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Metabolic Syndrome

Genetic and physiological insights into the metabolic syndrome

Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute and University of Western Ontario, London, Ontario, Canada

Submitted 15 April 2005 ; accepted in final form 6 May 2005

	ABSTRACT

TOP ABSTRACT EXAMPLE 1: PARTIAL LIPODYSTROPHY... EXAMPLE 2: METABOLIC SYNDROME... GRANTS REFERENCES

 
The metabolic syndrome (MetS) is a common phenotype that is clinically defined by threshold values applied to measures of central obesity, dysglycemia, dyslipidemia, and/or elevated blood pressure, which must be present concurrently in any one of a variety of combinations. Insulin resistance, although not a defining component of the MetS, is nonetheless considered to be a core feature. MetS is important because it is rapidly growing in prevalence and is strongly related to the development of cardiovascular disease. To define etiology, pathogenesis and expression of MetS, we have studied patients, specifically Canadian families and communities. One example is familial partial lipodystrophy (FPLD), a rare monogenic form of insulin resistance caused by mutations in either LMNA, encoding nuclear lamin A/C (subtype FPLD2), or in PPARG, encoding peroxisomal proliferator-activated receptor- (subtype FPLD3). Because it evolves slowly and recapitulates key clinical and biochemical attributes, FPLD seems to be a useful monogenic model of MetS. A second example is the disparate MetS prevalence between two Canadian aboriginal groups that is mirrored by disparate prevalence of diabetes and cardiovascular disease. Careful phenotypic evaluation of such special cases of human MetS by using a wide range of diagnostic methods, an approach called "phenomics," may help uncover early presymptomatic disease biomarkers, which in turn might reveal new pathways and targets for interventions for MetS, diabetes, and atherosclerosis.

dyslipidemia; insulin resistance; cardiovascular disease; Canadian aboriginals; genetics

MetS is considered to result from the interaction of environmental factors, such as caloric excess and physical inactivity, with genetic susceptibility factors (22, 37, 47). The resistance of such tissues as skeletal muscle, fat, and liver to insulin, while not a defining component of the MetS, is nonetheless considered to be a core feature. Indeed, the terms "MetS" and "insulin resistance syndrome" are often used interchangeably. Study of monogenic insulin resistance syndromes might help to understand the common MetS, just as the study of patients with familial hypercholesterolemia (FH) (9) helped improve understanding of cholesterol metabolism, leading ultimately to development of statin drugs, which have profoundly affected clinical cardiology. In this article, we present two examples of how the study of specific presentations of the MetS in Canadian kindreds and communities has revealed certain features that may be relevant to common MetS. These patients provide an opportunity to systematically search for early presymptomatic phenotypes or biomarkers of cardiovascular risk in mutation carriers by using an approach that has been called "phenomics" (13, 16, 23, 49).

	EXAMPLE 1: PARTIAL LIPODYSTROPHY SYNDROMES (FPLD2 AND FPLD3)

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History and definition of FPLD. Lipodystrophy is characterized by loss of fat stores in some anatomical sites, with excess accumulation of fat in nondystrophic adipose tissue and such sites as liver and muscle (14). Lipodystrophies can be genetic or acquired. The most rapidly growing type of lipodystrophy seen clinically is the one associated with the use of highly active antiretroviral treatment (HAART) (5). Among inherited lipodystrophies, some have been characterized at the molecular genetic level, including the Berardinelli-Seip form of generalized lipodystrophy and the Dunnigan-type familial partial lipodystrophy (FPLD) (20). Of these, FPLD, which may affect 1:100,000 individuals of Northern European descent, evolves more slowly and may provide a better model reflecting the metabolic evolution of MetS.

Kobberling and Dunnigan (32) described patients who were normal at birth but who during puberty lost subcutaneous fat from extremities and the gluteal region, resulting in prominent, well-defined musculature, together with excess fat deposition within the face and neck, axillae, back, and intra-abdominally. Imaging studies showed absence of subcutaneous fat but preservation of inter- and intramuscular, intra-abdominal, intrathoracic, and bone marrow fat (15). The hallmark of FPLD is insulin resistance. Type 2 diabetes presents later in adulthood. Dyslipidemia and hypertension are common, but acanthosis nigricans, hirsutism, and polycystic ovaries are variable. The FPLD locus was mapped to chromosome 1q21 (42), and candidate gene sequencing of Canadian FPLD subjects identified a mutation in LMNA encoding the nuclear envelope protein lamin A/C (10), a finding confirmed by others (50, 51). At present, the mechanisms by which LMNA mutations cause disease are incompletely defined, and speculation exceeds the scope of this review [see Mounkes et al. (39)].

