|Beta Cell with Insulin Granules dotted in Red Marker|
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To understand what happens as your blood sugar deteriorates from normal to pre-diabetes, and finally, to full-fledged diabetes you first need to understand how blood sugar control works in a normal body. The most important factor here is the role played by special cells called beta cells. These tiny cells are scattered through an organ called the pancreas which is located just under your stomach. The job of the beta cell is to produce insulin, store it, and release it into the blood stream at appropriate times.
You can learn how blood sugar fluctuates during the day in people with normal blood sugar, those with mildly diabetic blood sugars, and those with full fledged Type 2 Diabetes on this page: Blood Sugar Throughout the Day.
Healthy beta-cells are continually making insulin, storing it within the cell in little granules you can see in the illustration above. This insulin is released into the blood stream in two different fashions. Some of it is secreted into the blood continually. This is called basal insulin. The rest is secreted only when blood sugars rise, which happens mostly after you eat foods containing carbohydrates. This kind of insulin is secreted in two separate phases. Let's look more closely at these different ways the pancreas secretes insulin.
Basal Insulin ReleaseThe beta-cells of a healthy person who has not eaten in a while release a small amount of insulin into the blood stream throughout the day and night in the form of very small pulses every few minutes. This is called "basal insulin release."
Maintaining this steady supply of insulin is important. It allows the cells of the body to utilize blood sugar even if some time has passed since a meal.
Insulin Levels Signal the Liver Whether More Glucose is NeededThe steady insulin level as another function, too. A dropping insulin level signals the liver that blood sugar is getting low and that it is time to add more glucose. When this happens, the liver converts the carbohydrate it has stored, (known as glycogen) into glucose, and dumps it into the blood stream. This raises the blood sugar back to its normal level.
If a person has exhausted their glycogen stores, as can happen on a low carbohydrate diet, the liver converts protein into glucose to provide the glucose it makes in response to a low level of insulin in the blood. The protein can come from dietary protein or from your body's own muscles. That is why dieters can lose significant amounts of muscle mass if they don't get enough protein when they diet.
First Phase Insulin ReleaseWhen a health person starts to eat a meal, the beta-cells kick into high gear. Their stored insulin is released immediately. Then, if the blood sugar concentration rises over 100 mg/dl, (5.5 mmol/L) the beta-cells start secreting more insulin into the blood stream. This early release of stored insulin after a meal is called "First Phase Insulin Release." In a healthy person it keeps the blood sugar from rising very high because it is available to meet most of the glucose that comes from the digestion of the current meal.
The amount of insulin secreted in the first phase response to a meal is usually determined by the amount of glucose encountered in the previous meal. In a healthy person, this first phase response peaks a few minutes after you've started your a meal. The blood sugar rise caused by the meal peaks about half an hour after you start eating.
Second Phase Insulin ReleaseAfter completing the first phase insulin release, the beta-cells pause. Then, if blood sugar is still not back under 100 mg/dl (5.5 mmol/L) ten to twenty minutes later, they push out another, smaller second phase insulin response which, in a healthy person, brings the blood sugar back down to its starting level, usually within an hour to an hour and a half after the start of a meal.
It is this combination of a robust first phase insulin response followed by a functional second phase insulin response that keeps the blood sugar of a normal person from ever rising over 140 mg/dl(7.8 mmol/L) even after a high carbohydrate meal. When first phase insulin response is completely functional, the blood sugar level at two hours should be back to the normal fasting blood sugar level which is somewhere in the mid 80 mg/dl range (4.5 mmol/L).
When first phase release fails, or when second phase insulin response is sluggish, blood sugars start to rise to higher levels after a meal and take longer to return to normal. This condition is called "impaired glucose tolerance." If the blood sugar rises over 200 mg/dl (11 mmol/L) after a meal the same condition is called "Diabetes."
