Novel adiponectin-resistin (AR) and insulin resistance (IRAR) indexes are useful integrated diagnostic biomarkers for insulin resistance, type 2 diabetes and metabolic syndrome: a case control study

Background

Adiponectin and resistin are adipokines which modulate insulin action, energy, glucose and lipid homeostasis. Meta-analyses showed that hypoadiponectinemia and hyperresistinemia are strongly associated with increased risk of insulin resistance, type 2 diabetes (T2DM), metabolic syndrome (MS) and cardiovascular disease. The aim of this study was to propose a novel adiponectin-resistin (AR) index by taking into account both adiponectin and resistin levels to povide a better indicator of the metabolic homeostasis and metabolic disorders. In addition, a novel insulin resistance (IR_AR) index was proposed by integration of the AR index into an existing insulin resistance index to provide an improved diagnostic biomarker of insulin sensitivity.

Methods

In this case control study, anthropometric clinical and metabolic parameters including fasting serum total adiponectin and resistin levels were determined in 809 Malaysian men (208 controls, 174 MS without T2DM, 171 T2DM without MS, 256 T2DM with MS) whose ages ranged between 40-70 years old. Significant differences in continuous variables among subject groups were confirmed by ANCOVA or MANCOVA test using 1,000 stratified bootstrap samples with bias corrected and accelerated (BCa) 95% CI. Spearman's rho rank correlation test was used to test the correlation between two variables.

Results

The AR index was formulated as 1+log₁₀(R₀)-log₁₀(A₀). The AR index was more strongly associated with increased risk of T2DM and MS than hypoadiponectinemia and hyperresistinemia alone. The AR index was more strongly correlated with the insulin resistance indexes and key metabolic endpoints of T2DM and MS than adiponectin and resistin levels alone. The AR index was also correlated with a higher number of MS components than adiponectin and resistin levels alone. The IR_AR index was formulated as log₁₀(I₀G₀)+log₁₀(I₀G₀)log₁₀(R₀/A₀). The normal reference range of the IR_AR index for insulin sensitive individuals was between 3.265 and 3.538. The minimum cut-off values of the IR_AR index for insulin resistance assessment were between 3.538 and 3.955.

Conclusions

The novel AR and IR_AR indexes are cost-effective, precise, reproducible and reliable integrated diagnostic biomarkers of insulin sensitivity for screening subjects with increased risk of future development of T2DM and MS.     

Obesity and Lowered Cognitive Performance in a Canadian First Nations Population

The association between obesity, other cardiovascular risk factors, and cognitive function in a Canadian First Nations population was investigated using a cross‐sectional design. Eligible individuals were aged ≥18 years, without a history of stroke, nonpregnant, with First Nations status, and who had undergone cognitive function assessment by the Clock Drawing Test (CDT) and Trail Making Test Parts A and B. Parts A and B were combined into an Executive Function Score (TMT‐exec). Hypertension, a previous history of cardiovascular disease, dyslipidemia, metabolic syndrome, insulin resistance, and the presence and duration of diabetes were examined in addition to obesity. In the case of TMT‐exec only, obese individuals were at an approximately fourfold increased risk for lowered cognitive performance compared to those who were not obese in multivariable models (odds ratio (OR): 3.77, 95% confidence interval (CI): 1.46–9.72) whereas there was no effect for overweight individuals compared to those with a normal weight in unadjusted analysis. Those having an increased waist circumference also had 5 times the risk compared to those without an increased waist circumference (OR: 5.41, 95% CI: 1.83–15.99). Adjusted for age, sex, and insulin resistance, individuals having the metabolic syndrome were at an approximately fourfold increased risk compared to those without the metabolic syndrome (OR: 3.67, 95% CI: 1.34–10.07). No other cardiovascular risk factors were associated. Obesity and metabolic syndrome were associated with lowered cognitive performance. These results highlight the importance of studying the health effects of obesity beyond traditional disease endpoints, even in a relatively youthful population.     

