The metabolism of isoforms of human adiponectin: studies in human subjects and in experimental animals

Abstract

Objective: Little is known of the metabolism of different isoforms of adiponectin. We therefore (a) characterised the size distribution of human adiponectin in relation to gender, body composition and following a challenge with a fat meal or oral glucose in humans, and (b) studied the metabolism of isoforms of human adiponectin in rabbits. Method: Electrophoresis, blotting and chromatography were used to characterise human adiponectin in 36 healthy subjects, including 15 with at least two first-degree relatives with type 2 diabetes, before and after consumption of a fatty meal or glucose. The metabolism of column-fractionated human adiponectin was studied in rabbits, some of which were coinjected with insulin. Results: Females had a higher proportion of high molecular weight (HMW) and hexameric adiponectin (P ¼ 0.002 and 0.004 respectively), and a lower proportion of trimers (P , 0.0001) than males. Females also showed a strong negative relationship between body fat measures and the proportion of HMW adiponectin. There were no differences in isoforms between insulin-resistant and -sensitive subjects, or following oral glucose or a fat meal. Adiponectin in rabbits had an extravascular/intravascular ratio of 0.71, and a half-life (T1/2) of 14.3 h. Metabolism was not influenced by insulin or reduction of sulphydryl bonds. HMW and trimeric isoforms had a significantly different T1/2 of 13.0 and 17.5 h respectively (P , 0.05), and these isoforms did not interconvert in vivo. Conclusions: Human adiponectin is present as trimers, hexamers and HMW forms. Females had a higher proportion and absolute amount of HMW species compared with males, and female, but not male, subjects showed a strong negative relationship between measures of body fat, and the proportion of HMW species. These isoforms did not respond to challenge in man with a fatty meal or oral glucose, and in the rabbit, to injected insulin. HMW adiponectin was more rapidly metabolised than the trimeric form, but both were stable in vivo, and did not interconvert. We conclude that human adiponectin is much longer-lived than is the case with other hormones, a finding with positive implications for the potential to supplement levels of adiponectin in man.European Journal of Endocrinology 153 409-417

Low plasma adiponectin concentration is an indicator of the metabolic syndrome

“…In the present study, we analysed a large population of middle-aged Finnish men and women to find out how plasma adiponectin levels are associated with MS defined on the basis of the new criteria. The study allowed us to consider sexspecific differences in adiponectin levels and their interaction with MS. As expected, the adiponectin levels were higher in women than in men (20). In both the sexes, we found that adiponectin was correlated negatively with measures of body fat, fasting plasma glucose and triglycerides and hs-CRP.…”

“…2). Interestingly, it has been found that females have higher proportions of high molecular weight and hexameric forms of adiponectin and lower proportions of trimers, and that the higher molecular form adiponectin serves as a precursor pool for activation by metabolic stimuli, such as an increased insulin level (20). Therefore, adiponectin could partly explain the better insulin sensitivity of females and could also be one reason why lower adiponectin levels have more deleterious effects in women.…”

Associations of Adiponectin Levels With Incident Impaired Glucose Metabolism and Type 2 Diabetes in Older Men and Women

“…Women have more HMW adiponectin than men (23), which may partly explain the differences that we have found between men and women.…”

“…Recent work has shown that adiponectin exists in different isoforms, low-molecular weight and highmolecular weight (HMW) complexes (2). Diabetic patients had a significantly decreased HMW-to-total adiponectin ratio (23), and HMW adiponectin correlated better with glucose tolerance than total adiponectin in Indo-Asian males (24). Also, a relatively larger increase in HMW adiponectin after weight reduction has been shown (25).…”

Reduced plasma adiponectin concentrations may contribute to impaired insulin activation of glycogen synthase in skeletal muscle of patients with type 2 diabetes

“…However, further studies are warranted to explore the direct molecular mechanisms by which these forms of circulating adiponectin sensitise muscle to insulin action. Females have higher circulating levels of total adiponectin, and in particular the proportion of HMW and hexameric adiponectin, than do males [1,40,41]. A selective inhibition of the secretion of HMW adiponectin by testosterone may contribute to these differences [42].…”