Chinese Succulent Plant Shilianhua Regulates Glucose Metabolism and Insulin Sensitivity by Inhibiting GSK-3β and NF-κB

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There are a number of recognized ‘blue zones’ around the world which are considered longevity hotspots where a certain amount of the population have long average life spans and a high number of centenarians.

One such blue zone is found in Western China on the slopes of the Himalayas called Bama Yao Autonomous County (aka Bama County):

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Figure 1.  Bama Yao Autonomous County

Bama County is a county in Guangxi, China and is under the administration of Hechi City.

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Figure 2.  Location of Bama Yao Autonomous County

Out of an approximate population of 230,000, Bama County has at least 79 men and women over 100 years old and still very physically active.  Their ratio of 3.52 centenarians per 10,000 people is the highest found anywhere in the world.  It is claimed that the residents of Bama County have the longest average life span of any other country in the world.

Centenarians say age is just a number

Figure 3.  Centenarian resident of Bama County

Among the many environmental factors attributed to blue zones, certain foods and diet play a significant role.  In the case of Bama County, a specific and unique food has been found to play a key role in the longevity of their residents.

A majority of the residents of Bama County consume daily a plant food called Shilianhua or “rock lotus’.  The botanical name of shilianhua is Sinocrassula and is a genus of succulent, subtropical plants of the family Crassulaceae.

The name “Sinocrassula” means “Chinese crassula” and is grown primarily in the province of Yunnan in the south of China, and also from the north of Burma. It grows at an altitude between 2,500 and 2,700 meters and typically blooms from June through August in the Northern Hemisphere. 

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Figure 4.  Sinocrassula indica, aka Shilianhua or rock lotus

The Pennington Biomedical Research Center, Louisiana State University System; and the Medicinal Plant Research Laboratory, School of Renewable Natural Resources, Louisiana State University Agricultural Center in Baton Rouge, Louisiana, published on 7 April 2009 in the American Journal of Physiology-Endocrinology and Metabolism a paper which examined the anti-diabetes effects of extracts of Shilianhua (SLH).  1

In this study, the researchers isolated the bioactive ingredients of SLH and explored the mechanisms of action of its F100 fraction. The result of the study suggests that the F100 fraction of SLH exhibited a significant activity in enhancing insulin sensitivity in mice.

After treatment with SLH for 8 weeks, fasting insulin and fasting blood glucose (FBG) were reduced by 43 and 27%, respectively.

Glucose consumption was induced significantly by F100 in 3T3-L1 adipocytes, L6 myotubes, and H4IIE hepatocytes in the absence of insulin. F100 also increased insulin-stimulated glucose consumption in L6 myotubes and H4IIE hepatocytes. It increased insulin-independent glucose uptake in 3T3-L1 adipocytes and insulin-dependent glucose uptake in L6 cells. The glucose transporter-1 (GLUT1) protein was induced in 3T3-L1 cells, and the GLUT4 protein was induced in L6 cells by F100.

The data suggest that F100 can act in an insulin- independent manner to stimulate glucose utilization.  F100 may use the insulin-signaling pathway to enhance the glucose consumption.

These results suggest that F100 induces glucose consumption in adipocytes, muscle cells, and hepatocytes in a dose-dependent manner. It may promote insulin activity in cell type-dependent manner (myotubes and hepatocytes). 

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Figure 5.  Effects of F100 in the KK.Cg-Ay/+ diabetic mice. A: effects of F100 on body weight, fat content, food intake, and serum insulin of KK.Cg-Ay/+ mice (n = 9). B: effect of F100 on fasting blood glucose (FBG) of the mice. C: effects of F100 on insulin tolerance of the mice (n = 9). AUC, area under the curve in the insulin tolerance test. Compared with control: *P < 0.05.  (Source)

SLH’s significant activity in enhancing insulin sensitivity in mice may be related to the inhibition by the F100 fraction in SLH of:

  • Glycogen Synthase Kinase-3 Enzyme (GSK-3) (specifcially  (GSK-3β)
  • Nuclear factor kappa-light-chain-enhancer of activated B cells  (NF-κB)

Glycogen Synthase Kinase-3 Enzyme (GSK-3)

Glycogen Synthase Kinase-3 Enzyme (GSK-3) is an enzyme in the body that, when normally activated, is part of the system regulating glucose metabolism.

However, when GSK-3 is overly and excessively activated, it tends to damage cellular structures.  Excessively activated GSK-3 can result in the following health issues in the body:  2 3 4

  • Accelerates aging in heart and muscle
  • Accelerates aging in the skeletal system
  • Accelerates aging in the stomach and liver
  • Develops type II diabetes
  • Develops Alzheimer’s disease  5
  • Impairs autophagy which clears toxic debris inside cells
  • Increases pro-inflammatory cytokines

Glycogen Synthase Kinase-3 Enzyme (GSK-3) Contributes to Alzheimer’s disease

The structural changes and defects that occur in the aging brain which develops into dementia and eventually Alzheimer’s disease include accumulation of beta amyloid plaque and damaged tau proteins.  Both of these results in neurofibrillary tangles which lead to neuron death.

Increased or aberrant over-expressive activity of the GSK-3 enzyme is a contributing factor in these structural changes.