The impact of central obesity as a prerequisite for the diagnosis of metabolic syndrome

Objective: To compare the prevalence of metabolic syndrome (MS) defined according to the American Heart Association (AHA)/National Heart Lung and Blood Institute (NHLBI) and the International Diabetes Federation (IDF) and to determine the effect of the presence of central obesity on the phenotype (insulin resistance and other cardiovascular risk factors) associated with MS. Research Methods and Procedures: We studied 4723 Chinese, Malays, and Asian Indians living in Singapore. Each individual was categorized according to the five criteria for MS as defined by the AHA/NHLBI and the IDF. The population was categorized according to the presence of three or more criteria and then further subcategorized according to the presence or absence of central obesity. Characteristics of each group were compared using ANOVA and the χ² test. Results: MS was present in 20.2% (IDF) and 26.9% (AHA/NHLBI) of the population. Of the population, 6.7% exhibited three or more features of MS without central obesity. Use of the IDF definition, which requires central obesity, is associated with greater insulin resistance but similar levels of other cardiovascular disease risk factors than the use of the AHA/NHLBI definition, which does not require central obesity. Discussion: In this Southeast Asian population, the IDF and the AHA/NHLBI definitions of MS identify different segments of the MS population. The IDF definition may be more appropriate for the identification of those with insulin resistance and increased risk of type 2 diabetes. In contrast, the AHA/NHLBI definition may better identify those at increased risk of cardiovascular disease.     

A central role of eNOS in the protective effect of wine against metabolic syndrome

The positive health effects derived from moderate wine consumption are pleiotropic. They appear as improvements in cardiovascular risk factors such as plasma lipids, haemostatic mechanisms, endothelial function and antioxidant defences. The active principles would be ethanol and mainly polyphenols. Results from our and other laboratories support the unifying hypothesis that the improvements in risk factors after red wine consumption are mediated by endothelial nitric oxide synthase (eNOS). Many genes are involved, but the participation of eNOS would be a constant feature.The metabolic syndrome is a cluster of metabolic risk factors associated with high risk of cardiovascular disease (CVD). The National Cholesterol Education Programmmes Adult Treatment Panel III (NCEPATP III) clinical definition of the metabolic syndrome requires the presence of at least three risk factors, from among abdominal obesity, high plasma triacylglycerols, low plasma HDL, high blood pressure and high fasting plasma glucose. The molecular mechanisms responsible for the metabolic syndrome are not known. Since metabolic syndrome apparently affects 10-30% of the population in the world, research on its pathogenesis and control is needed.The recent finding that eNOS knockout mice present a cluster of cardiovascular risk factors comparable to those of the metabolic syndrome suggests that defects in eNOS function may cause human metabolic syndrome. These mice are hypertensive, insulin resistant and dyslipidemic. Further support for a pathogenic role of eNOS comes from the finding in humans that eNOS polymorphisms associate with insulin resistance and diabetes, with hypertension, with inflammatory and oxidative stress markers and with albuminuria. So, the data sustain the hypothesis that eNOS enhancement should reduce metabolic syndrome incidence and its consequences. Therefore red wine, since it enhances eNOS function, should be considered as a potential tool for the control of metabolic syndrome. This hypothesis is supported by epidemiological observations and needs experimental validation in human intervention studies.     

Diagnosis of the metabolic syndrome in children

PURPOSE OF REVIEW: The metabolic syndrome, a cluster of potent risk factors for atherosclerotic cardiovascular disease and type 2 diabetes mellitus in adults, is composed of insulin resistance, obesity, hypertension and hyperlipidemia. Of significant impact in the adult population, atherosclerotic cardiovascular disease and death are rarely seen in the young, but the pathologic processes and risk factors associated with its development have been shown to begin during childhood. The current review summarizes the work published during the past year in the following areas: childhood obesity, insulin resistance, dyslipidemia, hypertension and type 2 diabetes mellitus. RECENT FINDINGS: Recent studies have revealed the presence of components of the metabolic syndrome in children and adolescents. Obesity has a central role in the syndrome. There is an increasing amount of data to show that being overweight during childhood and adolescence is significantly associated with insulin resistance, abnormal lipids, and elevated blood pressure in young adulthood. Weight loss in these situations results in a decrease in insulin concentration and an increase in insulin sensitivity toward normalcy. With cardiovascular disease, obesity, and type 2 diabetes reaching epidemic proportions, it is of great importance to understand and control the risk factors at an early age. SUMMARY: The information obtained during the past year has improved our understanding of the pathogenesis, diagnosis and treatment of components of the metabolic syndrome in children, and potentially could improve the risk profiles for cardiovascular disease as children make the transition toward adolescence and young adulthood.     

