This study they looked at the withdrawal of cortisol on glucose homeostasis. The point is that cortisol has profound effects on glucose homeostasis. Elevated cortisol or exogenous intake reduces T3 and increases insulin resistance.
acute GC secretion during stress mobilizes peripheral amino acids from muscle as well as fatty acids and glycerol
from peripheral fat stores to provide substrates for glucose synthesis by the liver
chronically elevated GC levels
alter body fat distribution and increase visceral adiposity as well as metabolic abnormalities in a fashion reminiscent of
metabolic syndrome
This local production may
play an important role in the onset of obesity and insulin resistance.
In adipocytes, cortisol inhibits lipid mobilization in the presence of insulin, thus leading to triglyceride accumulation
and retention.
Since the density of GC receptors is higher in intra-abdominal (visceral) fat than in other fat depots, the
activity of cortisol leading to accumulation of fat is accentuated in visceral adipose tissue (24, 158), providing a mechanism by which excessive endogenous or exogenous GC lead to abdominal obesity and IR
obese patients generally have normal or subnormal
plasma cortisol concentrations
This may be explained by an increased intratissular/cellular concentration of cortisol in adipose tissues
Intracellular GC may be produced from recycling of GC metabolites such as cortisone in adipose tissues
Local GC recycling metabolism is mediated by 11β-hydroxysteroid dehydrogenase enzymes (11β-HSD1 and 11β-HSD2
Cortisol also increases 11β-HSD1 expression in human adipocytes
In humans, elevated 11β-HSD1 expression in visceral adipose tissue is also associated with obesity
even if obese patients generally have normal or subnormal plasma cortisol concentrations
(131, 158), triglyceride accumulation in visceral adipose tissue may be due, at least in part, to the local production of GC in insulin-
and GC-responsive organs such as adipose tissue, liver, and skeletal muscle
To date nearly half of known human tumors show a dysregulation of the WNT signaling pathway
It should be also noted that the WNT pathway is not exclusively employed during development or overactivated in cancer. In adults many healthy tissues rely on it for renewal and homeostasis maintenance, most notably the intestine, haematopoietic system, hair, bones and skin. Therefore one might expect adverse reactions in all these organ systems, which has indeed been observed for many WNT-targeting compounds upon attempts to push them into the clinics
The intestine seems to be the most vulnerable in this regard
Ivermectin inhibits proliferation of human colon cancer and lung cancer cells both in vitro and in vivo
The anti-proliferative action, affecting both the bulk tumor cells and CSCs, was linked in this study to inhibition of WNT signaling
the anti-WNT IC50 of ivermectin is 5–10 times (~1–2 µM vs. 10 µM) lower than that of its toxic effect against chloride channels
oral bioavailability of the drug, as for other antiparasitic drugs discussed in this section, is very low
Toxicity studies in vivo have also demonstrated a wide therapeutic index for ivermectin
Its anti-proliferative activity has been demonstrated in a wide array of cancer cell lines representative of WNT-dependent cancers: non-small lung carcinoma [96], multiple myeloma [97], hepatoma [98], adrenocortical carcinoma [99], ovarian cancer [100] and glioblastoma
Niclosamide inhibits the canonical WNT pathway
In addition to inhibiting the canonical WNT pathway, niclosamide may mediate its anticancer activities through several other signaling pathways such as NOTCH [107], MTOR [108], NF-κB [97] and STAT3 [96]
review article highlights older medications that have anti-Wnt pathway effects in cancer. Roughly, 50% of cancer involve upregulated Wnt pathway activity. Other drugs of note: metformin