Why Insulin Release Fails
Insulin ResistanceFirst and second phase insulin release may fail to do their jobs for several reasons. The most common is a condition called insulin resistance in which some receptors in the liver and the muscle cells stop responding properly to insulin. This means that though there is lots of insulin circulating in the body, the muscles and liver (but not, alas, the fat cells) don't respond until the insulin levels rise much higher
So when a person's cells become insulin resistant, it will take a lot more insulin than usual to push circulating glucose into cells. In this case, while a person might have a perfectly normal first and second phase insulin response, the first phase response might not produce enough insulin to clear the circulating blood glucose resulting from eating a high carbohydrate meal. Then the second phase response might be prolonged because it takes a long time for beta-cells to secrete of the large amounts of insulin needed to counter the insulin resistance. Eventually the body may not be able to produce enough insulin to clear all the dietary carbohydrate from the bloodstream and blood sugars will rise to abnormal levels.
If your beta-cells are normal, and if insulin resistance at the muscles and liver is your only problem, over time you may be able to grow new pancreas islets filled with new beta-cells that can store even more insulin for use in first and second phase insulin response. In this case, though your blood sugar may continue to rise into the impaired range and take longer than normal to go back down to normal levels, your blood sugar response may never deteriorate past the impaired glucose tolerance stage to full-fledged diabetes. This is what happens to most people who have what is called "Metabolic Syndrome." Unfortunately, if you have impaired glucose tolerance, there is no way of knowing if you fall into this group or if your rising blood sugars are caused by failing or dying beta-cells.
Failing beta-cellsFirst phase insulin release also fails because beta-cells are dysfunctional or dying. This can happen along with insulin resistance, or without it. Studies have found that some thin, non-insulin resistant relatives of people with Type 2 Diabetes already show signs of beta cell dysfunction.
If beta-cells are dying or not working properly the remaining beta-cells may be working full-time just to keep up with the need for a basal insulin release so they can't store any excess in those granules for later release.
Some people with type 2 diabetes appear to have a defect which makes their beta-cells die when they attempt to reproduce in response to a need for more insulin. For these people, insulin resistance can cause the beta-cells to try to divide and then die, hastening on the degenerative process.
It is also possible that some people who develop type 2 diabetes have a genetic defect which prevents their beta-cells from storing insulin though their beta-cells are still capable of secreting it.
Scientists have discovered dozens of different genetic defects which cause beta-cells to fail or die in humans and animals. Many genes are expressed in the process that leads to the correct functioning of the beta-cells and many others in the cell receptors which respond to insulin. This means that one person's Type 2 Diabetes can behave quite differently from that of another person, depending on what exactly is broken in their blood sugar control system. This is why drugs that work well for one person may do little for another person. By understanding your own pattern of blood sugar response you may get some insight into what might be malfunctioning in your individual case.
Rising Blood Sugar Concentrations Further Damage Your Ability to Produce Insulin
Glucose ToxicityWhatever the reason for the failing first phase insulin release there's an ugly feedback mechanism that kicks in when blood sugar levels rise because of that failing first phase insulin release: High levels of circulating glucose themselves are toxic to beta-cells, a phenomenon called "glucose toxicity". So as blood sugars rise these high blood sugar concentrations further damage and or kill more beta-cells, making first and second phase insulin release even less able to control blood sugar concentrations.
Increased Insulin ResistanceIf your beta-cells are still able to secrete enough insulin to provide a second phase insulin release, your body may be able to bring the blood sugar back down to a normal level by 3 hours and may then go back to secreting the small amounts of basal insulin which maintain a normal or near-normal blood sugar level while you are between meals or asleep. But when first phase insulin release is weak or missing your blood sugar may easily rise over the 200 mg/dl (11 mmol/L) level currently defined as "diabetes."
At that point, two bad things happen. When the concentration of glucose in your blood reaches 200 mg/dl (11 mmol/L) your cells become insulin resistant even if they weren't insulin resistant before, so it takes a lot more insulin to lower your blood sugar from that point on.
And, even worse, the lack of a robust insulin response to the rising glucose may erroneously be interpreted by your liver as a sign that blood sugar is too low and that it is time to dump more glucose into the bloodstream. So in addition to the glucose coming in from your recent meal you also have to contend with additional glucose dumped by your poor old confused liver.