Calpain-10 variants and haplotypes are associated with polycystic ovary syndrome in Caucasians

PCOS is known to be associated with an increased risk of T2DM and has been proposed to share a common genetic background with T2DM. Recent studies suggest that the Calpain-10 gene (CAPN10) is an interesting candidate gene for PCOS susceptibility. However, contradictory results were reported concerning the contribution of certain CAPN10 variants, especially of UCSNP-44, to genetic predisposition to T2DM, hirsutism, and PCOS. By means of MALDI-TOF MS technique, we genotyped an expanded single nucleotide polymorphism panel, including the CAPN10 UCSNP-44, -43, -56, ins/del-19, -110, -58, -63, and -22 in a sample of 146 German PCOS women and 606 population-based controls. Statistical analysis revealed an association between UCSNP-56 and susceptibility to PCOS with an odds ratio (OR) of 2.91 (95% CI=1.51-5.61) for women carrying an AA genotype compared with GG. As expected, the 22-genotype of the ins/del-19 variant, which is in high linkage disequilibrium (r2=0.98) with UCSNP-56, was also significantly associated (OR=2.98, 95% CI=1.55-5.73). None of the additionally tested variants alone showed any significant association with PCOS. A meta-analysis including our study (altogether 623 PCOS cases and 1,224 controls) also showed significant association only with ins/del-19. The most common haplotype TGG3AGCA was significantly associated with a lower risk for PCOS (OR=0.487, P=0.0057). In contrast, the TGA2AGCA haplotype was associated with an increased risk for PCOS (OR=3.557, P=0.0011). By investigating a broad panel of CAPN10 variants, our results pointed to an allele dose-dependent association of UCSNP-56 and ins/del-19 with PCOS.     

Leptin Predicts a Worsening of the Features of the Metabolic Syndrome Independently of Obesity

Objective: The term metabolic syndrome (MS) describes a cluster of cardiovascular risk factors including dyslipidemia, glucose intolerance, insulin resistance, and hypertension. Obesity increases the risk of MS, but as obesity is neither necessary nor sufficient to cause the syndrome, there is considerable interest in identifying obesity‐independent pathways. One such pathway may involve the actions of the adipokine leptin, which is associated cross‐sectionally with MS and prospectively with coronary heart disease and stroke, independently of obesity. Our goal was to test the hypothesis that leptin predicts the development of the features of MS independently of obesity. Research Methods and Procedures: This study used a prospective population‐based cohort of 748 middle‐aged whites in whom baseline measures of leptin and repeated measurement of the subcomponents of the MS at 5 and 10 years were available. The features of the MS were characterized as five factors (obesity, dyslipidemia, elevated blood pressure, glucose intolerance, and insulin resistance), which were combined to create an MS summary score. Results: Baseline leptin significantly predicted the development of obesity (p = 0.001) and, after adjustment for BMI, development of glucose intolerance (p = 0.016) and insulin resistance (p < 0.0001). Leptin levels did not independently predict a change in lipids or blood pressure. Leptin levels significantly predicted the development of the MS (p = 0.036), independently of baseline BMI. Discussion: Leptin predicts the development of the MS independently of baseline obesity. This association is specifically related to the development of glucose intolerance and insulin resistance. The extent to which these relationships are explained through residual confounding by obesity remains to be determined.     

The relationship of body fat to metabolic disease: Influence of sex and ethnicity

Clinical investigations designed to determine risk profiles for the development of cardiovascular disease (CVD) and type 2 diabetes mellitus (DM) are usually performed in homogenous populations and often focus on body mass index (BMI), waist circumference (WC), and fasting triglyceride (TG) levels. However, there are major ethnic differences in the relationship of these risk factors to outcomes. For example, the BMI risk threshold may be higher in blacks than in whites and higher in women than in men. Furthermore, a WC that predicts an obese BMI in white women only predicts a BMI in the overweight category in black women. In addition, overweight black men have a greater risk of developing type 2 DM than do overweight black women. Although TG levels are excellent predictors of insulin resistance in whites, they are not effective markers of insulin resistance in blacks. Among the criteria sets currently available to predict the development of CVD and type 2 DM, the most well known is the metabolic syndrome. The metabolic syndrome has 5 criteria: central obesity, hypertriglyceridemia, low high-density lipoprotein (HDL) levels, fasting hyperglycemia, and hypertension. To make the diagnosis of the metabolic syndrome, 3 of the 5 factors must be present. For central obesity and low HDL, the metabolic syndrome guidelines are sex specific. Diagnostic guidelines should also take ethnic differences into account, particularly in the diagnosis of central obesity and hypertriglyceridemia.     

