Type-2 Diabetes

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Hypothesizes

There is no confirmed theory of what causes obesity/T2D/metabolic disease - appears to be permanent damage - symptoms can be worked around via Low-Carb, but regression seems limited.

T2D has high BG - and chronically elevated insulin. Might be better called insulin tolerance.

Much of what is claimed falls under 'post hoc ergo propter hoc' (after this, therefore because of this) - a fallacy known from the example that the rooster crowing does not make the sun rise. Correlations do not show causation.

Careful treading - with high waders on is required. Strangely, despite T2D rising for decades we don't even know which tissue/organ is damaged.

If we accept that the damage is permanent - it begs the question: "Which tissue is damaged?"

Which tissue is damaged?

Liver

Can store AND release glucose as glycogen being the form stored. ~ 400Calories

Pancreas

Gut flora (microbiome)

Adipose tissue

Obesity is associated with macrophage accumulation in adipose tissue
https://en.wikipedia.org/wiki/Adipose_tissue_macrophages
(It seems that macrophages are involved in lipolysis regulation in some way )

Brain and Sympathetic nervous system

Neural peptide Y NPY

Inflammation

poorly defined term

leaky gut

Fecal transplant -

Muscle Tissue

Can store energy as glycogen - but not release it (~16000Calories)

Theories pushed by people

Lustig Hypothesizes

Leptin based.
Fructose - NAFLD - causative?
Mitochondrial dysfunction
Insulin makes liver sick - pancreas portal to liver.
Liver backs up causing pancreas to hyper secrete more insulin.
Elevated insulin blocks Leptin - increasing appetite.
Elevated insulin thus causes elevated leptin.
Cause: processed foods - particularly sugar and lack of fiber.
Sugar causes Methylglyoxal - poisons mitochondria in liver
(Seems unaware of sweetness receptors in intestine?).
(Seems aware of the proton-switch - but not PUFAs roll?)
fructose induces leaky-gut
Mucous layer attacked due to lack of fiber? - (this theory doesn't work ???)
Trans-fats make ROSes
Fructose produces AGEs at a high rate.
Emulsifiers create leaky gut
Thickeners also produce leaky-gut
Monoglycerides - glycol ethers - leaky gut
3-MCPD carcinogen
NAFPD (Non Alcoholic Fatty Panaceas Disease) T1D? reduces insulin..
Re-normalization of ALT levels on blood tests hides fatty liver.. should be under 25 - the old limit
Re-normalization of uric-acid levels - high from fructose - should be below 5 - not 7

Mucous layer attacked due to lack of fiber? - (this theory doesn't work ??? - Feed the bacteria that eat mucous fiber and you have more)
Lustig appears wrong about fructose not used in human biology - seems to be manufactured and important for sperm? - (not that dietary fructose is a good thing). Body converts glucose to fructose in some cases.
He is also appears wrong about the role of Cholesterol in CVD.
Also, is more way sure about transfats than he should be - confounded with PUFAs
Seems certain about things that are not well grounded.

Tucker Goodrich

Seed oils damage liver - elevates 4-HNE, 4-ONE, 4-HHE, pentanal( valeraldehyde), methylglyoxal, and glyoxal
Seed Oils Oxidize Cardiolipin and Damage Your Mitochondria
impairs GSIS(Glucose‐stimulated insulin secretion)

Good evidence that PUFA - LA can cause liver failure in high dosages.

Unger

Unger which is called glucagon-centric view of diabetes, there is no damage to liver, but the critical thing is impaired communication between alpha and beta cells of pancreas leading to hyperglucagonemia and excessive production of hepatic glucose.

Marc Gerardot

- possibly vaccines

Petro - Proton switch (burning or growth)

PUFA changes FADH2:NADH ratio - which changes insulin sensitivity among other things.

Kinase phosphorylation status tells whether they are on or off - the ROS switch controls the phosphorylation status.
PI3- kinase - opens cell to glucose
AMP kinase - make more MT (metformin mucks with this).
mTOR kinase - tells cell to divide ( ups protein synthesis)
Increases insulin release

Effects insulin sensitivity - depends on tissue type?

People become insulin resistant as an adaptive and essential response to the inability to suppress lipolysis in the presence of high glucose and insulin. Basal lipolysis is fundamental to this.
So it is perfectly possible for an adipocyte to be highly insulin sensitive (LA) yet be spewing FFAs by basal lipolysis secondary to adipocyte size.

These FFAs are repackaged by the liver to VLDLs and sent back to adipocytes where they reinflate the lipid droplets so increase basal lipolysis so… Round and round.

Fructose is a lipolytic agent if it gets as far as adipocytes so it augments the already high basal lipolysis in the presence of insulin.
Fructose, like ethanol, triggers DNL in the liver in the short term. Both are adipocyte lipolytics, in the short term and long term.

