Discussion
To the best of our knowledge, Tsai et al.32 conducted the only systematic review and meta-analysis found in the literature regarding the effect of isotretinoin treatment on glucose metabolism in patients with acne. They concluded that treating acne patients with isotretinoin does not substantially change the HOMA-IR values but significantly increases the serum adiponectin level. In our updated systematic review and meta-analysis, we included 3 more subsequently published studies, and our results were consistent to the ones of Tsai et al.’s.
All-trans retinoic acid (ATRA), the result of 13-cis-retinoic acid isomerization by sebocytes, changes gene expression by binding to and activating the retinoic acid receptors (RARs)33. In human keratinocytes, both the expression of p53 and proapoptotic caspases are increased by ATRA, which is also responsible for the apoptosis of the former. Furthermore, neutrophil apoptosis caused by ATRA and p53 possibly minimizes inflammation in acne. During treatment, isotretinoin induces the death of sebocytes and consequently reduces sebum production, while the microscopic image of it is the involution of sebaceous glands34. In those glands, nuclear levels of Forkhead box protein O1 and O3 (FoxO1, FoxO3) are increased by ATRA as well, further reducing sebum production 35.
Although the exact mechanisms behind the regulation of fluctuation of adiponectin levels in plasma and cells are yet to be revealed, recent studies’ results lean towards the possibility that adiponectin is controlled during and post transcription. Peroxisome proliferator-activated receptor-g (PPARγ), CCAAT-enhancer-binding protein a and FoxO1 appear to be transcription factors that increase adiponectin expression while agonists of the nuclear receptor and PPARγ additionally increase its multimerization and secretion36. It has also been shown that the activation of the latter not only multiplies small, sensitive to insulin adipocytes by facilitating the process of their creation but increases the response of adipose-derived hormone adiponectin as well 37. On the other hand, FoxO1, one of the Forkhead box O transcription factors, participates in the adjustment of adipocyte differentiation. More specifically, even though FoxO1 seems to upregulate adiponectin transcription, it also appears to suppress PPARγ gene expression and its interaction with CCAAT/enhancer-binding protein α obscurely increases adiponectin gene transcription 38,39.
Laboratory results were contradictory. To begin with, Landrier et al.40 observed a decreased expression of adiponectin in white muscle adipose tissue during high in Vitamin A diet while Kovács et al.20 reported that isotretinoin treatment decreases adiponectin mRNA expression in human sebaceous cells. According to Kalisz et al.41, treatment with all-trans-retinoic acid increases both synthesis and secretion of adiponectin by perivascular adipose tissue in apolipoprotein E deficient mice, without though significantly increasing its levels in visceral adipose tissue. It is possible that adiponectin is secreted by different cell types and its levels in sebaceous cells do not reflect the ones measured in serum in clinical practice. In addition, the post isotretinoin treatment adiponectin increase in acne patients may be triggered by the anti-inflammatory mechanisms of isotretinoin. More research is needed to clarify these mechanisms and bridge the gap between scientific findings and clinical measurements.
Adipocytes of a growing adipose tissue are the first to develop insulin resistance, while ectopic fat storage in organs such as the liver and muscles as a result of its unsuccessful deposition in the adipose tissue is considered to be the spread mechanism of such resistance in those organs. The above-mentioned ectopic lipid storage appears to be controlled by usual genetic mutations as well 42.
Not long ago, ApoC3 polymorphisms were associated with the lean male population’s susceptibility to NAFLD and insulin resistance leading to a rise in ApoC3 plasma levels by approximately 30% and postprandial hypertriglyceridemia caused by ApoC3’s altering effect on lipoprotein lipase activity. It was also found that this alteration consequently increased the amount of chylomicron remnants stored in the liver. In addition, increased hepatic triacylglycerol (TAG)/DAG concentration was observed in transgenic mice on a high-fat diet that overexpressed human ApoC3 in the liver due to the activation of hepatic PKCε (Protein Kinase Cε) and the development of hepatic insulin resistance43. The isomerization of isotretinoin to ATRA takes place inside human sebaceous cells, increasing nuclear levels of FoxO133,35. This particular protein raises apolipoprotein C3 levels, which subsequently favorizes the storage of very low-density lipoprotein (VLDL) over lipids into cells, causing hypertriglyceridemia44. Both lipid profiles of patients receiving isotretinoin treatment and those with insulin resistance were found to share the same disorders. More specifically, an increase in triglycerides and decrease in high-density lipoprotein (HDL-C) were the most common laboratory findings. Finally, although FoxO1 plays a major role in the insulin signaling pathway, not much is known about its association with insulin resistance in adipocytes, the most critical cell type in developing it 41,45.