The Uyghur population and genetic susceptibility to type 2 diabetes: potential role for variants in CAPN10, APM1 and FUT6 genes

Genome‐wide association studies have successfully identified over 70 loci associated with the risk of type 2 diabetes mellitus (T2DM) in multiple populations of European ancestry. However, the risk attributable to an individual variant is modest and does not yet provide convincing evidence for clinical utility. Association between these established genetic variants and T2DM in general populations is hitherto understudied in the isolated populations, such as the Uyghurs, resident in Hetian, far southern Xinjiang Uyghur Autonomous Region, China. In this case–control study, we genotyped 13 single‐nucleotide polymorphisms (SNPs) at 10 genes associated with diabetes in 130 cases with T2DM and 135 healthy controls of Uyghur, a Chinese minority ethnic group. Three of the 13 SNPs demonstrated significant association with T2DM in the Uyghur population. There were significant differences between the T2DM patients and controls in the risk allele distributions of rs3792267 (CAPN10) (P = 0.002), rs1501299 (APM1) (P = 0.017), and rs3760776 (FUT6) (P = 0.031). Allelic carriers of rs3792267‐A, rs1501299‐T, and rs3760776‐T had a 2.24‐fold [OR (95% CI): 1.35–3.71], 0.59‐fold [OR (95% CI): 0.39–0.91], 0.57‐fold [OR (95% CI): 0.34–0.95] increased risk for T2DM respectively. We further confirmed that the cumulative risk allelic scores calculated from the 13 susceptibility loci for T2DM differed significantly between the T2DM patients and controls (P = 0.001), and the effect of obesity/overweight on T2DM was only observed in the subjects with a combined risk allelic score under a value of 17. This study observed that the SNPs rs3792267 in CAPN10, rs1501299 in APM1, and rs3760776 in FUT6 might serve as potential susceptible biomarkers for T2DM in Uyghurs. The cumulative risk allelic scores of multiple loci with modest individual effects are also significant risk factors in Uyghurs for T2DM, particularly among non‐obese individuals. This is the first investigation having observed/found genetic variations on genetic loci functionally linked with glycosylation associated with the risk of T2DM in a Uyghur population.     

Bradykinin B2 receptor gene C-58T polymorphism and insulin resistance. A study on obese patients.

The bradykinin B2 receptor (B2R) gene is a candidate in the pathogenesis of insulin resistance, which often clusters with other abnormalities in metabolic syndrome. We investigated the distribution of the C-58T B2R gene polymorphism within a population of overweight/obese patients (BMI > or = 25 kg/m2) potentially characterised by different levels of insulin resistance. Patients with type 2 diabetes, dyslipidemia and hypertension were excluded in order to distinguish the effect of obesity on insulin sensitivity from that of confounding factors. Ninety-two unrelated adults (41 men and 51 women, aged 33.7 +/- 11.6 years) were recruited by random sampling from a general population evaluated for cardiovascular risk stratification. Measurements included BMI, waist circumference, body composition, blood pressure, serum leptin, and lipid profile. Insulin sensitivity was calculated according to the homeostasis model assessment (HOMA) method. C-58T genotypes--CC (n = 20), CT (n = 47) and TT (n = 25)--were determined by restriction fragment-length polymorphism PCR. Patients subdivided on the basis of C-58T polymorphism, showed no difference in any of the parameters examined, including HOMA index values, after adjustment for age, sex, BMI and waist circumference. The results indicate that the C-58T B2R gene polymorphism is not associated with different levels of insulin resistance within a population of obese patients.     

