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The dysmetabolic syndrome
Abstract
Groop L, Orho-Melander M (Wallenberg Laboratory, Lund University, Malmö, Sweden). The dysmetabolic syndrome. J Intern Med 2001; 250: 105–120.
The first unifying definition for the metabolic syndrome was proposed by WHO in 1998. In accordance to this, patients with type 2 diabetes mellitus or impaired glucose tolerane have the syndrome if they fulfil two of the criteria: hypertension, dyslipidaemia, obesity/abdominal obesity and microalbuminuria. Persons with normal glucose tolerance (NGT) should also be insulin resistant. About 40% of persons with impaired glucose tolerance (IGT) and 70% of patients with type 2 diabetes have features of the syndrome. Importantly, presence of the dysmetabolic syndrome is associated with reduced survival, particularly because of increased cardiovascular mortality. The dysmetabolic syndrome most likely results from interplay between several genes and an affluent environment. Compatible with the thrifty gene theory, common variants in genes regulating lipolysis, thermogenesis and glucose uptake in skeletal muscle account for a large part of such thrifty genes. However, hitherto unknown genes may still be identified by random gene approaches.
... Furthermore, cardiovascular and endocrine disorders are very common health problems associated with long-term exposure to gasoline, which could be related to carbon monoxide toxicity (10). in a similar manner, people with ischemic heart disease are at special risk of developing signs and symptoms of heart attack due to the decreased coronary artery blood flow (1,10). The incidence of arterial hypertension is significantly higher in workers who are exposed to high levels of benzene and xylene in their workplaces (11). Chronic exposure to gasoline compounds causes serious damages to the homeostasis cardiovascular systems(1), leading to disturbances in blood pressure. ...
... The most common endocrinedisrupting chemicals found in gasoline are Polychlorinated Biphenyls (PCBs), which are chlorinated compounds used as coolants and lubricants (12). PCBs are toxic to multiple organs including liver and thyroid and are linked to increased incidence of obesity and diabetes in people with long-term contact with these compounds (11,13). ...
... In addition, lead enhances low density lipoprotein (LDL), peroxidation, and cardiovascular disease via inactivation of paraoxonase, an inhibitor of LDL oxidation (17). Moreover, in this study it was identified that the incidence of arterial hypertension was significantly increased in workers who were exposed to benzene and xylene in their workplace (11). Similarly, both preeclampsia and hypertension in pregnant women were highly related to solvent exposure (18). ...
Background: Gasoline poses a threat to the public health, in general, and gasoline station workers, in particular. Cardiometabolic syndrome is a very common health problem among gasoline station workers throughout the world. In spite of its significance, few health assessments studies (if any) are available exploring the health risk effects of gasoline in relation to occupational exposure in Iraq. Trying to fill this gap, the present study aimed to evaluate health risk effects of gasoline on gasoline station workers in Iraq. Methods: The study population (N=134) was composed of randomly selected male gasoline pump workers (N=83) in Basrah, Iraq. Unexposed healthy individuals (N=51) without any systemic or mental illness were used as a control group. Body mass index (BMI), blood pressure, and blood glucose level were measured in both groups. Results: The results indicated that the BMI, blood pressure, and blood glucose levels were significantly higher among gasoline station workers in comparison to those in the control group. Conclusion: Based on the results, it can be claimed that exposure to gasoline could increase the potential risk of many disorders such as metabolic syndrome, high blood pressure, and elevated blood glucose level. It is highly recommended to consider preventive measures that protect gasoline station workers from such health threats. In addition, learning about the importance of wearing gloves, special coats, and face mask is believed to considerably reduce the risk of getting involved with such health problems.
... Furthermore, cardiovascular and endocrine disorders are very common health problems associated with long-term exposure to gasoline, which could be related to carbon monoxide toxicity (10). in a similar manner, people with ischemic heart disease are at special risk of developing signs and symptoms of heart attack due to the decreased coronary artery blood flow (1,10). The incidence of arterial hypertension is significantly higher in workers who are exposed to high levels of benzene and xylene in their workplaces (11). Chronic exposure to gasoline compounds causes serious damages to the homeostasis cardiovascular systems(1), leading to disturbances in blood pressure. ...
... The most common endocrinedisrupting chemicals found in gasoline are Polychlorinated Biphenyls (PCBs), which are chlorinated compounds used as coolants and lubricants (12). PCBs are toxic to multiple organs including liver and thyroid and are linked to increased incidence of obesity and diabetes in people with long-term contact with these compounds (11,13). ...
... In addition, lead enhances low density lipoprotein (LDL), peroxidation, and cardiovascular disease via inactivation of paraoxonase, an inhibitor of LDL oxidation (17). Moreover, in this study it was identified that the incidence of arterial hypertension was significantly increased in workers who were exposed to benzene and xylene in their workplace (11). Similarly, both preeclampsia and hypertension in pregnant women were highly related to solvent exposure (18). ...
Background: Gasoline poses a threat to the public health, in general, and gasoline station workers, in particular. Cardiometabolic syndrome is a very common health problem among gasoline station workers throughout the world. In spite of its significance, few health assessments studies (if any) are available exploring the health risk effects of gasoline in relation to occupational exposure in Iraq. Trying to fill this gap, the present study aimed to evaluate health risk effects of gasoline on gasoline station workers in Iraq. Methods: The study population (N=134) was composed of randomly selected male gasoline pump workers (N=83) in Basrah, Iraq. Unexposed healthy individuals (N=51) without any systemic or mental illness were used as a control group. Body mass index (BMI), blood pressure, and blood glucose level were measured in both groups. Results: The results indicated that the BMI, blood pressure, and blood glucose levels were significantly higher among gasoline station workers in comparison to those in the control group. Conclusion: Based on the results, it can be claimed that exposure to gasoline could increase the potential risk of many disorders such as metabolic syndrome, high blood pressure, and elevated blood glucose level. It is highly recommended to consider preventive measures that protect gasoline station workers from such health threats. In addition, learning about the importance of wearing gloves, special coats, and face mask is believed to considerably reduce the risk of getting involved with such health problems.
... Other components are centripetal obesity, hypertension, dyslipidemia (low HDL, high TG, small dense oxidized LDL) and endothelial dysfunction (microalbuminuria). 6 Recently, a prothrombotic state, characterized by abnormalities in platelet function and elevated circulating levels of C-reactive protein (CRP), PAI-1 and fibrinogen, has been recognized as a component of the metabolic syndrome. Microvascular complications (retinopathy, nephropathy and neuropathy) contribute importantly to the increased morbidity in DM as retinopathy and nephropathy are major causes of blindness and end-stage renal disease, respectively. ...
... Diabetes also worsens early and late outcomes in acute coronary syndromes and after coronary interventions. 6,7 Platelet in diabetes mellitus have dysregulated signaling pathway that lead to an increased activation and aggregation in response to a given stimulus, thus triggering thrombus formation and causing micropapillary embolization with release of constrictive ,oxidative and mitogenic substances such as PDGF and VEGF that accelerate progression of local vascular lesion like the neovascularization of lens in diabetic retinopathies. 23 Diabetic group was also divided into two groups on the bases of HbA1C value. ...
Background: Diabetes Mellitus is a global pandemic disease. The increased platelet activity is emphasized to play a role in the development of vascular complications of the metabolic disorder. Mean platelet volume (MPV) is an indicator of average size and activity of platelets. This study was conducted to find correlation of platelet indices with HbA1c in diabetic patients with absence/presence of vascular complications.Methods: Total of 100 subjects was enrolled in the study. Sample for glucose estimation and platelet indices were collected and estimation were carried out by the auto-analyzers. The statistical evaluation is done using SPSS version 22. Student t- test was used for doing comparison between two variables namely HbA1c <7 and HbA1c ≥7 and diabetics with vascular complications v/s without vascular complications.Results: MPV, is significantly higher in patients with type -2 diabetes mellitus with HbA1C ≥7 and those with vascular complications in comparison to patients having HbA1c <7 and those without vascular complications ( p- value <0.001 which is highly significant).Conclusions: MPV might be used as a simple and cost-effective laboratory test in the follow up of diabetes mellitus along with HbA1c and thereby help to reduce the morbidity and mortality.
... The concept of MetS integrates the clinical manifestations of insulin resistance. It predicts the development of T2DM and leads to increased cardiovascular morbidity [11]. In the USA, the estimated prevalence rates of MetS in men and women are 35% and 33%, respectively [12]. ...
... This is consistent with the position published in 2009 by Alberti et al. [38] regarding the harmonization of MetS criteria. Still, the same controversy persists for Caucasians and the initially accepted threshold (102 cm in men and 88 in 11 This article is protected by copyright. All rights reserved. ...
Background:
The prevalence of obesity has increased worldwide in parallel with associated metabolic disturbances such as diabetes and nonalcoholic fatty liver disease.
Objective:
To underscore discrepancies in the standard anthropometric cutoff values and the presence of metabolic disturbances including diabetes and nonalcoholic fatty liver disease caused by biological and ethnic variations.
Materials and methods:
We performed a literature review regarding the diagnosis and prevalence of obesity, diabetes, metabolic syndrome, and nonalcoholic fatty liver disease and about the different available indicators to define obesity.
Results:
There is an ongoing epidemic of these chronic diseases, partially attributed to the increased prevalence of obesity. The available markers to indicate adiposity are imperfect and the selection of accurate cutoff points is still not clear.
Conclusion:
Methods to quantify adiposity that are useful in clinical practice should be developed to better classify individuals and to reflect metabolic risk more appropriately. This article is protected by copyright. All rights reserved.
... There is no internationally agreed definition for the metabolic syndrome but working definitions were proposed by the WHO in 1998 [1] and by the National Cholesterol Education Program (NCEP) in 2001 [99]. According to the WHO definition, the metabolic syndrome includes patients with impaired glucose tolerance/diabetes or with normal glucose tolerance if they are insulin resistant and in addition fulfill two out of four criteria: 1.Hypertension: >160/90 mmHg; 2. Hypertriglyceridaemia: >1.7mmol/L and/or low high-density lipoprotein cholesterol: <0.9 mmol/L in men, <1.0 mmol/L in women; 3. Central obesity: men: waist to hip ratio >0.90, women: waist to hip ratio >0.85 and/or BMI >30 kg/m2; 4. Microalbuminuria: urinary albumin excretion rate >20 ug/min or albumin: creatinine ratio >20 mg/g [1,100,101]. In 1999 the European Group for the Study of Insulin Resistance (EGIR) refined the WHO definition of the metabolic syndrome and they suggest that insulin resistance syndrome is a more appropriate name [88]. ...
... The prevalence of the metabolic syndrome depends on the definition but irrespective of that it is associated with increased cardiovascular and allcause mortality [104]. According to the Botnia study in Finland and Sweden, using the WHO definition, about 10% of persons with normal glucose tolerance, 40% of persons with impaired glucose tolerance and 85% of patients with type 2 diabetes would have the metabolic syndrome [100,101]. The prevalence in 1988-1994 of the metabolic syndrome among American adults according to NCEP´s criteria [99] in participants 20-29, 60-69 and >70 years was 6.9, 43.5 and 42%, respectively [102]. ...
... In 1988, Reaven and colleagues described "the metabolic syndrome" as a link between insulin resistance and hypertension, dyslipidemia, type 2 diabetes, and other metabolic abnormalities associated with an increased risk of atherosclerotic cardiovascular diseasese, in adults [1]. In 1989, Kaplan renamed this syndrome "the deadly quartet" for the association of upper body obesity, glucose intolerance, hypertriglyceridemia and hypertension It was only in 2001 that the National Cholesterol Education Program (NCEP) proposed the term "metabolic syndrome" and which is defined by the presence of 3 out of 5 criteria which are central obesity, hyperglycemia, hypertriglyceridemia, decreased highdensity lipoprotein (HDL) and high blood pressure (hypertension) [2,3]. ...
Introduction: Metabolic syndrome is one of the complications of obesity with a significant impact on health. This MS is diagnosed according to the International Diabetes Federation 2007 in children aged 10 to 16 years with waist circumference > 90th percentile according to the curves of McCarthy and two of the following metabolic characteristics: HDL C < 40 mg/dL, TG≥150 mg/dL, blood glucose ≥ 100 mg/dL and blood pressure≥130/85mmHg. Goals: We performed a retrospective and prospective study at the pediatric obesity consultation. The main objective is to assess the metabolic syndrome in a population of obese children and dolescents. The secondary objectives are the evaluation of the various criteria of the metabolic syndrome, and the impact of the degree of obesity, the search for comorbidities and their repercussions, and finally the evaluation of the care.
