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Category: Health & Wellness
Sugar, the simple sugar glucose that is, was a rarity in the diet of our hunter-gather ancestors. Today, processed sugar is so pervasive that we may be inadvertently overloading our cells in their effort to metabolize this now readily available energy source. While diet, exercise, drinking plenty of water and getting adequate sleep are all important in promoting proper health, other factors such as inflammation, hormones, genetics and environmental toxins also have to be taken into account in mitigating the increasing incidence of diabetes.1
Glucose is the body’s primary metabolic substrate
Glucose is the most important energy source for nearly all life on earth. For mammals, it is the only fuel source our brains can use under non-starvation conditions and it is the only fuel source for red blood cells. Glucose is a simple molecule containing 6 carbon atoms, 12 hydrogen atoms and 6 oxygen atoms typically arranged in a ring and conveniently written as C6H12O6. Incredibly, glucose and other similar simple sugars were present on earth even before life began.2 Life evolved to use glucose as an energy source because glucose has a very stable chemical structure and it does not react as readily with proteins compared to other simple sugars such as glyceraldehyde-3-phopshate, fructose, and glucose-6-phosphate.3
Metabolism can be thought of as the sum of all the chemical reactions that take place in our bodies. These reactions have defined pathways and involve energy in the form of adenosine triphosphate (ATP).4 Our bodies use the energy from the breakdown of the molecules in the food we eat to move, breathe, generate heat and make new molecules and cells that eventually replace the hair, skin, muscle, bone etc. that we lose over time. Metabolism can be divided into two categories:
Catabolism – The breakdown of complex molecules to yield the energy used in carrying out bodily functions.
Anabolism – The use of energy to make molecules important in growth and maintenance of body systems.
Healthy Glucose Metabolism
Normal glucose metabolism involves two well-regulated pathways, one anabolic and the other catabolic. The catabolic pathway consists of the two processes glycolysis and glycogenolysis. The anabolic pathway consists of gluconeogenesis, glycogenesis and the pentose phosphate pathway.
- This is an anaerobic process and among the oldest and most highly conserved of all metabolic pathways. It is found in both prokaryotes and eukaryotes and is present at least in some part in nearly every living cell.
- It involves the splitting of glucose into two molecules of pyruvate yielding two net ATP molecules
- Very strictly regulated by: ATP consumption, NADPH (a reducing agent also produced by glycolysis) regeneration rate, allosteric modifications of glycolytic enzymes and fluctuations in metabolite concentration.4
- On a longer time scale, the hormones glucagon, insulin and epinephrine also play an important role in glycolysis.
- This is the removal of one glucose molecule from glycogen which acts as a storage molecule for glucose. More than half the total glucose in our body is stored as glycogen in the liver and muscles. The liberated glucose is then free to enter the blood stream and take part in other reactions.
- Glycogenolysis is very carefully regulated by the interplay of the hormones insulin, glucagon and epinephrine. Allosteric regulators such as adenosine monophosphate (AMP) also play a role in regulating glycogenolysis.
- Unlike glycolysis, the hormones regulating glycogenolysis produce very immediate effects.
- This is the synthesis of glucose from non-carbohydrate sources such as lactate.
- It complements the supply of glucose when glycogenolysis is not sufficient between meals. It also occurs during long fasts or after vigorous exercise when glycogen is depleted.
- Regulated by substrate concentrations, allosteric effectors and hormones.
- This process replenishes glycogen stores in cells
- Occurs after a meal when glucose levels spike.
- Excess glucose is polymerized and stored as granules in the liver by several enzymes.
Pentose Phosphate Pathway
- Converts glucose to ribose-5-phosphate, a precursor to nucleotides and nucleic acids
- Also produces NADPH used in many other anabolic processes.
- Occurs readily in cells where lipid biosynthesis is high such as adipose, adrenal cortex, mammary glands and liver.
- Regulated by NADPH and ribose-5-phosphate concentrations.
