Insulin-sensitizing effects of thiazolidinediones are not linked to adiponectin receptor expression in human fat or muscle

Abstract

Circulating adiponectin levels are increased by the thiazolidinedione (TZD) class of PPARgamma agonists in concert with their insulin-sensitizing effects. Two receptors for adiponectin (AdipoR1 and AdipoR2) are widely expressed in many tissues, but their physiological significance to human insulin resistance remains to be fully elucidated. We examined the expression patterns of AdipoR1 and AdipoR2 in fat and skeletal muscle of human subjects, their relationship to insulin action, and whether they are regulated by TZDs. Expression patterns of both AdipoRs were similar in subcutaneous and omental fat depots, with higher expression in adipocytes than in stromal cells and macrophages. To determine the effects of TZDs on AdipoR expression, subcutaneous fat and quadriceps muscle were biopsied in 14 insulin-resistant subjects with type 2 diabetes mellitus after 45 mg pioglitazone or placebo for 21 days. This duration of pioglitazone improved insulin's suppression of glucose production by 41% and enhanced stimulation of glucose uptake by 27% in concert with increased gene expression and plasma levels of adiponectin. Pioglitazone did not affect AdipoR expression in muscle, whole fat, or cellular adipose fractions, and receptor expression did not correlate with baseline or TZD-enhanced insulin action. In summary, both adiponectin receptors are expressed in cellular fractions of human fat, particularly adipocytes. TZD administration for sufficient duration to improve insulin action and increase adiponectin levels did not affect expression of AdipoR1 or AdipoR2. Although TZDs probably exert many of their effects via adiponectin, changes in these receptors do not appear to be necessary for their insulin-sensitizing effects.

Gene Expression of Adiponectin Receptors in Human Visceral and Subcutaneous Adipose Tissue Is Related to Insulin Resistance and Metabolic Parameters and Is Altered in Response to Physical Training

“…Only a limited number of studies have examined adiponectin receptor expression in adipose tissue in a small number of humans and have yielded inconclusive results (13,15,23). A recent cross-sectional study reported decreased AdipoR2 expression, similar to our study, but no differences in AdipoR1 expression in intra-abdominal adipose tissue among obese subjects with and without diabetes compared with lean control subjects (23).…”

“…Both adiponectin receptors are expressed in human adipocytes (13)(14)(15) and muscle cells (16). Moreover, we have demonstrated that adiponectin receptor expression in skeletal muscle is increased in conditions of insulin resistance and type 2 diabetes, and an exercise intervention for 4 weeks, which improves metabolic parameters, also increases circulating adiponectin levels and upregulates expression of both adiponectin receptors in skeletal muscle (16).…”

“…Moreover, we have demonstrated that adiponectin receptor expression in skeletal muscle is increased in conditions of insulin resistance and type 2 diabetes, and an exercise intervention for 4 weeks, which improves metabolic parameters, also increases circulating adiponectin levels and upregulates expression of both adiponectin receptors in skeletal muscle (16). It was recently shown that improvement of in-sulin sensitivity by thiazolidinediones is not related to AdipoR1/AdipoR2 expression changes (15).…”

Relationship between adiponectin, obesity and insulin resistance

“…It has been shown that some agents belonging to the ARB family, such as telmisartan and, to a lesser degree, candesartan, act modulating PPARγ receptors. 35 Takagi e Umemoto, 36 in a meta-analysis, suggest that telmisartan therapy can increase adiponectin levels by 16% over other ARB therapies in patients without restriction, which proved to be robust in sensitivity analyzes. However, the main limitation of the study is heterogeneity in terms of follow-up time (3-12 months) and baseline insulin sensitiv- ity in patients with high blood pressure (hypertension without glucose tolerance, with poor glycemic control) in the included trials.…”

“…Insulin sensitizers thiazolidinediones, which are PPAR-γ (peroxisome proliferator-activated receptor gamma) agonist and widely used in the treatment of T2DM, increase circulating adiponectin levels in humans. 35 Another interesting class of drugs extensively used in the fields of cardiology and also related to adiponectin is angiotensin receptor type 1 blockers (ARB family). It has been shown that some agents belonging to the ARB family, such as telmisartan and, to a lesser degree, candesartan, act modulating PPARγ receptors.…”