... The identification, concretion, and acceptance of this novel set of syndromic pathologies took considerable time and effort [5,[11][12][13]. The first agreed upon main disorders of the syndrome: diabetes, obesity, hyperlipidemia, and arterial hypertension (AHT), affecting (together) the same patients [14][15][16], have been expanded to include practically all forms of inflammation and an almost complete recollection of age and lifestyle-related pathologic traits, universally affecting body systems and functions [17,18]. ...
This review focuses on the question of metabolic syndrome (MS) being a complex, but essentially monophyletic, galaxy of associated diseases/disorders, or just a syndrome of related but rather independent pathologies. The human nature of MS (its exceptionality in Nature and its close interdependence with human action and evolution) is presented and discussed. The text also describes the close interdependence of its components, with special emphasis on the description of their interrelations (including their syndromic development and recruitment), as well as their consequences upon energy handling and partition. The main theories on MS’s origin and development are presented in relation to hepatic steatosis, type 2 diabetes, and obesity, but encompass most of the MS components described so far. The differential effects of sex and its biological consequences are considered under the light of human social needs and evolution, which are also directly related to MS epidemiology, severity, and relations with senescence. The triggering and maintenance factors of MS are discussed, with especial emphasis on inflammation, a complex process affecting different levels of organization and which is a critical element for MS development. Inflammation is also related to the operation of connective tissue (including the adipose organ) and the widely studied and acknowledged influence of diet. The role of diet composition, including the transcendence of the anaplerotic maintenance of the Krebs cycle from dietary amino acid supply (and its timing), is developed in the context of testosterone and β-estradiol control of the insulin-glycaemia hepatic core system of carbohydrate-triacylglycerol energy handling. The high probability of MS acting as a unique complex biological control system (essentially monophyletic) is presented, together with additional perspectives/considerations on the treatment of this ‘very’ human disease.
... In 1998, the WHO proposed a unifying definition for "the syndrome of abnormal metabolism" and chose to call it the metabolic syndrome rather than the IR syndrome [256]. The main reason was that it was not considered established that IR is the cause of all the components of the syndrome (e.g., hypertension, dyslipidemia, visceral obesity or microalbuminuria) [256,257]. ...
The comprehensive anabolic effects of insulin throughout the body, in addition to the control of glycemia, also include ensuring lipid homeostasis and anti-inflammatory modulation, especially in adipose tissue (AT). The prevalence of obesity, defined as a body mass index (BMI) ≥ 30 kg/m2, has been increasing worldwide on a pandemic scale with accompanying syndemic health problems, including glucose intolerance, insulin resistance (IR) and diabetes. Impaired tissue sensitivity to insulin or IR paradoxically leads to diseases with an inflammatory component despite hyperinsulinemia. Therefore, an excess of visceral AT in obesity initiates chronic low-grade inflammatory conditions that interfere with insulin signaling via insulin receptor (INSR). Moreover, in response to IR, hyperglycemia itself stimulates a primarily defensive inflammatory response associated with the subsequent release of numerous inflammatory cytokines and a real threat of organ function deterioration. In this review, all components of this vicious cycle are characterized with particular emphasis on the interplay between insulin signaling and both the innate and adaptive immune responses related to obesity. Increased visceral AT accumulation in obesity should be considered the main environmental factor responsible for the disruption in the epigenetic regulatory mechanisms in the immune system, resulting in autoimmunity and inflammation.
... In 1998, the WHO proposed a unifying definition for "the syndrome of abnormal metabolism" and chose to call it the metabolic syndrome rather than the IR syndrome [267]. The main reason was that it was not considered established that IR is the cause of all the components of the syndrome (e.g., hypertension, dyslipidemia, visceral obesity, or microalbuminuria) [267,268]. ...
The comprehensive anabolic effects of insulin throughout the body, in addition to the control of glycemia, include ensuring lipid homeostasis and anti-inflammatory modulation, especially in adipose tissue (AT). The prevalence of obesity, defined as a body mass index (BMI) ≥ 30 kg/m2, has been increasing worldwide on a pandemic scale with accompanying syndemic health problems, including glucose intolerance, insulin resistance (IR), and diabetes. Impaired tissue sensitivity to insulin or IR paradoxically leads to diseases with an inflammatory component despite hyperinsulinemia. Therefore, an excess of visceral AT in obesity initiates chronic low-grade inflammatory conditions that interfere with insulin signaling via insulin receptors (INSRs). Moreover, in response to IR, hyperglycemia itself stimulates a primarily defensive inflammatory response associated with the subsequent release of numerous inflammatory cytokines and a real threat of organ function deterioration. In this review, all components of this vicious cycle are characterized with particular emphasis on the interplay between insulin signaling and both the innate and adaptive immune responses related to obesity. Increased visceral AT accumulation in obesity should be considered the main environmental factor responsible for the disruption in the epigenetic regulatory mechanisms in the immune system, resulting in autoimmunity and inflammation.
... Because of their coincidence and interactions, it is useful to consider these abnormalities together. Various terms and definitions for clusters of CVM factors have been described, e.g., metabolic syndrome, dysmetabolic syndrome, syndrome X and insulin resistance syndrome (Eckel et al., 2005;Groop and Orho-Melander, 2001;Rao, 2001;Reaven, 2004;Timar et al., 2000). ...
Several cardiovascular and metabolic indicators, such as cholesterol and blood pressure have been associated with altered neural and cognitive health as well as increased risk of dementia and Alzheimer's disease in later life. In this cross-sectional study, we examined how an aggregate index of cardiovascular and metabolic risk factor measures was associated with correlation-based estimates of resting-state functional connectivity (FC) across a broad adult age-span (36-100+ years) from 930 volunteers in the Human Connectome Project Aging (HCP-A). Increased (i.e., worse) aggregate cardiometabolic scores were associated with reduced FC globally, with especially strong effects in insular, medial frontal, medial parietal, and superior temporal regions. Additionally, at the network-level, FC between core brain networks, such as default-mode and cingulo-opercular, as well as dorsal attention networks, showed strong effects of cardiometabolic risk. These findings highlight the lifespan impact of cardiovascular and metabolic health on whole-brain functional integrity and how these conditions may disrupt higher-order network integrity.
... Insulin resistance plays a central role in this syndrome. 2 Diabetes and uncontrolled hyperglycaemia are known to play a significant role in the development of cardiovascular disease since Framingham study. 3,4 Additionally, besides the diabetes and classical risk factors, the presences of microvascular complications are also predictor of coronary heart events especially when it is prolonged and/or poorly controlled. ...
Background: Depending on the aetiology of the DM, factors contributing to hyperglycaemia include reduced insulin secretion, decreased glucose utilization, and increased glucose production. Mean platelet volume (MPV) and platelet distribution width (PDW) are important, simple, effortless, and cost-effective tools measured by hematology analyser which assess the volume and function of platelets. Analysing the platelet parameters can act as an alarm for progression of complications of DM. Hence, we studied the platelet parameters in diabetic patients with good and poor glycaemic control and their association in microvascular complications. Methods: This study was conducted on 100 patients having diabetes mellitus. All the patients were subjected to detailed history regarding age, sex, occupation, socioeconomic status, GPE and systemic examination. Results: Out of 100 cases, 29 patients had a good glycemic control (HbA1c<7%) and 71 had poor glycemic control (HbA1c>7%). Mean FBS was 118.59±19.36 mg/dl in good control group and 158.79±29.21 mg/dl in poor control (p<0.001). Mean PPBS was 159.86±37.78 mg/dl in good control group and 235.80±53.28 mg/dl in poor control group (p<0.001). Good glycemic control group had mean MPV of 7.89±0.63 fl and poor glycemic control group had mean MPV 10.06 fl (p<0.001). Mean PDW was 12.32±1.94 in good control group and 13.81±2.25 in poor control group. Conclusions: Our study indicates that MPV and PDW are increased in diabetic patients, more so in patients with microvascular complications than in those without complications. Hence, they can be used as markers in predicting the microvascular complications in diabetes mellitus.
... These conditions are also risk factors for the development of type 2 diabetes (and can worsen its metabolic control) or are associated with diabetes in the context of the dysmetabolic syndrome. 4 Therefore, not unexpectedly the occurrence of multiple CVD risk factors is often observed in people with diabetes, further contributing to the emergence of CV complications. 5,6 Multi-factorial interventions, such as appropriate treatments and lifestyle improvements, can substantially reduce the risk of important CV outcomes in this population. ...
Background
Cardiovascular (CV) diseases are a major cause of the disease burden worldwide and contribute substantially to health care costs, in particular in people with diabetes. Their incidence can be reduced by multi-factorial interventions. This study intends to describe the occurrence of CV risk and protective/preventive factors in the adult population resident in Italy, to better target public health interventions.
Methods
Data collected in 2016–19 from adults aged 18–69 years, participating in the Italian Behavioural Risk Factor Surveillance System (PASSI) based on a cross-sectional design, were used. The frequency of CV risk/protective factors was estimated in people with and without diabetes. The contribution of socioeconomic level (SEL) to CV risk was also explored.
Results
Among 129 989 respondents, 4.7% received a diagnosis of diabetes. Many CV risk factors were significantly more frequent in people with diabetes, who often presented multiple risk factors. At the same time, they adopted protective behaviours and received treatments and preventive interventions more often than those without diabetes. Relevant disparities were observed between SEL groups in diabetic people, with the least advantaged showing a worse risk profile.
Conclusions
Adults resident in Italy with diabetes are exposed to CV risk factors more often than those without diabetes. However, they show an increased attention to control these factors and receive more frequent health care, although less than ideal in absolute terms. There is an opportunity to reduce the important CV disease burden in the population through preventive/health promotion targeted interventions, prioritizing people with diabetes and of lower SEL.
... It has been observed that an increased risk of type 2 diabetes positively correlates with a patient's bust size [46]. According to Groop and Orho-Melander, both the amount of visceral adipose tissue and central obesity significantly correlate with insulin resistance [47]. ...
Background and objectives:
The aim was to compare body composition and levels of biochemical blood parameters and identify relationships between biochemical parameters and body composition of women with type 2 diabetes and healthy ones, both in perimenopausal period (172 women aged between 45 and 65 come from the West Pomeranian Voivodeship, Poland).
Materials and methods:
The study consisted of an interview, body composition analysis with Jawon Medical IOI-353 (Yuseong, South Korea) analyser and venous blood biochemical analysis (lipid profile, levels of glucose, insulin, CRP, glycated haemoglobin).
Results:
The vast majority of body composition measurements varied between study and control groups in a statistically significant way (p < 0.05) except protein and soft lean mass of the torso. Statistically significant differences between the two groups have been observed in case of all biochemical parameters (p < 0.001).
Conclusions:
Body composition of women suffering from type 2 diabetes significantly varied from body composition of healthy women. Results of the first group were characterised by higher values, especially in case of general parameters, abdominal area, content of adipose tissue and soft tissues. Relationship between body composition and biochemical results may be observed, especially in level of triglycerides, CRP and insulin. Higher concentrations of these parameters were associated with increased values of majority of body composition measurements regardless of type 2 diabetes incidence.
... Nationwide, the ARETAEUS1 study showed that patients with newly diagnosed type 2 diabetes were overweight (37.4%) and obese (51.9%) [25]. Studies have shown that visceral fat tissue mass and visceral obesity are significantly correlated with insulin resistance [26,27]. ...
Menopause is a natural period resulting from the decrease in hormonal activity of the ovaries. Growing hormonal deficiencies and changes in the body influence a variety of functions in women, leading to depression and decreased quality of life. The relationship between body composition, the severity of depressive and climacteric symptoms and the quality of life of women with type 2 diabetes and healthy women in the perimenopausal period was studied. Statistically significant differences were observed between the study and control groups regarding all body composition parameters except for protein and the content of torso soft tissues (p < 0.05). In both the study and control groups, resulting symptoms were significantly correlated with numerous body composition parameters (e.g., body mass, fat tissue mass, minerals, abdominal circumference), while symptoms of depression were significantly correlated with similar parameters only in the control group. A statistically relevant relationship was observed between the study and control groups with respect to quality of life in certain domains. The quality of life of women suffering from type 2 diabetes was worse compared with healthy women. Analysis of body composition showed significant differences between healthy women and those with type 2 diabetes. Healthy women showed a tendency to establish a link between body composition and depressiveness.
