How to make an animal model type-2 diabetic

If we scour the research literature a bit, and most especially the older literature, we find how to make an animal model (e.g. a mouse) diabetic. All that is required is to feed a small rodent on pure glucose water. For 10 days. That is it – nothing else. To produce a diabetic animal model for basic research into T2DM.
Herbivores (and mice are this kind of feeder/digester) do NOT absorb any significant glucose as monomer through gut into blood (portal vein, initially). No, that is not how it works.
For all of those who believe in the nonsense of claims that these animals metabolize (or store) most energy directly in the form of glucose, think again I suggest. And most certainly carnivores do not do this (we modern hominids are carnivores, for the most part).
No, herbivores ALL have vast-capacity (in comparison to that of carnivores) fermentative gut mechanisms to predigest the carb’s, including the fiber. This process produces short-chain FAs (fatty acids) that are absorbed through gut into the body. And eliminates the carb’s while still in gut. That is why a well-aged cheese has essentially zero carb content, while the original milk is just loaded with sugar (lactose, a disaccharide or dimer of glucose and galactose).
While in the gut (lumen), the food is still OUTSIDE the body and blood and cells.
Humans can, at most if supremely adapted to a heavy plantfood diet, derive at most 200kCal’s of energy (maybe 7% of minimim daily requirement for health of an adult male) from fiber, from the puny amount of bacteria we have in gut. Beyond this we go into severe and acute gut distress which would be lethal if we persisted. This is not controversial – it is well known. Our capacity to derive energy from fiber (cellulose, a complex or large polymer of glucose) is severely limited. It is, essentially for all practical purposes, zero. We are NOT herbivores. Look at the massive belly of a gorilla, which has many tens of feet of length of large intestine to ferment the fiber, as a hindgut fermenter (foregut fermenters are also known as ruminants). We shed this capacity millions of years ago, coming down from the trees and shedding also our fur, to become first early homo (habilus). Thereafter modern hominids, with uniquely enormous brains. The huge energy requirements of an herbivore gut and of a large brain cannot coexist in nature. That’s called the “expensive tissue hypothesis”.
Our gut is that of a pure carnivore. We have no cecum (except the vestige from pre-homo predecessor species who still were up in the trees – called the “appendix”), like a pig and other simple-gut omnivores.
Anyway, 10 days of pure glucose makes a pure herbivore (the mouse) a full-blown, raging T2D. It is bulletproof. Works EVERY time.
For anyone who thinks that we, a carnivore species, or ANY animal is evolved to absorb fuel first as glucose, and then in liver (by a very expensive process called de novo lipogenesis, or DNL) to convert this to Tg (triglycerides, the storage form of FAs) for storage in adipose, what can I say? Read some basic textbooks on basic physiology and anatomy, maybe. Just for starters.
These things are not controversial amongst animal biologists. Very elementary textbook stuff.
But I do recognize that MDs advise diabetics to eat carb’s. And most look up to MDs.
Anyway, if one believes the MDs one should carefully consider the earliest and most basic (and best, I think – it truly emulates the process by which type 2 diabetes is actually produced in us modern humans, rather than more quickly and cheaply killing beta cells with a selective toxin) form of producing the diabetic animal model starting from the nondiabetic (normal) animal model. Still used by some researchers, by the way – old-school.
To boot, it is very important to consider that transient hyperglycemia results from a meal containing significant carbohydrate, portally absorbed as glucose (monomer of nearly all dietary/plant carbohydrate). Even the youngest and most robust study cohort member will peak at 125 mg/dL in response to a standard OGTT (oral glucose tolerance test) of 75g of dextrose/glucose.
Whereas there is NO hyperglycemia from a protein/Tg meal. None. BG stays level. That is what is supposed to happen, within evolutionary context. In all animals. Transient hyperglycemia (from meals) causes the complications of diabetes. We did not evolve with this. The cells cannot adapt, within the timespan of a few hours or less, to a transient of many tens of mg/dL, much less hundreds. So they are damaged, gradually – that is, killed off slowly by excessive apoptosis. Especially the neural cells. Take a look at research of Michael Brownlee, who won the Banting Award in 2004 for essentially figuring out the entire biology and metabolic/molecular derangement causing the complications of diabetes, and this has been essentially universally accepted ever since. Not controversial in the least.
And next the microvascular cells, partly because they cannot live normally without local neurological tissues. Death of vasculature is largely secondary to death of local neural tissues.
And then some macrovascular tissues come next. Monckeberg’s arteriosclerosis is one of the nearly universal conditions of any long-term diabetic, only requiring a few years of uncontrolled hyperglycemia. Monckeberg’s is in macrovasculature (artery) in lower leg. The media becomes dead and calcified – turned to stone. Like mine was, probably already well before age 10. Easy to test for, but this is never done anymore by MDs. Why bother? Eat carb’s and take drugs and call me in the morning.
Both beta and alpha cells DIRECTLY respond to islet/portal AAs. Only beta cells respond to portal/islet glucose, for the most part – i.e. during the prandial interval. And then the alpha cells are inversely regulated by islet insulin produced by the beta cells. Because the forward/direct regulation of insulin secretion as a function of islet blood concentration of glucose CANNOT be mimicked for alpha cells with the inverse I/O relationship. That is not molecularly/biochemically/metabolically possible. So alpha cells sense islet BG INDIRECTLY via islet blood insulin (IBI). Which has enormous implications.
In the nondiabetic everything works pretty flawlessly. In the diabetic all balance that makes, most especially, the alpha-cell indirect sensing of both glucose and AAs work properly is thrown badly out of whack (or balance), and this really wreaks havoc.
Importantly, though, negative feedback with respect to regulation of glucagon secretion is still maintained for AAs. But it is not for glucose – this turns to positive feedback for the duration of the prandial interval. Instability, that is – lack of regulation. Bad news. All of this (for both AAs and glucose) is diabetes in most forms (excepting MODY-2).
It is also important to understand that there are three major, virtually independent, strata of BG in body. There is most of the whole-body blood that we measure in capillary, crudely and with lag (vs. venous blood or serum). This is peripheral to portal/hepatic blood. Then there is the portal blood, in which nutrients (prandially) and islets hormones have much higher concentrations. Hence, the separation/independence. Then finally there is islets blood, in which the hormones are much higher in concentration still (prandially, again), thus isolating the islets from the portal vein and liver hormonally. This makes the paracrine endocrinology of the islets work, indepedent of portal hormone concentrations in response to meals. The
“acute” glucagon and insulin responses, so-called.
Barbara Corkey is a diabetes researcher at BU (Boston University). She and others have focused upon the mechanisms of sensing islet blood AAs and glucose concentrations and regulating the secretion rates of glucagon and insulin (and secondary hormones) by alpha and beta cells, respectively. Important stuff. We need to think about this if we are to understand the biology of BG (and other) regulation in animals and in ourselves. Guess I should write something more about this. Maybe I will, at some point.
But the mechanics of the beta cells are reasonably well understood, and more simple. Those of alpha cells are less so, and more complex, and hopefully this is unsurprising for those who have read above.
The work of Brownlee pretty much demonstrates that excessive continuous during constant/chronic transient hyperglycemia in response to meals (in a diabetic) results in excessive free-radical stress causing the complications of diabetes over time. In T2DM and the decompensation phase of prediabetes it is the same cause/origin. How could it not be? It is the same. We simply cannot tolerate a modern urban diet with the cellular machinery that we have evolved, thus far.
Corkey points out that, of necessity, the intracellular protections against free-radical stress built into nearly all non-beta (i.e. other) cells cannot be included in the differentiation of beta cells. Because this would preclude the basic islet AA and glucose sensing mechanism, and its direct coupling to insulin secretion. So the beta cells are much more susceptible to overstress by excessive free-radical generation intracellularly. Makes sense, no? I think so. Of course, Corkey is not the only one to have recognized this. But she is good one to start with. Read up.
Anyway, T2DM is caused by modern urban diet. Nothing else, for the most part. That is it. Just diet, all of a sudden available at the grocery store and convenience store, 24/7 as they say, in a blip of evolutionary time. Never before.
Are whole plant foods better? Yes, somewhat. But we cannot tolerate starchy things like potatoes – not most, not all, by any means. We are just not adapted. One need only take a BG reading with a meter while absorbing such a food. Take a look at a middle-aged nondiabetic’s response – peak BG will be maybe 150 to 200 mg/dL! Not to mention any kind of diabetic (other than MODY-2). I am not capable, myself, of getting up to even 200 mg/dL with any meal whatsoever. I have massive complications and loss of major sections of vagus nerve, from what many would consider moderate prandial hyperglycemia, unrecognized and uncompensated for (by insulin intervention) for over five decades. Lots of destruction of tissue from that.
Plant foods contain oxalates. One had better never have any form of leaky gut within a lifespan (few can achieve this), or else the oxalates will get into the blood and into the cells and can weak havoc.
Plants defend themselves by biochemical warfare. Herbivores, if we look carefully, all have evolved to feed on a very narrow and selective range or type of plant, and only that one. Giraffes eat eucalyptus leaves. Gorillas eat leafy greens and termites and insects (on the leaves), but not fruits. Monkeys eat the fruits but not the leaves. Each herbivore is specialized to eat just one type of plant component/species, and needs to constantly adapt to keep pace with, and stay a bit ahead of, that plant’s own adaptation to prevent its being eaten by predators. This is evolution, resulting in species-specific genome and biology.
And we are NOT herbivores, nor any semblance of such.

