] and implications in testosterone replacement therapy [66]are still under investigation.Moreover, the role of gonadal steroids in the regulation ofsystemic antioxidants is not known. We therefore investigatedthe role of CoQ10, a lipidic antioxidant [67], and the totalantioxidant capacity (TAC) of blood plasma in secondary malehypogonadism [47]. Conflicting results do not allow unequivocalconclusions on the role of androgens in coronary artery disease,as in important reviews [44,68]. Many confounding factorscontribute in making this question very complex. Endogenousandrogen levels depend on different mechanisms, such asgender-specific gene expression, distribution of body fat,vascular factors, and adaptation to aging. Similarly, studies onexogenous androgen administration are influenced by dose,route of administration, duration of treatment, and again patientsvariables such as gender, age, and condition of recipients.The knowledge about the role of androgens in CV system iscontinuously growing and there is still not a clear overview onit. Therefore, data on antioxidant regulation by steroids can beuseful to clarify molecular mechanisms of testosterone action.Insulin 16.3104.713582.79012.0NoNoNo3/7
Mancini et al. (2014)Email:CentralTestosterone therapy reported values toward the same levelsobserved in normogonadic patients, with a significant increasein CoQ10 concentrations. TAC, expressed as LAG (latency phasebefore the appearance of radicals in a tested sample after inducedoxidative stress) [68,69], which exhibited a trend toward lowervalues in hypogonadal subjects, also increased significantly withtestosterone treatment [47].These previously reported data reinforce the concept thathypogonadism could represent a condition of oxidative stress.Although the small number of patients studied does not allowdefinitive conclusions, lower levels of CoQ10 were discovered inisolated hypogonadal compared with normogonadal patients. Toour knowledge, we for the first time reported of the testosteroneeffect on antioxidant systems in humans. Further studiescan clarify the relationship of this datum with the increasedcardiovascular risk in such patients.Different studies report metabolic alterations in KS (Table2, with references indicated in square brackets), as reviewed byBojesen et al. [38].The clinical impact of the physiopatology of hypogonadismand MS obviously concern the possible role of T replacementtherapy and its beneficial effects, not only on sexual aspects (asoriginally believed) but also on anthropometric and metabolicparameters. A number of studies have been performed (Table 3),even if the heterogeneity of treatment (duration and/or doses,kind of replacement therapy, classes of patients and controls, andso on) does not allow definitive conclusions [70].Among the reported study, the one from Jones et al. (the lastone) is particularly significant, due to the number of involvedpatients and the methodology (prospective, randomized, doubleblind, placebo-controlled; it was conducted in hypogonadal menwith type 2 diabetes and/or MS, showing after 6 month period, abeneficial effect of transdermal T replacement therapy on insulinresistance, total and LDL-cholesterol, Lpa and sexual health [82].A meta-analysis , with a comprehensive search of randomizedclinical trials, was published by Isidori et al. [95]: overall, 1083subjects were evaluated (625 randomized to T, 427 to placeboand 31 to observation; T treatment produced a reduction of totalbody fat, increase in fat free mass, decrease in total cholesterol,improvement of bone mineral density (BMD) at the lumbar spine;Table 2: Metabolic alterations in patients with Klinefelter’s syndrome.Also our patients 45,X male previously reported alloweddifferent considerations on the relationship betweenhypogonadism and MS [52]. The presence of a male phenotypein a 45, X-chromosome constitution is a very rare condition[98-108], but no paper describes the natural history of suchpatients. Despite Y-material traslocation, allowing normal maledifferential, in our patient small testes were observed in adultage, with primary hypogonadism. The interest of this case,therefore, strongly reinforces the metabolic role of testosteroneand suggests that hypogonadism could cover a role in thedevelopment of a metabolic syndrome in our patient.Despite conflicting results do not allow unequivocalconclusions on the role of androgens in coronary artery disease,as reviewed by Wu and Liu [46,68], the reported case underlinesthe need of metabolic, and not only