... 'syndrome X' une constellation d'anomalies associées à l'IR qui en est l'élément central [Reaven 1988]. Après cela, d'autres dénominations ont été proposées : le 'deadly quartet' [Kaplan 1989], le syndrome d'IR [DeFronzo et Ferrannini 1991] ou encore le syndrome dysmétabolique [Groop et Orho-Melander 2001]. ...
Le syndrome métabolique (SM) augmente le risque de diabète et de maladies cardiovasculaires. Les composantes de cet état sont l'obésité, l'hypertension, le profil lipidique, la résistance à l'insuline, l'inflammation et l'atteinte hépatique. L'accumulation excessive de la masse grasse, surtout abdominale, entraîne une inflammation systémique de faible niveau. En effet, le tissu adipeux secrète des adipokines (leptine, visfatine, IL-6 et TNF-a) qui sont impliquées dans l'inflammation. Notre but a été d'étudier : 1) les associations de l'évolution de 5 ans de l'indice de masse corporelle (IMC) et de la leptine circulante avec les facteurs du SM et 2) l'expression de certaines adipokines dans les lymphocytes. Pour ces études, la cohorte STANISLAS a été un outil parfait (recueil des données sur les facteurs du SM, bio-banques : lymphocytes, sérum, plasma, ADN). L'étude longitudinale a démontré que certains de facteurs du SM évoluent ensemble au fil du temps et que ces groupes de facteurs sont liés à l'IMC en fonction du sexe. Ensuite, nous avons constaté des associations de la leptine avec des facteurs de risque du SM, différentes en fonction du sexe, indépendamment de la masse grasse. Enfin, nous avons détecté l'ARNm de nos adipokines et sa quantification a démontré des associations de la visfatine avec l'IMC et l'expression du TNF-a, et de la leptine avec la pression artérielle. L'ensemble de nos résultats souligne le rôle-médiateur de la leptine et l'impact du sexe sur les actions de cette hormone et ouvre de nouvelles perspectives pour étudier les adipokines dans le contexte de l'inflammation, en proposant un modèle d'étude : les lymphocytes.
... Since the 1980s it has been emphasized that inappropriate diet, lack of exercise and sociocultural influence are not the only factors responsible for the development of metabolic syndrome but that genetic factors also play a role. Groop and others described in detail the genetic factors in the development of obesity and emphasized the sociocultural influence [13].The most recent studies on the metabolic syndrome and insulin resistance focus on such factors as subclinical inflammatory process and hormonal activity of the adipose tissue [14]. ...
... O È vervikt och framfö r allt bukfetma, är vanligt fö rekommande och viktiga kliniska karakteristika, liksom hypertoni och dyslipidemi i form av hö ga triglycerider och la Ê ga H D L-niva Ê er samt sma Ê täta aterogena LD L-partiklar. N edsatt brinolytisk fö rma Ê ga, hyperurikemi och mikroalbuminuri är andra komponenter ofta fö rekommande i det metabola syndromet (3,4). Epidemiologiska studier som publicerats det senaste decenniet har visat att det metabola syndromet ö kar risken fö r insjuknande i kardiovaskulära sjukdomar och diabetes typ II (5). ...
The prevalence of overweight, central obesity and the metabolic syndrome is increasing in Sweden. Physical inactivity plays an important role in the pathogenesis of the metabolic syndrome. Physical activity increases energy expenditure and will affect body weight and central obesity. Furthermore, physical activity positively affects lipoprotein metabolism, blood pressure, peripheral insulin sensitivity and fibrinolysis. Consequently, physical activity plays an important role in the prevention and treatment of the metabolic syndrome. Daily low-intensity physical activity and aerobic exercise of moderate intensity for 30 min or more at least twice a week is recommended. Keywords: Physical activity, metabolic syndrome
... Microangiopathic complications of untreated or inadequately treated diabetes include neuropathy, nephropathy, retinopathy, obesity, dyslipidemia, hypertension, and other cardiovascular diseases. These are believed to be triggered by excessive protein glycation due to the higher level of circulating glucose, i.e., hyperglycemia [5][6][7][8][9]. Hence, in recent years, several researchers have focused their attention on development of dual-acting (blood glucose and lipid lowering) drugs [10][11][12][13][14][15][16]. ...
We report synthesis and in vivo antihyperglycemic evaluation of new 3-substituted phenyl-2-(4-(tetrazolo[1,5-a]quinolin-4-ylmethoxy)phenyl)thiazolidin-4-ones (8a–l). The title 4-thiazolidinones were synthesized by one-pot cyclocondensation of new 4-(tetrazolo[1,5-a]quinolin-4-ylmethoxy)benzaldehyde (5), anilines, and mercaptoacetic acid in PEG-400. The required aldehyde (5) was also synthesized, starting from 2-chloroquinoline-3-carbaldehyde via a successive multistep route. The newly synthesized products were thoroughly characterized based on their spectral data. Amongst them, compounds 8a–g, j exhibited notable in vivo antihyperglycemic activity. Compounds 8f, g showed percentage improvement in oral glucose tolerance of 18.9 and 20.7, respectively, compared with 28.3 for the reference metformin.
Graphical Abstract
... The MetS represents a constellation of findings related to dyslipidemia, dysregulated glucose handling, hypertension and abdominal obesity [3][4][5][6][7][8]. While the prevalence of the MetS varies widely according to the various criteria used to define it, the prevalence has increased dramatically in the past 20 years. ...
The objective of the current study was to explore our hypothesis that average consumption of fructose and fructose containing sugars would not increase risk factors for cardiovascular disease (CVD) and the metabolic syndrome (MetS). A randomized, double blind, parallel group study was conducted where 267 individuals with BMI between 23 and 35 kg/m² consumed low fat sugar sweetened milk, daily for ten weeks as part of usual weight-maintenance diet. One group consumed 18% of calories from high fructose corn syrup (HFCS), another group consumed 18% of calories from sucrose, a third group consumed 9% of calories from fructose, and the fourth group consumed 9% of calories from glucose. There was a small change in waist circumference (80.9 ± 9.5 vs. 81.5 ± 9.5 cm) in the entire cohort, as well as in total cholesterol (4.6 ± 1.0 vs. 4.7 ± 1.0 mmol/L, p < 0.01), triglycerides (TGs) (11.5 ± 6.4 vs. 12.6 ± 8.9 mmol/L, p < 0.01), and systolic (109.2 ± 10.2 vs. 106.1 ± 10.4 mmHg, p < 0.01) and diastolic blood pressure (69.8 ± 8.7 vs. 68.1 ± 9.7 mmHg, p < 0.01). The effects of commonly consumed sugars on components of the MetS and CVD risk factors are minimal, mixed and not clinically significant.
... Рисунок 15.3 Метаболический синдром и его ассоциация с комобидными состояниями Кроме того, для многих коморбидных состояний, включающих синдром обструктивного апноэ во время сна, ГЭРБ, синдром склерокистозных яичников, ХОЗЛ, желчекаменную болезнь, а также для ряда эндокринных заболеваний, сопровождающихся гиперкортицизмом или гиперандрогенемией, описана устойчивая ассоциация с ожирением (Deedwania P.C., Volkova N., 2007;Groop L., Orho-Melander M, 2001;Ronti T., Lupattelli G., Monnarino E., 2006). Таким образом, величина кардиометаболического риска для многих состояний может не являться единственно определяющей при прогнозировании наступления клинических исходов (Dieterle C., Landgraf R., 2006;Hanefeld M., Ceriello A., Schwarz P.E., Bornstein S.R., 2007). ...
... Le sue caratteristiche essenziali sono proprio la presenza di dismetabolismo glucidico e lipidico, ipertensione e obesità di tipo centrale combinati in varia misura fra di loro. Anche l'albuminuria viene riportata quale importante fattore di rischio cardiovascolare associato a tale sindrome [3]. ...
BACKGROUND Metabolic Syndrome (MetS), currently defined as slight differences in the criteria of diagnosis – depending on which authority is quoted [i.e.: NCEP-ATP III (National Cholesterol Education Program/Adult Treatment Panel III); WHO (World Health Organization); IDF (International Diabetes Federation); AACE (American Association of Clinical Endocrinologists)], designates a cluster of metabolic risk factors that come together in a single individual, leading to cardiovascular disease. MetS is quite common, approximately 20-30% of the population in industrialized countries being affected. However, most of epidemiological data regarding MetS are derived from populations consisting mostly of middle-aged and younger subjects. AIM OF THE STUDY To assess the prevalence of the MetS in Internal Medicine wards and to determine its related comorbidities, including other clinical forms of atherosclerotic disease such as CHD risk equivalents. METHODS Our study was performed in patients admitted in Internal Medicine wards and selected as a randomization list in 12 Emilia Romagna-Marche FADOI centers. 1.316 patients were registered. According to explicit inclusion/exclusion criteria, we studied overall 902 participants (50.6% men, mean of age: 71-73 years). RESULTS According to NCEP-ATP III and IDF criteria the prevalence of MetS was 45.3% (IC 95%: 41.6-49.1) and 38.6% (IC 95%: 34.9-42.3), respectively. Patients with MetS presented a higher significant rate of ALT increase, syncope, atrial fibrillation, COPD, unstable angina, chronic kidney disease, cancer, valvular heart disease, peripheral arterial disease and carotid plaques. A strong association between IDF-MetS and congestive heart failure was observed, suggesting a role of central obesity as an independent risk factor in the elderly. DISCUSSION World-wide populations are becoming older. Aging and MetS are two conditions that represent an important part of health-care spending. Trunkal fatness increases in old age, potentially increasing existing abdominal fatness prevalent during middle age which is already related to increased size, cardiovascular disease and the metabolic syndrome. In this study we sought to assess the high impact of MetS in Internal Medicine wards, confirming its significant relationships to many comorbidities among older adults. CONCLUSIONS Our study emphasizes the importance of MetS and related diseases, pointing out the emerging problem of its real impact on management of these complex patients. Further research is needed to define the optimal body composition for older adults and to identify interventions that reduce morbidity and healthcare costs of MetS for this age group.
... 2 Skeletal muscle insulin resistance and accompanying hyperinsulanemia play a critical role in Type 2 (NIDDM) diabetes. 3 Additionally, increase in hepatic glucose production aggravates the state of glucose dysregulation. 4 Therefore intervention that can ameliorate insulin resistance and hepatic glucose production helps to reduce conversion rates from conditions of impaired tolerance and Pre-diabetic to overt Type 2 diabetes. 5,6 The etiology of skeletal muscle insulin resistance is multifactorial and involves defective expression and functionality of multiple elements in insulin signaling cascade that regulates glucose transport process. ...
Glycogen Synthase Kinase (GSK-3) is a key enzyme involved in glycogen metabolism, protein synthesis, etc
and overexpression of GSK-3 in skeletal muscle of humans is associated with impaired ability of insulin to
activate glucose disposal leading to development of type-2 diabetes. Studies have demonstrated that selective
and sensitive inhibition of GSK-3 causes improvements in insulin stimulated glucose transport activity.
Identifying the binding sites and selectively targeting GSK-3 with GSK-3 inhibitors may emerge as a new
strategy for the treatment of diabetes
... The research also concluded that cardiovascular disease and mortality from it in men and in people with metabolic syndrome even in those who have not been diagnosed with diabetes has increased. Early identification, treatment and prevention of the disease and deal with the epidemic of sedentary lifestyle and weight gain are a major challenge in the treatment group (Groop & Orho-Melander, 2001). Finally, research suggests that metabolic syndrome is significantly associated with a history of stroke and heart attack and also concluded that cardiovascular disease and mortality from it in men and in people with metabolic syndrome even in those who have not been diagnosed with diabetes has increased. ...
