- Email: [email protected]
Genetics, obesity, and the metabolic syndrome
International Congress Series 1262 (2004) 19 – 24
www.ics-elsevier.com
Genetics, obesity, and the metabolic syndrome: The Professor Donald S. Fredrickson Memorial Lecture Scott M. Grundy * University of Texas Southwestern Medical Center at Dallas, Center for Human Nutrition, 5323 Harry Hines Boulevard, Y3.206, Dallas, TX 75390-9052, USA
Abstract. The metabolic syndrome consists of a clustering of metabolic risk factors in one individual. These risk factors consist of atherogenic dyslipidemia (high triglycerides, high apolipoprotein B [apo B], small LDL particles, and low HDL), elevated blood pressure, insulin resistance F elevated plasma glucose, a prothrombotic state, and a proinflammatory state. Although the metabolic syndrome is increasingly common around the world and represents an important cause of cardiovascular disease (CVD), its pathogenesis is not well understood. The two major underlying causes appear to be obesity or other disorders of adipose tissue and insulin resistance. There is little doubt that genetic susceptibility plays an important role in the development of the metabolic syndrome. This paper addresses the question of the interaction between obesity and genetic susceptibility in the etiology of the metabolic syndrome. Genetic susceptibility appears to exist at three levels: within adipose tissue itself, in insulin signaling pathways, and in regulation of individual risk factors. A major research challenge for the future is to unravel the complex genetic architecture that gives rise to the metabolic syndrome once a person becomes obese. D 2003 Published by Elsevier B.V. Keywords: Metabolic syndrome; Insulin resistance; Obesity; Genetic susceptibility
The metabolic syndrome is a multiplex risk factor for cardiovascular disease (CVD). It has emerged as one of the most important contributing causes of CVD in the world. Its prevalence is increasing rapidly in many countries. This increased occurrence is due in large part to the ‘‘epidemic’’ of obesity in both developed and developing countries. The metabolic syndrome is characterized by a clustering of metabolic risk factors in one person. The principal CVD risk factors of the metabolic syndrome include:
atherogenic dyslipidemia elevated blood pressure insulin resistance F elevated glucose proinflammatory state prothrombotic state
* Tel.: +1-214-648-2890; fax: +1-214-648-4837. E-mail address: [email protected] (S.M. Grundy). 0531-5131/ D 2003 Published by Elsevier B.V. doi:10.1016/S0531-5131(03)01817-X
20
S.M. Grundy / International Congress Series 1262 (2004) 19–24
Atherogenic dyslipidemia consists of elevations of serum triglycerides, remnant lipoproteins, total apolipoprotein B (apo B), and small LDL particles along with reductions in serum HDL cholesterol. Blood pressure often is increased only moderately. Insulin resistance is present in most persons with the metabolic syndrome, and it predisposes to development of elevated glucose in some persons. When the glucose level reaches a defined threshold, the person is said to have type 2 diabetes. Arterial wall inflammation is secondary to several factors including proinflammatory lipoproteins, elevated blood pressure, possibly insulin resistance, elevated glucose, and inflammatory cytokines. The presence of arterial wall inflammation can be recognized clinically by elevations of Creactive protein (CRP). Finally, a prothrombotic state is identified by elevations of plasma fibrinogen and PAI-I. The United States National Cholesterol Education Programs (NCEP) Adult Treatment Panel III (ATP III) [1] recently proposed a simple way to recognize the metabolic syndrome in clinical practice. ATP III proposed that a diagnosis of the metabolic syndrome can be made in any person who has three of five for the following characteristics:
Abdominal obesity (elevated waist circumference) Serum triglycerides z 150 mg/dl Serum HDL cholesterol < 40 mg/dl in men and < 50 mg/dl in women Blood pressure z 130/85 mm Hg Plasma glucose z 110 mg/dl