sexual, evaluation in generelated hypogonadism.Finally, the role of biological factor in transexualism isstill far to be elucidated. Most attempts to identify biologicalunderpinnings of gender identity and sexual orientation inhumans have investigated effects of sex steroids, so pivotal in thedifferentiation of the genitalia, showing strong parallels betweenanimals and the human. The information on humans is derivedfrom the so-called ‘experiments of nature’, clinical entities witha lesser-than-normal androgen exposure in XY subjects and ahigher than normal androgen exposure in XX subjects. PrenatalAuthorYearKlinefelter [71]1942Becker et al [73]196650 KS196931 KSIncreased prevalence of glucose intolerance (39%)13 KSIncreased fasting insulin, but not altered insulin sensitivity60 KS34% prevalence of MS, in comparison with azoospermic controls71 KSStriking difference in body composition without difference in BMIJackson et al [72]Zuppinger et alNielsen et al. [75]1966[74]Pei et al. [76]1967Number of patientson the contrary, an heterogenous response was observed onmuscle strength, HDL-cholesterol, femoral neck BMD, dependingon the dose/type of T employed. For these Authors, furtherinterventional studies were justified by the incouraging results.However a conclusion will be drawn with long-term evaluation,since caution has been suggested following a recent studyshowing an increase in cardiovascular event in testosteronetreated, frail, elderly men [96]. The effects of sexual steroids onrenal-vascular system are complex: conflicting data have beenreport. While acute T admistration seems to decrease vasculartone, the long-term net effect seems to be vasoconstriction, dueto upregulation of thromboxane A2 expression, norepinephrinesynthesis, angiotensin II expression, endothelin action [97]. Theaccurate choice of candidates to this treatment and an overallconsideration of anthropometric, metabolic, cardiovascular,skeletal and sexual parameters is recommended.8 KS24 KS19887 KS/7 HHBojesen et al [78]200670 KSAksglaede et al. [80]200824 KSYesilova et al. [77]Ishikawa [79]Bojesen et al. [81]200520082006J Endocrinol Diabetes Obes 2(2): 1040 (2014)Metabolic alterationOriginal description of abdominal obesity1/8 with mild diabetes5/50 with diabetesOvert diabetes in 2 and glucose intolerance in 4Elevated fasting insulin vs controlsHalf of the patients with ATPIII criteria of MSIncreased fat mass using DXA4/7
Mancini et al. (2014)Email:CentralTable 3: Studies on testosterone treatment.AuthorYearNumber of patientsDuration of treatment Metabolic effectsMarin et al. [82]199223 obese men8 monthsMauras et al. [83]1998Snyder et al. [84]1999Bhasin et al. [85]2001Singh et al. [86]2002Steidle et al. [87]2003Wittert et al. [88]2003Wang et al. [89]2004Page et al. [90]2005Kapoor et al. [91]2006Bojesen et al. [81]2006Mancini et al. [48]2008Caminiti et al. [92]Singh et al. [93]Jones etTIMES2Study [94]al.2009–201120116 healthy lean men, before and10 weeksafter GnRH analog108 65 ys men (T or placebo) 36 months61 eugonadal men (GnRH plus20 weeksgraded T)61 eugonadal men (GnRH plus20 weeksgraded T)406 hypogonadal men76 healthy 60 ys3 months1 year163 hypogonadal men42 months10 secondary hypogonadism6 monthsReduction in visceral obesity and increase in insulinsensitivityInduced Hypogonadism caused increase in fat mass anddecrease in REE, lean body mass, muscle strengthIncrease in lean body mass and decrease in fat massDose-dependent increase in free-fat massNo difference in insulin resistanceIncrease in lean body mass and decrease in fat massIncrease in lean body mass and decrease in fat massIncrease in lean body mass and decrease in fat mass77 hypogonadal men (T with36 monthsIncrease in lean body mass and decrease in fat massplacebo or finasteride)24 hypogonadal men with typeDecrease in insulin resistance and improvement of3 months2 diabetesglycemic controlTreated at the moment Non significant trend in reduction in truncal fat, total35 KSof the studycholesterol, fasting plasma glucose and leptin70 Elderly men63 MS and 32 controls12 weeks3 months220 Hypogonadic with type 2Diabetes6 monthsor MSandrogenization appears to predispose to a male gender identitydevelopment, but this is not mandatory, since 40-50% of 46,XY intersexed children with a history of prenatal androgenexposure do not develop a male gender identity. Male-to-femaletranssexuals, with a normal androgen exposure prenatally (sincethere is clear evidence of the contrary) develop a female genderidentity, through unknown biological mechanisms