Eating meals irregularly: a novel environmental risk factor for the metabolic syndrome

Background: Skipping meals is a common practice in our current society; however, it is not clear whether eating meals regularly is associated with the metabolic syndrome. Objective: Our aim was to assess the association of eating meals regularly with parameters of the metabolic syndrome and insulin resistance in a representative population‐based cohort of 60‐year‐old men and women. Methods and Procedures: A population‐based cross‐sectional study of 3,607 individuals (1,686 men and 1,921 women), aged 60 years, was conducted in Stockholm County, Sweden. Medical history, socioeconomic factors, and lifestyle data were collected by a questionnaire and a medical examination, which included laboratory tests. Results: Of the subjects who were regular eaters, 20% fulfilled the criteria for the metabolic syndrome vs. 27% of subjects who were irregular eaters (P < 0.0001). The adjusted odds ratio (OR) for having the greatest number of components of the metabolic syndrome in subjects who were regular eaters was 0.27 (95% confidence interval (CI), 0.13–0.54) using subjects who did not fulfill any criteria for the metabolic syndrome as a reference group. Eating meals regularly was also inversely related to insulin resistance (OR, 0.68 (95% CI, 0.48–0.97)) and to γ‐glutamyl transferase (OR, 0.52 (95% CI, 0.33–83)) after full adjustment. Discussion: Eating meals regularly is inversely associated to the metabolic syndrome, insulin resistance and (high) serum concentrations of γ‐glutamyl transferase. These findings suggest that eating meals irregularly may be part of several potential environmental risk factors that are associated with the metabolic syndrome and may have future implications in giving dietary advice to prevent and/or treat the syndrome.     

Metabolic syndrome in rheumatic diseases: epidemiology,pathophysiology, and clinical implications

Subjects with metabolic syndrome–a constellation of cardiovascular risk factors of which central obesity and insulin resistance are the most characteristic–are at increased risk for developing diabetes mellitus and cardiovascular disease. In these subjects, abdominal adipose tissue is a source of inflammatory cytokines such as tumor necrosis factor-alpha, known to promote insulin resistance. The presence of inflammatory cytokines together with the well-documented increased risk for cardiovascular diseases in patients with inflammatory arthritides and systemic lupus erythematosus has prompted studies to examine the prevalence of the metabolic syndrome in an effort to identify subjects at risk in addition to that conferred by traditional cardiovascular risk factors. These studies have documented a high prevalence of metabolic syndrome which correlates with disease activity and markers of atherosclerosis. The correlation of inflammatory disease activity with metabolic syndrome provides additional evidence for a link between inflammation and metabolic disturbances/vascular morbidity.     

Role of calpains in diabetes mellitus: a mini review

Type 2 diabetes mellitus (T2DM) is characterized by defects in haepatic glucose production, insulin action and insulin secretion, which can also lead to a variety of secondary disorders. The disease can lead to death without treatment and it has been predicted that T2DM will affect 215 million people world-wide by 2010. T2DM is a multifactorial condition whose precise genetic causes and biochemical defects have not been fully elucidated but at both levels, calpains appear to play a role. Positional cloning studies mapped T2DM susceptibility to CAPN10, the gene encoding the intracellular cysteine protease, calpain 10. Further studies have shown a number of non-coding polymorphisms in CAPN10 to be functionally associated with T2DM whilst the identification of coding polymorphisms, suggested that mutant calpain 10 proteins may also contribute to the disease. The presence of both calpain 10 and its mRNA have been demonstrated in tissues from several mammalian species whilst calpain 10 appears to be associated with pathways involved in glucose metabolism, insulin secretion and insulin action. It appears that other calpains may also participate in these pathways and here we present an overview of recent studies on calpains and their putative role in T2DM.     

Glycemia and Cardiova Scular Disease in Type 1 Diabetes Mellitus

ObjectiveTo evaluate the role of glycemic control in the development of cardiovascular disease (CVD) in type 1 diabetes mellitus (DM).MethodsWe review the literature regarding coronary atherosclerosis, coronary artery calcification, and the epidemiologic studies related to the role of glycemia and the classic risk factors for coronary artery disease (CAD) in type 1 DM.ResultsFour prospective studies (Wisconsin Epidemiologic Study of Diabetic Retinopathy, EURODIAB, Steno Diabetes Center Study of Adults With Type 1 DM, and Pittsburgh Epidemiology of Diabetes Complications study) do not show that glycemic control predicts CAD occurrence. Findings from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study show that compared with conventional insulin therapy, intensive insulin therapy reduces CVD among patients with type 1 DM and is associated with lower prevalence of coronary artery calcification. The discrepancies between the findings from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study and the Pittsburgh Epidemiology of Diabetes Complication study are likely due to differences between the study populations and the lower prevalence of renal disease in the former study. Besides duration of DM and albuminuria/overt nephropathy, insulin resistance is a major determinant of CAD associated with type 1 DM.ConclusionsDiscrepant study results regarding the relationship between glycemia and CAD/coronary artery calcification may be related to the prevalence of renal disease and the presence of the metabolic syndrome. Published data suggest that addressing traditional risk factors including albuminuria, the metabolic syndrome, and inflammatory markers is better for preventing and treating CAD than focusing exclusively on glycemic control, which is still necessary for preventing microvascular complications. Furthermore, there is a synergistic effect of glycemic control and albuminuria on the development of CVD. (Endocr Pract. 2008;14:912-923)     