For the United States, an elevated waist circumferences was defined as z 102 cm in men and z 88 cm in women. This level of waist circumference usually is associated with a significant degree of insulin resistance. An elevated waist circumference can be taken as a surrogate marker for insulin resistance. ATP III noted that many men have insulin resistance when the waist circumference is in the range of 94 – 101.9 cm; this range can be used as one of the criteria. In other regions, significant insulin resistance develops at lesser degrees of abdominal obesity; thus, lower waist circumferences will be used to define abdominal obesity in some countries. Elevations of triglyceride and reductions of HDL cholesterol are indicative of atherogenic dyslipidemia. Most patients with higher triglyceride and lower HDL cholesterol with or without elevated fasting glucose will be insulin resistant. According to ATP III, the metabolic syndrome is still present in a person who has glucose levels >126 mg/dl (categorical hyperglycemia) if other defining components are present. The presence of elevations in CRP ( z 3 mg/l), fibrinogen, and PAI-1 are not required for a clinical diagnosis of metabolic syndrome; however, if such abnormalities are detected, their presence will add confirmation for the existence of the syndrome. 1. Obesity versus insulin resistance as the dominant underlying cause The metabolic syndrome is a complex disorder that undoubtedly is multifactorial in origin. ATP III identified obesity as the major driving force underlying the increasing prevalence of metabolic syndrome in the United States. Many studies have shown that obesity is associated with the presence of several of the metabolic risk factors. On the other
S.M. Grundy / International Congress Series 1262 (2004) 19–24
21
hand, some investigators [2, 3] hold that insulin resistance plays a direct causative role in causation of the other metabolic risk factors. Various mechanisms have been proposed whereby insulin resistance is linked causally with these risk factors. These investigators believe that at the least, insulin resistance is more central in the development of the syndrome than is obesity. This viewpoint is illustrated by the World Health Organization (WHO) criteria [4] for diagnosis of the syndrome. These criteria require more direct evidence for the presence of insulin resistance than the indirect evidence required by ATP III. For example, to qualify for having the metabolic syndrome, WHO require either elevated glucose, hyperinsulinemia, or reduced glucose disposal under glucose-clamp conditions. At present, it is not possible to determine whether obesity or insulin resistance is mechanistically the more closely related to the metabolic syndrome. Both are strongly associated, and the mechanisms underlying the metabolic risk factors are not well understood. Moreover, obesity and insulin resistance are tightly interrelated themselves. Perhaps a more interesting question is how do obesity and insulin resistance interact together to produce the metabolic syndrome. 2. Acquired versus genetic causes There is growing evidence that both acquired factors and genetic factors contribute to the metabolic syndrome. The major acquired factor is obesity, although others, such as physical inactivity, also appear to be involved as well [1]. A role for obesity is suggested by the correlation between rise in prevalence rates of both metabolic syndrome and obesity in the United States and other populations [5]. On the other hand, only about a third of people who are obese develop the metabolic syndrome. This suggests that other factors, such as genetic, also play an important role. One attractive hypothesis is that the syndrome develops largely through the interaction between obesity and genetics. The current manuscript will explore this hypothesis. If the metabolic syndrome results largely from the interaction of obesity and genetic factors, the three levels of genetic variation can be visualized. The first is at the level of adipose tissue itself. Various genetic abnormalities in adipose tissue metabolism could be accentuated with weight gain. Second, individuals could have genetic forms of insulin resistance that adversely affect metabolic risk factors. Third, there could be genetic variation at the level of risk factor regulation. At this level, too, obesity could have an adverse influence. Genetic variation at each of these three levels can be considered for the impact of increasing obesity. 3. Adipose tissue variations and disorders The most recognized variant in adipose tissue distribution associated with the metabolic syndrome is upper body obesity. This pattern is usually called ‘‘abdominal obesity’’ because it is recognized clinically by increased waist circumference. In reality, however, upper body obesity is accompanied by increases in adipose tissue in both truncal subcutaneous and intra-abdominal regions. Persons with this pattern can be contrasted to those with lower body obesity in which most of the excess body fat occurs in the gluteofemoral region. Persons with predominant lower body obesity are less prone to the metabolic syndrome than are those with upper body obesity. The causes of upper body
22
S.M. Grundy / International Congress Series 1262 (2004) 19–24