FPLD2 phenomics: evaluation of intermediate quantitative traits. Identification of carriers of mutant LMNA in FPLD2 before the onset of type 2 diabetes and the concomitant gross distortion of metabolic variables allowed us to evaluate whether at-risk carriers had any early biochemical changes (28). We studied 35 nondiabetic adult FPLD2 subjects with either the LMNA R482Q or R482W missense mutations and 51 matched normal first-degree relatives, who were also matched for glucose and glycated hemoglobin. We found that, compared with normal controls, LMNA mutation carriers had significantly higher plasma concentrations of insulin, triglycerides (TG), nonesterified free fatty acids (FFA), and C-reactive protein (CRP), together with significantly lower plasma high-density lipoprotein (HDL) cholesterol, leptin, and adiponectin (28). Furthermore, these differences were more pronounced in women. Resistin, fibrinogen, and plasminogen activator inhibitor-1 were not different between the groups. The characteristic biochemical abnormalities were present long before diabetes developed, because diabetic LMNA mutation carriers in these families were 10 yr older than nondiabetic carriers (25, 28). This indicates that a characteristic cluster of biochemical abnormalities in carriers antedates the decompensation of glycemia.

To confirm the clinical impression of increased atherosclerosis risk in FPLD2, subjects >35 yr were stratified by genotype for a LMNA codon 482 missense mutation (24). LMNA mutation carriers had significantly more type 2 diabetes, hypertension, and dyslipidemia than did normal family control subjects (24). Eight LMNA mutation carriers had suffered from coronary heart disease (CHD) end points compared with one normal control [odds ratio 5.9, 95% confidence interval (CI) 1.2 to 30.2]. Among female LMNA mutation carriers, 28.6% (4 of 14) had been hospitalized between ages 35 and 54 yr for coronary arterial bypass graft surgery (CABG) (24). In contrast, data from the general Canadian population indicated that only 0.014% of women had been hospitalized between ages 35 and 54 yr for CABG (24). Thus female LMNA mutation carriers of ages 35 to 54 yr had a hospitalization rate for CABG that was several orders of magnitude higher than that of the general Canadian population. Importantly, all LMNA mutation carriers with CHD also had type 2 diabetes, suggesting that development of clinical end points required the presence of diabetes.

FPLD3: a subtype of partial lipodystrophy due to mutation in PPARG. Whereas mutations in LMNA have been found in 50% of families with FPLD, a substantial number of individuals referred with this phenotype had no mutation in the LMNA coding region, intron-exon boundaries, promoter, or 5'- and 3'-untranslated regions, implying genetic heterogeneity. PPARG encodes peroxisome proliferator-activated receptor- (PPAR-), a nuclear receptor that induces transcription of genes involved in insulin sensitivity, adipocyte differentiation, and inflammation (52). PPAR- mediates the pharmacological enhancement of insulin signaling by thiazolidinedione (TZD) drugs (52), which have earned an established place in the management of insulin resistance and type 2 diabetes. Because PPAR- has an important role in adipocyte biology, PPARG was a good candidate gene to analyze in lipodystrophic subjects with normal LMNA sequence.

In a three-generation Canadian kindred with partial lipodystrophy and a normal LMNA sequence, we found heterozygotes for the PPARG F388L mutation (26), which was absent from normal alleles and cosegregated with the disease. The in vitro transcriptional activity of the mutant receptor was three times lower than that of wild-type receptor, but transcriptional activities were similar with a saturating amount of the TZD rosiglitazone (26). Dose-response curves showed that F388L had reduced affinity for ligands. The F388L mutation altered a highly conserved residue but had neither reduced protein expression nor dominant negative activity against the wild-type receptor (26). Because the PPAR- agonist TZD drugs are widely used to treat insulin-resistant patients, the demonstration that PPAR- deficiency causes insulin resistance underscores the importance of the gene product in the MetS.

Earlier studies indicated that germline PPARG mutations did not cause lipodystrophy (6, 40). Later reevaluation of some subjects with PPARG mutations confirmed the findings from the F388L kindred that PPARG mutations also caused lipodystrophy (48). Furthermore, heterozygosity for PPARG R425C was found in a single patient who was ascertained on the basis of a clinical diagnosis of partial lipodystrophy (1). We also reported a Dutch FPLD3 kindred with a –14AG mutation within the promoter of the 4 isoform that was associated with decreased expression and no qualitative protein abnormalities (2). These findings together indicated that mutations resulting in PPAR- deficiency cause partial lipodystrophy. An unresolved issue is whether the metabolic abnormalities follow primarily from the adipose loss or whether the PPARG mutations themselves have other independent effects in various target tissues (29). One clue may come from careful evaluation of phenotypic distinctions between partial lipodystrophy due to mutant PPARG and that due to mutant LMNA.

Phenomics: comparison of FPLD2 and FPLD3 subtypes. Our data are consistent with genuine clinical and biochemical differences between FPLD2 and FPLD3 subtypes (2, 21). Specifically, there were no limb or gluteal fat stores in FPLD2 subjects, whereas FPLD3 subjects had some upper arm and gluteal fat. The age of diabetes onset was 10 yr sooner in FPLD3 compared with FPLD2. Hypertension was particularly severe in FPLD3. Systemic signs of insulin resistance, such as acanthosis nigricans, hepatic steatosis, and polycystic ovarian disease, were more severe in FPLD3. FPLD2 was associated with early CHD, whereas among the PPARG mutations, only F388L was clearly associated with CHD (26). Dyslipidemia was common among subjects with both FPLD2 and FPLD3. However, mean insulin concentrations were increased to a greater degree in FPLD3 than in FPLD2, consistent with more severe insulin resistance in FPLD3. Concentrations of FFA and CRP, where measured, were similarly increased with both partial lipodystrophy types. Concentrations of leptin and adiponectin were depressed in both partial lipodystrophy types, with quite marked depression in subjects with the PPARG P467L mutation. There was less responsiveness to TZDs in FPLD3 subjects (21).

