Thread: Beta cell downregulation?
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09-10-2015, 10:39 PM #1
Insulin induced receptor internalization?
Did I post this in the wrong section? Or am I in the wrong place discussing metabolism on the cellular level?
Considering the negative feedback loop and homeostatic mechanisms associated with a great deal of our body's regulatory processes, would the exogenous administration of insulin in regards to its perceived increase in nutrient utilization and apparent anabolic nature eventually lead to a down regulation at some stage of the cellular activity? (disruption of beta cells or reduced enzyme activity from tyrosine kinase transport)
I know Type II Diabetes involves a different set of circumstances revolving around excessive fatty acid accretion eventually inhibiting the insulin molecules ability to successfully bind with the tyrosine kinase.. I believe. However I wouldn't consider that "desensitization" because it isn't 100% a protein, but rather a kinase that actively modifies proteins. (along with a mirage of other cascading alterations)
I'm trying to reference my material from school. So I know beta cells utilize glucokinase as the first step regarding phosphorylation (glucose>glucose-6-phosphate), but I'm having trouble establishing what protein is directly regulating the metabolic processes at the cellular level. I find rather paradoxical information regarding GKRP's role as well as F2,6BP (fructose-2,6-biphosphate) involvement. Or even irreversible damage to the functionality of cAMP by impairing expression?
Or should I be looking more towards a hormonal regulatory activity such as glucagon?
Or exogenous insulin administration in improper dosages (supraphysiological) causes insulin-induced receptor internalization?
F2,6BP is involved with the allosterical regulation of glycolysis and gluconeogenesis as well as cAMP which happened to contribute to this thought. I know gluconeogenesis is the opposite of glycolysis, yet they have similar enzymes interacting and can theoretically be actively occurring in two separate organs.
I tried to provide some scientific journals to reference a few points for the nature of sourcing, but I figured out I'm too new to post any links.Last edited by Splifton; 09-11-2015 at 07:29 AM.
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To brainy for me lol
“If you can't explain it to a second grader, you probably don't understand it yourself.” Albert Einstein
"Juice slow, train smart, it's a long journey."
BG
"In a world full of pussies, being a redneck is not a bad thing."
OB
Body building is a way of life..........but can not get in the way of your life.
BG
No Source Check Please, I don't know of any.
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09-11-2015, 09:59 AM #3
Short answer: no. High doses of insulin (and concurrent use of shitloads of carbs) will contribute to insulin resistance (bear in mind that AAS decrease insulin resistance, so they largely balance each other out), but there is no reason why it would negatively affect the pancreas.
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09-11-2015, 10:39 AM #4Banned
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09-11-2015, 10:50 AM #5
And it's not like one's pancreas stops producing insulin just because they are using insulin for BB'ing purposes. We only take one or two doses daily of fast-acting insulin, so there is still plenty of opportunity for the pancreas to secrete insulin.
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09-11-2015, 11:42 AM #6
Appreciate the response. I presumed that its secretion and receptor activity would be comparable to the negative feedback mechanism associated with endocrine regulation considering its an internal endocrine organ as well as an exocrine digestive gland. You mentioned one or two doses daily, so the total dosing of exogenous administration is minuscule in comparison to the body's endogenous total secretion in a given day considering the variables are static for ease of measurement?
I wish I could post some of the studies that led me to that presumption. Here is the abstract if it offers any sort of insight in my original connections. I have it in PDF.
Oxidative stress: the vulnerable β-cell
Sigurd Lenzen1 Institute of Clinical Biochemistry, Hannover Medical School, 30625 Hannover, Germany
Antioxidative defence mechanisms of pancreatic β-cells are particularly weak and can be overwhelmed by redox imbalance arising from overproduction of reactive oxygen and reactive nitrogen species. The consequences of this redox imbalance are lipid peroxidation, oxidation of proteins, DNA damage and interference of reactive species with signal transduction pathways, which contribute significantly to βcell dysfunction and death in Type 1 and Type 2 diabetes mellitus. Reactive oxygen species, superoxide radicals (O2•−), hydrogen peroxide (H2O2) and, in a final iron-catalysed reaction step, the most reactive and toxic hydroxyl radicals (OH•) are produced during both pro-inflammatory cytokine-mediated β-cell attack in Type 1 diabetes and glucolipotoxicity-mediated β-cell dysfunction in Type 2 diabetes. In combination with NO•, which is toxic in itself, as well as through its reaction with the O2•− and subsequent formation of peroxynitrite,reactivespeciesplayacentralroleinβ-celldeathduringthedeteriorationofglucosetolerance in the development of diabetes.Last edited by Splifton; 09-11-2015 at 11:58 AM.
