Medical Forum / Diseases and Disorders / Diabetes / March 2008
Down Regulation & Insulin Resistance?
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Kumar - 15 Mar 2008 08:19 GMT Hello,
Following article is very important if valid. I tried to check it from other reputed people in diabetes, who don't deny or agree on this possibilty. In such consideration, why increased insulin's exposure ( natural or medicated) to target cells, which can be common in type2 people, address one mechanism for getting insulin's resistance and hyperglycemia in type2 diabetes?
"Downregulation Downregulation is the process by which a cell decreases the number of a cellular component, such as RNA or protein, in response to an external variable. An increase of component is called upregulation.
For example, the cell decreases the number of receptors to a given hormone or neurotransmitter to reduce its sensitivity to this molecule. This is a locally acting negative feedback mechanism.
[edit] Receptor downregulation
[edit] Mechanism For insulin, the process of downregulation occurs when there are elevated levels of the hormone in the blood. When insulin binds to its receptors on the surface of a cell, endocytosis of the hormone receptor complex is initiated, only to be subsequently attacked by intracellular lysosomal enzymes. The internalization is multi- purposed, as it provides the pathway for degradation of the hormone and also a way to regulate the number of sites that are available for binding on the cellʼs surface. At high plasma concentrations, the number of surface receptors for insulin is gradually reduced by the accelerated rate of receptor internalization and degradation brought about by increased hormonal binding. The rate of synthesis of new receptors within the endoplasmic reticulum and their insertion in the plasma membrane do not keep pace with their rate of destruction. Over time, this self-induced loss of target cell receptors for insulin reduces the target cellʼs sensitivity to the elevated hormone concentration. The process of decreasing the number of receptor sites is virtually the same for all hormones; it only varies in the receptor hormone complex.
[edit] Cases To illustrate this process we shall look at the insulin receptor sites on the target cells of a type 2 diabetic. Due to the elevated levels of blood glucose from excessive feeding in an overweight individual, the β-cells (islets of Langerhans) in the pancreas must release more insulin than normally emitted to match the demand and return the blood to homeostatic levels. The near-constant increase in blood insulin levels results from an effort to match the increase in blood glucose, which will cause receptor sites on the personʼs cell to downregulate and decrease the number of receptors for insulin, increasing the subjectʼs resistance by decreasing sensitivity to this hormone. There is also a hepatic decrease in sensitivity to insulin. This can be seen in the continuing gluconeogenesis in the liver even when blood glucose levels are elevated. This is the more common process of insulin resistance, which in turn leads to adult onset diabetes in that subject. Other cases include Diabetes insipidus; here the kidneys become insensitive to arginine vasopressin.
[edit] Reversal There are ways to counteract this process; using the previous example a type 2 diabetic may increase their sensitivity to insulin through proper diet and regular exercise producing weight loss; some may even return to their pre-diabetic state following this regimen." http://en.wikipedia.org/wiki/Downregulation
Anja Lange - 15 Mar 2008 10:31 GMT > Following article is very important if valid. I tried to check it from > other reputed people in diabetes, who don't deny or agree on this > possibilty. If you understand german I recommend the following link to read some facts and practical advice on that subject: http://www.chrostek.de/index.php/Curriculum/up%20und%20down%20Regulation
The concept is used in insulin pump therapy but the mechanism applies to all.
Anja
Kumar - 15 Mar 2008 11:45 GMT > > Following article is very important if valid. I tried to check it from > > other reputed people in diabetes, who don't deny or agree on this [quoted text clipped - 7 lines] > > Anja Thanks but sorry I don't understand german. Can you or other brief it in english or provide an english link.
Marshall Price - 21 Mar 2008 07:04 GMT >>> Following article is very important if valid. I tried to check it from >>> other reputed people in diabetes, who don't deny or agree on this [quoted text clipped - 9 lines] > Thanks but sorry I don't understand german. Can you or other brief it > in english or provide an english link. It's mainly about glucose transporters (GLUT).
