Glycogen synthase kinase 3 beta — or just “GSK3β” for short — is an important enzyme that may be involved in a number of different important functions throughout the body. For example, GSK3B has been implicated in energy metabolism, cell development, and immune system regulation. Additionally, some research may suggest that inhibiting this enzyme could have some potential “beneficial” effects — but what does the current science really say? Read on to learn more about GSK3B, what it does, and some lifestyle, environmental, dietary, and genetic factors that may affect it!
What is GSK3B?
Glycogen synthase kinase 3 beta — or just “GSK3β” for short — is an enzyme that has been linked to many important functions throughout the body and brain, including energy metabolism, neuronal cell development, and the regulation of the immune system [1].
Some early research has also implicated GSK3B in the development or progression of various health conditions such as diabetes, inflammation, cancer, Alzheimer’s and bipolar disorder [2].
Glycogen synthase kinase 3 (GSK-3) acts as an essential “brake” on many growth-signaling pathways, including WNT and insulin. GSK-3 has high activity in resting tissues, and is inhibited upon cellular stimulation [3].
Purported Benefits of GSK3B Inhibition
Some preliminary research has suggested a variety of potential “benefits” associated with inhibiting the activity of the GSK3B enzyme.
In the sections below, we’ll discuss some of the various roles or effects that GSK3B (or its inhibition) has been reported to have in a variety of health conditions. However, keep in mind that the science behind these effects is still preliminary, and none of these effects have been confirmed in humans — nor have they been officially adopted for any medical or other purposes.
In other words, there is still “insufficient evidence” for these effects of GSK3B in humans, and much more research will be needed to confirm them, as well as determine how they might be relevant to the development or treatment of any particular health condition.
As always, be sure to discuss any significant lifestyle, dietary, or other changes with your doctor first!
INSUFFICIENT EVIDENCE:
1) Metabolic Disorders
Glycogen synthase kinase-3 (GSK-3) is believed by some researchers to have an important role in the regulation of glycogen synthesis, protein synthesis, gene transcription, and the development (differentiation) of several types of cells throughout the body [4].
According to some early research in animals, increased levels of GSK3 have been reported in certain metabolic health conditions, such as type-II diabetes and obesity [2].
In studies of cells and animals, compounds that inhibit GSK3 have been reported to have some potential “anti-diabetic” effects [5]. Some of these effects may be due to the effects of GSK3B on insulin sensitivity, glucose levels, and glycogen synthesis [6, 2].
Additionally, one study has reported that over-expression or over-activity of GSK3 may impair the ability of insulin to stimulate the disposal of glucose and the activity of the enzyme of glycogen synthase. These mechanisms, in turn, have been hypothesized to play some yet-unclear role in the development of obesity (in rats) or type-2 diabetes (in humans) [4].
Another study in animals has reported that the levels of GSK3B activity in the hypothalamus may be involved in the regulation of appetite and overall food intake. The authors of this study have hypothesized that this may be due to GSK3B’s interactions with the appetite-related hormone leptin, and that these interactions may, in turn, be responsible for weight gain and glucose intolerance (especially in animals with high-fat diets) [7].
Nonetheless, much more research will be needed to pin down the precise roles of GSK3B in humans, and what potential mechanisms might be involved.
2) Inflammation and Pain
According to some early research, inhibitors of GSK3β have been reported to have a potential effect on the symptoms of some neuro-inflammatory conditions, such as Alzheimer’s disease, multiple sclerosis, and AIDS-related dementia [8].
Additionally, one cell study has implicated GSK3B in resistance to oxidative stress, which further suggests a potential connection to inflammation [9].
While the precise mechanisms involved are not yet known, some preliminary evidence from animal- and cell-based studies have suggested a few potential mechanisms and effects. According to these studies, inhibiting GSK3B may result in:
- Decreasing the activity of “toll-like” receptors (TLRs) [10]
- Suppressing the activity of pro-inflammatory cytokines such as NF-kB, TNF, IL-6, IL-1b and IL-12/IL-23 and IL-17 [11]
Because of these potential mechanisms, some researchers have proposed that GSK3B inhibition may have future potential for treating some of the elevated immune system and inflammatory responses observed in certain inflammatory bowel diseases [10].