obesity may be multifactorial. Men are especially likely to have this pattern, thus, its alternate name ‘‘android obesity;’’ in contrast, women typically manifest lower body obesity (gluteofemoral or ‘‘gynoid’’ obesity). Hormonal factors thus likely are one factor responsible for the difference. Still, genetic influences may be at play because some women exhibit upper body obesity, whereas men vary in the distribution of fat between upper and lower body. The mechanistic connections between upper body obesity and metabolic syndrome are not well understood. Nonetheless, those with upper body obesity typically have greater insulin resistance and metabolic risk factors are more severe than in persons with lower body obesity [6]. For the general population, the more severe forms of upper body obesity may have a polygenic origin; on the other hand, there are rare monogenic disorders of adipose tissue in which the distribution of body fat is markedly deranged, and the metabolic syndrome is severe. One of these rare disorders is called familial partial lipodystrophy. This condition is characterized by progressive loss of subcutaneous adipose tissue and overloading of intraabdominal adipose tissue pools with fat. Patients with familial partial lipodystrophy commonly manifest insulin resistance and atherogenic dyslipidemia. They often develop premature type 2 diabetes. Several monogenic conditions have been identified as being responsible for this condition. They include mutations in the structural protein lamin A/C [7– 9], a protein required for the conversion of prelamin to lamin [10], and PPAR gamma [11]. Another monogenic disorder of adipose tissue is congenital partial lipodystrophy. It is characterized by almost total loss of adipose tissue, severe insulin resistance, severe hypertriglyceridemia, and premature diabetes; it further results from a mutation in the enzyme required for the synthesis of triglyceride in adipose tissue [12]. Although these disorders are responsible for severe forms of metabolic syndrome, it is possible that less severe mutations or sets of polymorphisms in adipose tissue function contribute to more common forms of upper body obesity that are associated with this syndrome. 4. Primary insulin resistance Since insulin resistance is strongly associated with other metabolic risk factors, some investigators [3, 4] hypothesize that genetic forms of insulin resistance are critical for development of the metabolic syndrome in populations. Strong support for this hypothesis is the apparent genetic susceptibility of certain populations for insulin resistance and premature type 2 diabetes. Most notable is the population of South Asia. In this population, insulin resistance is commonly observed with even mild obesity [13]. Furthermore, in the Caucasian population, there is considerable variability in insulin resistance at given levels of body fat content [14]. Rare mutations of the insulin receptor produce severe insulin resistance, but whether they are associated with other metabolic risk factors has not been extensively studied. More likely, common forms of reduced insulin sensitivity have a polygenic basis. A variety of gene polymorphisms have been reported to be associated with reduced insulin sensitivity. However, these associations have not been extensively replicated in various cohorts. One polymorphism of interest occurs in the membrane protein PC-1, which has been reported to be associated with increased insulin resistance [15]. In a recent study, Abate et al. [16] found that this polymorphism is strongly associated with insulin resistance in the South Asian population.
S.M. Grundy / International Congress Series 1262 (2004) 19–24
23
However, it is doubtful that this polymorphism alone can account for all of the insulin resistance that is observed in this population. Nonetheless, variation in PC-1 could be one of several genes responsible for the high prevalence of insulin resistance among South Asians. When primary insulin resistance is associated with obesity, insulin resistance likely will be increased further, as will the frequency of other metabolic risk factors. 