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Kumar - 21 Mar 2008 09:11 GMT > >>> Following article is very important if valid. I tried to check it from > >>> other reputed people in diabetes, who don't deny or agree on this [quoted text clipped - 17 lines] > > - Show quoted text - Sorry but GLUT4 are insulin-regulated glucose transporter.
Kumar - 21 Mar 2008 09:38 GMT > > >>> Following article is very important if valid. I tried to check it from > > >>> other reputed people in diabetes, who don't deny or agree on this [quoted text clipped - 21 lines] > > - Show quoted text - Following quote also tells ;Insulin induces the redistribution of GLUT4
"GLUT4 is the insulin-regulated glucose transporter found in adipose tissues and striated muscle (skeletal and cardiac) that is responsible for insulin-regulated glucose disposal. [edit] Reaction to insulin In the absence of insulin, GLUT4 is sequestered in the interior of muscle and fat cells, within the lipid bilayer of vesicles.
Insulin induces the redistribution of GLUT4 from intracellular storage sites to the plasma membrane." http://en.wikipedia.org/wiki/GLUT4
Kumar - 21 Mar 2008 09:55 GMT > > >>> Following article is very important if valid. I tried to check it from > > >>> other reputed people in diabetes, who don't deny or agree on this [quoted text clipped - 21 lines] > > - Show quoted text - Direct and indirect affects can be as under;
"Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1) which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesis (6). http://en.wikipedia.org/wiki/Insulin_receptor "
Marshall Price - 23 Mar 2008 14:31 GMT >>>>> Following article is very important if valid. I tried to check it from >>>>> other reputed people in diabetes, who don't deny or agree on this [quoted text clipped - 7 lines] >>> in english or provide an english link. >> It's mainly about glucose transporters (GLUT).
> Sorry but GLUT4 are insulin-regulated glucose transporter. Righty-o.
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Marshall Price - 21 Mar 2008 07:02 GMT > Following article is very important if valid. I tried to check it from > other reputed people in diabetes, who don't deny or agree on this > possibilty.
> http://en.wikipedia.org/wiki/Downregulation I disagree; the topic may be "important," but as it stands, it's a lousy article.
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Kumar - 21 Mar 2008 09:06 GMT > > Following article is very important if valid. I tried to check it from > > other reputed people in diabetes, who don't deny or agree on this [quoted text clipped - 7 lines] > Marshall Price of Miami > Known to Yahoo as d021317c Pls look at it;
http://www.childrenwithdiabetes.com/dteam/2008-03/d_0d_f3e.htm
I aso checked about possibility of such downregulation with Diabetics UK. Why such downregulation of insulin's receptors can't happen and adress one reason to so called insulin resistance esp. when other hormones can cause downregulations of thir receptors?
Possible clues, which can indicate excessive exposures of insulin can be;
1. IR commonly happens in type2 diabetics, naturally or medicated. 2. IR looks to be reversed in later stages of type2, probably, on getting frank diabetes or when beta cells are really damaged due to previous over burdens on them. 3. Obesity may also be linked to either increase insulins secretion or its decreases use, still overexposed to target cells.
4. Irregular and over-eating & opting Sed. and modern lifestyle may be resuting increased and irregular insulin's secretion & exposures.
Looks, real issues are predisposed or acquired excessive cravings to eat, opting sed./modern lifestyles & chronic stressors in crowded cities--pollutions, noise, lighting, crowdings etc.
Today, I looked at my daugter force feeding her 2 years old boy. Such aided/forced or excessive feeding to kids can be common in most mothers as a practice, misconception ot just sentiment-- love & affection. Can't it cause an aquired habit to overeat and expose more insulin to target cells and mediating diabetes2?
Do normal kids really need to be forced(aided? feeded, even when they don't demand?