Association of CAPN10 SNPs and haplotypes with polycystic ovary syndrome among South Indian Women

Polycystic Ovary Syndrome (PCOS) is known to be characterized by metabolic disorder in which hyperinsulinemia and peripheral insulin resistance are central features. Given the physiological overlap between PCOS and type-2 diabetes (T2DM), and calpain 10 gene (CAPN10) being a strong candidate for T2DM, a number of studies have analyzed CAPN10 SNPs among PCOS women yielding contradictory results. Our study is first of its kind to investigate the association pattern of CAPN10 polymorphisms (UCSNP-44, 43, 56, 19 and 63) with PCOS among Indian women. 250 PCOS cases and 299 controls from Southern India were recruited for this study. Allele and genotype frequencies of the SNPs were determined and compared between the cases and controls. Results show significant association of UCSNP-44 genotype CC with PCOS (p = 0.007) with highly significant odds ratio when compared to TC (OR = 2.51, p = 0.003, 95% CI = 1.37–4.61) as well as TT (OR = 1.94, p = 0.016, 95% CI = 1.13–3.34). While the haplotype carrying the SNP-44 and SNP-19 variants (21121) exhibited a 2 fold increase in the risk for PCOS (OR = 2.37, p = 0.03), the haplotype containing SNP-56 and SNP-19 variants (11221) seems to have a protective role against PCOS (OR = 0.20, p = 0.004). Our results support the earlier evidence for a possible role of UCSNP-44 of the CAPN10 gene in the manifestation of PCOS.     

Metabolic stress in insulin's target cells leads to ROS accumulation - a hypothetical common pathway causing insulin resistance

The metabolic syndrome is a cluster of cardiovascular risk factors, and visceral adiposity is a central component that is also strongly associated with insulin resistance. Both visceral obesity and insulin resistance are important risk factors for the development of type 2 diabetes. It is likely that adipose tissue, particularly in the intra-abdominal depot, is part of a complex interplay involving several tissues and that dysregulated hormonal, metabolic and neural signalling within and between organs can trigger development of metabolic disease. One attractive hypothesis is that many factors leading to insulin resistance are mediated via the generation of abnormal amounts of reactive oxygen species (ROS). There is much evidence supporting that detrimental effects of glucose, fatty acids, hormones and cytokines leading to insulin resistance can be exerted via such a common pathway. This review paper mainly focuses on metabolic and other 'stress' factors that affect insulin's target cells, in particular adipocytes, and it will highlight oxidative stress as a potential unifying mechanism by which these stress factors promote insulin resistance and the development and progression of type 2 diabetes.     

Macroangiopathy in adults and children with diabetes: from molecular mechanisms to vascular damage (part 1).

Type 2 diabetes mellitus (T2DM) is an increasing problem in childhood; however type 1 diabetes mellitus (T1DM) remains by far the most common type of diabetes in this age group. In this review we will focus on T1DM, because this will have the greatest implication for patients diagnosed in childhood. During the atherosclerotic process, several molecular, receptorial and cellular factors provide a continous mechanism of vascular damage. In diabetic children this state seems to be enhanced and facilitated so that accelerated atherosclerosis is associated with an increased risk of cardiovascular events in respect to the non diabetic population. Hyperglycemia PER SE and associated with diabetes is an important risk factor for atherosclerosis. At present a substantial part of children with diabetes do not reach satisfactory glycemic control. Other risk factors for the development and progression of atherosclerosis may be inherited or develop in the course of the disease: hypertension, dyslipidemia, insulin resistance, obesity, cigarette smoking, physical inactivity, disturbance of platelet function, coagulation and fibrinolysis. The development and progression of atherosclerosis should be blocked at an early age, if possible. Primary prevention to all risk factors for cardiovascular disease is important and intervention is indicated if necessary. At the moment the best therapeutic strategy is to maintain metabolic control at a physiologic level and perform screening and early intervention for vascular complications.     