5. Genetic regulation of metabolic risk factors The third level of genetic variation affecting metabolic risk factors exists at the risk factors themselves. In other words, there is genetic control of lipoprotein metabolism, blood pressure, insulin secretion, and inflammatory and thrombotic responses. Variation in the genetics of risk factor regulation is high in the general population. For example, it has been estimated that approximately 40 –50% of the variation in serum levels of triglycerides and HDL is genetically determined. The same undoubtedly holds for hypertension. Only a portion of obese and/or insulin-resistant persons will develop type 2 diabetes; this is because of variation in ability to secrete insulin to offset insulin resistance. To date, little is known about the sources of genetic variation in risk-factor control in the population. Indeed, in the fields of lipoproteins and blood pressure, debate continues whether variation in expression of these parameters is determined by a few major genes or many, i.e., whether dyslipidemia and hypertension are largely oligogenic or polygenic in origin. Regardless, this third level of control undoubtedly plays a significant role in the expression of the metabolic risk factors in patients who are obese and/or insulin resistant. 6. Interaction of obesity and genetics in causation of the metabolic syndrome In summary, the metabolic syndrome appears to represent an important example of the interaction of acquired factors (especially obesity) and genetic factors in the causation of cardiovascular risk. Genetic variation exists at three levels: adipose tissue, insulin responsiveness, and risk factor regulation. The rise in prevalence of the metabolic syndrome worldwide is being fueled largely by increasing obesity. However, the pattern and severity of metabolic risk factors within and between populations varies greatly depending on the genetic substratum. Gradually, more information is accruing on the genetic architecture of the metabolic syndrome. However, much remains to be determined. One important question is whether the interaction of obesity and genetics is additive for risk factors, or whether it is synergistic. The answer to this question awaits further investigation. References [1] 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). Final Report, Circulation 106 (2002) 3143 – 3421. [2] G.M. Reaven, Banting lecture 1988. Role of insulin resistance in human disease, Diabetes 37 (1988) 1595 – 1607. [3] E. Ferrannini, S.M. Haffner, B.D. Mitchell, M.P. Stern, Hyperinsulinemia: the key feature of a cardiovascular and metabolic syndrome, Diabetologia 34 (1991) 416 – 422. [4] K.G. Alberti, P.Z. Zimmet, Definition, diagnosis and classification of diabetes mellitus and its complica-
24
[5] [6] [7] [8] [9]
[10] [11] [12] [13]
[14]
[15]
[16]
S.M. Grundy / International Congress Series 1262 (2004) 19–24 tions: part 1. Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation, Diabet. Med. 15 (1998) 539 – 553. E.S. Ford, W.H. Giles, W.H. Dietz, Prevalence of the metabolic syndrome among US adults. Findings from the Third National Health and Nutrition Survey, JAMA 287 (2002) 356 – 359. P. Bjorntorp, Body fat distribution, insulin resistance, and metabolic diseases, Nutrition 13 (9) (1997) 795 – 803. J.M. Peters, R. Barnes, L. Bennett, W.M. Gitomer, A.M. Bowcock, A. Garg, Localization of the gene for familial partial lipodystrophy (Dunnigan variety) to chromosome 1q21 – 22, Nat. Genet. 18 (1998) 292 – 295. H. Cao, R.A Hegele, Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunningan-type familial partial lipodystrophy, Hum. Mol. Genet. 9 (2000) 109 – 112. R.A. Speckman, A. Garg, F. Du, et al, 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 (2000) 1192 – 1198. A.K. Agarwal, J.P. Fryns, R.J. Auchus, A. Garg, Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia, Hum. Mol. Genet. 12 (2003) 1995 – 2001. A.K. Agarwal, A. Garg, A novel heterozygous mutation in peroxisome proliferator-activated receptorgamma gene in a patient with familial partial lipodystrophy, J. Clin. Endocrinol. Metab. 87 (2002) 408 – 411. A.K. Agarwal, E. Arioglu, S. De Almeida, et al, AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34, Nat. Genet. 31 (2002) 21 – 23. M. Chandalia, N. Abate, A. Garg, J. Stray-Gundersen, S.M. Grundy, Relationship between generalized and upper body obesity to insulin resistance in Asian Indian men, J. Clin. Endocrinol. Metab. 84 (1999) 2329 – 2335. C.N.O. Jones, F. Abbasi, M. Carantoni, K.S. Polonsky, G.M. Reaven, Roles of insulin resistance and obesity in regulation of plasma insulin concentrations, Am. J. Physiol. Endocrinol. Metab. 278 (2000) E501 – E508. A. Pizzutti, L. Frittitta, A. Argiolas, R. Baratta, I.D. Goldfine, M. Bozzali, T. Ercolino, G. Scarlato, L. Iacoviello, R. Vigneri, V. Tassi, V. Trischitta, A polymorphism (K121Q) of the human glycoprotein PC-1 gene coding region is strongly associated with insulin resistance, Diabetes 48 (1999) 1881 – 1884. N. Abate, L. Carull, A. Cabo-Chan, Jr., M. Chandalia, P.G. Snell, S.M. Grundy, Genetic polymorphism PC-1 K121Q and ethnic susceptibility to insulin resistance, J. Clin. Endocrinol. Metab. (in press).