Marshall Price - 23 Mar 2008 14:38 GMT > Today, I looked at my daughter force-feeding her 2-year-old boy. Such > aided/forced or excessive feeding to kids can be common in most > mothers as a practice, misconception or just sentiment-- love & > affection. Can't it cause an acquired habit to overeat and expose more > insulin to target cells and mediating diabetes2? I'd say she needs help -- either a book or a psychiatrist! What she's doing is a well known, serious problem.
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Kumar - 23 Mar 2008 14:51 GMT > > Today, I looked at my daughter force-feeding her 2-year-old boy. Such > > aided/forced or excessive feeding to kids can be common in most [quoted text clipped - 8 lines] > Marshall Price of Miami > Known to Yahoo as d021317c Yes, but how it can be relevant to getting diabetes2 afterwords?
Marshall Price - 23 Mar 2008 17:37 GMT >>> Today, I looked at my daughter force-feeding her 2-year-old boy. Such >>> aided/forced or excessive feeding to kids can be common in most [quoted text clipped - 5 lines] > > Yes, but how it can be relevant to getting diabetes2 afterwards? There are at least three varieties of type 2 diabetes mellitus (DM2), which is usually characterized by defective insulin secretion plus resistance to the action of insulin. One variety is "maturity-onset diabetes of the young" (MODY). (And there are six subtypes of MODY.)
Though I've got a book on diabetes and half a dozen with extended discussions of it, it never particularly interested me, but I do know it's both *complicated* and incompletely understood -- and I have no idea why you're concerned about it, or how I can help.
However, common sense tells me (a) that force-feeding anybody (including geese) is unhealthy and cruel, and (b) that you cannot draw upon fat reserves in your body when they're "locked down" by insulin, which is an unhealthy condition to be in, except briefly and immediately after a meal.
If you only put fat into your tissues and never take it out (all anabolism and no catabolism: remember, "metabolism" means both!), and you force your glucose transporters to react to insulin all the time, and beyond their capacity, you're asking for trouble, such as fewer and less responsive glucose transporters, which causes insulin resistance, which means trouble.
But every book on childrearing contains advice on feeding infants, and if your daughter really cared about her child, she'd pick one up and read it. And if she doesn't, why don't you?
I'm reminded of the difference between returning opossums and raccoons to the wild. Opossums are very stupid and live by instinct. As soon as they're weaned, you can just let them go. But raccoons are very intelligent and require a lot of education from their parents. If they're brought up in captivity, they can never be released; there's just too much they don't know, and nobody to teach them.
Well, humans need the most education of all. It's the way we've evolved, learning from each other. Our instincts are gone, but our minds are active, curious, and absorbent; and we've gotten used to it, so we're stuck with it. We must either learn or be ignorant -- and if we choose to be ignorant, we will surely suffer.
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Nico Kadel-Garcia - 23 Mar 2008 16:40 GMT >> Today, I looked at my daughter force-feeding her 2-year-old boy. Such >> aided/forced or excessive feeding to kids can be common in most [quoted text clipped - 4 lines] > I'd say she needs help -- either a book or a psychiatrist! What she's > doing is a well known, serious problem. And it's irrelevant to Type 1 diabetes, and the causality of Type 2 and obesity is often reversed: the Type 2 and high insulin levels trigger hunger, and weight gain, exacerbating the diabetes. So force feeding infants is something to worry about for plenty of other reasons, I'd consider the risk of diabetes to be one of the least critical concerns.
Marshall Price - 23 Mar 2008 18:04 GMT >>> Today, I looked at my daughter force-feeding her 2-year-old boy. Such >>> aided/forced or excessive feeding to kids can be common in most [quoted text clipped - 9 lines] > something to worry about for plenty of other reasons, I'd consider the risk of > diabetes to be one of the least critical concerns. Here's a good, brief page of advice for Kumar, assuming the baby's on solid food.
http://www.aap.org/publiced/BR_NutritionABC.htm
It's from the American Academy of Pediatrics. I hope the text is legible:
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American Academy of Pediatrics
Nutrition
How do I know if my child is eating enough?
