In the world of blood glucose and elevated markers here, we are without limit in the number of folks who struggle to manage their blood glucose levels in the U.S. Could there be other factors in play besides consuming pounds of sugar each week :). ? Um, yes. A partial review of some of the genetics in play so one can dial in what to monitor and what may be supportive.
GLUT4
Is a glucose transport enzyme, that is involved in glucose uptake in the presence of insulin, its needed in sufficient quantity to prevent glucose from rising. Guess what mineral works to activate GLUT4, and enhances glucose transport into cells ? Chromium:). Cinnamon has been shown to increase GLUT4 numbers too. Hmmm. We have always heard of these things related to managing blood sugar, now we know the mechanism of action and can check the status of our genetics on GLUT4:).
PPAR Gamma
These are metabolic sensors, which are responsible for insulin sensitivity, improving glucose uptake and lowering blood sugar, and mediates the expression of GLUT4. Cinnamon also increases the production of PPAR Gamma. Berberine also increases the expression of PPAR Gamma, along with Danshen, Circumin, and Hawthorne. Hmm. Getting interesting. [6,9] PPAR Gamma is also involved in lipid metabolism, so thats interesting too [6].
"Muscle tissue is the major site for insulin-stimulated glucose uptake in vivo, due primarily to the recruitment of the insulin sensitive glucose transporter (GLUT4) to the plasma membrane. Surprisingly, virtually all cultured muscle cells express little or no GLUT4. We show here that adenovirus-mediated expression of the transcriptional coactivator PGC-1 {PPARGC1A}, which is expressed in muscle in vivo but is also deficient in cultured muscle cells, causes the total restoration of GLUT4 mRNA levels to those observed in vivo. This increased GLUT4 expression correlates with a 3-fold increase in glucose transport, although much of this protein is transported to the plasma membrane even in the absence of insulin. PGC-1 mediates this increased GLUT4 expression, in large part, by binding to and coactivating the muscle-selective transcription factor MEF2C. These data indicate that PGC-1 is a coactivator of MEF2C and can control the level of endogenous GLUT4 gene expression in muscle." [2]. GLUT4 gene expression is regulated by a variety of stimuli, both physiological and pharmacological. For example, strepto-zotocin-induced diabetes and denervation result in decreased GLUT4 mRNA in skeletal muscle; whereas cold exposure, exercise training, and triiodo-L-thyronine treatment increase GLUT4 mRNA in skeletal muscle (11, 23–28). The ability of PGC-1 {PPARGC1A} to regulate GLUT4 gene expression in muscle suggests that PGC-1 potentially could be a therapeutic target in various diabetic states. [2]
MEF2C - Cardio isnt all bad after all:)
This gene like PPAR Gamma, also mediates GLUT4 expression, and has been significantly down regulated in the hearts of diabetic rats. Uh oh. "Taken together, the results of this study indicated that six weeks of moderate-intensity endurance training allowed more effective control of glucose homeostasis, increased testosterone levels, and induced up-regulation of MEF2C and down-regulation of HDAC4 and CaMKII in cardiac tissue of diabetic rats. These results suggest improvements in managing the diabetic-induced cardiac dysfunction. However, future studies should cover our limitation by analyzing angiogenesis markers as well." [7] ME2FC regulates Beta Pancreatic Cell proliferation - that sounds important! [8].
Our friend VEGF rears its head:)
"VEGF induced MEF2C expression in a dose- and time-dependent fashion. This induction was completely abrogated by the inhibition of protein kinase C and was partially blocked by the inhibition of PKC-β and PKC-δ. In addition to regulating MEF2C expression, VEGF stimulated transcription from an MEF2-dependent promoter. VEGF stimulation of transcription was significantly reduced by the inhibition of calcineurin, CaMKII, p38 MAPK, and PKC, but not by the inhibition of ERK1/2 or BMK1/ERK5. Transfection of a dominant-negative mutant of MEF2C significantly inhibited VEGF-stimulated endothelial cell migration. conclusions. These results implicate VEGF as a key regulator of MEF2C and suggest that MEF2 may be an important mediator of VEGF in endothelial cells." [1]
Regular aerobic exercise increased VEGF levels in both soleus and gastrocnemius muscles correlated with hippocampal learning and VEGF levels.[14]
IRS1
"Insulin receptor substrate 1 (IRS1) is a ligand of the insulin receptor tyrosine kinase and is central to the insulin receptor signal transduction pathway. Deregulation in IRS1 expression and function has been reported in insulin-resistant states such as obesity and type 2 diabetes."[10]. Guess what herb regulates IRS1, you guessed it, Cinnamon. [11]
G6Pase
"Vanadium compounds are known to control hyperglycemia but the exact focus of where they work is a matter of debate. A proposed mechanism of action is that it inhibits glucose-6-phosphatase, a key enzyme in the development of insulin resistance and thus type 2 diabetes. This paper looks at the inhibitory effects of vanadium salts on glucose-6-phosphatase and also studies the mechanism of inhibition, the hypothesis being that the two vanadium compounds, vanadyl sulphate (VOSO4) and vanadyl acetylacetonate (Vace) will inhibit glucose-6-phosphatase. This was achieved by using a proof of principle study by extracting glucose-6-phosphatase from bovine liver microsomes using differential centrifugation, and then the enzyme was assayed in the presence and absence of vanadium compounds. The study found that vanadyl compounds inhibit glucose-6-phosphatase." [13]
What to monitor
Chromium, Vanadium are both easily monitored on hair mineral tests by labs such as doctors data available on Amazon for $125. Herbs like cinnamon, berberine, and hawthorne, all have multiple mechanisms of action, so best to choose wisely, and understand if they indeed are support for your genetic particulars. Various mineral supplements are good sources of chromium and vanadium, Life Extension has several, Nutricost a good combo, Solaray, etc. Find out where your weak link is, and start there:).