www.ics-elsevier.com
Genetics, obesity, and the metabolic syndrome: The Professor Donald S. Fredrickson Memorial Lecture Scott M. Grundy * University of Texas Southwestern Medical Center at Dallas, Center for Human Nutrition, 5323 Harry Hines Boulevard, Y3.206, Dallas, TX 75390-9052, USA
Abstract. The metabolic syndrome consists of a clustering of metabolic risk factors in one individual. These risk factors consist of atherogenic dyslipidemia (high triglycerides, high apolipoprotein B [apo B], small LDL particles, and low HDL), elevated blood pressure, insulin resistance F elevated plasma glucose, a prothrombotic state, and a proinflammatory state. Although the metabolic syndrome is increasingly common around the world and represents an important cause of cardiovascular disease (CVD), its pathogenesis is not well understood. The two major underlying causes appear to be obesity or other disorders of adipose tissue and insulin resistance. There is little doubt that genetic susceptibility plays an important role in the development of the metabolic syndrome. This paper addresses the question of the interaction between obesity and genetic susceptibility in the etiology of the metabolic syndrome. Genetic susceptibility appears to exist at three levels: within adipose tissue itself, in insulin signaling pathways, and in regulation of individual risk factors. A major research challenge for the future is to unravel the complex genetic architecture that gives rise to the metabolic syndrome once a person becomes obese. D 2003 Published by Elsevier B.V. Keywords: Metabolic syndrome; Insulin resistance; Obesity; Genetic susceptibility
The metabolic syndrome is a multiplex risk factor for cardiovascular disease (CVD). It has emerged as one of the most important contributing causes of CVD in the world. Its prevalence is increasing rapidly in many countries. This increased occurrence is due in large part to the ‘‘epidemic’’ of obesity in both developed and developing countries. The metabolic syndrome is characterized by a clustering of metabolic risk factors in one person. The principal CVD risk factors of the metabolic syndrome include:
atherogenic dyslipidemia elevated blood pressure insulin resistance F elevated glucose proinflammatory state prothrombotic state
* Tel.: +1-214-648-2890; fax: +1-214-648-4837. E-mail address: [email protected] (S.M. Grundy). 0531-5131/ D 2003 Published by Elsevier B.V. doi:10.1016/S0531-5131(03)01817-X
20
S.M. Grundy / International Congress Series 1262 (2004) 19–24
Atherogenic dyslipidemia consists of elevations of serum triglycerides, remnant lipoproteins, total apolipoprotein B (apo B), and small LDL particles along with reductions in serum HDL cholesterol. Blood pressure often is increased only moderately. Insulin resistance is present in most persons with the metabolic syndrome, and it predisposes to development of elevated glucose in some persons. When the glucose level reaches a defined threshold, the person is said to have type 2 diabetes. Arterial wall inflammation is secondary to several factors including proinflammatory lipoproteins, elevated blood pressure, possibly insulin resistance, elevated glucose, and inflammatory cytokines. The presence of arterial wall inflammation can be recognized clinically by elevations of Creactive protein (CRP). Finally, a prothrombotic state is identified by elevations of plasma fibrinogen and PAI-I. The United States National Cholesterol Education Programs (NCEP) Adult Treatment Panel III (ATP III) [1] recently proposed a simple way to recognize the metabolic syndrome in clinical practice. ATP III proposed that a diagnosis of the metabolic syndrome can be made in any person who has three of five for the following characteristics:
Abdominal obesity (elevated waist circumference) Serum triglycerides z 150 mg/dl Serum HDL cholesterol < 40 mg/dl in men and < 50 mg/dl in women Blood pressure z 130/85 mm Hg Plasma glucose z 110 mg/dl
For the United States, an elevated waist circumferences was defined as z 102 cm in men and z 88 cm in women. This level of waist circumference usually is associated with a significant degree of insulin resistance. An elevated waist circumference can be taken as a surrogate marker for insulin resistance. ATP III noted that many men have insulin resistance when the waist circumference is in the range of 94 – 101.9 cm; this range can be used as one of the criteria. In other regions, significant insulin resistance develops at lesser degrees of abdominal obesity; thus, lower waist circumferences will be used to define abdominal obesity in some countries. Elevations of triglyceride and reductions of HDL cholesterol are indicative of atherogenic dyslipidemia. Most patients with higher triglyceride and lower HDL cholesterol with or without elevated fasting glucose will be insulin resistant. According to ATP III, the metabolic syndrome is still present in a person who has glucose levels >126 mg/dl (categorical hyperglycemia) if other defining components are present. The presence of elevations in CRP ( z 3 mg/l), fibrinogen, and PAI-1 are not required for a clinical diagnosis of metabolic syndrome; however, if such abnormalities are detected, their presence will add confirmation for the existence of the syndrome. 