Children eat when they are hungry and usually stop when they are full. Some parents worry because young children appear to eat very small amounts of food, especially when compared to adult portions. A child who is growing well is getting enough to eat.
To check your child's eating pattern, pay attention to his or her food choices.
* Make sure no one food group is completely left out. If this happens for a few days, don't worry. But prolonged neglect of a food group could keep your child from getting enough nutrients. * Encourage your child to be adventurous and eat a variety of foods within the food groups, too. Even within a food group, different foods provide different nutrients.
Child-size servings
For youngsters, adult-size servings can be overwhelming. Offering child-size servings encourages food acceptance.
Here's an easy guide to child-size servings:
* Serve one-fourth to one-third of the adult portion size, or one measuring tablespoon for each year of the young child's age. * Give less than you think the child will eat. Let the child ask for more if he or she is still hungry.
Snacks count
Snacks make up an important part of childhood nutrition. Children must eat frequently. With their small stomachs, they cannot eat enough at meals alone for their high energy needs. Three meals and two or three healthful snacks a day help youngsters meet their daily nutrition needs.
To make the most of snacks, parents and caregivers should control the type of snack and time it is served.
* Type. Offer a variety of food-group snacks. Choose mostly snack foods that supply enough nutrients to justify their energy, or calories. * Timing. Plan snacks. Schedule snacks around normal daily events, and space them at least two hours before meals. Children should learn to get and feel hungry, instead of feeling full all the time.
Foods to choose
* From the Bread, Cereal, Rice and Pasta Group: a whole-grain bread, crackers, cereal, grits, pasta, rice, bagel, tortilla, cornbread, pita bread, muffin, English muffin, matzo crackers, rice cake, pancakes, breadsticks, pretzels * From the Vegetable Group: asparagus, beets, bok choy, broccoli, carrot, cauliflower, collard greens, corn, cucumber, green and red peppers, green beans, jicama, kale, okra, peas, potato, pumpkin, snow peas, squash, spinach, sweet potato, tomato, vegetable juices, zucchini * From the Fruit Group: apple, applesauce, apricot, banana, berries, cantaloupe, fruit cocktail, figs, fruit juices, grapefruit, kiwifruit, mango, nectarine, orange, papaya, peach, pear, plum, pineapple, raisins, prunes, starfruit, strawberries, tangerine, watermelon * From the Milk, Yogurt and Cheese Group: skim, 1%, 2% and whole* milk, yogurt, cheese, string cheese, cottage cheese, pudding, custard, frozen yogurt, ice milk, calcium-fortified soybean milk * From the Meat, Poultry, Fish, Dry Beans, Eggs and Nuts** Group: lean cuts of beef, veal, pork, ham and lamb; skinless chicken and turkey; fish; shellfish; cooked beans (kidney beans, black-eyed peas, pinto beans, lentils, black beans); refried beans (made without lard); peanut butter; eggs; reduced-fat deli meats; tofu; nuts**; peanuts**
*Children under two years of age should only drink whole milk.
**Nuts, peanuts and seeds are not recommended for children under four years of age because they are a choking hazard. Small pieces of hard, uncooked fruits and vegetables also pose a choking hazard to children under age four.
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 Signature Marshall Price of Miami Known to Yahoo as d021317c
Kumar - 24 Mar 2008 10:03 GMT > >>> Today, I looked at my daughter force-feeding her 2-year-old boy. Such > >>> aided/forced or excessive feeding to kids can be common in most [quoted text clipped - 116 lines] > > - Show quoted text - Good article, thanks I shall send it to my daughter.
However, I am bit concerned about common feeding habit by mothers esp. in developing countries, can be a reason to getting diabetes2 due to 1. Decreased insulin's occilations, decreased insulin's degradations and increased insulin's exposure to target cells resuting downregulation of insulin receptors?
