https://www.austincc.edu/apreview/EmphasisItems/Glucose_regulation.html excellent description and diagrams
Damaging compounds, called advanced glycation end products (AGEs), are produced when simple sugars, such as glucose or fructose molecules, bind by a non-enzymatic process (called glycosylation), with proteins, lipids and nucleic acids. AGEs alter the structure and function of various cells and tissues throughout the body and can promote damage to blood vessels, peripheral nerves and organ tissues and an associated inflammatory reaction. E.g. AGEs derived from glucose binding to hemoglobin (oxygen-carrying protein in red blood cells) are shown to accelerate atherosclerosis (build up of arterial plaque), contributing to an increase in the risk of a heart attack or stroke. In patients with chronic diabetes, AGEs are also implicated in peripheral arterial disease (which can cause gangrene and lead to amputations), peripheral neuropathy (nerve damage in the limbs), retinopathy (eye damage), and nephropathy (kidney damage). An example study is that High circulating AGEs and RAGE predict cardiovascular disease mortality among older community-dwelling women. Semba RD, Ferrucci L, Sun K, et al. Advanced glycation end products and their circulating receptors predict cardiovascular disease mortality in older community-dwelling women. Aging Clin Exp Res. 2009;21(2):182-190. doi:10.1007/BF03325227
AGEs can also enter the body from exogenous sources such as diet (especially foods exposed to high temperatures, during e.g. grilling, frying, or toasting) or tobacco smoke.
Chronic (ongoing) inflammation causes damage to body's cells / tissues. Such damage can lead to health problems, including heart attacks, stroke, kidney disease or infections. Donath & Shoelson, 2011
Researchers have shown that inflammation (with particular mention of the cytokine TNF-alpha, produced by the immune system in response to inflammation) activates and increases the expression of several proteins that suppress insulin-signaling pathways, making the human body less responsive to insulin and increasing the risk for insulin resistance.
A1C is produced when glucose molecules bind to hemoglobin (hemoglobin is the oxygen-carrying protein in red blood cells (RBCs)) . The percentage of glycated hemoglobin in the blood increases as blood cells are exposed to elevated sugar levels over time. Since RBCs can live for up to 120 days in the body, A1C levels provide an accurate average blood sugar level for the previous 2 to 3 months. A healthy person typically has an A1C of ~5%, whereas diabetics often have A1C levels as high as 8-9%, which according to the American Diabetes Associationcan can go as high as 25% during long poorly controlled periods.
Epidemic of T2D in the U.S.
The current T2D epidemic occurring in the Western world is mainly a consequence of the overconsumption of carbohydrates i.e. sugar and starches, which metabolize to the simple sugars: glucose, galactose and fructose in the small intestine and are then transported into the bloodstream. When blood glucose concentration exceeds a certain level , in order to prevent health problems, the pancreatic beta cells produce INSULIN to remove glucose from the blood (storing it as energy).
Over time, when a person chronically overconsumes carbohydrates, cells eventually become resistant to INSULIN's "message" to take in glucose from the blood - a situation termed INSULIN Resistance (IR). SInce the blood glucose is still present, the pancreas ups INSULIN output in a futile effort to solve the high sugar problem, but the cells are just not responding as they used to.
Another contributing factor in T2D involves the overzealous inflammatory response to tissue-damage (resulting from excessive carb consumption), as a consequence of the underconsumption of anti-inflammation-promoting fatty acids.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2246086/
Chicken and egg situation. In a study published in the August online version of Diabetes, H. Henry Dong and his colleagues at the University of Pittsburgh showed that a protein called FOXO1 serves as a master switch that turns on the expression of another key inflammatory cytokine, interleukin 1-beta, which also interferes with insulin signaling. Normally insulin keeps FOXO1 in check; it "rapidly inhibits FOXO1" by moving it out of the nucleus so it can be targeted for degradation, Dong says. But when a person becomes insulin-resistant and pancreatic cells no longer produce enough insulin to overcome the resistance, activity of FOXO1 increases.
Also https://europepmc.org/article/med/28213398#free-full-text
When it is doing its job properly, INSULIN increases glucose transport into most (but not all) INSULIN sensitive cells --- primarily the liver, resting muscle cells and adipose tissue (where it is synthesized into triglycerides, adding to the size of your waistline). BTW -The brain utilizes glucose but is not INSULIN dependent.