Relationship between Metabolic Syndrome and Myocardial Infarction
Authors: Aghakhani N1, Khademvatan K2
Background/Introduction: The metabolic syndrome is one a major public health problems of this century. It is a constellation of other diseases and abnormalities, commonly occurring together, that increases an individual's risk for development of cardiovascular disease like myocardial infarction. If the current trend continues, premature deaths and disabilities resulting from these conditions will increase the financial burden in developed and developing countries. The aim of this study was to determine the relationship between metabolic syndrome and myocardial infarction.
Methods: A case-control study was carried out by a demographic questionnaire of patients, laboratory results needed for the survey (fasting blood glucose, triglycerides and HDL) with waist circumference size, blood pressure, height and weight were examined. Data was analyzed using SPSS statistical software.
Results: In this study of 172 patients with myocardial infarction, 56 patients (38.4%) patients were females and 112 (17.9%) were males. 1.2% of the patients were single, 84.8% were married, 0.6 were divorced and 13.5% were widowed, 116 patients (67.4%) had features of metabolic syndrome and 56 patients (32.6%) were lacking. There was also a significant relationship between age and sex and having or not having a family history of heart failure, having or not having history of certain drugs and BMI of patient with metabolic syndrome. There was a significant relationship between the marital status, education, residence, income, previous history of heart disease, PCI, LDL, history of drug use, type of infarction, the extent of ejection and location with syndrome patients. In terms of survival, because none of the subjects in the study period had expired, this extent was not quantifiable.
Conclusion: Efforts towards lifestyle changes particularly healthy diets, physical activity, weight management and blood pressure, especially in women should be considered.
... Although the term metabolic syndrome is now generally established, there is not yet universal agreement about the name of the condition. For example some authors suggest that the syndrome should be named "the dysmetabolic syndrome" [21] while other authors suggest "the insulin resistance syndrome" [22,23]. ...
... On the other hand, elevated serum TG could result in lower concentrations of HDL cholesterol. High intra abdominal fat would also cause free fatty acid concentrations to increase in body tissues, which in turn could result in the development of insulin resistance and hyperinsulinemia [26], which combine to form the fundamental metabolic defect underlying the metabolic syndrome and metabolic abnormalities [27][28][29]. Taken together, these findings highlight the more important role of some combination of MetS components. ...
p>In a group of middle-aged men we measured blood pressure, fasting lipids and glucose, BMI, waist circumference, skin fold thickness, total fat on DEXA, bioimpedance, and plethysmography and visceral fat on MRI. We measured insulin sensitivity in muscle and liver using a euglycaemic, hyperinsulinaemic clamp technique with deuterated glucose, and suppression of non-esterified fatty acids during an oral glucose tolerance test. We demonstrated that BMI and waist correlate strongly with measures of visceral and truncal fat and also to insulin sensitivity and other metabolic syndrome features. We measured hepatic steatosis using ultrasonography and demonstrated that fatty liver is associated with impaired suppression of non-esterified fatty acids, independently of body fat, indicating that men with fatty liver have abnormal adipocytes function.
We found that a strong correlation between metabolism of cortisol measured by clearance of a tracer bolus of deuterated cortisol and insulin sensitivity in muscle and adipose tissue which was independent of body fat, suggesting that exposure to cortisol is higher in insulin-resistant individuals.
We measured fitness by oxygen uptake during maximal exercise, and physical activity energy expenditure using heart-rate monitoring. We did not find that either fitness of energy expenditure were related to insulin sensitivity independently of body fat suggesting that the beneficial effects of exercise are mediated through changes in body composition.</p
A two-step reaction method was used to synthesize a series of rhodanine-based Schiff bases (2–33) that were characterized using spectroscopic techniques. All compounds were assessed for α-amylase inhibitory and radical scavenging (DPPH and ABTS) activities. In comparison to the standard acarbose (IC50 = 9.08 ± 0.07 µM), all compounds demonstrated good to moderate α-amylase inhibitory activity (IC50 = 10.91 ± 0.08–61.89 ± 0.102 µM). Compounds also demonstrated significantly higher DPPH (IC50 = 10.33 ± 0.02–96.65 ± 0.03 µM) and ABTS (IC50 = 12.01 ± 0.12–97.47 ± 0.13 µM) radical scavenging activities than ascorbic acid (DPPH, IC50 = 15.08 ± 0.03 µM; ABTS, IC50 = 16.09 ± 0.17 µM). The limited structure-activity relationship (SAR) suggests that the position and nature of the substituted groups on the phenyl ring have a vital role in varying inhibitory potential. Among the series, compounds with an electron-withdrawing group at the para position showed the highest potency. Kinetic studies revealed that the compounds followed a competitive mode of inhibition. Molecular docking results are found to agree with experimental findings, showing that compounds reside in the active pocket due to the main rhodanine moiety.
Graphical abstract
The metabolic syndrome was recognized more than 80 years ago in medical literature and it has received since then several denominations. It is not a unique disease, but an association of health problems that may appear in a simultaneous or sequential way in the same individual caused by the combination of genetic and environmental factors associated with the life style, in which insulin resistance is considered as the main pathogenic component. The presence of metabolic syndrome is related to a significant increase of risk for diabetes, coronary disease and cerebrovascular disease, with a decrease of survival, particularly due to a 5-fold rise in cardiovascular mortality. Aspects connected with its pathogeny, epidemiology and diagnosis were dealt with in the present review. Emphasis was made on the importance of identifying and treating opportunely the comorbidities present in these patients as a strategy in the prevention of cardiovascular diseases.
Intervention studies on population at risk aimed at lowering the frequency of occurrence of type 2 diabetes mellitus(DM2) are considered as guiding lines for the work with these patients. The objective of the present study is to review the results of research works aimed at lowering the risk of suffering from type 2 diabetes mellitus. The studied subjects presented with some of the following conditions: altered glucose at fasting or altered glucose tolerance, personal history of gestational diabetes and individuals with metabolic syndrome. The following studies are quoted among others: DPP (diabetes prevention program), DPS (diabetes prevention study), STOP-NIDDM (study to prevent non-insulin dependent diabetes mellitus), Hyperglycemia at fasting, DAISI (Dutch acarbose intervention trial), Da Quing (a Chinese study), TRIPOD (troglitazone in the prevention of diabetes), XENDOS (xenical in the prevention of diabetes in obese subjects), WOSCOPS (west of Scotland coronary prevention study), EDIT( early diabetes intervention trial), NAVIGATOR (nateglinide and valsartan in impaired glucose tolerance outcomes research), DREAM (diabetes reduction assessment with ramipril and rosiglitazone medication). These research works consisted in changes of lifestyle (fundamentally systematic physical exercising and nutritional orientations) and/or therapeutic interventions. It is concluded that in persons aged 25 years or more of both sexes, having risk of suffering from type 2 diabetes mellitus, the adoption of a healthy life style reduces the risk of diabetic syndrome. In subjects with high type 2 diabetes mellitus risk, drugs that exhibit the best and more consistent results are metformin and acarbose. Other drugs as nateglidine, rosiglitazone, ramipril and valsartan are under research at present.
Der Anteil der über Sechzigjährigen in der Bevölkerung nimmt kontinuierlich zu: Während im Jahr 1900 nur etwa 8% der deutschen Bevölkerung älter als 60 Jahre waren, betrug der Anteil 1993 bereits 20%. Im Jahr 2030 sollen es bereits 33% sein. (Bundesinstitut für Bevölkerungsforschung, Wiesbaden). Der Altersaufbau der Bevölkerung wird sich von einer Bevölkerungspyramide zu einem Bevölkerungspilz im Jahre 2050 wandeln (Abb. 1.4.1). 1999 entfielen 53% des gesamten Fertigarzneimittelumsatzes der gesetzlich krankenversicherten Patienten auf die Gruppe der über Sechzigjährigen. Im Durchschnitt wird jeder über Sechzigjährige mit etwa zweieinhalb Arzneimitteln pro Tag in Dauertherapie behandelt (Schröder et al. 2001). Es besteht hinsichtlich der körperlichen und geistigen Leistungsfähigkeit von alten Menschen jedoch eine erhebliche Variabilität. Viele liegen trotz fortgeschrittenen Alters mit ihren Werten innerhalb der Normgrenzen weitaus jüngerer Personen, was die Unterscheidung zwischen „normal“ und „pathologisch“ bei alten Menschen besonders erschwert (Rowe et al. 1987).
Abdominal obesity and Type 2 diabetes mellitus represent a frequent association, leading to an increased morbidity and mortality from atherogenic macrovascular disease. The key feature which links visceral obesity, Type 2 diabetes mellitus and cardiovascular risk is considered to be insulin resistance. It induces a cluster of metabolic, vascular, prothrombotic anomalies, known as metabolic syndrome. The cardiovascular risk related to metabolic syndrome consists of an amplified action of each component, leading to high and early probability of developing atherosclerotic pathology. As demonstrated by clinical trials, most of the newly-diagnosed obese Type 2 diabetic patients have a high cardiovascular risk due to the presence of cardiovascular risk factors. To reduce cardiovascular risk, an aggressive approach is required, in terms of risk factor identification, global risk evaluation, targeted and multifactorial interventions. Structured programme as: therapy, education, monitoring, evaluation should be applied. Weight loss is a major therapeutic goal. Lifestyle optimization, through hypocaloric diet and physical activity and specific medication for obesity, are methods to be considered.
Background:
Metabolic Syndrome (MetS) is associated with elevated risk for developing diabetes and cardiovascular disease. A key component of MetS is the development of insulin resistance (IR). The homeostatic model assessment (HOMA) model can determine IR by using insulin or C-peptide concentrations; however, the efficiency of insulin and C-peptide to determine MetS has not been compared. The aim of the study was to compare the efficiency of C-peptide and insulin to determine MetS in Mexicans.
Methods:
Anthropometrics, glucose, insulin, C-peptide, triglycerides, and high-density lipoproteins were determined in 156 nonpregnant females and 114 males. Subjects were separated into normal or positive for MetS. IR was determined by the HOMA2 calculator using insulin or C-peptide. Correlations were calculated using the Spearman correlation coefficient (ρ). Differences between correlations were determined by calculating Steiger's Z. The sensitivity was determined by the area under receiver operating characteristics curve (AUC) analysis.
Results:
Independent of the MetS definition [Adult Treatment Panel III (ATP III), International Diabetes Federation (IDF), or World Health Organization (WHO)], C-peptide and insulin were significantly higher in MetS subjects (P < 0.05). C-peptide and insulin correlated with all components of MetS; however, for waist circumference, waist-to-hip ratio, and fasting plasma glucose, C-peptide correlated better than insulin (P < 0.05). Moreover, C-peptide (AUC = 0.72-0.78) was a better marker than insulin (AUC = 0.62-0.72) for MetS (P < 0.05). Finally, HOMA2-IR calculated with C-peptide (AUC = 0.80-0.84) was more accurate than HOMA2-IR calculated with insulin (AUC = 0.68-0.75, P < 0.05) at determining MetS.
Conclusion:
C-peptide is a strong indicator of MetS. Since C-peptide has recently emerged as a biomolecule with significant importance for inflammatory diseases, monitoring C-peptide levels will aid clinicians in preventing MetS.
The importance of the metabolic syndrome is increasingly recognized due to its increasing prevalence and to its role as cardiovascular risk factor. The prevalence of this syndrome is directly related to age. The age related increase of the metabolic syndrome is due to the age related increase in insulin resistance, obesity, diabetes, hypertension, and dyslipidaemia. Also in the elderly the metabolic syndrome is associated to an increased frequency of cardiovascular diseases. Several treatments aimed to treat the specific alterations present in the metabolic syndrome are useful to reduce the cardiovascular disease incidence in these patients.
Insulin resistance syndrome and its associated abnormalities are recognised as major public health issues. Abnormalities associated with the syndrome include, but are not limited to, cardiovascular disease, hypertension, diabetes and polycystic ovary syndrome. Identifying the insulin resistance syndrome in practice has been clinically challenging in recent years. The American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) have published a position statement on insulin resistance syndrome, indicating how to clearly identify the syndrome and recognise associated abnormalities. Obesity is a factor that contributes to an increased risk of developing the insulin resistance syndrome; however, insulin resistance does not cause obesity. Dietary and lifestyle factors that facilitate weight reduction will reduce an individual's risk for developing the insulin resistance syndrome. Furthermore, dietary factors can positively affect some of the abnormalities associated with the syndrome such as cardiovascular disease, diabetes and hypertension. This review further illustrates that the manipulation of macronutrient intake and macronutrient subtypes within an appropriate energy restriction may further be of benefit and directly impact on insulin sensitivity and hyperinsulinaemia associated with the insulin resistance syndrome.