Impaired Fasting Glucose
Why Fasting Blood Sugar Levels are Often the Last to DeteriorateAs you become more diabetic, and your second phase insulin response grows weaker, it may take four or five hours for your beta-cells to secrete enough insulin to bring your blood sugar level down to its fasting level. And, in fact, during the day your blood sugar may never get back to its fasting level because the glucose coming in from your next meal comes into the bloodstream before the glucose from the previous meal has completely cleared. Only at night, while you are sleeping, may your beta-cells finally secrete enough insulin to get your blood sugar down low enough that you wake up with a normal fasting blood sugar.
However, since it took all the insulin your beta-cells could make to get back to that normal blood sugar and they will have had no chance to store any extra insulin to take care of your breakfast. As soon as you throw that morning bagel down the hatch, blood glucose will rise, and once again your beta-cells will have to spend many hours trying to bring it back down.
Eventually, even the long hours of the night will not be enough time for your beta-cells to produce enough insulin to bring your blood sugar back to normal, and now, perhaps a decade after you achieved diabetic post-meal numbers, you will finally start seeing diabetic fasting blood sugar levels.
This process explains why for many people who become diabetic--particularly middle-aged women, the fasting blood sugar level is the very last measurement to become abnormal. Only when a whole night isn't long enough for your beta-cells to bring your blood sugar back down to normal or near-normal levels will you become diabetic by a fasting blood sugar test.
The Fasting Blood Sugar Death SpiralWhen the beta-cells are no longer to keep fasting blood sugar normal, this is often a sign that the pancreas no longer has enough beta cell capacity to keep up even with the production of even low levels of insulin needed for basal insulin secretion. This usually signals that a critical amount of irreversible beta-cell death has occurred.
When this happens, blood sugar control can deteriorate very swiftly. This is because when the beta cells can no longer provide a steady basal insulin release, the liver interprets the very low fasting insulin level as a sign that it is time to raise blood sugar, Then, no matter what the actual concentration of sugar in your blood, the liver dumps a large dose of glucose into the bloodstream.
This effect explains why fasting blood sugar tends not to deteriorate slowly and steadily but often takes a sudden upward surge of 50 mg/dl (2.8 mmol/L) or more. That sudden surge is a sign that the insulin level has dropped so low that the liver has interpreted it as a sign of dangerously low blood sugar and has started to dump glucose.
A Different Syndrome: Impaired Fasting Glucose with Normal Post-Meal ControlThere is are a small number of people, often men, whose fasting blood sugar rises quite high, perhaps even into the diabetic range, while their post meal blood sugars remain normal or neal normal. This appears to be a slightly different syndrome. Scientists speculate, that these people may have a defect that affects their ability to secrete the basal insulin release that takes place during fasting and sleep.
The Point of No Return for Fasting Blood Sugar?A study of 344 people published in November 2007 examined the relationship of their fasting blood sugar to the presence of metabolic syndrome. They broke their study subjects into four groups by fasting blood sugar rather than the usual three. The groups were: Normal (<101 mg/dl or 5.6 mmol/L), FBG1 (101-109 mg/dl 5.6 and 6.0 mmol/L), FBG2 (110-124 mg/dl 6.1-6.9 mmol/L) and Diabetic (>125 mg/dl 7 mmol/L).
This is unusual, because most studies will lump people with fasting blood sugars between 100 and 110 mg/dl (the FBG1 group) with the either the normal or the pre-diabetic group. By breaking that group out separately it was possible to discover a relationship between fasting blood sugar and health that might have otherwise been missed. And that is exactly what happened.
This study found that people in the FBG2 group had the same cardiovascular and metabolic syndrome incidence as people with diabetes. Which backs up what we have seen above: for most people, the deterioration of fasting blood sugar over 110 mg/dl occurs only after many years of exposure to very high post-meal blood sugars and by the time fasting blood sugar deteriorates this much, diabetic complications, most notably heart disease are well established.