*Chronic* ethanol does NOT induce hepatic DNL. Chronic fructose does. Yet the histopathology is identical.

The problem always goes back to the adipocyte and insulin resistance is always the defense against adipocyte dysfunction. When adipocytes become insulin resistant all hell breaks loose.

thanol -> acetaldehyde -> acetate -> TCA -> lipogenesis
Fructose -> pyruvate -> acetate -> TCA -> parthenogenesis
Ethanol + beef fat -> no liver damage. Ethanol + PUFA = cirrhosis.
Fructose + beef fat -> no one knows. But I agree absolutely fructose + PUFA = Badness

John Speakman

Change in basal metabolism - metabolic rate. Even body temperature.

Signals that this started much earlier - 1910-1920 Kick up in the 1960s

Talks of one study - the more sat-fat the higher the metabolic rate.
Confounding data..

The more PUFA in cell membranes the lower the metabolic rate vs palmate(satfat) .

Brings up the idea that LA => arachidonic acid => endocannabinoids => canabaloid receptors ( pot munchies? ).. (still in study).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700518/

Other Hypothesizes

Epigenetic effect on GLP-1? (GLP-1 is packaged in secretory granules and secreted into the hepatic portal system by the intestinal L-cells located primarily in the distal ileum and colon, but also found in the jejunum and duodenum - info on this is contradictory and varies by source) Glucagon and GLP-1 are catabolic hormones.

Added Niacin

Has excess niacin been shown to promote obesity?
ChatGPT4o

Excess niacin (vitamin B3) has been linked to metabolic disturbances that could potentially promote obesity, although the evidence is not entirely conclusive and more research is needed. Here are some key points:

    Role in Metabolism:
        Niacin is essential for energy metabolism and is involved in the function of NAD and NADP, which are crucial coenzymes in cellular metabolic processes.

    Insulin Resistance:
        Some studies suggest that high doses of niacin may induce insulin resistance, which is a risk factor for obesity and type 2 diabetes. Insulin resistance impairs the body's ability to use glucose effectively, leading to increased fat storage.

    Lipid Metabolism:
        Niacin is known to affect lipid metabolism. While therapeutic doses of niacin are used to improve lipid profiles by increasing HDL cholesterol and decreasing LDL cholesterol and triglycerides, excessive intake may have adverse effects.

    Brown Adipose Tissue:
        Research on rodents has indicated that excessive niacin intake may reduce the activity of brown adipose tissue (BAT), which is involved in burning calories to produce heat. Reduced BAT activity could contribute to weight gain.

    Appetite Regulation:
        Some animal studies suggest that high levels of niacin might influence appetite-regulating hormones, potentially leading to increased food intake and weight gain.

    Human Studies:
        In humans, the data is less clear. While some observational studies suggest a link between high niacin intake and increased body weight, controlled clinical trials are necessary to establish causality.

4-HNE reduces leptin

ROS

ROS seems to be confounded with the 'proton switch' which appears to be a normal - very ancient signal that uses ROS as the signal. ROS outside normal ranges is different.

That everything is ROS vs antiox is quite ungrounded - Most antiox are very poorly absorbed - might act only on intestinal flora? Real antiox can do harm - probably by disrupting the 'proton switch'.
tributal tin ups ROS

Western diet ups ROS

AGE (Advanced Glycation End-products)

Artificial Sweeteners

Receptors are not only in the mouth - but also down the digestive track. If they are not broken down, they continue to stimulate more insulin secretion.

Uric acid (fructose in sugar(sucrose) drives uric acid)

Uric acid causes cellular dysfunction and insulin resistance, including oxidative stress, inflammation, and even preventing insulin from getting out of the blood stream effectively. dietary and environmental factors that generate uric acid, including fructose, purine rich foods and umami foods, dehydration, alcohol, and more. Glucose to fructose conversion may have evolved to deal with dehydration.

Is Uric acid a signal to get ready for food scarcity in fall (fructose => uric acid )?

Uric acid is actually a powerful antioxidant.

uric acid is a signal of tissue injury, a mobilizer of repair systems and, in particular, a recruiter of endothelial progenitor cells

There seems to be little doubt that an acute rise in uric acid is beneficial and chronically elevated uric acid may be less so

Small amount of glucose will lower uric acid.

Vitamin c aids in uric acid excretion

Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver

Does Uric acid help drive the proton-switch (ROS)??

quite a lot of evidence to suggest that physiological levels of uric acid production might be beneficial

Reduces NO - required for insulin to work.

Uric acid should be below 5 - not 7?

Insulin inhibits uric acid excretion

Uric acid increases hunger . Increases risk taking(helps find food).

Too much salt can increase.

Quercetin and ludiolin help drop uric acid levels.

HNE is causative of Alzheimer's disease

Japanese researcher..