Obesity is associated with an increased risk of atherosclerotic coronary heart disease (CHD). This fact combined with the rapid increase in the prevalence of obesity in the United States population threatens to reverse many of the advances made in reducing CHD morbidity and mortality and drives major problems with morbidity, mortality, and health care costs (1). Uncertainty remains as to whether excess weight is independently associated with CHD, or whether the association between obesity and CHD is mediated through other risk factors linked to obesity such as physical inactivity, hypertension, dyslipidemia, and abnormal glucose metabolism. If obesity causes or accelerates atherogenesis, the responsible mechanisms remain largely unknown. Adiposity and obesity may exacerbate the development, progression, and destabilization of atherosclerotic heart disease via direct adverse effects on fat and glucose metabolism. Beyond the metabolic effects associated with obesity, adiposity may also contribute to CHD via inflammatory mechanisms mediated by adipocytokines, especially those mediators associated with visceral fat accumulation. All of these issues establish the need for a greater understanding of the complex biologic and clinical interplay between excess adiposity and cardiovascular disease (CVD).
Pietro Avogaro and myself in 1965 described a new syndrome characterized by an association of metabolic abnormalities and specifically hyperlipidemia, obesity and diabetes. Interestingly we also pointed out the presence quite often of hypertension in association with these metabolic abnormalities, as well as the high risk of coronary artery disease in carriers of this cluster of metabolic abnormalities. Over the last 35 years the definition of plurimetabolic syndrome has evolved from the original description with the addition of a more detailed definition of the typical abnormalities. The latest definition of Metabolic Syndrome has been given more recently by the ATP III panel, which defined it as the concurrent presence of three or more of the following abnormalities: intra-abdominal obesity, glucose intolerance or diabetes, hypertriglyceridemia, low HDL-C, hypertension.
A new series of 2-amino[5′(4-sulphonylbenzylidine)-2,4- thiazolidinedione]-7-chloro-6-fluorobenzothiazole were synthesized. The structures of the compounds were continued by UV-Vis, IR and NMR spectroscopy. The title compounds were screened for their antidiabetic activity on albino rats.
This study was performed to evaluate the distribution of homeostasis model assessment of insulin resistance (HOMA-IR), a surrogate marker of insulin resistance, and its association with metabolic risk factors among Korean adolescents.
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease of unknown etiology. In lupus patients there is an increased cardiovascular risk due to an accelerated atherogenesis. Furthermore, Metabolic Syndrome (MS) adds an independent risk for developing Cardiovascular Disease (CVD) in the population. Therefore, it is important to determine whether lupus patients have an increased risk of developing Cardiovascular Disease in the presence of MS. To estimate the prognostic value of MS in the incidence of cardiovascular events in a cohort of premenopausal patients with SLE.
Cohort study in 238 patients was carried out. Clinical, biochemical, dietetic and anthropometric evaluations were performed. Patients were classified according to the prevalence of MS in 2001. There was a patient follow-up from 2001 to 2008. In 2008, after studying the records, we obtained the "cases" (patients with CVD) and the "no cases" (patients without CVD).
The basal prevalence of MS in the cohort was of 21.8% (ATPIII). The MS component with the highest prevalence in the population studied in 2001 was low HDL-Cholesterol (<50mg/dL) with a prevalence of 55.0%. The cumulative incidence of CVD in the group with MS was 17.3% and in the group without MS it was 7.0% with a Relative Risk (RR) of 2.48 (1.12-5.46) and p<0.05. In the multivariable analysis it was noted that MS is a predictive factor of CVD.
We observed the prognostic value of MS for an increased risk of cardiovascular damage in premenopausal patients with lupus.
Copyright © 2014 Elsevier España, S.L.U. All rights reserved.
Because visceral obesity predicts insulin resistance, we studied whether alterations in the gene encoding for the beta 3-adrenergic receptor in visceral fat are associated with insulin resistance.
We studied the frequency of a cytosine-to-thymidine mutation that results in the replacement of tryptophan by arginine at position 64 (Trp64Arg) of the beta 3-adrenergic receptor by restriction-enzyme digestion with BstOl in 335 subjects from western Finland, 207 of whom were nondiabetic and 128 of whom had non-insulin-dependent diabetes mellitus (NIDDM). We also determined the frequency of the mutation in 156 subjects from southern Finland. Sensitivity to insulin was measured by the hyperinsulinemic-euglycemic clamp technique in 66 randomly selected nondiabetic subjects.
In the subjects from western Finland, the frequency of the mutated allele was similar in the nondiabetic subjects and the subjects with NIDDM (12 vs. 11 percent). The mean age of the subjects at the onset of diabetes was lower among those with the mutation than those without it (56 vs. 61 years, P = 0.04). Among the nondiabetic subjects, those with the mutation had a higher ratio of waist to hip circumference (P = 0.02), a greater increase in the serum insulin response after the oral administration of glucose (P = 0.05), a higher diastolic blood pressure (82 vs. 78 mm Hg, P = 0.01), and a lower rate of glucose disposal during the clamp study (5.3 vs. 6.5 mg [29 vs. 36 mumol] per kilogram of body weight per minute; P = 0.04) than the subjects without the mutated allele. In an analysis of sibling pairs, the siblings with the mutation generally had higher waist:hip ratios (P = 0.05) and higher responses of blood glucose and serum insulin after the oral administration of glucose than their siblings without the mutation (P = 0.02 and P = 0.005, respectively).
The Trp64Arg allele of the beta 3-adrenergic receptor is associated with abdominal obesity and resistance to insulin and may contribute to the early onset of NIDDM:
The peroxisome proliferator-activated receptor-γ (PPARγ) is a transcription factor that has a pivotal role in adipocyte differentiation and expression of adipocyte-specific genes. The PPARγ1 and γ2 isoforms result from alternative splicing and have ligand-dependent and -independent activation domains. PPARγ2 has an additional 28 amino acids at its amino terminus that renders its ligand-independent activation domain 5-10-fold more effective than that of PPARγ1. Insulin stimulates the ligand-independent activation of PPARγ1 and γ2 (ref. 5), however, obesity and nutritional factors only influence the expression of PPARγ2 in human adipocytes. Here, we report that a relatively common Pro12Ala substitution in PPARγ2 is associated with lower body mass index (BMI; P=0.027; 0.015) and improved insulin sensitivity among middle-aged and elderly Finns. A significant odds ratio (4.35, P=0.028) for the association of the Pro/Pro genotype with type 2 diabetes was observed among Japanese Americans. The PPARγ2 Ala allele showed decreased binding affinity to the cognate promoter element and reduced ability to transactivate responsive promoters. These findings suggest that the PPARγ2 Pro12Ala variant may contribute to the observed variability in BMI and insulin sensitivity in the general population.
The mitochondrial uncoupling protein (UCP) in the mitochondrial inner membrane of mammalian brown adipose tissue generates heat by uncoupling oxidative phosphorylation. This process protects against cold and regulates energy balance. Manipulation of thermogenesis could be an effective strategy against obesity. Here we determine the role of UCP in the regulation of body mass by targeted inactivation of the gene encoding it. We find that UCP-deficient mice consume less oxygen after treatment with a beta3-adrenergic-receptor agonist and that they are sensitive to cold, indicating that their thermoregulation is defective. However, this deficiency caused neither hyperphagia nor obesity in mice fed on either a standard or a high-fat diet. We propose that the loss of UCP may be compensated by UCP2, a newly discovered homologue of UCP; this gene is ubiquitously expressed and is induced in the brown fat of UCP-deficient mice.
Human obesity has an inherited component, but in contrast to rodent obesity, precise genetic defects have yet to be defined1. A mutation of carboxypeptidase E (CPE), an enzyme active in the processing and sorting of prohormones, causes obesity in the fat/fat mouse2,3. We have previously described a woman with extreme childhood obesity (Fig. 1), abnormal glucose homeostasis, hypogonadotrophic hypogonadism, hypocortisolism and elevated plasma proinsulin and pro-opiomelanocortin (POMC) concentrations but a very low insulin level, suggestive of a defective prohormone processing by the endopeptidase, prohormone convertase 1 (PC1; ref. 4). We now report this proband to be a compound heterozygote for mutations in PC1. GlyArg483 prevents processing of proPd and leads to its retention in the endoplasmic reticulum (ER). AC+4 of the intron-5 donor splice site causes skipping of exon 5 leading to loss of 26 residues, a frameshift and creation of a premature stop codon within the catalytic domain. PC1 acts proximally to CPE in the pathway of post-translational processing of prohormones and neuropeptides. In view of the similarity between the proband and the fat/fat mouse phenotype, we infer that molecular defects in prohormone conversion may represent a generic mechanism for obesity, common to humans and rodents.
Previous linkage studies in Mexican-Americans localized a major susceptibility locus for type 2 diabetes, NIDDM1, to chromosome 2q. This evidence for linkage to type 2 diabetes was recently found to be associated with a common G→A polymorphism (UCSNP-43) within the CAPN10 gene. The at-risk genotype was homozygous for the UCSNP-43 G allele. In the present study among Pima Indians, the UCSNP-43 G/G genotype was not associated with an increased prevalence of type 2 diabetes. However, Pima Indians with normal glucose tolerance, who have a G/G genotype at UCSNP-43, were found to have decreased rates of postabsorptive and insulin-stimulated glucose turnover that appear to result from decreased rates of glucose oxidation. In addition, G/G homozygotes were found to have reduced CAPN10 mRNA expression in their skeletal muscle. A decreased rate of insulin-mediated glucose turnover, or insulin resistance, is one mechanism by which the polymorphism in CAPN10 may increase susceptibility to type 2 diabetes mellitus in older persons.
We are conducting a genome scan at an average resolution of 10 centimorgans (cM) for type 2 diabetes susceptibility genes in 716 affected sib pairs from 477 Finnish families. To date, our best evidence for linkage is on chromosome 20 with potentially separable peaks located on both the long and short arms. The unweighted multipoint maximum logarithm of odds score (MLS) was 3.08 on 20p (location, x̂ = 19.5 cM) under an additive model, whereas the weighted MLS was 2.06 on 20q (x̂ = 57 cM, recurrence risk, λ̂s = 1.25, P = 0.009). Weighted logarithm of odds scores of 2.00 (x̂ = 69.5 cM, P = 0.010) and 1.92 (x̂ = 18.5 cM, P = 0.013) were also observed. Ordered subset analyses based on sibships with extreme mean values of diabetes-related quantitative traits yielded sets of families who contributed disproportionately to the peaks. Two-hour glucose levels in offspring of diabetic individuals gave a MLS of 2.12 (P = 0.0018) at 9.5 cM. Evidence from this and other studies suggests at least two diabetes-susceptibility genes on chromosome 20. We have also screened the gene for maturity-onset diabetes of the young 1, hepatic nuclear factor 4-a (HNF-4α) in 64 affected sibships with evidence for high chromosomal sharing at its location on chromosome 20q. We found no evidence that sequence changes in this gene accounted for the linkage results we observed.
Since the discovery of insulin nearly 70 years ago, there has been no problem more fundamental to diabetes research than understanding how insulin works at the cellular level. Insulin binds to the alpha subunit of the insulin receptor which activates the tyrosine kinase in the beta subunit, but the molecular events linking the receptor kinase to insulin-sensitive enzymes and transport processes are unknown. Our discovery that insulin stimulates tyrosine phosphorylation of a protein of relative molecular mass between 165,000 and 185,000, collectively called pp185, showed that the insulin receptor kinase has specific cellular substrates. The pp185 is a minor cytoplasmic phosphoprotein found in most cells and tissues; its phosphorylation is decreased in cells expressing mutant receptors defective in signalling. We have now cloned IRS-1, which encodes a component of the pp185 band. IRS-1 contains over ten potential tyrosine phosphorylation sites, six of which are in Tyr-Met-X-Met motifs. During insulin stimulation, the IRS-1 protein undergoes tyrosine phosphorylation and binds phosphatidylinositol 3-kinase, suggesting that IRS-1 acts as a multisite 'docking' protein to bind signal-transducing molecules containing Src-homology 2 and Src-homology-3 domains. Thus IRS-1 may link the insulin receptor kinase and enzymes regulating cellular growth and metabolism.