1. Obesity versus insulin resistance as the dominant underlying cause The metabolic syndrome is a complex disorder that undoubtedly is multifactorial in origin. ATP III identified obesity as the major driving force underlying the increasing prevalence of metabolic syndrome in the United States. Many studies have shown that obesity is associated with the presence of several of the metabolic risk factors. On the other
S.M. Grundy / International Congress Series 1262 (2004) 19–24
21
hand, some investigators [2, 3] hold that insulin resistance plays a direct causative role in causation of the other metabolic risk factors. Various mechanisms have been proposed whereby insulin resistance is linked causally with these risk factors. These investigators believe that at the least, insulin resistance is more central in the development of the syndrome than is obesity. This viewpoint is illustrated by the World Health Organization (WHO) criteria [4] for diagnosis of the syndrome. These criteria require more direct evidence for the presence of insulin resistance than the indirect evidence required by ATP III. For example, to qualify for having the metabolic syndrome, WHO require either elevated glucose, hyperinsulinemia, or reduced glucose disposal under glucose-clamp conditions. At present, it is not possible to determine whether obesity or insulin resistance is mechanistically the more closely related to the metabolic syndrome. Both are strongly associated, and the mechanisms underlying the metabolic risk factors are not well understood. Moreover, obesity and insulin resistance are tightly interrelated themselves. Perhaps a more interesting question is how do obesity and insulin resistance interact together to produce the metabolic syndrome. 2. Acquired versus genetic causes There is growing evidence that both acquired factors and genetic factors contribute to the metabolic syndrome. The major acquired factor is obesity, although others, such as physical inactivity, also appear to be involved as well [1]. A role for obesity is suggested by the correlation between rise in prevalence rates of both metabolic syndrome and obesity in the United States and other populations [5]. On the other hand, only about a third of people who are obese develop the metabolic syndrome. This suggests that other factors, such as genetic, also play an important role. One attractive hypothesis is that the syndrome develops largely through the interaction between obesity and genetics. The current manuscript will explore this hypothesis. If the metabolic syndrome results largely from the interaction of obesity and genetic factors, the three levels of genetic variation can be visualized. The first is at the level of adipose tissue itself. Various genetic abnormalities in adipose tissue metabolism could be accentuated with weight gain. Second, individuals could have genetic forms of insulin resistance that adversely affect metabolic risk factors. Third, there could be genetic variation at the level of risk factor regulation. At this level, too, obesity could have an adverse influence. Genetic variation at each of these three levels can be considered for the impact of increasing obesity. 3. Adipose tissue variations and disorders The most recognized variant in adipose tissue distribution associated with the metabolic syndrome is upper body obesity. This pattern is usually called ‘‘abdominal obesity’’ because it is recognized clinically by increased waist circumference. In reality, however, upper body obesity is accompanied by increases in adipose tissue in both truncal subcutaneous and intra-abdominal regions. Persons with this pattern can be contrasted to those with lower body obesity in which most of the excess body fat occurs in the gluteofemoral region. Persons with predominant lower body obesity are less prone to the metabolic syndrome than are those with upper body obesity. The causes of upper body
22
S.M. Grundy / International Congress Series 1262 (2004) 19–24