Thus, compared with FPLD2, FPLD3 is associated with 1) less extensive adipose tissue loss, 2) more severe biochemical and clinical signs of insulin resistance, 3) more severe hypertension, and 4) earlier onset of type 2 diabetes. Early atherosclerosis was clearly seen in women with FPLD2 compared with those with FPLD3, although numbers of reported patients are small for the latter partial lipodystrophy type. The clinical and biochemical abnormalities in subjects with FPLD3 appear to be out of proportion to the extent of lipodystrophy when compared with subjects with FPLD2, implying that PPARG mutations may have additional and independent effects on metabolism (29).

Reconstructing metabolic progression in FPLD. Using the accumulated clinical experience and genetic insights from the FPLD kindreds, we have been able to define a pattern of disease evolution with parallel treatment strategies for each disease stage. Figure 1 schematically shows the temporal progression of the clinical and biochemical features seen among patients with FPLD2, but the pattern is similar for FPLD3. The germline mutation is present at birth. Clinically, the first manifestation in early adolescence is fat redistribution. Although no treatment is accepted for this early stage, future treatments might be directed toward impeding adipose tissue loss, stimulating regrowth, or replacing lost tissue.

View larger version (21K): [in this window] [in a new window]   Fig. 1. An example of phenomic evaluation in familial partial lipodystrophy (FPLD) is shown. The schematic shows the temporal progression of clinical and biochemical features in FPLD2, but a similar pattern applies for FPLD3. The abscissa refers to passage of time moving from left to right. The germline LMNA mutation is present at birth. Clinically, the first manifestation is redistribution of fat in early adolescence, which most investigators agree is the triggering event. In young adulthood, the biochemical profile seen in FPLD2 includes elevated plasma concentrations of free fatty acids (FFA), insulin and C-peptide, triglycerides (TG), and C-reactive protein (CRP), with depressed plasma concentrations of high-density lipoprotein (HDL) cholesterol, leptin, and adiponectin. Hypertension usually presents next, later in adulthood, followed by diabetes that causes profound changes in the quantitative traits. Premature atherosclerosis is a feature of FPLD2, although almost all subjects with cardiovascular end points had developed type 2 diabetes, suggesting that this is necessary for expression of vascular disease. Examination of plasma of prediabetic carriers may reveal additional biochemical abnormalities associated with the insulin-resistant atherosclerosis susceptible state.

Late-stage disease is characterized by development of diabetes, which causes profound metabolic changes. Treatment at this stage is focused on intensive control of glycemia, dyslipidemia, and hypertension to prevent complications. Future treatments may include leptin with or without adiponectin.

Final stage disease is characterized by the development of diabetic macro- and microvascular complications. Premature atherosclerosis is a feature of patients with FPLD2 (26), although most subjects with CHD were diabetic, suggesting that diabetes is necessary for expression of vascular disease. Therapies include stabilization of metabolic variables, palliation, and secondary prevention of vascular disease.

Based on this construction of disease evolution, there are some theoretical therapeutic options in treatment of partial lipodystrophy. Treatments might come from among new agents under development, including new selective agonists for PPAR-, -, and -, dual ligands for PPAR- and -, and target gene-selective PPAR receptor modulators (SPPARMs) that might selectively affect adipose differentiation and viability (38) in subjects with FPLD2 and possibly even FPLD3. Newer drugs for dyslipidemia (7) also might be appropriate for managing hypertriglyceridemia, prophylaxis of pancreatitis, and secondary prevention of vascular disease in partial lipodystrophy. Finally, leptin administration over a relatively short period has been shown to improve the metabolic disturbances in FPLD (41).

FPLD: a helpful model for MetS. There are several reasons why partial lipodystrophy resulting from mutations in either LMNA (FPLD2) or PPARG (FPLD3), among all lipodystrophies, may be a superior model of the common MetS in addition to the lipodystrophy syndrome associated with HAART. These include the following: 1) FPLD is characterized by gradual fat redistribution to central depots rather than outright global fat loss; 2) FPLD is progressive, evolving relatively slowly by defined stages over years; and 3) FPLD recapitulates many clinical and biochemical attributes of the common MetS. Future treatments for maintaining balanced distribution of adipose stores, improving insulin sensitivity, improving glycemic control, improving metabolic control, and reducing micro- and macrovascular complications in partial lipodystrophy also may find application in management of MetS, type 2 diabetes, and/or acquired lipodystrophy syndromes.