Since the classification of beta-adrenergic receptors (beta-ARs) into beta 1 and beta 2 subtypes, additional beta-ARs have been implicated in the control of various metabolic processes by catecholamines. A human gene has been isolated that encodes a third beta-AR, here referred to as the "beta 3-adrenergic receptor." Exposure of eukaryotic cells transfected with this gene to adrenaline or noradrenaline promotes the accumulation of adenosine 3',5'-monophosphate; only 2 of 11 classical beta-AR blockers efficiently inhibited this effect, whereas two others behaved as beta 3-AR agonists. The potency order of beta-AR agonists for the beta 3-AR correlates with their rank order for stimulating various metabolic processes in tissues where atypical adrenergic sites are thought to exist. In particular, novel beta-AR agonists having high thermogenic, antiobesity, and antidiabetic activities in animal models are among the most potent stimulators of the beta 3-AR.
Hypertension and glucose intolerance, determined in a random population sample (n = 2,475), showed a highly significant (P less than 0.001) association from the mildest levels of both conditions, independent of the confounding effects of age, sex, obesity, and antihypertensive medications. Summary rate ratios for hypertension were 1.48 (1.18-1.87) in abnormal tolerance and 2.26 (1.69-2.84) in diabetes compared with normal tolerance. Altogether, 83.4% of the hypertensives were either glucose-intolerant or obese--both established insulin-resistant conditions. Fasting and post-load insulin levels in a representative subgroup (n = 1,241) were significantly elevated in hypertension independent of obesity, glucose intolerance, age, and antihypertensive medications. The mean increment in summed 1- and 2-h insulin levels (milliunits per liter) compared with nonobese normotensives with normal tolerance was 12 for hypertension alone, 47 for obesity alone, 52 for abnormal tolerance alone, and 124 when all three conditions were present. The prevalence of concentrations (milliequivalents per liter) of erythrocyte Na+ greater than or equal to 7.0, K+ less than 92.5, and plasma K+ greater than or equal to 4.5 in a subsample of 59 individuals with all combinations of abnormal tolerance obesity and hypertension was compared with those in 30 individuals free of these conditions. Altogether, 88.1% of the former vs. 40.0% of the latter group presented at least one of these three markers of internal cation imbalance (P less than 0.001). We conclude that insulin resistance and/or hyperinsulinemia (a) are present in the majority of hypertensives, (b) constitute a common pathophysiologic feature of obesity, glucose intolerance, and hypertension, possibly explaining their ubiquitous association, and (c) may be linked to the increased peripheral vascular resistance of hypertension, which is putatively related to elevated intracellular sodium concentration.
The β2 -adrenergic receptor has been cloned, mutated, and recombinantly expressed such that many structural features involved in receptor function have been defined. Agonists bind in a pocket formed by transmembrane spanning domains 3, 5, and 6, where key contact points initiate receptor activation. An interaction with the β-hydroxyl group of β-agonists and Asn293 of the latter transmembrane domain is the basis of the stereoselectivity of R- vs S-isomers of catecholamine-like agonists. Sites within the receptor that serve to dampen the signal with continuous agonist exposure have also been identified and include sites for phosphorylation by protein kinase A and G-protein–coupled receptor kinases and structural features that direct the receptor toward degradation (downregulation). Several regions of the β2 -adrenergic receptor show genetic diversity within the human population, such that expression, coupling, and agonist regulation may be different in individuals with these polymorphisms. (J Allergy Clin Immunol 1999;103:S42-6.)
The beta 3-adrenergic receptor, located mainly in adipose tissue, is involved in the regulation of lipolysis and thermogenesis. The potential relevance of this receptor to obesity in humans led us to screen obese French patients for a recently identified mutation in the gene for the receptor.
We used the polymerase chain reaction to amplify a region of the gene for the beta 3-adrenergic receptor encoding amino acid residues 27 to 110 in genomic DNA extracted from leukocytes from 185 patients with morbid obesity (body-mass index [the weight in kilograms divided by the square of the height in meters], > 40) and 94 normal subjects. A mutation resulting in the replacement of tryptophan by arginine at position 64 (Trp64Arg) was detected by an analysis of restriction-fragment-length polymorphisms with the use of the endonuclease BstNl, which discriminates between the normal and mutant sequences.
The frequency of the Trp64Arg allele was similar in the morbidly obese patients and the normal subjects (0.08 and 0.10, respectively). However, the patients with morbid obesity who were heterozygous for the Trp64Arg mutation had an increased capacity to gain weight; the mean weight in the 14 heterozygous patients was 140 kg, as compared with 126 kg in the 171 patients without the mutation (P = 0.03). There were no homozygotes in this sample. The cumulative 25-year change in weight (from the age of 20 years) was 67 kg in the Trp64Arg heterozygotes, as compared with 51 kg in those without the mutation. The maximal weight differential (the maximal lifetime weight minus the weight at 20 years of age) in the Trp64Arg heterozygotes was 74 kg, as compared with 59 kg in the patients without the mutation (P = 0.02).
People with the Trp64Arg mutation of the gene for the beta 3-adrenergic receptor may have an increased capacity to gain weight.
We investigated whether the polymorphism of the β
3-adrenergic receptor (β
3-AR) gene, which is associated with insulin resistance in non-diabetic subjects and an earlier onset of non-insulin-dependent diabetes mellitus in Pima Indians, was associated with visceral fat obesity and features of the insulin resistance syndrome in Japanese premenopausal obese women. There was no difference between 131 obese women and 256 control subjects (0.23 vs 0.17, p = 0.112) in the frequency of the Arg64 allele. The visceral fat area measured by computerised tomography scan was greater in homozygous Arg64Arg (172 ± 17 cm2, n = 6) and heterozygous Trp64Arg (178 ± 47 cm2, n = 48) women than in women homozygous for the Trp64Trp (121 ± 46 cm2, n = 77) genotype (p < 0.01). This was also reflected by increased total body fat but not by increased body mass index. The association between the Trp64 allele and visceral fat mass by multiple regression analysis, was independent of age, body mass index and total fat mass (p < 0.004). Moreover, homozygous carriers of the Arg64 allele had higher systolic blood pressure, higher fasting and post-load glucose and insulin concentrations, higher cholesterol, and triglyceride and lower HDL-cholesterol concentrations than homozygous carriers of the Trp64 allele. Some of these differences were also observed between heterozygous Trp64Arg and homozygous Trp64Trp genotypes (glucose tolerance, insulin and cholesterol concentration). We conclude that in obese women the β
3-AR polymorphism may be used as a genetic marker for visceral fat obesity and the insulin resistance syndrome. [Diabetologia (1997) 40: 200–204]
MOST patients with non-insulin-dependent diabetes mellitus are resistant to both endogenous and exogenous insulin1. Insulin resistance precedes the onset of this disease2 -4, suggesting that it may be an initial abnormality. Insulin-receptor kinase activity is impaired in muscle, fibroblasts and other tissues of many patients with non-insulin-dependent diabetes mellitus5, but abnormalities in the insulin-receptor gene do not appear to be the cause of this decreased kinase activity6, 7. Skin fibroblasts from certain insulin-resistant patients contain an inhibitor of insulin-receptor tyrosine kinase8, 9. Here we show that this inhibitor is a membrane glycoprotein, termed PC-1 (refs 10,11). We find that PC-1 activity is increased in fibroblasts from seven of nine patients with typical non-insulin-dependent diabetes mellitus. In addition, overexpression of PC-1 in transfected cultured cells reduces insulin-stimulated tyrosine kinase activity. These studies raise the possibility that PC-1 has a role in the insulin resistance of non-insulin-dependent diabetes mellitus.
Resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) and in ∼25% of nonobese individuals with normal oral glucose tolerance. In these conditions, deterioration of glucose tolerance can only be prevented if the β-cell is able to increase its insulin secretory response and maintain a state of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation of glucose homeostasis occurs. The relationship between insulin resistance, plasma insulin level, and glucose intolerance is mediated to a significant degree by changes in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations can be reduced by relatively small increments in insulin concentration.Consequently, elevations of circulating plasma FFA concentration can be prevented if large amounts of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration will not be suppressed normally, and the resulting increase in plasma FFA concentration will lead to increased hepatic glucose production. Because these events take place in individuals who are quite resistant to insulinstimulated glucose uptake, it is apparent that even small increases in hepatic glucose production are likely to lead to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals, this compensatory response of the endocrine pancreas is not without its price. Patients with hypertension, treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic. In addition, a direct relationship between plasma insulin concentration and blood pressure has been noted. Hypertension can also be produced in normal rats when they are fed a fructose-enriched diet, an intervention that also leads to the development of insulin resistance and hyperinsulinemia. The development of hypertension in normal rats by an experimental manipulation known to induce insulin resistance and hyperinsulinemia provides further support for the view that the relationship between the three variables may be a causal one. However, even if insulin resistance and hyperinsulinemia are not involved in the etiology of hypertension, it is likely that the increased risk of coronary artery disease (CAD) in patients with hypertension and the fact that this risk if not reduced with antihypertensive treatment are due to the clustering of risk factors for CAD, in addition to high blood pressure, associated with insulin resistance. These include hyperinsulinemia, IGT, increased plasma triglyceride concentration, and decreased high-density lipoprotein cholesterol concentration, all of which are associated with increased risk for CAD. It is likely that the same risk factors play a significant role in the genesis of CAD in the population as a whole. Based on these considerations the possibility is raised that resistance to insulin-stimulated glucose uptake and hyperinsulinemia are involved in the etiology and clinical course of three major related diseases— NIDDM, hypertension, and CAD.
The adipocyte-specific hormone leptin, the product of the obese (ob) gene,regulates adipose-tissue mass through hypothalamic effects on satiety and energy expenditure1, 2, 3, 4. Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine-receptor family5, 6, 7. In rodents, homozygous mutations ingenes encoding leptin1 or the leptin receptor6 cause early-onsetmorbid obesity, hyperphagia and reduced energy expenditure. These rodents also show hypercortisolaemia, alterations in glucose homeostasis, dyslipidaemia, and infertility due to hypogonadotropic hypogonadism8. In humans, leptin deficiency due to a mutation in the leptin gene is associated with early-onset obesity9. Here we describe a homozygous mutation in the human leptin receptor gene that results in a truncated leptin receptor lacking both the transmembrane and the intracellular domains. In addition to their early-onset morbid obesity, patients homozygous for this mutation have no pubertal development and their secretion of growth hormone and thyrotropin is reduced. These results indicate that leptin is an important physiological regulator of several endocrine functions in humans.
Obesity is a major predisposing factor for the development of several chronic diseases including non-insulin dependent diabetes mellitus (NIDDM) and coronary heart disease (CHD). Leptin is a serum protein which is secreted by adipocytes1−4 and thought to play a role in the regulation of body fat5−8. Leptin levels in humans have been found to be highly correlated with an individual's total adiposity8,9. We performed a genome-wide scan and conducted multipoint linkage analysis using a general pedigree-based variance component approach to identify genes with measurable effects on quantitative variation in leptin levels in Mexican Americans. A microsatellite polymorphism, D2S1788, mapped to chromosome 2p21 (approximately 74 cM from the tip of the short arm) and showed strong evidence of linkage with serum leptin levels with a lod score of 4.95 (P = 9 10-7). This locus accounted for 47% of the variation in serum leptin levels, with a residual additive genetic component contributing an additional 24%. This region contains several potential candidate genes for obesity, including glucokinase regulatory protein (GCKR) and pro-opiomelanocortin (POMC). Our results show strong evidence of linkage of this region of chromosome 2 with serum leptin levels and indicate that this region could contain an important human obesity gene.