Disruption of Glucose Metabolism
The most common disruptions of glucose metabolism involve the transport of glucose into cells. The resulting excess glucose in the blood, hyperglycemia, is the proximate cause of all forms of diabetes. This devastating metabolic disorder affecting 9.4% of the US population5 can result from either direct or indirect causes of hyperglycemia. It is of two main forms: diabetes insipidus and diabetes mellitus. The former is rarer (1:25,000) and is caused by renal dysfunction6 while the latter is far more common and is of two types:
Type 1: Formally known as juvenile-onset or insulin-dependent diabetes, this type is caused by autoimmune destruction of pancreatic ß-cells. It accounts for only 5%-10% of diabetes cases.1,7
Type 2: Formally known as adult-onset or insulin-dependent diabetes, is primarily due to insulin resistance.1,7 It accounts for 90%-95% of cases.5
The insulin deficiency or insulin resistance of target cells (liver, muscle and adipose) is accompanied by dyslipidemia, abnormal levels of lipids and lipoproteins in the blood, since proper lipid metabolism particularly in the liver and adipose tissue is also dependent on insulin action.7 Hyperglycemia is exacerbated by the fact that gluconeogenesis and glycogenolysis are normally suppressed by insulin and so add even more glucose to the blood in its absence. A fasting blood glucose (FBG) level at or above 126 mg/dL (normal = 100 mg/dL) is considered a clinical sign of diabetes.7
Target cells possess a natural ability to protect themselves from being overstimulated by hormones. Through a process known as desensitization, cell-surface receptors are internalized via endocytosis and can either be recycled to the surface or degraded. In the latter case new receptors would need to be synthesized.8 This leads to a reduction in the ability of insulin to decrease blood glucose levels and a subsequent increase in blood insulin levels (hyperinsulinemia) as pancreatic ß-cells try to correct the hyperglycemia. The function of the ß-cells themselves can also become compromised as amyloid plaques, aggregation of misfolded proteins, build up from the hyperinsulinemia causing apoptosis or cell death.9
Insulin resistance not only plays a role in diabetes but is also one of a group of clinical disorders known collectively as metabolic syndrome. Metabolic syndrome includes insulin resistance, obesity, hypertension (high blood pressure) and dyslipidemia. Insulin resistance is in fact one of the earliest signs of metabolic syndrome. Obesity is a pro-inflammatory disorder and has been associated with systemic inflammatory markers such as C-reactive protein (CRP), tumor necrosis factor-alpha (TNFa), interleukin (IL)-6 and IL-18.8,9,10 Obesity (BMI at or above 25kg/m2) was identified in 87.5% of diabetes cases.5 Excess adipose tissue, particularly around the abdomen, was shown to be especially pro-inflammatory. High levels of these inflammatory molecules are also thought to augment insulin resistance when coupled with genetic factors such as the presence of the HLA-DR3 and HLA-DR4 genes or environmental factors such as gut microbiome composition.1,7
While it may seem as if there is no overcoming insulin resistance once the process gets underway, especially given all the other factors that feed into it, it is important to note that sustained muscular activity promotes cellular uptake of glucose even without the action of insulin.10,11 A diet rich in complex carbohydrates releases glucose far slower than a diet rich in sucrose and fructose10 and so modulates blood sugar levels. With medications such as sulfonylureas that promote insulin secretion and inhibit gluconeogenesis and glycogenolysis1 it becomes possible for glucose to be taken up by remaining insulin sensitive cells over time. Metformins also inhibit hepatic gluconeogenesis and promote glucose uptake as well as lipid metabolism1 and can therefore reduce both hyperglycemia and dyslipidemia.
There are numerous dietary changes that have been shown to mitigate metabolic syndrome. These dietary supplements, herbs, fruits, vegetables and so on mainly work by combatting the inflammation that exacerbates metabolic syndrome or by directly targeting glucose in the blood itself.
Herbs and extracts
- The popular Chinese herb commonly known as Gan Sui (Euphorbia kansui) has bene show to reduce FBG, insulin resistance and expression of, TNF?? and IL-6 genes.12
- Garlic (Allium sativum) has been shown to have both anti-inflammatory and hypertension-reducing properties.13
- Ginseng (P. Ginseng) is known to reduce both postprandial and FBG levels.14
- Fenugreek (Trigonella foenum-graceum L.) extracts, although shown to aid in the reduction of insulin resistance, obesity and dyslipidemia associated with polycystic ovary disease15, has been shown to exacerbate hyperinsulinemia.16
- Chromium as a dietary supplement has excellent blood glucose-reducing properties13,17 by improving the efficiency of pancreatic cells.