Nonetheless, much more research will still be needed before GSK3B-based treatments for inflammatory conditions can become a reality.
3) Mood-Related Conditions
Some preliminary research work has suggested that GSK3B activity may be involved in certain mood-related psychiatric conditions, such as depression and anxiety.
For example, according to one study, patients with depression or bipolar disorder have been reported to show elevated GSK3B activity (especially during acute “episodes”). Relatedly, higher baseline GSK3B activity has also been reported in elderly patients with depression, as well as patients with severe depression-related cognitive impairments [12].
Conversely, some early studies have reported that GSK3B inhibitors may have some potential effects on reducing symptoms of anxiety and depression. Although the mechanisms have yet to be identified, some have proposed that these potential effects may be due to the influence of GSK3B on the serotonin pathways in the prefrontal cortex [13].
4) Social Behavior and Stress
According to one preliminary study, inhibition of GSK3B activity in the prefrontal cortex has been associated with increased social behavior [13].
Relatedly, inhibition of GSK3B (in the hippocampus and striatum) has been potentially linked to increased resilience against social stress (“social defeat” stress) in mice [13].
Theoretically, this could make GSK3B relevant in understanding or treating certain conditions that are believed to affect social behavior, such as autism [13]. However, the current evidence is still much too early to draw any solid conclusions from, and much more additional research will still be needed to confirm and extend these preliminary findings.
5) Purported Cognitive Effects
Some very early lines of research have suggested that GSK3B (and its inhibition) may have some potential effects on cognition [14].
For example, GSK3 has been implicated in brain development and synaptic plasticity. Relatedly, some studies have also potentially linked GSK3 to neurogenesis (the growth and development of new brain cells. Due to these early reports, some researchers have suggested that GSK3 may play a role in age-related neurological conditions and diseases, such as Alzheimer’s disease and mild cognitive impairment (MCI) [14, 15].
Although the exact mechanisms behind these potential effects are not known for certain, some preliminary research has reported that inhibiting GSK3B may stimulate the regeneration of brain cells responsible for creating myelin, the fatty coating that helps neurons conduct electrical signals efficiently [16, 17].
Alternatively, other studies have reported that GSK3B inhibition may be associated with increased long-term potentiation (LTP), a critical aspect of synaptic plasticity [18, 14].
Finally, one cell-based study has reported that GSK3B inhibitors may stimulate the activation of CREB, a protein that has previously been linked to several different aspects of cognition [11].
However, it is important to note that all of the above findings have several major limitations. First, they have mostly been reported only by animal- or cell-based studies, so their relevance to humans is unverified. Secondly, many of these effects have only been reported in cells or animals with underlying brain damage or other adverse health conditions — so it’s still unknown whether GSK3(B) would have similar effects in healthy tissue or animals.
Overall, much more research will be needed to confirm any potential “cognitive” effects in humans, and until more data is available, it is not possible to come to any firm conclusions about any of the potential effects of GSK3B inhibition in healthy human users.
6) Circadian Rhythms
According to some early research, GSK3 activity status may be regulated by the circadian clock — and GSK3 is believed to “feed back” to regulate the molecular clock amplitude in the suprachiasmatic nucleus (SCN) [19].
For example, one study has reported that GSK3 may interact with up to five distinct core circadian-rhythm-related proteins. It also reportedly exhibits significant daily variability in its own levels and activity, as significant circadian rhythmicity of phosphorylated GSK3 (α and β) has been observed in the SCN of mice [19].
According to studies in cells, chronic activation of GSK3 may impair the daily rhythm of BMAL1, a known circadian rhythm gene. Elevated GSK3 activation may also interfere with other circadian genes, such as PER2 [19].
Finally, GSK3B has also been reported to increase Rev-Erb-A, while helping to break down ARNTL/BMAL1, CLOCK, and PER2 [20].
Altogether, while this research suggests a role of GSK3(B) in regulating the circadian rhythm, the overall significance and exact mechanisms related in this potential role remain unclear, and more research will be needed.
