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.