Small for gestational age and the metabolic syndrome: which mechanism is suggested by epidemiological and clinical studies?

The metabolic and cardiovascular complications associated with in-utero undernutrition have been identified during the past 10 years. Reduced fetal growth is independently associated with an increased risk of development of cardiovascular diseases, the insulin-resistance syndrome or one of its components (i.e., hypertension, dyslipidaemia, impaired glucose tolerance and type 2 diabetes). Insulin resistance appears to be a key component underlying these metabolic complications. Although the mechanism remains unclear, several pieces of evidence support an active role of adipose tissue in the emergence of insulin resistance (an abnormal growth pattern and repartition, hypersensitivity to catecholamines, regulation of leptin and adiponectin secretion and modulation of peroxisome proliferator-activated receptor gamma). Among individuals born SGA, those who are more at risk of gaining excess adiposity are those who are thin at birth following a period of fetal growth restriction. This period of undernutrition is followed by a neonatal period of catch-up growth and renutrition. This pattern induces important modifications in adipose tissue, with long-term consequences, among which is a high risk of early development of insulin resistance. Not all individuals born SGA will show such modifications in adipose tissue, meaning that not all of those born SGA are at risk of insulin resistance and diabetes. From a broader point of view, several hypotheses have been proposed over the past 10 years to explain this unexpected association between being born SGA and the later development of disease. Each of them points to a detrimental fetal environment, to a genetic susceptibility or to interactions between these two components playing a critical role in this context. Although not confirmed, the hypothesis suggesting that this association could be the consequence of genetic/environmental interactions remains the most attractive.     

Cardiac Health in Women With Metabolic Syndrome: Clinical Aspects and Pathophysiology

Although the classical cardiovascular risk factors (e.g., smoking and hypertension) are becoming more effectively managed, a continuous increase of the so‐called “cardiometabolic risk” is noted. Starting from this century, the nomenclature “metabolic syndrome” has become more popular to identify a cluster of disorders including obesity, dyslipidemia, hypertension, and insulin resistance. It is a primary risk factor for diabetes and cardiovascular disease in both genders. Interestingly, the metabolic diseases display a distinct gender disparity with an apparent “female advantage” in the premenopausal women compared with age‐matched men. However, women usually lose such “sex protection” following menopause or affliction of metabolic syndrome especially insulin resistance. A controversy exists in the medical literature concerning whether metabolic syndrome is a real syndrome or simply a cluster of risk factors. Several scenarios are speculated to contribute to the gender dimorphism in the cardiovascular sequelae in patients with metabolic syndrome including sex hormones, intrinsic organ function, and the risk factor profile (e.g., hypertension, dyslipidemia, obesity, sedentary lifestyle, and atherogenic diet). With the alarming rise of obesity prevalence, heart problems in metabolic syndrome continue to rise with a distinct gender dimorphism. Although female hearts seem to better tolerate the stress insults compared with the male counterparts, the female sex hormones such as estrogen can interact with certain risk factors to precipitate myopathic changes in the hearts. This synthetic review of recent literature suggests a role of gender disparity in myopathic factors and risk attributable to each metabolic component in the different prevalence of metabolic syndrome.     

Role of calpains in diabetes mellitus: A mini review

Type 2 diabetes mellitus (T2DM) is characterized by defects in haepatic glucose production, insulin action and insulin secretion, which can also lead to a variety of secondary disorders. The disease can lead to death without treatment and it has been predicted that T2DM will affect 215 million people world-wide by 2010. T2DM is a multifactorial condition whose precise genetic causes and biochemical defects have not been fully elucidated but at both levels, calpains appear to play a role. Positional cloning studies mapped T2DM susceptibility to CAPN10, the gene encoding the intracellular cysteine protease, calpain 10. Further studies have shown a number of non-coding polymorphisms in CAPN10 to be functionally associated with T2DM whilst the identification of coding polymorphisms, suggested that mutant calpain 10 proteins may also contribute to the disease. The presence of both calpain 10 and its mRNA have been demonstrated in tissues from several mammalian species whilst calpain 10 appears to be associated with pathways involved in glucose metabolism, insulin secretion and insulin action. It appears that other calpains may also participate in these pathways and here we present an overview of recent studies on calpains and their putative role in T2DM. (Mol Cell Biochem 261: 161–167, 2004)