	EXAMPLE 2: METABOLIC SYNDROME IN ABORIGINAL CANADIANS

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Canadian aboriginal populations have been called "populations in transition," as the introduction of sedentary activities and the Western diet impacts their traditional lifestyle. Over the past few decades, new health issues, such as diabetes (62), obesity (59), childhood obesity (60), and cardiovascular disease (4), have emerged in epidemic proportions in many communities. For instance, based on survey data of Northern Ontario Oji-Cree from the early 1990s, the combined prevalence of type 2 diabetes and impaired glucose tolerance was 40%, one of the highest in the world (18). Alongside this rise in diabetes has been a tripling in hospitalizations for coronary heart disease despite declining trends in the general Canadian population (19). The Inuit, on the other hand, have been considered to be healthier, in terms of diabetes and cardiovascular disease, than the general population (61, 63). Arctic peoples have a much shorter and less intense history of Western contact and acculturation, which may explain the lower rates of associated chronic diseases; however, the situation may easily change. Given the recent identification of MetS as a new risk factor for type 2 diabetes and cardiovascular disease, we have taken this opportunity to estimate the prevalence of MetS and its individual components in the Keewatin Inuit and the Oji-Cree of Northern Ontario, two distinctive populations in terms of cardiovascular disease and diabetes risk, in hopes of drawing some insight into the characterization of this phenotype.

Inuit of the Keewatin region. The Inuit in our study were from a 1989–1991 survey of eight communities in the Keewatin region of Nunavut. According to the standard NCEP ATP III criteria for MetS diagnosis, the Inuit were found to have a lower prevalence of MetS (13.1%) compared with both resident Caucasian controls from the Keewatin region (20.8%) and with Caucasian subjects from a larger contemporaneous American survey (23.8%) (45). Similarly, the prevalence of diabetes was also markedly lower in the Keewatin Inuit, with only 2% diagnosed diabetes cases (Table 1). Not only was the Inuit prevalence of MetS low, but also a significant portion of the Inuit was free from meeting the cutoff criteria for any of the metabolic abnormalities. The low prevalence of MetS was largely due to the low prevalence of MetS in the male Inuit population; female Inuit had a significant approximately sevenfold increase in MetS prevalence (Table 1). Such a disparity in MetS prevalence between genders also has been observed in African Americans and Hispanics (12), although not in Caucasian populations, highlighting the importance of both gender and ethnicity in MetS expression.

View this table: [in this window] [in a new window]   Table 1. Demographics, MetS prevalence, and components of MetS for Inuit and Oji-Cree (18 yr old)

Although the lower prevalence of MetS in the Inuit was consistent with the previous impression of lower cardiovascular disease and diabetes prevalence, there is no guarantee that this population will remain free from the rising tide of MetS. There is already a high degree of elevated fasting glucose, with >50% of the population at the 6.1 mmol/l NCEP ATP III cutoff, hinting at a strong prediabetic susceptibility. If even one-third of this population develops diabetes, the incidence rise would be alarming. However, with early identification of high-risk individuals and culturally appropriate intervention, we believe that the expected increase in the onset of diabetes and cardiovascular disease in the Inuit can be reduced.

Oji-Cree of Northern Ontario. Hundreds of kilometers to the south, the Oji-Cree are nestled in the subarctic boreal forest of Northern Ontario, still isolated, yet closer to the influence of the greater Canadian population. Lifestyle changes over just the past few decades (new high-fat, high-sugar food choices and modern conveniences requiring less physical exertion) have ushered in a wave of diabetes into what was once an almost "diabetes-free" zone (34, 58). As would be expected, in contrast to the Keewatin Inuit, the prevalence of MetS for the Oji-Cree was high, with almost 1 of 3 individuals meeting the NCEP ATP III criteria and only one-fifth of the population completely free of any MetS component (Table 1) (43). Similar to the Inuit, the majority of subjects with MetS were females. The high prevalence of MetS in the female Oji-Cree population also mirrored the larger numbers of female Oji-Cree with type 2 diabetes. These MetS rates observed for the Oji-Cree, reaching up to 45% when adults 35 yr of age were considered, are some of the highest rates in any subpopulation (43).

Increased abdominal obesity and depressed HDL cholesterol were the most dominant features of MetS for the Oji-Cree, among females especially, whereas increased blood pressure was the least prevalent feature (Table 1). Abdominal obesity is indeed one of the most frequently found MetS components observed in a number of population studies, irrespective of ethnicity (8, 12, 31). Questions have been raised regarding the use of uniform cutoff points for abdominal obesity, drawing to attention the necessity of ethnic-specific guidelines (46). Some investigators have already employed modified MetS criteria to better identify Asian individuals with MetS (53), yet clearly more investigation is required in this respect. Interestingly, other components, such as blood pressure, show distinctive variability between ethnic groups, being dominant features in African American populations (12) and Korean males (31), yet quite infrequent in both the Inuit and Oji-Cree populations. Do these cutoff points, and those for the other MetS components, have the necessary sensitivity and specificity required to appropriately identify those with MetS, given the ethnic variability?

