Adiponectin circulates in human plasma mainly as a 180-kDa low molecular weight (LMW) hexamer and a high molecular weight (HMW) multimer of approximately 360 kDa. We comprehensively examined the relationships between circulating levels of total adiponectin, adiponectin multimers, and the relative distribution (i.e., ratio) of multimeric forms with key features of the metabolic syndrome. Total adiponectin (r = 0.45), HMW (r = 0.47), LMW (r = 0.31), and HMW-to-total adiponectin ratio (r = 0.29) were significantly correlated with insulin-stimulated glucose disposal rate. Similarly, total (r = -0.30), HMW (r = -0.38), and HMW-to-total adiponectin ratio (r = -0.34) were correlated with central fat distribution but not with total fat mass or BMI. Regarding energy metabolism, although there were no effects on resting metabolic rate, total (r = 0.41) and HMW (r = 0.44) were associated with increasing rates of fat oxidation. HMW-to-total adiponectin ratio increased as a function of total adiponectin, and it was HMW quantity (not total or HMW-to-total adiponectin ratio or LMW) that was primarily responsible for all of these relationships. Impact on nuclear magnetic resonance lipoprotein subclasses was assessed. HMW and total adiponectin were correlated with decreases in large VLDL (r = -0.44 and -0.41); decreases in small LDL (r = -0.41 and -0.36) and increases in large LDL (r = 0.36 and 0.30) particle concentrations accompanied by increased LDL particle size (r = 0.47 and 0.39); and increases in large HDL (r = 0.45 and 0.37) and HDL particle size (r = 0.53 and 0.47). Most of these correlations persisted after adjustment for metabolic covariables. In conclusion, first, serum adiponectin is associated with increased insulin sensitivity, reduced abdominal fat, and high basal lipid oxidation; however, it is HMW quantity, not total or HMW-to-total adiponectin ratio, that is primarily responsible for these relationships. Second, reduced quantities of HMW independently recapitulate the lipoprotein subclass profile associated with insulin resistance after correcting for glucose disposal rate and BMI. Finally, HMW adiponectin is an important factor in explaining the metabolic syndrome.

Recent studies emphasize the role played by adiponectin in the homeostasis of adipose tissue and in the pathogenesis of the metabolic syndrome, type 2 diabetes, and atherosclerosis. These pleiotropic effects make it an attractive therapeutic target for obesity-related conditions.

Insulin Resistance SyndromeInsulin resistance antedates the development of type 2 diabetes mellitus (T2DM) and also helps maintain the diabetic state. In non-diabetic individuals, insulin resistance commonly clusters with several anthropometric, metabolic, and hemodynamic traits including upper body fat distribution, glucose intolerance, dysfibrinolysis, relative hypertension, and dyslipidemia characterized by high triglycerides, low HDL cholesterol, and small dense LDL particles [1]. The term insulin resistance syndrome (IRS) or Metabolic Syndrome is used to refer to this cluster of interrelated traits, which predicts the future development of both T2DM and atherosclerotic disease [2]. While several sets of diagnostic criteria (e.g., ATPIII criteria) have been purported for clinical diagnosis, these diagnostic criteria can exhibit poor sensitivity for identifying patients with insulin resistance and dyslipidemia, and do not take in consideration the effect of age, race, ethnicity, and other variables [3]. Furthermore, the IRS incorporates multiple additional traits not recognized by established diagnostic criteria including markers of sub-clinical inflammation [4], altered circulating levels of factors derived from adipose tissue (adipokines) and the vasculature, and, importantly, intracellular lipid accumulation in liver and skeletal muscle, all of which are closely linked to the development of insulin resistance. Therefore, our use of the term insulin resistance syndrome will refer to the pathophysiological process responsible for the cardiometabolic trait cluster, without deference to Metabolic Syndrome diagnostic criteria. In this review, we will emphasize intrahepatocellular and intramyocellular lipid accumulation as components of the IRS, and the mechanisms responsible for the inter-relationships among ectopic fat deposition, insulin resistance, and associated metabolic traits. edu (email).Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The pathophysiology of the IRS is likely to be multifactorial; however, the trait complex consistently involves some degree of relative insulin resistance [5,6]. It is likely that interactions involving age, behavior, environment, and genetic factors impact the relative severity of cardiometabolic risk factors that is associated with any given degree of insulin resistance. Obesity is also commonly implicated as a key pathogenic factor. While obesity can exacerbate insulin resistance and associated traits, only a small percentage of individual differences in insulin sensitivity can be attributed to differences in body mass index [7,...