References
[1] Vascular Endothelial Growth Factor Induces MEF2C and MEF2-Dependent Activity in Endothelial Cells; Retinal Cell Biology, August 2008. Debasish Maiti; Zhenhua Xu; Elia J. Duh. Author Affiliations Investigative Ophthalmology & Visual Science August 2008, Vol.49, 3640-3648. doi:https://doi.org/10.1167/iovs.08-1760
[2] Restoration of insulin-sensitive glucose transporter(GLUT4) gene expression in muscle cells by thetranscriptional coactivator PGC-1. Laura F. Michael*, Zhidan Wu*, et al. Diabetes Center, Department of Medicine, Harvard Medical School,Boston, MA 02115; and‡Center for Cardiovascular Research, Department of Medicine and Molecular Biology and Pharmacology,Washington University School of Medicine, St. Louis, MO 63110. Communicated by C. Ronald Kahn, Harvard Medical School, Boston, MA, January 22, 2001 (received for review October 10, 2000). PNAS March 27, 2001 vol. 98 no. 7, pages 3820-3825. www.pnas.orgycgiydoiy10.1073ypnas.061035098.
[4] Transcription factor Mef2c is required for B cell proliferation and survival after antigen receptor stimulation. Peter R Wilker, et al. Department of Pathology and Center for Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA. Howard Hughes Medical Institute, Published as: Nat Immunol. 2008 June ; 9(6): 603–612.
[5] Vanadium and diabetes. P Poucheret, S Verma, M D Grynpas, J H McNeill. Molecular Cell Biochemistry, 1998 Nov;188(1-2):73-80. Affiliations. PMID: 9823013.
[6] Research Article, Improved Insulin Resistance and Lipid Metabolism by Cinnamon Extract through Activation of Peroxisome
Proliferator-Activated Receptors. Xiaoyan Sheng, et al. Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of CAS, Chinese Academy of Sciences, 319 Yue Yang Road, Shanghai 200031, China
Correspondence should be addressed to Ying Qin Zang, yqin@sibs.ac.cn. Received 10 September 2008; Accepted 2 November 2008
Recommended by N.Wang. Hindawi Publishing Corporation. PPAR Research. Volume 2008, Article ID 581348, 9 pages
doi:10.1155/2008/581348
[7] Endurance Training Regulates Expression of Some Angiogenesis-Related Genes in Cardiac Tissue of Experimentally Induced Diabetic Rats Mojdeh Khajehlandi Biomolecules. 2021 Apr; 11(4): 498. Published online 2021 Mar 25. doi: 10.3390/biom11040498. PMCID: PMC8066303 PMID: 33806202.
[8] RESEARCH ARTICLE MEF2C and EBF1 Co-regulate B Cell-Specific Transcription Nikki R. Kong. PLOS Genetics | DOI:10.1371/journal.pgen.1005845 February 22, 2016
[9] Lipid-Regulating Effect of Traditional Chinese Medicine: Mechanisms of Actions. Wei-Jian Bei,1 Jiao Guo, et al. Key Unit of Modulating Liver to Treat Hyperlipidemia of SATCM, State Administration of Traditional Chinese Medicine (SATCM). Guangzhou 510006, China
2 Institute of Geriatric Cardiology, Chinese PLA General Hospital, Beijing 100853, China
Correspondence should be addressed to Jiao Guo, gyguoyz@163.com
Received 27 October 2011; Accepted 8 February 2012; Hindawi Publishing Corporation
Evidence-Based Complementary and Alternative Medicine; Volume 2012, Article ID 970635, 10 pages; doi:10.1155/2012/970635
[10] Insulin receptor substrate 1 (IRS1) variants confer risk of diabetes in the Boston Puerto Rican Health Study. Xiang Feng, MD, PhD,1,2 Katherine L Tucker, PhDAsia Pac J Clin Nutr. Author manuscript; available in PMC 2015 May 12. Published in final edited form as: Asia Pac J Clin Nutr. 2013; 22(1): 150–159. doi: 10.6133/apjcn.2013.22.1.09. PMCID: PMC4428925. NIHMSID: NIHMS685498. PMID: 23353623
[11] Maternal chromium restriction induces insulin resistance in adult mice offspring through miRNA
Qian Zhang, et al. Key Laboratory of Endocrinology, Translational Medicine Centre, Ministry of Health, Department of Endocrinology,
Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences,
Beijing 100730; Received November 10, 2016; Accepted December 8, 2017
DOI: 10.3892/ijmm.2017.3328
[13] The potential effect of vanadium compounds on glucose-6-phosphataseâ€
Saima Shehzad Author Notes. Bioscience Horizons: The International Journal of Student Research, Volume 6, 2013, hzt002, https://doi.org/10.1093/biohorizons/hzt002. Published: 02 May 2013
[14] Regular aerobic exercise increased VEGF levels in both soleus and gastrocnemius muscles correlated with hippocampal learning and VEGF levels. Asli Karakilic, et al. Acta Neurobiol Exp (Wars) . 2021;81(1):1-9. doi: 10.21307/ane-2021-001. PMID: 33949164. DOI: 10.21307/ane-2021-001