Although lifestyle changes, namely, increased caloric intake and decreased physical activity levels (34, 58), certainly have had a major impact on the higher prevalence of MetS observed for the Oji-Cree, underlying genetic factors are also likely important. In our study of genetic determinants for MetS, we found that functional polymorphisms in three candidate genes for plasma lipoproteins and blood pressure (AGT T174M, GNB3 825CT, and APOC3 –455TC) were all significantly associated with MetS for female adults (43). A recent study found similar associations for APOC3 with MetS in a southern Indian population (17). However, genetic associations appear to be minor, and susceptibility to MetS appears to be greater than the sum of susceptibility to the individual parts, because no association with other genes involved in obesity and fasting glucose levels was observed.

Part of the elevated risk of type 2 diabetes in the Oji-Cree population stems from the presence of a genetic susceptibility allele: a private nonsynonymous mutation (G319S) in HNF1A encoding hepatic nuclear factor-1 (27, 54). In vitro studies have shown a decreased transactivation ability for the mutant transcription factor (54). In a cross-sectional analysis, HNF1A G319S was present in 40% of diabetic subjects and had a strong statistical association with type 2 diabetes, and each dose of the S319 allele accelerated the age of diabetes onset by 7 yr (27, 54). Interestingly, in our analysis of type 2 diabetes risk, we observed that Oji-Cree with MetS (modified to exclude the fasting glucose component) had a diabetes risk similar to that of HNF1A G319S carriers (odds ratio 5) (44), confirming the important role of the MetS phenotype on diabetes expression. Furthermore, subjects with the inopportune combination of both the HNF1A S319 allele and modified MetS had an 20-fold increased risk for type 2 diabetes (44).

The MetS message from studies in aboriginal Canadians. Through our studies in two unique aboriginal Canadian groups, we have observed that MetS prevalence mirrors the prevalence of diabetes and cardiovascular disease. For the Inuit, the low prevalence of MetS corresponds to the low prevalence of diabetes, and likewise the high MetS prevalence for the Oji-Cree is accompanied by high rates of both diabetes and cardiovascular disease. Variability was observed in the distribution of MetS components between these groups, with abdominal obesity being the predominant feature of Oji-Cree subjects, whereas high fasting glucose predominates among the Inuit. Ethnic-specific criteria for MetS probably will be required for optimal identification of at-risk individuals, considering the inherent variability that exists between groups, such as defining appropriate waist circumference ranges. Finally, it is clear that both genetic and environmental components, whose relations may differ between genders, are involved with MetS. Although modest associations with MetS were found with a few genes involved in blood pressure and lipid metabolism for the Oji-Cree, it is likely that environmental influences, such as dietary habits, probably play an equal or bigger role in MetS expression.

In conclusion, these examples of MetS provide some evidence for the potential benefits of careful phenomic assessment to better understand the components of a complex phenotype such as MetS, in addition to clarifying temporal relationships and novel pathways that could be targets for interventions. For instance, FPLD2 implicates structural abnormalities of the nuclear envelope as causing insulin resistance, diabetes, and, ultimately, atherosclerosis (22–25). FPLD3 proves that inherited partial lipodystrophy is clinically and genetically heterogeneous, clarifying the metabolic phenotype of PPAR--deficiency due to mutant PPARG and confirming the key role of PPAR- in adipogenesis and metabolism. FPLD3 shows less severe lipodystrophy and more severe insulin resistance, suggesting that additional mechanisms underlie insulin resistance and metabolic changes beyond those that can be attributed solely to adipose tissue loss. This further suggests that intervening on the PPARG pathway could have multiple beneficial effects on metabolic phenotypes and downstream complications such as atherosclerosis. The metabolic progression for both FPLD subtypes indicates that disturbances in fat and lipid metabolism precede the development of carbohydrate disturbances, particularly diabetes as a result of the relative breakdown of glycemic control mechanisms.

The examples of Oji-Cree and Inuit highlight population-specific differences in expression of MetS. Also, the findings indicate that different thresholds, applied to critical defining values for key quantitative phenotypes in different populations, may be required. In both communities, the importance of environmental factors is underscored. In Oji-Cree, we are working with the community to stem the tide of MetS and diabetes by increasing levels of activity and modifying diet to one that more closely reflects a "traditional diet." In Inuit, the full wrath of MetS has not yet struck, and it remains possible that the complications can be avoided at an early stage with preventive measures.

	GRANTS

TOP ABSTRACT EXAMPLE 1: PARTIAL LIPODYSTROPHY... EXAMPLE 2: METABOLIC SYNDROME... GRANTS REFERENCES

 
R. A. Hegele is supported by a Canada Research Chair (Tier I) in Human Genetics and a Career Investigator Award from the Heart and Stroke Foundation of Ontario. R. L. Pollex is supported by a Natural Sciences and Engineering Research Council of Canada Graduate Scholarship and the Canadian Institute of Health Research Strategic Training Program in Vascular Research. Support has come from the Canadian Institutes for Health Research, the Canadian Genetic Diseases Network, the Canadian Diabetes Association, and the Blackburn group.