Excessive GSK-3 damages (through the process of the hyperphosphorylation of tau proteins) tau proteins and is thought to directly promote amyloid beta production which leads to neurofibrillary tangles.  6

As mentioned, GSK-3 normally regulates glucose/insulin metabolism.  However, excessive GSK-3 may increase the development of Type II diabetes with glucose impairment and insulin resistance.  It is clear that Type II diabetes increases accumulations of beta amyloid and damaged tau proteins.  7

Because of this correlation, Alzheimer’s disease is often called Type III diabetes.

This conclusion lead to the Alzheimer’s strategy of inhibiting GSK-3 as a means to effectively lower blood glucose, while increasing insulin sensitivity.  8

GSK-3 Inhibitors

Targeted inhibition of GSK-3 may have therapeutic effects with regards to mild cognitive impairment and dementia (including Alzheimer’s disease).  The identified GSK-3 inhibitors are of diverse chemotypes and mechanisms of action, which include inhibitors isolated from natural sources, cations (minerals), and synthetic small molecules.

Shilianhua as a GSK-3 Inhibitor

GSK-3 inhibitors have been reported to improve insulin sensitivity in cellular and animal models.  9  GSK-3β may be a target of F100 in insulin sensitization.

The inhibition of GSK-3 leads to an increase in glycogen synthesis, which promotes insulin sensitivity. The activation of GSK-3 leads to reduction in glycogen synthesis and decrease in insulin sensitivity.

In response to insulin, the enzyme activity of GSK-3 is inhibited through Akt-mediated phosphorylation. The researchers suggested that this inhibitory mechanism may be used by F100 to stimulate glucose uptake in the cellular models and increase insulin sensitivity in mice.

Nuclear factor kappa-light-chain-enhancer of activated B cells  (NF-κB)

NF-κB is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens.

NF-κB has long been considered a prototypical pro-inflammatory signaling pathway, largely based on the activation of NF-κB by pro-inflammatory cytokines such as interleukin 1 (IL-1) and tumor necrosis factor α (TNFα), and the role of NF-κB in the expression of other pro-inflammatory genes including cytokines, chemokines, and adhesion molecules

NF-κB is found to be chronically active in many inflammatory diseases, such as:

  • inflammatory bowel disease
  • arthritis
  • sepsis
  • gastritis
  • asthma
  • atherosclerosis

NF-κB has long been considered the “holy grail” as a target for new anti-inflammatory substances, both nutraceutical and pharmaceutical.

In this study the researchers found that NF-κB was strongly inhibited by the F100 fraction in SLH.  Inhibition of inflammation may also contribute to the insulin sensitization by F100. In response to F100, the LPS-induced cytokine (TNFα and MCP-1) expression was reduced in RAW 264.7 macrophages.

The NF-κB inhibition may be a result of GSK-3β suppression by F100.

In conclusion, the researchers stated:

“In summary, we conclude that F100 is a bioactive component in SLH and able to regulate glucose metabolism and insulin sensitivity in mice and in cells. The data suggest that the activity of F100 may be related to the inhibition of GSK-3β. The inhibition may improve insulin signaling in cell. Indirectly, F100 may protect insulin sensitivity by inhibition of NF-κB activity.”  10

U.S. Patents on Shilianhua

Two U.S. Patents have been filed on the medicinal use of Shilianhua, one on June 5, 1999 and the other on October 5, 2006:

US 5911993 A  Homeopathic antidiabetic treatment

A highly effective pure, natural, ingestible antidiabetic may be made from Shilianhua (Echevaria glauca, Sinocrassula berger, Crassulaceae) by washing leaves and/or stems of the Shilianhua plant, crushing them in a grinder, breaking the cell walls to form a filterable material, filtering the material to produce a filtrate, and decompressing and concentrating the filtrate to produce a concentrated solution.

Treatment of, or to prevent, diabetes by lowering blood sugar at least 10% (e. g. about 50%) is practiced by daily administration of about 50-100 mg of powdered extract of Echevaria glauca, Sinocrassula berger, Crassulaceae, or about 20-40 mg of concentrated powdered extract of Echevaria glauca, Sinocrassula berger, Crassulaceae.
WO 2006105407 A1  Medical uses of shilianhua

Shilianhua (SLH) extract has been discovered to display bioactivity in the regulation of fatty acid and glucose metabolism, and in inhibition of an inflammatory response. In addition, an active fraction of SLH extract has been characterized. An active SLH extract protected against insulin resistance through multiple mechanisms, including inhibition of IKK/NF-κB, stimulation of adiponectin secretion, promotion of fatty acid oxidation, and activation of p38.

SLH can be used in the prevention and treatment of diseases in which insulin resistance plays a major role, which includes hyperglycemia, cardiovascular diseases (such as hypertension, heart disease), stroke, renal failure, blindness, and non-traumatic limb amputation. SLH can be used to treat obesity and hyperlipidemia-related diseases by promotion of fatty acid oxidation and energy expenditure. SLH extracts may be used for prevention and treatment of inflammation and oxidative stress, and other diseases in which NF-κB plays a major role, such as arthritis, aging and cancer.