obesity may be multifactorial. Men are especially likely to have this pattern, thus, its alternate name ‘‘android obesity;’’ in contrast, women typically manifest lower body obesity (gluteofemoral or ‘‘gynoid’’ obesity). Hormonal factors thus likely are one factor responsible for the difference. Still, genetic influences may be at play because some women exhibit upper body obesity, whereas men vary in the distribution of fat between upper and lower body. The mechanistic connections between upper body obesity and metabolic syndrome are not well understood. Nonetheless, those with upper body obesity typically have greater insulin resistance and metabolic risk factors are more severe than in persons with lower body obesity [6]. For the general population, the more severe forms of upper body obesity may have a polygenic origin; on the other hand, there are rare monogenic disorders of adipose tissue in which the distribution of body fat is markedly deranged, and the metabolic syndrome is severe. One of these rare disorders is called familial partial lipodystrophy. This condition is characterized by progressive loss of subcutaneous adipose tissue and overloading of intraabdominal adipose tissue pools with fat. Patients with familial partial lipodystrophy commonly manifest insulin resistance and atherogenic dyslipidemia. They often develop premature type 2 diabetes. Several monogenic conditions have been identified as being responsible for this condition. They include mutations in the structural protein lamin A/C [7– 9], a protein required for the conversion of prelamin to lamin [10], and PPAR gamma [11]. Another monogenic disorder of adipose tissue is congenital partial lipodystrophy. It is characterized by almost total loss of adipose tissue, severe insulin resistance, severe hypertriglyceridemia, and premature diabetes; it further results from a mutation in the enzyme required for the synthesis of triglyceride in adipose tissue [12]. Although these disorders are responsible for severe forms of metabolic syndrome, it is possible that less severe mutations or sets of polymorphisms in adipose tissue function contribute to more common forms of upper body obesity that are associated with this syndrome. 4. Primary insulin resistance Since insulin resistance is strongly associated with other metabolic risk factors, some investigators [3, 4] hypothesize that genetic forms of insulin resistance are critical for development of the metabolic syndrome in populations. Strong support for this hypothesis is the apparent genetic susceptibility of certain populations for insulin resistance and premature type 2 diabetes. Most notable is the population of South Asia. In this population, insulin resistance is commonly observed with even mild obesity [13]. Furthermore, in the Caucasian population, there is considerable variability in insulin resistance at given levels of body fat content [14]. Rare mutations of the insulin receptor produce severe insulin resistance, but whether they are associated with other metabolic risk factors has not been extensively studied. More likely, common forms of reduced insulin sensitivity have a polygenic basis. A variety of gene polymorphisms have been reported to be associated with reduced insulin sensitivity. However, these associations have not been extensively replicated in various cohorts. One polymorphism of interest occurs in the membrane protein PC-1, which has been reported to be associated with increased insulin resistance [15]. In a recent study, Abate et al. [16] found that this polymorphism is strongly associated with insulin resistance in the South Asian population.
S.M. Grundy / International Congress Series 1262 (2004) 19–24
23
However, it is doubtful that this polymorphism alone can account for all of the insulin resistance that is observed in this population. Nonetheless, variation in PC-1 could be one of several genes responsible for the high prevalence of insulin resistance among South Asians. When primary insulin resistance is associated with obesity, insulin resistance likely will be increased further, as will the frequency of other metabolic risk factors. 