Marshall Price - 24 Mar 2008 21:53 GMT >>>>> Today, I looked at my daughter force-feeding her 2-year-old boy. Such >>>>> aided/forced or excessive feeding to kids can be common in most [quoted text clipped - 20 lines] > and increased insulin's exposure to target cells resuting > downregulation of insulin receptors? I suspect you're right. In addition to beta-cell problems leading to decreased insulin production, there are others which produce rare forms of insulin, the "insulinopathies." Then, there are problems with insulin's effectiveness not only throughout the body, but especially in the pancreas and liver. Insulin not only stimulates insulin receptors to take glucose into cells (the glucose transporters) and inhibit fatty acid release and gluconeogenesis, etc., but it also affects them in other ways, by causing them to shut down, to change, to stop being produced, to proliferate, and so on. If you want to look into it, I'm sure you'll find plenty to investigate!
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Kumar - 25 Mar 2008 05:21 GMT > >>>>> Today, I looked at my daughter force-feeding her 2-year-old boy. Such > >>>>> aided/forced or excessive feeding to kids can be common in most [quoted text clipped - 37 lines] > > - Show quoted text - I checked up;
Insulin http://en.wikipedia.org/wiki/Insulin
Insulin degradation http://edrv.endojournals.org/cgi/content/full/19/5/608#F1
Insulin Oscillations http://en.wikipedia.org/wiki/Insulin_release_oscillations
Downregulation http://en.wikipedia.org/wiki/Downregulation
These suggest me that abnormalities in insulin's exposure, normal degradation & oscillation can cause increased exposure to target cells resulting downregulation so decreased senstivity.
Jefferson - 25 Mar 2008 21:05 GMT > I checked up; > > Insulin > http://en.wikipedia.org/wiki/Insulin The quality of wikipedia articles is quite varied so I did not look at them at this point.
> Insulin degradation > http://edrv.endojournals.org/cgi/content/full/19/5/608#F1 This article was extensively cited. Also note " Degradation of Amylin by Insulin-degrading Enzyme" - http://www.jbc.org/cgi/content/full/275/47/36621 (There are significant cites to this article as well including "Islet Amyloid: A Critical Entity in the Pathogenesis of Type 2 Diabetes" - http://jcem.endojournals.org/cgi/content/full/89/8/3629
> Insulin Oscillations > http://en.wikipedia.org/wiki/Insulin_release_oscillations > > Downregulation > http://en.wikipedia.org/wiki/Downregulation Frank
Kumar - 26 Mar 2008 04:20 GMT > > I checked up; > [quoted text clipped - 19 lines] > > Frank That can be possible. But still, do you deny these aspects? About down- regulation, I checked up with few other agencies. It is not negative.
Kumar - 28 Mar 2008 04:51 GMT > > > I checked up; > [quoted text clipped - 24 lines] > > - Show quoted text - "Release
Beta cells in the islets of Langerhans release insulin in response to increased blood glucose levels through the following mechanism (see figure to the right):
Glucose enters the beta cells through the glucose transporter GLUT2 Glucose goes into the glycolysis and the respiratory cycle where multiple high-energy ATP molecules are produced by oxidation Dependent on ATP levels, and hence blood glucose levels, the ATP- controlled potassium channels (K+) close and the cell membrane depolarizes On depolarisation, voltage controlled calcium channels (Ca2+) open and calcium flows into the cells An increased calcium level causes activation of phospholipase C, which cleaves the membrane phospholipid phosphatidyl inositol 4,5- bisphosphate into inositol 1,4,5-triphosphate and diacylglycerol. Inositol 1,4,5-triphosphate (IP3) binds to receptor proteins in the membrane of endoplasmic reticulum (ER). This allows the release of Ca2+ from the ER via IP3 gated channels, and further raises the cell concentration of calcium. Significantly increased amounts of calcium in the cells causes release of previously synthesised insulin, which has been stored in secretory vesicles Insulin http://en.wikipedia.org/wiki/Insulin "
Potassium homeostatis is got affected in hyperglycemic people & by insulin's effect. Probably, some instability in K/Ca (as above) may be linked to altered insulin's secretion.
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