Resistin, adipose tissue and...

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Resistin, adipose tissue and type 2 diabetes in humans

Original article
Resistin and type 2 diabetes: regulation of resistin expression by insulin and rosiglitazone and the effects of recombinant resistin on lipid and glucose metabolism in human differentiated adipocytes. McTernan PG, Fisher FM, Valsamakis G, Chetty R, Harte A, McTernan CL, Clark PMS, Smith SA, Barnett AH, Kumar S. J Clin Endocrinol Metab 2003; 88: 6098–106.
Summary and Comment:
Philippe Vague, Marseille, France

Summary

This study aimed to clarify the role of resistin and to establish whether it is an important cytokine contributing to the pathogenesis of obesity-related type 2 diabetes or whether it is a simple marker of diabetes status.
Among 45 obese type 2 diabetic patients circulating resistin levels estimated by a specific ELISA were 20% higher (16.6 ng/ml) than those of 34 non-diabetic obese individuals (13.5 ng/ml). Resistin levels were not associated with any markers of adiposity (BMI, waist circumference, insulin or leptin levels) nor with metabolic control. They were related, relatively weakly, to C-reactive protein but only in the diabetic group (r = 0.39).
In vitro, when applied to human subcutaneous adipocytes, insulin had no effect on resistin mRNA expression but stimulated protein secretion dose-dependently. This effect was abolished by rosiglitazone. On differentiated human preadipocytes recombinant resistin modestly decreased glucose uptake, suggesting that its role as an insulin-resistant factor is probably small. Neither leptin secretion nor lipid accumulation — markers of adipocyte differentiation — were modified by resistin during chronic treatment, suggesting that resistin has no role in adipocyte differentiation in humans.

Comment

Resistin belongs to a protein family known as resistin-like molecules that is probably involved in the inflammatory process, but various studies in rodent models have shown that resistin impairs glucose tolerance and insulin action and inhibits adipogenesis. As this protein is secreted by the adipocytes, it has been suggested that it is involved in the relationship between adipose tissue, insulin resistance and diabetes, especially as the expression of both gene and protein are high in visceral adipose tissue. The results of McTernan et al. enable a better evaluation of the role of resistin in the mechanism linking obesity with type 2 diabetes.
Circulating levels of resistin were slightly higher (by 20%) in obese diabetic patients than in obese non-diabetic subjects, but there was no correlation with BMI, waist circumference, leptin secretion, homeostasis model assessment indices of insulin resistance, or HbA1c. Diabetes status was the only parameter linked to higher resistin values, discounting a clinically significant role of circulating resistin levels in the insulin resistance observed in type 2 diabetes.
Resistin levels were related to C-reactive protein levels in the diabetic group but not in the non-diabetic group, although the levels ranged from <1 to 17 mg/l (a frankly high value) in the non-diabetic group (Fig. 1).

Fig. 1: Correlation of serum C-reactive protein with serum resistin in obese non-diabetic and obese type 2 diabetic subjects. The line of best fit is drawn to examine the correlation in both cohorts.

If resistin, like other cytokines, is indeed involved in the inflammatory process, this hypothesis needs further investigation.
The study also sought to determine whether the resistin-induced effects on rodent adipose tissue could be observed in human adipose tissue. On isolated human adipocytes insulin stimulates weakly, but dose-dependently, the secretion of resistin but not its mRNA expression. The effect was abolished by rosiglitazone. This abolition is probably related to the fact that a putative peroxisome proliferator-activated receptor (PPAR) binding site in the promoter of the resistin gene has been identified. However, the insulin effect that is suppressed by rosiglitazone — a PPAR agonist — is the stimulation of protein secretion, not its expression, and it is thus a post-transcriptional effect. This fact does not support the hypothesis that the powerful thiazolidinedione-sensitizing effect may be explained by a variation in circulating resistin levels.
It has been proposed that resistin impairs preadipocyte differentiation and therefore could limit obesity at the expense of glucose tolerance, at least in rodent models. The absence of a recombinant resistin effect on human differentiated preadipocytes to modify both leptin secretion and lipid accumulation — markers of fat mass accumulation — does not mean that the results observed in mice may be extended to humans.
Four years after its discovery, the role of resistin in the obesity-diabetes relationship remains unclear but is probably not significant. Its role (marker, factor?) in the inflammatory processes also remains to be determined.