Lowering blood sugar with drugs or insulin will neither improve one'shealth, "fix" the effects of diabetes, or reduce the risk of dying from diabetes-related health problems. In the 2008 "ACCORD" study, 10,000 patients were treated with insulin or blood sugar-lowering drugs or placebo and monitored/evaluated for risk of heart attack, strokes and death. The study was ended early because the medical intervention was leading to MORE deaths, heart attacks, and strokes. New England Journal of Medicine, 2008
To counter elevated blood glucose levels with diabetes, typically-used drugs either:
(1) increase INSULIN levels
or (2) increase cellular INSULIN sensitivity
or (3) prevent kidney's sugar reabsorption
These effects can exacerbate the negative, sometimes life-threatening side effects that they are intended to prevent. E.g. HBP, high LDL cholesterol, high triglycerides, strokes, blood clots, poor sex drive, infertility, kidney failure, infections, amputations, and also possibly promote cancer, depression, and Alzheimer's. Avandia®, one of the world'sbest-selling diabetes drugs, has over 50,000 lawsuits filed in the United States alone, because the drug makers failed to inform patients about possible life-threatening side-effects, including stroke, heart failure, heart attack, bone fractures, vision loss and death. Several studies have shown that diabetic patients on supplemental INSULIN develop up to a 30% greater risk for colon, breast or prostate cancers.
| Diabetes drugs | ||
|---|---|---|
| Drug | Method | Possible Side effects |
| Metformin | Increase cellular INSULIN sensitivity. Lowers liver's glucose production. | Nausea, diarrhea, weight gain. Also depletes B12, . Metformin may reduce B12 (further increasing risk for neuropathy) by interfering with absorption of calcium, required for small intestine receptors to take up B12 |
| Thiazolidinediones. E.g. Rosiglitazone (Avandia), Pioglitazone (Actos) | Increase cellular INSULIN sensitivity. | Weight gain, increased heart failure and fractures; |
| Sulfonylureas and Meglitinides | Increase INSULIN secretion | Low blood sugar and weight gain |
| SGLT2 inhibitors | Prevent the kidneys from reabsorbing sugar into the blood. Sugar is excreted in the urine | Yeast infections, urinary tract infections, increased urination and hypotension |
Tessaro et al, 2014
Omega-6 oils
In addition to telling liver and muscle cells to store glucose as glycogen, another effect of elevated insulin is to upregulate production of certain enzymes (delta 5, 6 and 9 desaturases, abbreviated d5d, d6d and d9d) responsible for converting essential fatty acids sitting in cell membranes from one form to another.
Thus, people promoting high insulin levels by eating a lot of carbohydrates together with an inadequate intake of anti-inflammatory omega-3 fats (thereby creating a shortage of anti-inflammatory eicosanoids in their cell membranes) put their body into a chronic low-level pro-inflammatory state (with its long-term negative health consequences) by creating an excess of inflammatory eicosonoids over anti-inflammatory eicosanoids. In a healthy body, inflammatory fatty acid AA has a balanced presence with anti-inflammatory fatty acids: EFA and DGLA in cell membranes to yield an appropriatiately balanced immune response to damaged tissue. https://www.gdx.net/core/interpretive-guides/Essential-Metabolic-Fatty-Acids-Interp-Guide.pdf
In a positive feedback cycle, any inflammation promotes more insulin resistance, leading to further increases in blood sugar and insulin levels --- and more inflammation.
The fix for IR is to inhibit delta 5 desaturase production and AA production and enhance delta 6 desaturase production and DGLA production.
To prevent great tissue damage, eicosanoids also control the inflammatory resolution and tissue repair process [7, 8]. Imbalances in eicosanoid synthesis have been reported to drive chronic inflammation [1, 9], which deregulates signaling pathways and/or cellular events leading to abnormal immune functions [6, 10]. In particular, circulating and local mediators, such as eicosanoids, interleukin- (IL-) 1β, tumor necrosis factor- (TNF-) α, IL-6, IL-8, macrophage migration inhibitory factor (MIF), and free radicals, create a state of low-chronic inflammation in diabetic patients [5, 10, 11]. Inflammation may lead to diabetes progression, including damage to the kidneys (diabetic nephropathy), eyes (diabetic retinopathy), nerves (diabetic neuropathy), and cardiovascular system [12] (Figure 2). Fernando et al, 2014
Donath MY, Shoelson SE. (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. ;11(2):98-107. PubMed
Fernando HG Tessaro, Thais S. Ayala, Joilson O. Martins (2014) Lipid Mediators Are Critical in Resolving Inflammation: A Review of the Emerging Roles of Eicosanoids in Diabetes Mellitus; BioMed Research International Volume 2015, Article ID 568408 pdf
Semba RD, Ferrucci L, Sun K, et al. (2009) Advanced glycation end products and their circulating receptors predict cardiovascular disease mortality in older community-dwelling women. Aging Clin Exp Res.;21(2):182-190. PubMed
Omega-6 oils http://www.cureddiabetes.com/insulin-resistance.html