In contrast, the intermediate FBG1 group was a lot more normal as far as cardiovascular and metabolic syndrome markers went. This suggests that the fasting blood sugar between 100 mg/dl and 110 mg/dl, should be treated as a major watershed and that if you test into this fasting blood sugar range on a screening, you should take aggressive steps to lower your post-meal blood sugars, because you have caught the abnormality early enough to be able to prevent cardiovascular deterioration.
Classical cardiovascular risk factors according to fasting plasma glucose levels Sergio Martinez-Hervasa, et al. European Journal of Internal Medicine Volume 19, Issue 3, May 2008, Pages 209-213
How Many Beta-Cells Have to Die to Permanently Mess Up Blood Sugar Control?This question was answered by a series of autopsies a team of researchers performed on pancreases taken from Mayo Clinic patients whose medical histories were known. They found that patients diagnosed as diabetic had 63% less beta cell mass than normal people--which they attributed to beta cell death, not shrinking in the size of the individual cells.
Obese people who were not diabetic had 50% more beta cells than normal.
They also found that the pancreases of obese patients not diabetic who were diagnosed as having impaired fasting glucose--defined as fasting blood sugars between 110 mg/dl and 125 mg/dl (6.1 and 6.9 mmol/L)had also lost significant amounts of cells--40% of them. The same study found that lean people with type 2 diabetes had more dead beta cells in their islets than obese people with diabetes.
Use this Understanding to Stop your Diabetes from ProgressingPeople whose fasting blood sugar numbers have risen along with their post-meal numbers have generally lost more beta-cell function than those who still maintain normal or near-normal fasting blood sugars. This is why as soon as you discover that your post-meal blood sugars are rising beyond a normal level, it is so important to start controlling those abnormal post-meal blood sugars immediately. By doing so, you may be able to lower any insulin resistance, preserve your remaining beta-cells and keep your fasting blood sugar from ever deteriorating.
Even after you have been diagnosed as having a type 2 diabetic fasting plasma glucose, you may still have a good number of beta-cells left--anywhere from 40 to 60%. If you can reduce your insulin resistance through weight loss, exercise, and the use of drugs that counter insulin resistance, and if you keep your carb intake low to avoid blood sugar spiking, those cells may be able to produce enough insulin to control your blood sugar.
Even more important, if you keep your blood sugar under the damage-limit of 140 mg/dl (7.8 mmol/L) at all times, you may be able to keep glucotoxicity from murdering the rest of those cells.
Some studies mostly in cell-cultures and animal models have demonstrated that giving stressed beta-cells a rest can sometimes restore function. A few studies suggest this can also be done in humans.
One way of "resting" beta-cells is to use injected insulin as soon as type 2 diabetes is diagnosed, particularly if your blood sugars are very high at the time of diagnosis. If you take the burden off your beta-cells by supplementing insulin, there's some suggestion that they may recover some of their ability to produce insulin later on so that you can go off insulin and retain much better control. You'll still have to limit carbs and address any problems you have with insulin resistance through weight loss, exercise, and insulin-sensitizing drugs. But you'll have an easier time doing it.
To Learn More
The Patterns in Which Diabetes Develops. A continuation of this discussion presented on this web site.
Phasic Insulin Release and Metabolic Regulation in Type 2 Diabetes. Stefano Del Prato, Piero Marchetti, and Riccardo C. Bonadonna. Diabetes 51:S109-S116, 2002
Is reduced first-phase insulin release the earliest detectable abnormality in individuals destined to develop type 2 diabetes? John E. Gerich. Diabetes 51:S117-S121, 2002
The Genetic Basis of Type 2 Diabetes Mellitus: Impaired Insulin Secretion versus Impaired Insulin Sensitivity. John E. Gerich. Diabetes, Feb, 2002 Endocrine Reviews 19 (4): 491-503
Beta-Cell Deficit and Increased Beta-Cell Apoptosis in Humans With Type 2 Diabetes. Alexandra E. Butler, Juliette Janson, Susan Bonner-Weir, Robert Ritzel, Robert A. Rizza, and Peter C. Butler. Diabetes 52:102-110, 2003