Adiponectin circulates in human plasma mainly as a 180-kDa low molecular weight (LMW) hexamer and a high molecular weight (HMW) multimer of ϳ360 kDa. We comprehensively examined the relationships between circulating levels of total adiponectin, adiponectin multimers, and the relative distribution (i.e., ratio) of multimeric forms with key features of the metabolic syndrome. Total adiponectin (r ‫؍‬ 0.45), HMW (r ‫؍‬ 0.47), LMW (r ‫؍‬ 0.31), and HMW-to-total adiponectin ratio (r ‫؍‬ 0.29) were significantly correlated with insulin-stimulated glucose disposal rate. Similarly, total (r ‫؍‬ ؊0.30), HMW (r ‫؍‬ ؊0.38), and HMW-to-total adiponectin ratio (r ‫؍‬ ؊0.34) were correlated with central fat distribution but not with total fat mass or BMI. Regarding energy metabolism, although there were no effects on resting metabolic rate, total (r ‫؍‬ 0.41) and HMW (r ‫؍‬ 0.44) were associated with increasing rates of fat oxidation. HMW-to-total adiponectin ratio increased as a function of total adiponectin, and it was HMW quantity (not total or HMW-to-total adiponectin ratio or LMW) that was primarily responsible for all of these relationships. Impact on nuclear magnetic resonance lipoprotein subclasses was assessed. HMW and total adiponectin were correlated with decreases in large VLDL (r ‫؍‬ ؊0.44 and ؊0.41); decreases in small LDL (r ‫؍‬ ؊0.41 and ؊0.36) and increases in large LDL (r ‫؍‬ 0.36 and 0.30) particle concentrations accompanied by increased LDL particle size (r ‫؍‬ 0.47 and 0.39); and increases in large HDL (r ‫؍‬ 0.45 and 0.37) and HDL particle size (r ‫؍‬ 0.53 and 0.47). Most of these correlations persisted after adjustment for metabolic covariables. In conclusion, first, serum adiponectin is associated with increased insulin sensitivity, reduced abdominal fat, and high basal lipid oxidation; however, it is HMW quantity, not total or HMW-to-total adiponectin ratio, that is primarily responsible for these relationships. Second, reduced quantities of HMW independently recapitulate the lipoprotein subclass profile associated with insulin resistance after correcting for glucose disposal rate and BMI. Finally, HMW adiponectin is an important factor in explaining the metabolic syndrome. Diabetes 55:249 -259, 2006

Recently, the transcription factor 7-like 2 (TCF7L2) gene on chromosome 10q25.2 has been linked with type 2 diabetes among Caucasians, with disease associations noted for single nucleotide polymorphisms (SNPs) rs12255372 and rs7903146. To investigate mechanisms by which TCF7L2 could contribute to type 2 diabetes, we examined the effects of these SNPs on clinical and metabolic traits affecting glucose homeostasis in 256 nondiabetic female subjects (138 European Americans and 118 African Americans) aged 7-57 years. Outcomes included BMI, percent body fat, insulin sensitivity (S i ), acute insulin response to glucose (AIR g ), and the disposition index (DI). Homozygosity for the minor allele (TT) of SNP rs12255372 occurred in 9% of individuals and was associated with a 31% reduction in DI values in a recessive model. The at-risk allele TT was also associated with lower AIR g adjusted for S i in both ethnic groups, whereas rs12255372 genotype was not associated with measures of adiposity or with S i . The T allele of rs12255372 was also associated with increased prevalence of impaired fasting glucose. Genotypes at rs7903146 were not associated with any metabolic trait. Lower S i and higher AIR g observed in the African-American compared with the European-American subgroup could not be explained by the TCF7L2 genotype. Our data suggest that the TCF7L2 gene is an important factor regulating insulin secretion, which could explain its association with type 2 diabetes. Diabetes 55: 3630 -3634, 2006 T ype 2 diabetes is a heterogeneous disorder characterized by insulin resistance combined with defects in insulin secretion (1). Genetic factors are suspected to affect both insulin secretion and insulin resistance but the causative genes remain elusive (2,3). Genome-wide linkage scans have localized regions on several chromosomes harboring type 2 diabetes susceptibility genes (4); however, with few exceptions, most identified genes confer small to moderate risk or have yielded inconsistent results in replication efforts (5,6). Intronic variation in the transcription factor 7-like 2 (TCF7L2) gene located on chromosome 10q has recently been associated with a twofold increase in risk for type 2 diabetes in an Icelandic population. This finding has been replicated in Danish and U.S. Caucasian cohorts (7). Allele T of single nucleotide polymorphisms (SNPs) rs12255372 and rs7903146 in the TCF7L2 gene were strongly correlated with the original microsatelite marker linked to type 2 diabetes risk, and variation within this gene accounted for 21% of type 2 diabetes risk (7). The mechanism of action of the TCF7L2 gene with respect to the pathogenesis of type 2 diabetes is not known.If variants in the TCF7L2 gene influence susceptibility to type 2 diabetes, they may be associated with insulin resistance and/or impaired insulin secretion. Abnormalities in insulin action and secretion precede the development of overt type 2 diabetes and represent quantitative traits that can help identify the mechanism conferring increased risk for the ...