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09-11-2015, 12:07 PM #7
here are two mechanisms for reduction in the level of cell surface insulin receptors by exposure to insulin.
-The first is receptor internalization.
- Surface insulin-receptor complexes are internalized by endocytosis.
Insulin is degraded in lysosomes while 90% of the receptors escape degradation
and recycle to the cell surface by exocytosis.
Since many of the receptors are transferred, transiently, to the various intracellular organelles involved in receptor recycling, fewer remain on the cell surface.
-The second mechanism is receptor degradation.
-Upon prolonged exposure to insulin, endocytosis and recycling of insulin receptors occurs continuously.
During each cycle of endocytosis a small portion (less than 10%) of the internalized receptors are degraded.
After several hours of endocytosis, the total number of insulin receptors is reduced substantially.
^from a lecture^
Attachment 159395
So increasing the possibility of receptor internalization or the prevalence of oxidative stress towards beta cells still wouldn't have a marginal negative effect on the pancreas' future functionality?Last edited by Splifton; 09-11-2015 at 12:09 PM.
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Islet cells become taxed with chronic exposure to high blood sugar. In type two diabetes the pancreas essentially is warn out by continually producing insulin and other pancreatic enzymes do to over consumption of high GI foods. A secondary effect that contributes and amplifies this is the insensitivity that insulin receptors experience as metabolic disease marches unrelentingly on in a sedentary individual.
Bodybuilders and fit individuals for that matter generally do not have their body chronically exposed to high circulating blood sugars AND their insulin receptors are much more sensitive to circulating insulin. Thus the pancreas has to release less insulin for the same cellular response thus it's not overworked.
Essentially a type II diabetic has over the course of years, warn down the pancreas and if can not longer produce the needed amount of insulin the body requires. Of course it's more complicated than that, but not really :-)“If you can't explain it to a second grader, you probably don't understand it yourself.” Albert Einstein
"Juice slow, train smart, it's a long journey."
BG
"In a world full of pussies, being a redneck is not a bad thing."
OB
Body building is a way of life..........but can not get in the way of your life.
BG
No Source Check Please, I don't know of any.
Depressed? Healthy Way Out!
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09-11-2015, 06:03 PM #9
Hey it gives me enough of a summary to know where I should be reading around at. I guess I had one premise correct....kinda.
EDIT...Last edited by Splifton; 09-11-2015 at 08:34 PM.
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09-11-2015, 06:30 PM #10
Are you all talking in english?!! Lol
Last edited by MrFreshmaker; 09-11-2015 at 06:38 PM.
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09-11-2015, 06:39 PM #11
Just some good ol' chemical equilibria.
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Originally Posted by Splifton“If you can't explain it to a second grader, you probably don't understand it yourself.” Albert Einstein
"Juice slow, train smart, it's a long journey."
BG
"In a world full of pussies, being a redneck is not a bad thing."
OB
Body building is a way of life..........but can not get in the way of your life.
BG
No Source Check Please, I don't know of any.
Depressed? Healthy Way Out!
Tips For Young Lifters
MuscleScience Training Log
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09-11-2015, 08:34 PM #13
So on my screen it looked perfectly normal, but I'm assuming that is how it was situated on your screen?
Acetone is shown below on the left. What will happen to the pKa after the addition of an azido group to one of its methyl groups (actually replacing one of the methyl hydrogens?) The site of deprotonation (and thus where the pKa directly refers to) is the hydrogens on the carbon where the azido group was substituted (the -CH2). The modified molecule (after azido addition) is shown in the middle, and the azido group itself is shown on the far right.