- Cod liver oil, Co-enzyme Q10, beta glycan, lipoic acid, potassium, magnesium, polyphenol and vanadium were all shown to have hypotensive properties.13
- Alpha-lipoic acid, omega 3 fatty acids, folic acid, selenium zinc and copper were all shown to possess hypoglycemic properties.13
Fruits and Vegetables
- Fruits and vegetables rich in vitamins E, B6 and C have both hypoglycemic and hypotensive properties.13
- Bitter melon (Momordica charntia) has been shown to aid in the transport of glucose across cell membranes.14
- Skyler JS, Barkris GL, Bonifacio E, et al. Differentiation of diabetes by pathophysiology, natural history, and prognosis. Diabetes. 15 December 2016DOI: 10.2337/db16-0806
- Saladino R, Carota E, Botta G, et al. Meteorite-catalyzed syntheses of nucleosides and of other prebiotic compounds from formamide under proton irradiation. Proceedings of the National Academy of Sciences of the United States of America. 2015;112(21):E2746-E2755. doi:10.1073/pnas.1422225112
- Goldin A, Beckman J, Schmidt AM, Creager M. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation. 2006;114(6)597-605. doi: https://doi.org/10.1161/CIRCULATIONAHA.106.621854
- Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th edition. New York: W H Freeman; 2002. Section 14.1, Metabolism Is Composed of Many Coupled, Interconnecting Reactions. Available from: https://www.ncbi.nlm.nih.gov/books/NBK22439/
- Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2017. Atlanta, GA: Centers for Disease Control and Prevention, US Department of Health and Human Services; 2017
- Kalra S, Zargar AH, Jain SM, et al. Diabetes insipidus: The other diabetes. Indian Journal of Endocrinology and Metabolism. 2016;20(1):9-21. doi:10.4103/2230-8210.172273.
- American Diabetes Association. Classification and diagnosis of diabetes. Diabetes Care. 2017 Jan; 40(Supplement 1): S11-S24. https://doi.org/10.2337/dc17-S005
- Stafeev IS, Vorotnikov AV, Ratner EI, Menshikov MY, Parfyonova YV. Latent Inflammation and Insulin Resistance in Adipose Tissue. International Journal of Endocrinology. 2017;2017:5076732. doi:10.1155/2017/5076732.
- Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. Journal of Clinical Investigation. 2003;112(12):1785-1788. doi:10.1172/JCI200320514.
- Roberts CK, Hevener AL, Barnard RJ. Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training. Compr Physiol. 2013 Jan; 3(1): 1–58. doi: 10.1002/cphy.c110062
- Ahlborg G, Felig P, Hagenfeldt L, Hendler R, Wahren J. Substrate Turnover during Prolonged Exercise in Man: SPLANCHNIC AND LEG METABOLISM OF GLUCOSE, FREE FATTY ACIDS, AND AMINO ACIDS. Journal of Clinical Investigation. 1974;53(4):1080-1090.
- Lee S, Na H, MH, Mia Kim, Lee B. Euphorbia kansui Attenuates Insulin Resistance in Obese Human Subjects and High-Fat Diet-Induced Obese Mice. Evidence-Based Complementary and Alternative Medicine, vol. 2017, Article ID 9058956, 9 pages, 2017. doi:10.1155/2017/9058956
- Afolayan AJ, Wintola OA. Dietary Supplements in the Management of Hypertension and Diabetes - A Review. African Journal of Traditional, Complementary, and Alternative Medicines. 2014;11(3):248-258.
- Forouhar E, Sack P. Non-traditional therapies for diabetes: fact or fiction. Journal of Community Hospital Internal Medicine Perspectives. 2012;2(2):10.3402/jchimp.v2i2.18447. doi:10.3402/jchimp.v2i2.18447.
- Hassanzadeh Bashtian M, Emami SA, Mousavifar N, Esmaily HA, Mahmoudi M, Mohammad Poor AH. Evaluation of Fenugreek (Trigonella foenum-graceum L.), Effects Seeds Extract on Insulin Resistance in Women with Polycystic Ovarian Syndrome. Iranian Journal of Pharmaceutical Research?: IJPR. 2013;12(2):475-481.
- Gaddam A, Galla C, Thummisetti S, Marikanty RK, Palanisamy UD, Rao PV. Role of Fenugreek in the prevention of type 2 diabetes mellitus in prediabetes. Journal of Diabetes and Metabolic Disorders. 2015;14:74. doi:10.1186/s40200-015-0208-4.
- Nahas R, Moher M. Complementary and alternative medicine for the treatment of type 2 diabetes. Canadian Family Physician. 2009;55(6):591-596.
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