	FOOTNOTES

 

Address for reprint requests and other correspondence: R. A. Hegele, 406-100 Perth Drive, London, Ontario, Canada N6A 5K8 (e-mail: hegele{at}robarts.ca)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

	REFERENCES

TOP ABSTRACT EXAMPLE 1: PARTIAL LIPODYSTROPHY... EXAMPLE 2: METABOLIC SYNDROME... GRANTS REFERENCES

 

1. Agarwal AK and Garg A. A novel heterozygous mutation in peroxisome proliferator-activated receptor- gene in a patient with familial partial lipodystrophy. J Clin Endocrinol Metab 87: 408–411, 2002.[Abstract/Free Full Text]
2. Al-Shali K, Cao H, Knoers N, Hermus AR, Tack CJ, and Hegele RA. A single-base mutation in the peroxisome proliferator-activated receptor 4 promoter associated with altered in vitro expression and partial lipodystrophy. J Clin Endocrinol Metab 89: 5655–5660, 2004.[Abstract/Free Full Text]
3. Alberti KG and Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15: 539–553, 1998.[CrossRef][Web of Science][Medline]
4. Anand SS, Yusuf S, Jacobs R, Davis AD, Yi Q, Gerstein H, Montague PA, and Lonn E. Risk factors, atherosclerosis, and cardiovascular disease among Aboriginal people in Canada: the Study of Health Assessment and Risk Evaluation in Aboriginal Peoples (SHARE-AP). Lancet 358: 1147–1153, 2001.[CrossRef][Web of Science][Medline]
5. Barbaro G. HIV-associated lipodystrophy: pathogenesis and clinical features. Adv Cardiol 40: 97–104, 2003.[Web of Science][Medline]
6. Barroso I, Gurnell M, Crowley VE, Agostini M, Schwabe JW, Soos MA, Maslen GL, Williams TD, Lewis H, Schafer AJ, Chatterjee VK, and O'Rahilly S. Dominant negative mutations in human PPAR associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 402: 880–883, 1999.[Medline]
7. Bays H and Stein EA. Pharmacotherapy for dyslipidaemia—current therapies and future agents. Expert Opin Pharmacother 4: 1901–1938, 2003.[Web of Science][Medline]
8. Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Bonadonna RC, and Muggeo M. Metabolic syndrome: epidemiology and more extensive phenotypic description. Cross-sectional data from the Bruneck Study. Int J Obes Relat Metab Disord 27: 1283–1289, 2003.[CrossRef][Web of Science][Medline]
9. Brown MS and Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science 232: 34–47, 1986.[Free Full Text]
10. Cao H and Hegele RA. Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Genet 9: 109–112, 2000.[Abstract/Free Full Text]
11. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 285: 2486–2497, 2001.[Free Full Text]
12. Ford ES, Giles WH, and Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 287: 356–359, 2002.[Abstract/Free Full Text]
13. Freimer N and Sabatti C. The human phenome project. Nat Genet 34: 15–21, 2003.[CrossRef][Web of Science][Medline]
14. Garg A. Lipodystrophies. Am J Med 108: 143–152, 2000.[CrossRef][Web of Science][Medline]
15. Garg A, Peshock RM, and Fleckenstein JL. Adipose tissue distribution pattern in patients with familial partial lipodystrophy (Dunnigan variety). J Clin Endocrinol Metab 84: 170–174, 1999.[Abstract/Free Full Text]
16. Gerlai R. Phenomics: fiction or the future? Trends Neurosci 25: 506–509, 2002.[CrossRef][Web of Science][Medline]
17. Guettier JM, Georgopoulos A, Tsai MY, Radha V, Shanthirani S, Deepa R, Gross M, Rao G, and Mohan V. Polymorphisms in the fatty acid-binding protein 2 and apolipoprotein C-III genes are associated with the metabolic syndrome and dyslipidemia in a South Indian population. J Clin Endocrinol Metab 90: 1705–1711, 2005.[Abstract/Free Full Text]
18. Harris SB, Gittelsohn J, Hanley A, Barnie A, Wolever TM, Gao J, Logan A, and Zinman B. The prevalence of NIDDM and associated risk factors in native Canadians. Diabetes Care 20: 185–187, 1997.[Abstract]
19. Harris SB, Zinman B, Hanley A, Gittelsohn J, Hegele R, Connelly PW, Shah B, and Hux JE. The impact of diabetes on cardiovascular risk factors and outcomes in a native Canadian population. Diabetes Res Clin Pract 55: 165–173, 2002.[CrossRef][Web of Science][Medline]
20. Hegele RA. Lamin mutations come of age. Nat Med 9: 644–645, 2003.[CrossRef][Web of Science][Medline]
21. Hegele RA. Lessons from human mutations in PPAR. Int J Obes Relat Metab Disord, 29 Suppl 1: S31–S35, 2005.
22. Hegele RA. Monogenic forms of insulin resistance: apertures that expose the common metabolic syndrome. Trends Endocrinol Metab 14: 371–377, 2003.[CrossRef][Web of Science][Medline]