7) Alzheimer’s Disease
According to one very preliminary cell-based study, GSK3B inhibition may reduce the formation of amyloid plaques, a hallmark neurological sign of Alzheimer’s disease [21].
8) Cancer
Some researchers have proposed that GSK3B inhibitors could someday be useful in preventing or treating prostate, glioblastoma, neuroblastoma, pancreatic, and colorectal cancers [6].
For example, GSK3B activity has been reported to stimulate ovarian cancer cell proliferation, and may also increase resistance to chemotherapy [6].
Relatedly, another study has reported that pancreatic cancer cells often contain a “pool” of active GSK3B, and that inhibition of GSK3B may lead to decreased cancer cell proliferation and survival in these cells [6].
Finally, one study of cells from colon cancer patients reported higher levels of GSK3B expression compared to cells from healthy subjects [6].
Nonetheless, the overall significance of these potential effects — and the possible mechanisms involved — will need to be verified and clarified by considerable additional research.
9) Addiction
According to one early animal study, cocaine injections in mice led to significantly increased GSK3B activity in a brain region called the caudate putamen. The authors of this study propose that this mechanism may play a role in the “stimulating” effects of cocaine (“cocaine-induced hyperactivity”), as well as possibly in the build-up of tolerance to this drug [22].
However, the potential relevance of these mechanisms to drug use in humans remains unclear.
Substances & Compounds That May Inhibit GSK3B
Because some preliminary research has suggested some potential benefits associated with GSK3B inhibition, there has also been some scientific interest in identifying various nutritional compounds, hormones, supplements, and drugs that may play a role in inhibiting the GSK3B enzyme.
However, the following effects are based predominantly on animal- and cell-based studies, and are, therefore “lacking evidence” from any appropriate human trials so far.
In other words, these are only potential “launching-points” for future clinical studies in humans: and no solid conclusions can be made about the effects of these compounds in humans until much more additional research is done.
As such, we do not officially recommend any of the following compounds. As always, be sure to discuss any lifestyle or dietary changes, as well as any new supplements you’re trying, with your doctor first!
LACKING EVIDENCE:
Minerals:
Lithium is the most “popular” compound used by some people to inhibit GSK3B. Although its precise mechanisms are not known for sure yet, some researchers have proposed that it may work by suppressing the transportation of magnesium into cells, which is needed in order to activate GSK3 [23, 24].
Some other dietary minerals that have been suggested to inhibit GSK3B enzyme activity include:
- Lithium (potent, IC50=1-2mM, but actual inhibition is more in-vivo) [25, 23]
- Zinc (potent, IC50 = 15 μM) [25]
- Copper (potent) [25, 26]
Hormones:
Supplements:
- Curcumin (very potent, IC50=66nM) [28]
- Butyrate [29]
- Quercetin (potent, IC50=2.0 μM) [30]
- Luteolin (potent, IC50=1.5 μM) [30]
- Apigenin (potent, IC50=1.9 μM) [30]
- Astaxanthin [31]
- Cinnamon [32]
- Angelica Sinensis [33]
- Berberine [34]
- Resveratrol [34]
Drugs:
- SSRIs [35]
- Ketamine [36]
- Trichostatin [29]
- Valproic acid [29]
- Antipsychotics
- Intranasal insulin (normalized high GSK3b in diabetic animals) [37]
Natural compounds:
Toxins:
The following substances/compounds have also been reported to inhibit GSK3B: but their effects are extremely strong and potentially toxic — therefore these should be definitively avoided:
Compounds & Other Factors That May Increase GSK3B
- Oxidative stress (H2O2) [42]
- Anthrax [43]
Genetic Factors Related to GSK3B
Some variations in genes related to GSK3B have been associated with biomarkers for Alzheimer’s disease and cognitive function [44].
According to these very preliminary genetics studies, some SNPs that may have a potentially significant influence on certain aspects of GSK3B activity include:
To learn more about the potential genetic factors involved in GSK3B, check out the GSK3B gene page on SelfDecode.