A. The pKa of the hydrogens of the azido-substituted molecule (the -CH2) will be lower than the hydrogens on the molecule without the azido (the -CH3) because the azido group stabilizes the conjugate base
B. The pKa of the hydrogens of the azido-substituted molecule (the -CH2) will be higher than the hydrogens on the molecule without the azido (the -CH3) because the azido group stabilizes the conjugate base
C. The pKa of the hydrogens of the azido-substituted molecule (the -CH2) will be lower than the hydrogens on the molecule without the azido (the -CH3) because the azido group destabilizes the conjugate base
D. The pKa of the hydrogens of the azido-substituted molecule (the -CH2) will be higher than the hydrogens on the molecule without the azido (the -CH3) because the azido group destabilizes the conjugate base
A terribly terribly structured question about acid/base equilia.Last edited by Splifton; 09-11-2015 at 08:38 PM.
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Oh...lol
“If you can't explain it to a second grader, you probably don't understand it yourself.” Albert Einstein
"Juice slow, train smart, it's a long journey."
BG
"In a world full of pussies, being a redneck is not a bad thing."
OB
Body building is a way of life..........but can not get in the way of your life.
BG
No Source Check Please, I don't know of any.
Depressed? Healthy Way Out!
Tips For Young Lifters
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09-12-2015, 05:43 PM #15
Why dwell on (poorly presented) in-vitro/classroom theory when we have plenty of in-vivo knowledge that contradicts your theory?
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09-12-2015, 08:46 PM #16
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I'm still confused what we are talking about :-;
“If you can't explain it to a second grader, you probably don't understand it yourself.” Albert Einstein
"Juice slow, train smart, it's a long journey."
BG
"In a world full of pussies, being a redneck is not a bad thing."
OB
Body building is a way of life..........but can not get in the way of your life.
BG
No Source Check Please, I don't know of any.
Depressed? Healthy Way Out!
Tips For Young Lifters
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09-12-2015, 09:58 PM #18
Lol that question was just something on an assignment and I saw the word "science" in your name so I just spewed it out.
It was A by the way on that terribly structured turd. Azido group allows the electrons to move off the carbon molecule and thus lowers the PKa and stabilizes the base.
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Oh it was a real question. I could have answered it for you. But I didn't read the big long paragraph. I have this thing now. If something is more than two sentence long, I won't read it. Lol
“If you can't explain it to a second grader, you probably don't understand it yourself.” Albert Einstein
"Juice slow, train smart, it's a long journey."
BG
"In a world full of pussies, being a redneck is not a bad thing."
OB
Body building is a way of life..........but can not get in the way of your life.
BG
No Source Check Please, I don't know of any.
Depressed? Healthy Way Out!
Tips For Young Lifters
MuscleScience Training Log
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09-12-2015, 10:15 PM #20
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My hero Einstein said,
If you can't explain something to a 6 year old and make them understand. You don't understand it yourself.“If you can't explain it to a second grader, you probably don't understand it yourself.” Albert Einstein
"Juice slow, train smart, it's a long journey."
BG
"In a world full of pussies, being a redneck is not a bad thing."
OB
Body building is a way of life..........but can not get in the way of your life.
BG
No Source Check Please, I don't know of any.
Depressed? Healthy Way Out!
Tips For Young Lifters
MuscleScience Training Log
-
09-12-2015, 10:23 PM #22
Well shit I might as well just drop out of school now because I can't explain something without an overtone of absolute confusion. Should have known those tasty paint chips would come back to haunt me.
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Originally Posted by Splifton“If you can't explain it to a second grader, you probably don't understand it yourself.” Albert Einstein
"Juice slow, train smart, it's a long journey."
BG
"In a world full of pussies, being a redneck is not a bad thing."
OB
Body building is a way of life..........but can not get in the way of your life.
BG
No Source Check Please, I don't know of any.
Depressed? Healthy Way Out!
Tips For Young Lifters
MuscleScience Training Log
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