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Type 2 diabetes (T2D)
https://www.austincc.edu/apreview/EmphasisItems/Glucose_regulation.html
excellent description and diagrams
What is T2D?
Too much sugar causes damage / inflammation
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.
T2D is an inflammatory disease
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
Inflammation promotes INSULIN resistance (IR)
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.
The level of inflammation severity in diabetes is associated with A1C (a.k.a. glycosylated hemoglobin (HbA1c)).
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.
What is causing T2D?
(1) Too many carbs
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.
(2) An overzealous immune reaction due to an imbalance of omega-6
and omega-3 fats
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.
(3) Obesity /Fat cells?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2246086/
(4) INSULIN Resistance (IR)
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
INSULIN / blood sugar lowering drugs are not a good long-term solution
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.
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
An imbalance of anti-inflammatory and inflammatory fats causes Insulin Resistance
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.
D5d. C onverts
DGLA into the
omega-6 fatty acid
AA, being the
the most potent source of
inflammatory eicosonoids
(Series 2 Prostaglandins, Series 2 thromboxanes,
Series 4 leukotrienes). D6d.
C onverts
omega-6 linoleic acid (LA) to the
omega-6 DGLA fatty acid, which is
the most potent source
of anti-inflammatory eicosonoids
(Series 1 Prostaglandins and
Series 1 Thromboxanes. Unfortunately, d6d
production declines with age , whereas
d5d does not, giving an edge to the
d5d conversion of
DGLA to inflammatory
AA, particularly
in the over 50's.
See:
EFAs Conversion Chart
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
AAanti-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
References 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