Type 2 diabetes is the most common form of diabetes, affecting approximately 5-10 % of the adult population in the United States [1,2]. Diabetes is caused by the interaction of multiple environmental and genetic factors and is, therefore, referred to as a complex genetic, polygenic disorder. Despite a great deal of effort, understanding the underlying genetic causes of diabetes has proven difficult. Two main approaches have been taken to try to identify the genes influencing disease: linkage analysis followed by positional cloning and candidate gene association studies. We review the results of these studies and discuss chromosomal regions and genes implicated by using these approaches. We focus on two recent examples, the positional cloning of CAPN10, encoding the calpain 10 protease (originally identified by using linkage analysis and called NIDDM1) [3,4], and the association between type 2 diabetes and the Pro12Ala variant in PPARG, encoding peroxisome proliferator activator receptor gamma (PPARγ) [5-7]. These two cases illustrate not only the challenges in determining the genetic causes of type 2 diabetes but also the great promise that modern approaches hold for understanding complex genetic diseases.
Learning Objectives:
* Describe the physiology and epidemiology of type 2 (non-insulin-dependent) diabetes as it relates to the genetic and/or environmental origin of the disease.
* Distinguish the strengths and drawbacks of the two major approaches to identifying genes that may contribute to type 2 diabetes.
* Identify the most accurate current view of how important genetic factors are in type 2 diabetes, and how they may contribute to the disorder.
To estimate the prevalence of and the cardiovascular risk associated with the metabolic syndrome using the new definition proposed by the World Health Organization
A total of 4,483 subjects aged 35-70 years participating in a large family study of type 2 diabetes in Finland and Sweden (the Botnia study) were included in the analysis of cardiovascular risk associated with the metabolic syndrome. In subjects who had type 2 diabetes (n = 1,697), impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) (n = 798) or insulin-resistance with normal glucose tolerance (NGT) (n = 1,988), the metabolic syndrome was defined as presence of at least two of the following risk factors: obesity, hypertension, dyslipidemia, or microalbuminuria. Cardiovascular mortality was assessed in 3,606 subjects with a median follow-up of 6.9 years.
In women and men, respectively, the metabolic syndrome was seen in 10 and 15% of subjects with NGT, 42 and 64% of those with IFG/IGT, and 78 and 84% of those with type 2 diabetes. The risk for coronary heart disease and stroke was increased threefold in subjects with the syndrome (P < 0.001). Cardiovascular mortality was markedly increased in subjects with the metabolic syndrome (12.0 vs. 2.2%, P < 0.001). Of the individual components of the metabolic syndrome, microalbuminuria conferred the strongest risk of cardiovascular death (RR 2.80; P = 0.002).
The WHO definition of the metabolic syndrome identifies subjects with increased cardiovascular morbidity and mortality and offers a tool for comparison of results from diferent studies.
The peroxisome proliferator-activated receptor gamma (PPARγ) quickly evolved over the last decade from a new orphan receptor to one of the best characterized nuclear receptors. This
fast pace in PPARγ research was triggered by two main discoveries. Firstly, that PPARγ was shown to have a key role in adipogenesis and be a master controller of the “thrifty gene response” leading to efficient
energy storage. Secondly, the discovery that its synthetic ligands, the thiazolidinediones, are promising insulin sensitizing
drugs, which are currently being developed for the treatment of Type II (non-insulin-dependent) diabetes mellitus. More recently
this nuclear receptor emerged from a role limited to metabolism (diabetes and obesity) to a power player in general transcriptional
control of numerous cellular processes, with implications in cell cycle control, carcinogenesis, inflammation, atherosclerosis
and immunomodulation. This widened role of PPARγ will certainly initiate a new flurry of research, which will not only refine our current often partial knowledge of PPARγ but more importantly also establish that this receptor has a definite role as a primary link adapting cellular, tissue and
whole body homeostasis to energy stores. [Diabetologia (1999) 42: 1033–1049]
To determine whether albuminuria is associated with insulin resistance in patients with type II (non-insulin-dependent) diabetes mellitus, we performed hyperinsulinemic (40 mU/m2/min) euglycemic clamp studies in patients with a urinary albumin excretion (UAE) rate greater than and in patients with a UAE less than . The UAE-positive group (n = 22) did not differ significantly from the UAE-negative group (n = 18) with respect to age, sex, treatment of diabetes, body mass index, fasting or postload blood glucose or plasma insulin levels, blood pressure, or known duration of diabetes. The mean glucose disposal rate (GDR) was significantly lower in the UAE-positive group than in the UAE-negative group (3.44 ± 0.29 v 4.75 ± 0.52 mg/kg/min, P < .05). When patients with hypertension were excluded, GDR was still markedly lower in the UAE-positive group than in the UAE-negative group (3.89 ± 0.54 v 6.68 ± 0.71 mg/kg/min, P = .01). The difference between groups persisted even after adjustment for body mass index, sex, and hypertension (ANCOVA; P < .05). These results indicate that the presence of microalbuminuria is associated with impaired insulin action in patients with type II diabetes mellitus.
To study whether heredity for hypertension influences intra-uterine growth and the relationship between fetal growth and adult blood pressure.
Five-year prospective follow-up study with retrospective collection of data on size at birth and gestational age from obstetric records.
Centre of preventive medicine in Malmo, Sweden.
Thirty normotensive men with and 27 without heredity for hypertension were investigated in 1990, and the majority (n = 28 and n = 20, respectively) in 1995 also.
Two measures of intra-uterine growth were compared between the groups and related to adult systolic blood pressure: the birth weight deviation from the expected birth weight based on ultrasonically derived intra-uterine growth curves, and the degree of thinness at birth (ponderal index = weight/length3).
The birth weight deviation in men with heredity for hypertension differed significantly from that in men without such heredity (%) (-6.9+/-12.0 versus +7.3+/-18.4; P = 0.002). Ponderal index was somewhat lower in the men with than in those without heredity for hypertension, but the difference did not reach statistical significance (kg/m3) (25.9+/-2.6 versus 27.0+/-2.2; P = 0.08). In the group with heredity for hypertension, systolic blood pressure correlated inversely with ponderal index both in 1990 (r = -0.44; P = 0.01) and 1995 (r = -0.49; P = 0.009), and the 5-year increase in systolic blood pressure correlated inversely with the birth weight deviation (r = -0.38; P = 0.04). No such correlations were found in the group without heredity for hypertension.
Our results suggest that genetic factors contributing to the development of hypertension may influence intra-uterine growth.
Resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) and in ∼25% of nonobese individuals with normal oral glucose tolerance. In these conditions, deterioration of glucose tolerance can only be prevented if the β-cell is able to increase its insulin secretory response and maintain a state of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation of glucose homeostasis occurs. The relationship between insulin resistance, plasma insulin level, and glucose intolerance is mediated to a significant degree by changes in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations can be reduced by relatively small increments in insulin concentration.Consequently, elevations of circulating plasma FFA concentration can be prevented if large amounts of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration will not be suppressed normally, and the resulting increase in plasma FFA concentration will lead to increased hepatic glucose production. Because these events take place in individuals who are quite resistant to insulinstimulated glucose uptake, it is apparent that even small increases in hepatic glucose production are likely to lead to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals, this compensatory response of the endocrine pancreas is not without its price. Patients with hypertension, treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic. In addition, a direct relationship between plasma insulin concentration and blood pressure has been noted. Hypertension can also be produced in normal rats when they are fed a fructose-enriched diet, an intervention that also leads to the development of insulin resistance and hyperinsulinemia. The development of hypertension in normal rats by an experimental manipulation known to induce insulin resistance and hyperinsulinemia provides further support for the view that the relationship between the three variables may be a causal one. However, even if insulin resistance and hyperinsulinemia are not involved in the etiology of hypertension, it is likely that the increased risk of coronary artery disease (CAD) in patients with hypertension and the fact that this risk if not reduced with antihypertensive treatment are due to the clustering of risk factors for CAD, in addition to high blood pressure, associated with insulin resistance. These include hyperinsulinemia, IGT, increased plasma triglyceride concentration, and decreased high-density lipoprotein cholesterol concentration, all of which are associated with increased risk for CAD. It is likely that the same risk factors play a significant role in the genesis of CAD in the population as a whole. Based on these considerations the possibility is raised that resistance to insulin-stimulated glucose uptake and hyperinsulinemia are involved in the etiology and clinical course of three major related diseases— NIDDM, hypertension, and CAD.
Type 2 diabetes mellitus is a complex disorder encompassing multiple metabolic defects. We report results from an autosomal genome scan for type 2 diabetes–related quantitative traits in 580 Finnish families ascertained for an affected sibling pair and analyzed by the variance components-based quantitative-trait locus (QTL) linkage approach. We analyzed diabetic and nondiabetic subjects separately, because of the possible impact of disease on the traits of interest. In diabetic individuals, our strongest results were observed on chromosomes 3 (fasting C-peptide/glucose: maximum LOD score [MLS] = 3.13 at 53.0 cM) and 13 (body-mass index: MLS = 3.28 at 5.0 cM). In nondiabetic individuals, the strongest results were observed on chromosomes 10 (acute insulin response: MLS = 3.11 at 21.0 cM), 13 (2-h insulin: MLS = 2.86 at 65.5 cM), and 17 (fasting insulin/glucose ratio: MLS = 3.20 at 9.0 cM). In several cases, there was evidence for overlapping signals between diabetic and nondiabetic individuals; therefore we performed joint analyses. In these joint analyses, we observed strong signals for chromosomes 3 (body-mass index: MLS = 3.43 at 59.5 cM), 17 (empirical insulin-resistance index: MLS = 3.61 at 0.0 cM), and 19 (empirical insulin-resistance index: MLS = 2.80 at 74.5 cM). Integrating genome-scan results from the companion article by Ghosh et al., we identify several regions that may harbor susceptibility genes for type 2 diabetes in the Finnish population.
The mouse mutant genes obese (ob) and diabetes (db) cause similar obesity-diabetes states in homozygotes. These obesity syndromes are characterized by a more efficient conversion of food to lipid and, once stored, a slower rate of catabolism on fasting. Heterozygous mice, either ob/+ or db/+, survived a prolonged fast significantly longer than normal homozygotes (+/+); this suggests that the heterozygotes exhibited increased metabolic efficiency, a feature normally associated with both homozygous mutants. The existence of this thriftiness trait, if manifested by heterozygous carriers in wild populations, would lend credence to the thrifty gene concept of diabetes. Beneficial effects of normally deleterious genes may have played a role in the development of diabetes-susceptible human populations, as well as having provided the survival advantage that has allowed both the development and successful establishment of species in desert and other less affluent regions.
Hypertriglyceridaemia, which is frequently seen in Type 2 (non-insulin-dependent) diabetes mellitus, is associated with insulin resistance. The connection between hypertriglyceridaemia and insulin resistance is not clear, but could be due to substrate competition between glucose and lipids. To address this question we measured glucose and lipid metabolism in 39 Type 2 diabetic patients with hypertriglyceridaemia, i.e. mean fasting serum triglyceride level equal to or above 2 mmol/l (age 59 +/- 1 years, BMI 27.4 +/- 0.5 kg/m2, HbA1c 8.0 +/- 0.2%, serum triglycerides 3.2 +/- 0.2 mmol/l) and 41 Type 2 diabetic patients with normotriglyceridaemia, i.e. mean fasting serum triglyceride level below 2 mmol/l (age 58 +/- 1 years, BMI 27.0 +/- 0.7 kg/m2, HbA1c 7.8 +/- 0.2%, serum triglycerides 1.4 +/- 0.1 mmol/l). Insulin sensitivity was assessed using a 340 pmol.(m2)-1 x min-1 euglycaemic insulin clamp. Substrate oxidation rates were measured with indirect calorimetry and hepatic glucose production was estimated using a primed (25 microCi)-constant (0.25 microCi/min) infusion of [3-3H]-glucose. Suppression of lipid oxidation by insulin was impaired in patients with hypertriglyceridaemia vs patients with normal triglyceride levels (3.5 +/- 0.2 vs 3.0 +/- 0.2 mumol.kg-1 x min-1; p < 0.05). Stimulation of glucose disposal by insulin was reduced in hypertriglyceridaemic vs normotriglyceridaemic patients (27.0 +/- 1.3 vs 31.9 +/- 1.6 mumol.kg-1 x min-1; p < 0.05) primarily due to impaired glucose storage (9.8 +/- 1.0 vs 14.6 +/- 1.4 mumol.kg-1 x min-1; p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Many studies have shown that hyperinsulinemia and/or insulin resistance are related to various metabolic and physiological disorders including hypertension, dyslipidemia, and non-insulin-dependent diabetes mellitus. This syndrome has been termed Syndrome X. An important limitation of previous studies has been that they all have been cross sectional, and thus the presence of insulin resistance could be a consequence of the underlying metabolic disorders rather than its cause. We examined the relationship of fasting insulin concentration (as an indicator of insulin resistance) to the incidence of multiple metabolic abnormalities in the 8-yr follow-up of the cohort enrolled in the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease in Mexican Americans and non-Hispanic whites. In univariate analyses, fasting insulin was related to the incidence of the following conditions: hypertension, decreased high-density lipoprotein cholesterol concentration, increased triglyceride concentration, and non-insulin-dependent diabetes mellitus. Hyperinsulinemia was not related to increased low-density lipoprotein or total cholesterol concentration. In multivariate analyses, after adjustment for obesity and body fat distribution, fasting insulin continued to be significantly related to the incidence of decreased high-density lipoprotein cholesterol and increased triglyceride concentrations and to the incidence of non-insulin-dependent diabetes mellitus. Baseline insulin concentrations were higher in subjects who subsequently developed multiple metabolic disorders. These results were not attributable to differences in baseline obesity and were similar in Mexican Americans and non-Hispanic whites. These results support the existence of a metabolic syndrome and the relationship of that syndrome to multiple metabolic disorders by showing that elevations of insulin concentration precede the development of numerous metabolic disorders.