23. Hegele RA. Phenomics, lipodystrophy, and the metabolic syndrome. Trends Cardiovasc Med 14: 133–137, 2004.[CrossRef][Web of Science][Medline]
24. Hegele RA. Premature atherosclerosis associated with monogenic insulin resistance. Circulation 103: 2225–2229, 2001.[Abstract/Free Full Text]
25. Hegele RA, Anderson CM, Wang J, Jones DC, and Cao H. Association between nuclear lamin A/C R482Q mutation and partial lipodystrophy with hyperinsulinemia, dyslipidemia, hypertension, and diabetes. Genome Res 10: 652–658, 2000.[Abstract/Free Full Text]
26. Hegele RA, Cao H, Frankowski C, Mathews ST, and Leff T. PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy. Diabetes 51: 3586–3590, 2002.[Abstract/Free Full Text]
27. Hegele RA, Cao H, Harris SB, Hanley AJ, and Zinman B. The hepatic nuclear factor-1 G319S variant is associated with early-onset type 2 diabetes in Canadian Oji-Cree. J Clin Endocrinol Metab 84: 1077–1082, 1999.[Abstract/Free Full Text]
28. Hegele RA, Kraw ME, Ban MR, Miskie BA, Huff MW, and Cao H. Elevated serum C-reactive protein and free fatty acids among nondiabetic carriers of missense mutations in the gene encoding lamin A/C (LMNA) with partial lipodystrophy. Arterioscler Thromb Vasc Biol 23: 111–116, 2003.[Abstract/Free Full Text]
29. Hegele RA and Leff T. Unbuckling lipodystrophy from insulin resistance and hypertension. J Clin Invest 114: 163–165, 2004.[CrossRef][Web of Science][Medline]
30. Juhan-Vague I, Alessi MC, and Morange PE. Hypofibrinolysis and increased PAI-1 are linked to atherothrombosis via insulin resistance and obesity. Ann Med 32, Suppl 1: 78–84, 2000.
31. Kim MH, Kim MK, Choi BY, and Shin YJ. Prevalence of the metabolic syndrome and its association with cardiovascular diseases in Korea. J Korean Med Sci 19: 195–201, 2004.[Web of Science][Medline]
32. Kobberling J and Dunnigan MG. Familial partial lipodystrophy: two types of an X linked dominant syndrome, lethal in the hemizygous state. J Med Genet 23: 120–127, 1986.[Abstract/Free Full Text]
33. Koenig W. Insulin resistance, heart disease and inflammation. Identifying the "at-risk" patient: the earlier the better? The role of inflammatory markers. Int J Clin Pract Suppl: 23–30, 2002.
34. Kriska AM, Hanley AJ, Harris SB, and Zinman B. Physical activity, physical fitness, and insulin and glucose concentrations in an isolated Native Canadian population experiencing rapid lifestyle change. Diabetes Care 24: 1787–1792, 2001.[Abstract/Free Full Text]
35. Laaksonen DE, Lakka HM, Niskanen LK, Kaplan GA, Salonen JT, and Lakka TA. Metabolic syndrome and development of diabetes mellitus: application and validation of recently suggested definitions of the metabolic syndrome in a prospective cohort study. Am J Epidemiol 156: 1070–1077, 2002.[Abstract/Free Full Text]
36. Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, and Salonen JT. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 288: 2709–2716, 2002.[Abstract/Free Full Text]
37. Liese AD, Mayer-Davis EJ, and Haffner SM. Development of the multiple metabolic syndrome: an epidemiologic perspective. Epidemiol Rev 20: 157–172, 1998.[Free Full Text]
38. Miller AR and Etgen GJ. Novel peroxisome proliferator-activated receptor ligands for type 2 diabetes and the metabolic syndrome. Expert Opin Investig Drugs 12: 1489–1500, 2003.[CrossRef][Web of Science][Medline]
39. Mounkes L, Kozlov S, Burke B, and Stewart CL. The laminopathies: nuclear structure meets disease. Curr Opin Genet Dev 13: 223–230, 2003.[CrossRef][Web of Science][Medline]
40. Okazawa H, Mori H, Tamori Y, Araki S, Niki T, Masugi J, Kawanishi M, Kubota T, Shinoda H, and Kasuga M. No coding mutations are detected in the peroxisome proliferator-activated receptor- gene in Japanese patients with lipoatrophic diabetes. Diabetes 46: 1904–1906, 1997.[Web of Science][Medline]
41. Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, DePaoli AM, Reitman ML, Taylor SI, Gorden P, and Garg A. Leptin-replacement therapy for lipodystrophy. N Engl J Med 346: 570–578, 2002.[Abstract/Free Full Text]
42. Peters JM, Barnes R, Bennett L, Gitomer WM, Bowcock AM, and Garg A. Localization of the gene for familial partial lipodystrophy (Dunnigan variety) to chromosome 1q21–22. Nat Genet 18: 292–295, 1998.[CrossRef][Web of Science][Medline]
43. Pollex RL, Hanley AJG, Zinman B, Harris SB, Khan HM, and Hegele RA. Metabolic syndrome in aboriginal Canadians: prevalence and genetic associations. Atherosclerosis. April 30, 2005 [Epub ahead of print].