apparentlyoverriding the effects of prenatal androgens. The latest studiesin 46, XX subjects exposed to prenatal androgens show thatprenatal androgenization of 46, XX fetuses leads to markedmasculinization of later gender-related behavior but does notlead to gender confusion/dysphoria. The example of femaleto-male transsexuals, without evidence of prenatal androgenexposure, indicates that a male gender identity can developwithout a significant androgen stimulus. So the role of hormonalimprinting on gender identity formation is still far away to becomprehended. [109,110]. However, also in this case, a metabolicevaluation, due to possible precocious alteration in hormonalmilieu and/or pharmacological modification of steroid levels,should be performed.In conclusion, hypogonadism is surely associated with MS,with a possible causative role or, at least, as a worsening factor.Most studies confirm a possible usefulness of T replacementtherapy, but still need definitive and personalized confirmation.CONFLICT OF INTERESTThe authors declare that they have no competing interests.This work was partially supported by funds for YoungInvestigators from the Italian Ministry of Health (Grant No.J Endocrinol Diabetes Obes 2(2): 1040 (2014)Increase in total antioxidant capacityImproved muscle strength, insulin sensitivity, maximal02 consumption and arterial baroreceptor cardiac reflexsensitivityImproved HOMA-IR in MS males with hypogonadismTransdermal T improved insulin resistance, total and LDLcholesterol, Lpa and sexual healthGR2008–1137632) to MB. 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Klinefelter's syndrome Gender identity. Review Article. Hypogonadism in Metabolic Syndrome: Cause or . Consequence? Lesson from Genetic Hypogonadism and Disorders of Gender Identity. . A 30 ys old male, with classical Klinefelter's Syndrome (KS) phenotype, was hospitalized for osteopenia and multinodular . Central Mancini et al. (2014)
ment of the metabolic syndrome (Table 1) [10]. Prevalence of the Metabolic Syndrome and Risk for Cardiovascular Events It is estimated that approximately one fifth of the US population has the metabolic syndrome, and prevalence increases with age. The prevalence of the metabolic syndrome in a healthy American population is approxi-mately 24% [11].
relation between nut consumption and metabolic syndrome (MetS). Metabolic Syndrome is a group of cardio-metabolic risk factors, which comprise of type 2 diabetes, high fasting plasma glucose, hyperglycemia, hyper-triglycerides, low HDL cholesterol and abdominal obesity [21]. Metabolic syndrome raises the risk of diabetes by 5 times and that of
REVIEW Trans Fats and Metabolic Syndrome Patrick Sundin 1 Two issues affecting health today are metabolic syndrome and trans fats. Metabolic syndrome is a common condition that has no single known cause. Trans fats are fatty acids that can be artificially made and added t
year. Metabolic syndrome (MetS) is known as an independent risk factor of coronary artery disease and stroke. Aim of the work: To investigate the relationship between metabolic syndrome and risk of ischemic stroke, whether stroke patients with metabolic syndrome differ from other ischemic stroke patients in demographic
Metabolic Syndrome and Obesity Metabolic syndrome refers to a group of risk factors that raise a person’s risk of heart disease, stroke, and other illnesses. Abdominal obesity is one component of metabolic syndrome. Other components of metabolic syndrome like high blood pressure and high blo
latent metabolic syndrome that warrants clinic al evaluation and risk factor modification. Though intricate and still incompletely understood, the gradual expansion of knowledge about inter-relationships between the metabolic syndrome, GDM and T2DM may provide us with opportunities to screen for and detect metabolic dysfunction at various stages of
on risk of metabolic syndrome Metabolic syndrome is defined as the cluster of central obesity, insulin resistance, hyper-tension, and dyslipidemia. Metabolic syn-drome increases a patient’s risk of diabetes 5-fold and cardiovascular disease 3-fold.1 Physical inactivity and eating
ED-OIG/A02-D0023 . Honorable César Rey-Hernández Secretary of Education Puerto Rico Department of Education Calle Teniente González, Esq. Calle Calaf – 12. th. Floor Urb. Tres Monjitas Hato Rey, Puerto Rico 00919 Dear Secretary Rey-Hernández: This is our Final Audit Report entitled . Puerto Rico Department of Education’s (PRDE) Salaries for the Period July 1, 1999 to June 30, 2003. The .