5. Genetic regulation of metabolic risk factors The third level of genetic variation affecting metabolic risk factors exists at the risk factors themselves. In other words, there is genetic control of lipoprotein metabolism, blood pressure, insulin secretion, and inflammatory and thrombotic responses. Variation in the genetics of risk factor regulation is high in the general population. For example, it has been estimated that approximately 40 –50% of the variation in serum levels of triglycerides and HDL is genetically determined. The same undoubtedly holds for hypertension. Only a portion of obese and/or insulin-resistant persons will develop type 2 diabetes; this is because of variation in ability to secrete insulin to offset insulin resistance. To date, little is known about the sources of genetic variation in risk-factor control in the population. Indeed, in the fields of lipoproteins and blood pressure, debate continues whether variation in expression of these parameters is determined by a few major genes or many, i.e., whether dyslipidemia and hypertension are largely oligogenic or polygenic in origin. Regardless, this third level of control undoubtedly plays a significant role in the expression of the metabolic risk factors in patients who are obese and/or insulin resistant. 6. Interaction of obesity and genetics in causation of the metabolic syndrome In summary, the metabolic syndrome appears to represent an important example of the interaction of acquired factors (especially obesity) and genetic factors in the causation of cardiovascular risk. Genetic variation exists at three levels: adipose tissue, insulin responsiveness, and risk factor regulation. The rise in prevalence of the metabolic syndrome worldwide is being fueled largely by increasing obesity. However, the pattern and severity of metabolic risk factors within and between populations varies greatly depending on the genetic substratum. Gradually, more information is accruing on the genetic architecture of the metabolic syndrome. However, much remains to be determined. One important question is whether the interaction of obesity and genetics is additive for risk factors, or whether it is synergistic. The answer to this question awaits further investigation. References [1] 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). Final Report, Circulation 106 (2002) 3143 – 3421. [2] G.M. Reaven, Banting lecture 1988. Role of insulin resistance in human disease, Diabetes 37 (1988) 1595 – 1607. [3] E. Ferrannini, S.M. Haffner, B.D. Mitchell, M.P. Stern, Hyperinsulinemia: the key feature of a cardiovascular and metabolic syndrome, Diabetologia 34 (1991) 416 – 422. [4] K.G. Alberti, P.Z. Zimmet, Definition, diagnosis and classification of diabetes mellitus and its complica-
24
[5] [6] [7] [8] [9]
[10] [11] [12] [13]
[14]
[15]
[16]
S.M. Grundy / International Congress Series 1262 (2004) 19–24 tions: part 1. Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation, Diabet. Med. 15 (1998) 539 – 553. E.S. Ford, W.H. Giles, W.H. Dietz, Prevalence of the metabolic syndrome among US adults. Findings from the Third National Health and Nutrition Survey, JAMA 287 (2002) 356 – 359. P. Bjorntorp, Body fat distribution, insulin resistance, and metabolic diseases, Nutrition 13 (9) (1997) 795 – 803. J.M. Peters, R. Barnes, L. Bennett, W.M. Gitomer, A.M. Bowcock, A. Garg, Localization of the gene for familial partial lipodystrophy (Dunnigan variety) to chromosome 1q21 – 22, Nat. Genet. 18 (1998) 292 – 295. H. Cao, R.A Hegele, Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunningan-type familial partial lipodystrophy, Hum. Mol. Genet. 9 (2000) 109 – 112. R.A. Speckman, A. Garg, F. Du, et al, 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 (2000) 1192 – 1198. A.K. Agarwal, J.P. Fryns, R.J. Auchus, A. Garg, Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia, Hum. Mol. Genet. 12 (2003) 1995 – 2001. A.K. Agarwal, A. Garg, A novel heterozygous mutation in peroxisome proliferator-activated receptorgamma gene in a patient with familial partial lipodystrophy, J. Clin. Endocrinol. Metab. 87 (2002) 408 – 411. A.K. Agarwal, E. Arioglu, S. De Almeida, et al, AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34, Nat. Genet. 31 (2002) 21 – 23. M. Chandalia, N. Abate, A. Garg, J. Stray-Gundersen, S.M. Grundy, Relationship between generalized and upper body obesity to insulin resistance in Asian Indian men, J. Clin. Endocrinol. Metab. 84 (1999) 2329 – 2335. C.N.O. Jones, F. Abbasi, M. Carantoni, K.S. Polonsky, G.M. Reaven, Roles of insulin resistance and obesity in regulation of plasma insulin concentrations, Am. J. Physiol. Endocrinol. Metab. 278 (2000) E501 – E508. A. Pizzutti, L. Frittitta, A. Argiolas, R. Baratta, I.D. Goldfine, M. Bozzali, T. Ercolino, G. Scarlato, L. Iacoviello, R. Vigneri, V. Tassi, V. Trischitta, A polymorphism (K121Q) of the human glycoprotein PC-1 gene coding region is strongly associated with insulin resistance, Diabetes 48 (1999) 1881 – 1884. N. Abate, L. Carull, A. Cabo-Chan, Jr., M. Chandalia, P.G. Snell, S.M. Grundy, Genetic polymorphism PC-1 K121Q and ethnic susceptibility to insulin resistance, J. Clin. Endocrinol. Metab. (in press).