44. Pollex RL, Hanley AJG, Zinman B, Harris SB, Khan HM, and Hegele RA. Synergism between mutant HNF1A and the metabolic syndrome in Oji-Cree type 2 diabetes. Diabet Med. In press.
45. Pollex RL, Khan HM, Connelly PW, Young TK, and Hegele RA. The metabolic syndrome in Inuit. Diabetes Care 27: 1517–1518, 2004.[Free Full Text]
46. Razak F, Anand S, Vuksan V, Davis B, Jacobs R, Teo KK, and Yusuf S. Ethnic differences in the relationships between obesity and glucose-metabolic abnormalities: a cross-sectional population-based study. Int J Obes Relat Metab Disord 29: 656–667, 2005.[CrossRef][Web of Science][Medline]
47. Reaven GM. Pathophysiology of insulin resistance in human disease. Physiol Rev 75: 473–486, 1995.[Abstract/Free Full Text]
48. Savage DB, Tan GD, Acerini CL, Jebb SA, Agostini M, Gurnell M, Williams RL, Umpleby AM, Thomas EL, Bell JD, Dixon AK, Dunne F, Boiani R, Cinti S, Vidal-Puig A, Karpe F, Chatterjee VK, and O'Rahilly S. Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma. Diabetes 52: 910–917, 2003.[Abstract/Free Full Text]
49. Schork NJ. Genetics of complex disease: approaches, problems, and solutions. Am J Respir Crit Care Med 156: S103–S109, 1997.[Abstract/Free Full Text]
50. Shackleton S, Lloyd DJ, Jackson SN, Evans R, Niermeijer MF, Singh BM, Schmidt H, Brabant G, Kumar S, Durrington PN, Gregory S, O'Rahilly S, and Trembath RC. LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nat Genet 24: 153–156, 2000.[CrossRef][Web of Science][Medline]
51. Speckman RA, Garg A, Du F, Bennett L, Veile R, Arioglu E, Taylor SI, Lovett M, and Bowcock AM. Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular C-terminal domain of lamin A/C. Am J Hum Genet 66: 1192–1198, 2000.[CrossRef][Web of Science][Medline]
52. Spiegelman BM. PPAR-: adipogenic regulator and thiazolidinedione receptor. Diabetes 47: 507–514, 1998.[Abstract]
53. Tan CE, Ma S, Wai D, Chew SK, and Tai ES. Can we apply the National Cholesterol Education Program Adult Treatment Panel definition of the metabolic syndrome to Asians? Diabetes Care 27: 1182–1186, 2004.[Abstract/Free Full Text]
54. Triggs-Raine BL, Kirkpatrick RD, Kelly SL, Norquay LD, Cattini PA, Yamagata K, Hanley AJ, Zinman B, Harris SB, Barrett PH, and Hegele RA. HNF-1 G319S, a transactivation-deficient mutant, is associated with altered dynamics of diabetes onset in an Oji-Cree community. Proc Natl Acad Sci USA 99: 4614–4619, 2002.[Abstract/Free Full Text]
55. Wang J, Burnett JR, Near S, Young K, Zinman B, Hanley AJ, Connelly PW, Harris SB, and Hegele RA. Common and rare ABCA1 variants affecting plasma HDL cholesterol. Arterioscler Thromb Vasc Biol 20: 1983–1989, 2000.[Abstract/Free Full Text]
56. Wilson PW and Grundy SM. The metabolic syndrome: practical guide to origins and treatment: part I. Circulation 108: 1422–1424, 2003.[Free Full Text]
57. Wilson PW and Grundy SM. The metabolic syndrome: a practical guide to origins and treatment: part II. Circulation 108: 1537–1540, 2003.[Free Full Text]
58. Wolever TM, Hamad S, Gittelsohn J, Gao J, Hanley AJ, Harris SB, and Zinman B. Low dietary fiber and high protein intakes associated with newly diagnosed diabetes in a remote aboriginal community. Am J Clin Nutr 66: 1470–1474, 1997.[Abstract/Free Full Text]
59. Young TK. Obesity among aboriginal peoples in North America: epidemiological patterns, risk factors and metabolic consequences. In: Progress in Obesity Research 7, edited by Angel A, Anderson H, Bouchard C, Lau D, Leiter L, and Mendelson R. London: John Libby, 1996, p. 337–342.
60. Young TK, Dean HJ, Flett B, and Wood-Steiman P. Childhood obesity in a population at high risk for type 2 diabetes. J Pediatr 136: 365–369, 2000.[CrossRef][Web of Science][Medline]
61. Young TK, Moffatt ME, and O'Neil JD. Cardiovascular diseases in a Canadian Arctic population. Am J Public Health 83: 881–887, 1993.[Abstract/Free Full Text]
62. Young TK, Reading J, Elias B, and O'Neil JD. Type 2 diabetes mellitus in Canada's first nations: status of an epidemic in progress. Can Med Assoc J 163: 561–566, 2000.[Abstract/Free Full Text]
63. Young TK, Schraer CD, Shubnikoff EV, Szathmary EJ, and Nikitin YP. Prevalence of diagnosed diabetes in circumpolar indigenous populations. Int J Epidemiol 21: 730–736, 1992.[Abstract/Free Full Text]

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