In this contribution we put forward a novel hypothesis concerning the aetiology of Type 2 (non-insulin-dependent) diabetes mellitus. The concept underlying our hypothesis is that poor fetal and early post-natal nutrition imposes mechanisms of nutritional thrift upon the growing individual. We propose that one of the major long-term consequences of inadequate early nutrition is impaired development of the endocrine pancreas and a greatly increased susceptibility to the development of Type 2 diabetes. In the first section we outline our research which has led to this hypothesis. We will then review the relevant literature. Finally we show that the hypothesis suggests a reinterpretation of some findings and an explanation of others which are at present not easy to understand.
High levels of some but not all dietary fats lead to insulin resistance in rats. The aim of this study was to investigate the important determinants underlying this observation. Insulin action was assessed with the euglycemic clamp. Diets high in saturated, monounsaturated (omega-9), or polyunsaturated (omega-6) fatty acids led to severe insulin resistance; glucose infusion rates [GIR] to maintain euglycemia at approximately 1000 pM insulin were 6.2 +/- 0.9, 8.9 +/- 0.9, and 9.7 +/- 0.4 mg.kg-1. min-1, respectively, versus 16.1 +/- 1.0 mg.kg-1.min-1 in chow-fed controls. Substituting 11% of fatty acids in the polyunsaturated fat diet with long-chain omega-3 fatty acids from fish oils normalized insulin action (GIR 15.0 +/- 1.3 mg.kg-1.min-1). Similar replacement with short-chain omega-3 (alpha-linolenic acid, 18:3 omega 3) was ineffective in the polyunsaturated diet (GIR 9.9 +/- 0.5 mg.kg-1.min-1) but completely prevented the insulin resistance induced by a saturated-fat diet (GIR 16.0 +/- 1.5 mg.kg-1.min-1) and did so in both the liver and peripheral tissues. Insulin sensitivity in skeletal muscle was inversely correlated with mean muscle triglyceride accumulation (r = 0.95 and 0.86 for soleus and red quadriceps, respectively; both P less than 0.01). Furthermore, percentage of long-chain omega-3 fatty acid in phospholipid measured in red quadriceps correlated highly with insulin action in that muscle (r = 0.97). We conclude that 1) the particular fatty acids and the lipid environment in which they are presented in high-fat diets determine insulin sensitivity in rats; 2) impaired insulin action in skeletal muscle relates to triglyceride accumulation, suggesting intracellular glucose-fatty acid cycle involvement; and 3) long-chain omega-3 fatty acids in phospholipid of skeletal muscle may be important for efficient insulin action.
Diabetes mellitus is commonly associated with systolic/diastolic hypertension, and a wealth of epidemiological data suggest that this association is independent of age and obesity. Much evidence indicates that the link between diabetes and essential hypertension is hyperinsulinemia. Thus, when hypertensive patients, whether obese or of normal body weight, are compared with age- and weight-matched normotensive control subjects, a heightened plasma insulin response to a glucose challenge is consistently found. A state of cellular resistance to insulin action subtends the observed hyperinsulinism. With the insulin/glucose-clamp technique, in combination with tracer glucose infusion and indirect calorimetry, it has been demonstrated that the insulin resistance of essential hypertension is located in peripheral tissues (muscle), is limited to nonoxidative pathways of glucose disposal (glycogen synthesis), and correlates directly with the severity of hypertension. The reasons for the association of insulin resistance and essential hypertension can be sought in at least four general types of mechanisms: Na+ retention, sympathetic nervous system overactivity, disturbed membrane ion transport, and proliferation of vascular smooth muscle cells. Physiological maneuvers, such as calorie restriction (in the overweight patient) and regular physical exercise, can improve tissue sensitivity to insulin; evidence indicates that these maneuvers can also lower blood pressure in both normotensive and hypertensive individuals. Insulin resistance and hyperinsulinemia are also associated with an atherogenic plasma lipid profile. Elevated plasma insulin concentrations enhance very-low-density lipoprotein (VLDL) synthesis, leading to hypertriglyceridemia. Progressive elimination of lipid and apolipoproteins from the VLDL particle leads to an increased formation of intermediate-density and low-density lipoproteins, both of which are atherogenic. Last, insulin, independent of its effects on blood pressure and plasma lipids, is known to be atherogenic. The hormone enhances cholesterol transport into arteriolar smooth muscle cells and increases endogenous lipid synthesis by these cells. Insulin also stimulates the proliferation of arteriolar smooth muscle cells, augments collagen synthesis in the vascular wall, increases the formation of and decreases the regression of lipid plaques, and stimulates the production of various growth factors. In summary, insulin resistance appears to be a syndrome that is associated with a clustering of metabolic disorders, including non-insulin-dependent diabetes mellitus, obesity, hypertension, lipid abnormalities, and atherosclerotic cardiovascular disease.
To determine the possible existence of a relationship between insulin resistance and sympathetic nervous system activity in essential hypertension, we calculated the double cross index for 14 hypertensive subjects and 14 normotensive subjects submitted to the oral glucose test. Plasma glucose and insulin levels were similar in hypertensive and normotensive subjects. After glucose loading, however, both parameters were significantly higher in hypertensive subjects. Five out of 14 hypertensive patients were hyperinsulinemic. The increase in double cross index following a glucose load was significantly higher in normotensive volunteers than in hyperinsulinemic hypertensive subjects. No change in double cross index was observed in normoinsulinemic hypertensive subjects. Thus, insulin resistance, high blood glucose level, impairment of cardiac response and hyperinsulinemia are present in a significant portion of hypertensive patients. Hyperinsulinemia may contribute to hypertension by stimulating sympathetic nervous system activity, by influencing the calcium transport across the cell membrane and/or by some other mechanism.
To identify early metabolic abnormalities in non-insulin-dependent diabetes mellitus (NIDDM), we measured sensitivity to insulin and insulin secretion in 26 first-degree relatives of patients with NIDDM and compared these subjects both with 14 healthy control subjects with no family history of NIDDM and with 19 patients with NIDDM. The euglycemic insulin-clamp technique, indirect calorimetry, and infusion of [3-3H]glucose were used to assess insulin sensitivity. Total-body glucose metabolism was impaired in the first-degree relatives as compared with the controls (P less than 0.01). The defect in glucose metabolism was almost completely accounted for by a defect in nonoxidative glucose metabolism (primarily the storage of glucose as glycogen). The relatives with normal rates of metabolism (mean +/- SEM, 1.81 +/- 0.27 mg per kilogram of body weight per minute) and impaired rates (1.40 +/- 0.22 mg per kilogram per minute) in oral glucose-tolerance tests had the same degree of impairment in glucose storage as compared with healthy control subjects (3.76 +/- 0.55 mg per kilogram per minute; P less than 0.01 for both comparisons). During hyperglycemic clamping, first-phase insulin secretion was lacking in patients with NIDDM (P less than 0.01) and severely impaired in their relatives with impaired glucose tolerance (P less than 0.05) as compared with control subjects; insulin secretion was normal in the relatives with normal glucose tolerance. We conclude that impaired glucose metabolism is common in the first-degree relatives of patients with NIDDM, despite their normal results on oral glucose-tolerance tests. Both insulin resistance and impaired insulin secretion are necessary for the development of impaired glucose tolerance in these subjects.
The ability of insulin to stimulate glucose uptake can vary substantially in non-obese individuals with no apparent disease (10). In addition, differences in either degree of obesity or level of habitual physical activity can also modulate in vivo insulin action (18,24). In an apparent attempt to maintain glucose homeostasis, the compensatory response to a decrease in insulin-stimulated glucose up take is an increase in plasma insulin concentration. A defect in the ability of insulin-stimulated glucose uptake has also been demonstrated (21) in patients with either impaired glucose tolerance (IGT) or non-insulin dependent diabetes mellitus (NIDDM). It has been suggested that the degree to which glucose tolerance deteriorates in these individuals is a function of the level of compensatory hyperinsulinemia that they can maintain, and the appearance of severe fasting hyperglycemia marks the failure of the pancreatic beta cell to sustain the necessary increase in insulin secretory response (21).
High blood pressure is prevalent in obesity and in diabetes, both conditions with insulin resistance. To test whether hypertension is associated with insulin resistance independently of obesity and glucose intolerance, we measured insulin sensitivity (using the euglycemic insulin-clamp technique), glucose turnover (using [3H]glucose isotope dilution), and whole-body glucose oxidation (using indirect calorimetry) in 13 young subjects (38 +/- 2 years [+/- SEM]) with untreated essential hypertension (165 +/- 6/112 +/- 3 mm Hg), normal body weight, and normal glucose tolerance. In the postabsorptive state, all measures of glucose metabolism were normal. During steady-state euglycemic hyperinsulinemia (about 60 microU per milliliter), hepatic glucose production and lipolysis were effectively suppressed, and glucose oxidation and potassium disposal were normally stimulated. However, total insulin-induced glucose uptake was markedly impaired (3.80 +/- 0.32 vs. 6.31 +/- 0.42 mg per minute per kilogram of body weight in 11 age- and weight-matched controls, P less than 0.001). Thus, reduced nonoxidative glucose disposal (glycogen synthesis and glycolysis) accounted for virtually all the defect in overall glucose uptake (1.19 +/- 0.24 vs. 3.34 +/- 0.44 mg per minute per kilogram, P less than 0.001). Total glucose uptake was inversely related to systolic or mean blood pressure (r = 0.76 for both, P less than 0.001). These results provide preliminary evidence that essential hypertension is an insulin-resistant state. We conclude that this insulin resistance involves glucose but not lipid or potassium metabolism, is located in peripheral tissues but not the liver, is limited to nonoxidative pathways of intracellular glucose disposal, and is directly correlated with the severity of hypertension.
Despite recent advances, controversy continues about the inheritance of the amount and distribution of body fat. We have studied the genetic and 'cultural' (nongenetic) transmission between generations of the body mass index, sum of six skinfold measurements, percentage of body fat, fat mass, fat-free mass, and two indicators of fat distribution. These data were obtained in 1698 members of 409 families, which included the following pairs of family members: spouses, (maximum number of pairs = 348), foster parent-adopted child (322), siblings by adoption (120), first-degree cousins (95), uncle/aunt-nephew/niece (88), parent-natural child (1239), full sibs (370), dizygotic twins (69), and monozygotic twins (87). The total transmissible variance ranged from about 40 percent for the amount of subcutaneous fat to 60 percent for the pattern of subcutaneous fat distribution. Biological inheritance accounted for only 5 percent of the variance for subcutaneous fat and the body mass index, but 20 to 30 percent for the percentage of body fat, fat mass, fat-free mass, and fat distribution. These data suggest that the amount of internal fat is influenced by heredity more than the amount of subcutaneous fat. Furthermore, we consistently found that nongenetic influences are quite important in determining the amount and distribution of body fat in the population. These estimates may differ in the subpopulation of obese individuals.