Humans are omnivores. We don’t fit into either specific group.
We can survive on either animal protein and fat, or plant based foods. Or a combination of both.
It is what has made humans resistant to drought and famine.
We can eat almost anything.

I think the key is diversity in food. If we go all animal, we get heart disease, all vegan and it’s very difficult to build muscle mass.

In all things moderation.

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Well I ate 30 carbs a day for 11 years and it was very hard on my body. I starting passing out quite often from low blood pressure, and I had horrible migraines. My LDL was also way too high.

I have eaten a low fat plant based diet for 5 yrs and I feel much better and have almost the same low A1c. My TIR is very good. I eat potatoes several times a week. I eat around 275 carbs daily and only take about 3 more units of insulin than I did when low carbing.

You might want to investigate the Mastering Diabetes site. Cyrus has degrees from Berkeley and a doctorate from Stanford. He has type 1. They help diabetics of all kinds.

That’s not just any mice, but mice that have the genetics or have been genetically altered to become type 2 diabetic.

It’s like the rats used in triglyceride and type 2 DM research, Wistar fatty rats. They are genetically disposed to both as well as obesity. When their water has 10% to 15% fructose dissolved in it triglycerides go through the roof.

The thing is, we who become strongly insulin resistant leading to type 2 DM have the genetic components in place which may be activated by modern diets and environmental factors. Others don’t have this and can’t become T2DM no matter what they eat or how overweight they are.

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