exphysed t1_j13sw33 wrote on December 21, 2022 at 1:45 PM

Muscle cells can take up glucose from the bloodstream through their own transporters without the need for insulin.

When you’re regularly active, your muscles pull the glucose out of the blood, effectively regulating your blood glucose without insulin needing to be involved. This allows all the cells in the body to readjust the number of insulin-receptors/glucose transporters needed, thereby making you more sensitive to insulin over time, and the pancreas won’t have to release as much insulin for any given amount of glucose in the blood.

derpderp3200 OP t1_j15mmwj wrote on December 21, 2022 at 9:03 PM

Is this what "peripheral insulin sensitivity"(term I've come across in literature) refers to? How does it differ from pancreatic insulin sensitivity?

Do I understand you correctly that in this sense, above-basal levels of insulin are the body's second line mechanism against supraphysiological elevations of glucose?

I wonder if this is why Pioglitazone acts as an insulin sensitizer, being an agonist of PPAR-gamma, one of the receptors involved in mediating the benefits of physical activity.

backroundagain t1_j15opxy wrote on December 21, 2022 at 9:17 PM

There's a chance you're conflating two different concepts. Peripheral insulin insensitivity is often a function of peripheral insulin receptor expression and/or cytosolic signal impedance. Exercise may improve this in a couple ways, including the "insulin like effect" of contracting skeletal muscle as mentioned above: https://www.ncbi.nlm.nih.gov/books/NBK537322/ to be clear though, this mechanism is not sufficient to completely replace pancreatic secretion, otherwise exercising type 1 diabetics wouldn't need to take insulin.

Pancreatic signaling for the release of insulin, the ability to release insulin via beta cells, and the production of viable insulin would be separate mechanisms with their own pathologies.

derpderp3200 OP t1_j15tw54 wrote on December 21, 2022 at 9:52 PM

What is "cytosolic signal impedance"? This is the first time I have come across this term.

Oh, I understand, so the impairments in beta cell function are a secondary, later, consequence of insulin insensitivity, which typically is at first driven by... what exactly?

Aside from uptake by muscle, what else plays a role here?

Beginning_Cat_4972 t1_j190rgw wrote on December 22, 2022 at 3:44 PM

Two things need to happen for insulin receptors (or really any receptors) to work. 1) The receptors need to be expressed. This is the actual production (transcription/translation)of the protein. There are a lot of steps between transcription and getting the insulin receptors to the cell membrane. Any of them could be disrupted and then there's always post translational modifications such as glycosylation that can muck things up. 2) Binding of the insulin receptor has result in an intracellular signal cascade, leading to glucose receptors being transported to the cell membrane. I think what is meant by cytosolic signal impedence is that something gets interrupted between insulin receptor binding to glucose receptor translocation. Or even cell signaling to initiate insulin receptor expression.

It's hard to accurately describe the process of insulin resistance as being linear or having a single inciting event. It's more of a breakdown of the entire, circular(ish) system. But I suppose I think of insulin resistance "starting" in the cells that have the most insulin receptors like fat cells.

derpderp3200 OP t1_j1ai4b8 wrote on December 22, 2022 at 9:33 PM

Glucose receptors, or transporters?

How does cytosolic signal impedance develop, here?

backroundagain t1_j1abhpe wrote on December 22, 2022 at 8:49 PM

What is "cytosolic signal impedance"? This is the first time I have come across this term.

The cellular mechanism of action of insulin can generally be grouped under a "second messenger system". This means that the signal its self (initiated by the insulin molecule) does not actually enter into the cell, but is transduced from the outside to a signal cascade on the inside (cytosolic side).

As such, a receptor system will have an extracellular component, a transmembrane component, and a cytosolic component. Cytosolic impedance (of the insulin signal) can occur as a function of the expression of a particular factor (protein) which interferes with the signal transduction on the cytosolic side of the receptor.

If you want to read the nitty gritty, here is a decent reference:

https://www.ncbi.nlm.nih.gov/books/NBK378978/

Oh, I understand, so the impairments in beta cell function are a secondary, later, consequence of insulin insensitivity, which typically is at first driven by... what exactly?

Beta cells are thought to be impaired by an autoimmune (or autoimmune like) attack on beta cells, though I think this is still up for debate. If they get taken out, you do not secret insulin, this is often a characteristic of a type 1 diabetic (vs. a type 2 in which you tend to see a decrease in the sensitivity down stream, in some cases as described above.)