Since high blood sugar is the hallmark of diabetes, and the cause of every long-term complication of the disease, it makes sense to discuss where blood sugar comes from and how it is used and not used.
Our dietary sources of blood sugar are carbohydrates and proteins. One reason the taste of sugar—a simple form of carbohydrate—delights us is that it fosters production of neurotransmitters in the brain that relieve anxiety and can create a sense of well-being or even euphoria. This makes carbohydrate quite addictive to certain people whose brains may have inadequate levels of or sensitivity to these neurotransmitters, the chemical messengers with which the brain communicates with itself and the rest of the body. When blood sugar levels are low, the liver, kidneys, and intestines can, through a process we will discuss shortly, convert proteins into glucose, but very slowly and inefficiently. The body cannot convert glucose back into protein, nor can it convert fat into sugar. Fat cells, however, with the help of insulin, do transform glucose into fat.
The taste of protein doesn’t excite us as much as that of carbohydrate— it would be the very unusual child who’d jump up and down in the grocery store and beg his mother for steak or fish instead of cookies. Dietary protein gives us a much slower and smaller blood sugar effect, which, as you will see, we diabetics can use to our advantage in normalizing blood sugars.
In the fasting nondiabetic, and even in most type 2 diabetics, the pancreas constantly releases a steady, low level of insulin. This baseline, or basal, insulin level prevents the liver, kidneys, and intestines from inappropriately converting bodily proteins (muscle, vital organs) into glucose and thereby raising blood sugar, a process known as gluconeogenesis. The nondiabetic ordinarily maintains blood sugar immaculately within a narrow range—usually between 80 and 100 mg/dl (milligrams per deciliter),* with most people hovering near 85 mg/dl. There are times when that range can briefly stretch up or down—as high as 160 mg/dl and as low as 65—but generally, for the nondiabetic, such swings are rare.
You will note that in some literature on diabetes, “normal” may be defined as 60–120 mg/dl, or even as high as 140 mg/dl. This “normal” is entirely relative. No nondiabetic will have blood sugar levels as high as 140 mg/dl except after consuming a lot of carbohydrate. “Normal” in this case has more to do with what is considered “cost-effective” for the average physician to treat. Since a postmeal (postprandial) blood sugar under 140 mg/dl is not classified as diabetes, and since the individual who experiences such a value will usually still have adequate insulin production eventually to bring it down to reasonable levels, many physicians would see no reason for treatment. Such an individual may be sent off with the admonition to watch his weight or her sugar intake. Despite the designation “normal,” an individual frequently displaying a blood sugar of 140 mg/dl is a good candidate for full-blown type 2 diabetes. I have seen “nondiabetics” with sustained blood sugars averaging 120 mg/dl develop diabetic complications.
Let’s take a look at how the average nondiabetic body makes and uses insulin. Suppose that Jane, a nondiabetic, arises in the morning and has a mixed breakfast, that is, one that contains both carbohydrate and protein. On the carbohydrate side, she has toast with jelly and a glass of orange juice; on the protein side, she has a boiled egg. Her basal (i.e., before-meals) insulin secretion has kept her blood sugar steady during the night, inhibiting gluconeogenesis. Shortly after the sugar in the juice or jelly hits her mouth, or the starchy carbohydrates in the toast reach certain enzymes in her saliva, glucose begins to enter her bloodstream. The rise in Jane’s blood sugar is a chemical signal to her pancreas to release the granules of insulin it has stored in order to prevent a jump in blood sugar (see Figure 1-2). This rapid release of stored insulin is called phase I insulin response. It quickly corrects the initial blood sugar increase and can prevent further increase from the ingested carbohydrate. As the pancreas runs out of stored insulin, it manufactures more, but it has to do so from scratch. The insulin released now is known as the phase II insulin response, and it’s secreted much more slowly. As Jane eats her boiled egg, the small amount of insulin of phase II can cover the glucose that, over a period of hours, is slowly produced from the protein of the egg.
Insulin acts in the nondiabetic as the means to admit glucose— fuel—into the cells. It does this by activating the movement of glucose“transporters” within the cells. These specialized protein molecules protrude from the cytoplasm of the cells and their surfaces to grab glucose from the blood and bring it to the interiors of the cells. Once inside the cells, glucose can be utilized to power energy requiring functions. Without insulin, the cells can absorb only a very small amount of glucose, not enough to sustain the body.
As glucose continues to enter Jane’s blood, and the beta cells in her pancreas continue to release insulin, some of her blood sugar is transformed to glycogen, a starchy substance stored in the muscles and liver. Once glycogen storage sites in the muscles and liver are filled, excess glucose remaining in the bloodstream is converted to and stored as fat. Later, as lunchtime nears but before Jane eats, if her blood sugar drops slightly low, the alpha cells of her pancreas will release another pancreatic hormone, glucagon, which will “instruct” her liver and muscles to begin converting glycogen to glucose, to raise blood sugar. When she eats again, her store of glycogen will be replenished.
This pattern of basal, phase I, then phase II insulin secretion is perfect for keeping Jane’s blood glucose levels in a safe range. Her body is nourished, and things work according to design. Her mixed meal is handled beautifully. This is not, however, how things work for either the type 1 or type 2 diabetic.
The Type 1 Diabetic
Let’s look at what would happen to me, a type 1 diabetic, if I had the same breakfast as Jane, our nondiabetic.
Unlike Jane, because of a condition peculiar to diabetics, if I take a long-acting insulin at bedtime, I might awaken with a normal blood sugar, but if I spend some time awake before breakfast, my blood sugar may rise, even if I haven’t had anything to eat. Ordinarily, the liver is constantly removing some insulin from the bloodstream, but during the first few hours after waking from a full night’s sleep, it clears insulin out of the blood at an accelerated rate. This dip in the level of my previously injected insulin is called the dawn phenomenon (see Chapter 6, “Strange Biology”). Because of it,my blood glucose can rise even though I haven’t eaten. A nondiabetic just makes more insulin to offset the increased insulin clearance. Those of us who are severely diabetic have to track the dawn phenomenon carefully by monitoring blood glucose levels, and can learn how to use injected insulin to prevent its effect upon blood sugar.
As with Jane, the minute the meal hits my mouth, the enzymes in my saliva begin to break down the sugars in the toast and juice, and almost immediately my blood sugar would begin to rise. Even if the toast had no jelly, the enzymes in my saliva and intestines and acid in my stomach would begin to transform the toast rapidly into glucose shortly after ingestion.
Since my beta cells have completely ceased functioning, there is no stored insulin to be released by my pancreas, so I have no phase I insulin response. My blood sugar (in the absence of injected insulin) will rise while I digest my meal. None of the glucose will be converted to fat, nor will any be converted to glycogen. Eventually much will be filtered out by my kidneys and passed out through the urine, but not before my body has endured damagingly high blood sugar levels— which won’t kill me on the spot but will do so over many years. The natural question is, wouldn’t injected insulin “cover” the carbohydrate in such a breakfast? Not adequately! This is a common misconception— even by those in the health care professions. Injected insulin— even with an insulin pump—doesn’t work the same as insulin created naturally in the body. Conventional insulin therapy resulting in high blood sugar after meals is a guaranteed incremental, “silent” death from the ravages of diabetic complications.
Normal phase I insulin is almost instantly in the bloodstream. Rapidly it begins to hustle blood sugar off to where it’s needed. Injected insulin, on the other hand, is injected either into fat or muscle (not into a vein) and absorbed slowly. The fastest insulin we have, lispro, starts to work in about 20 minutes, but its full effect is drawn out over a number of hours, not nearly fast enough to prevent a damaging upswing in blood sugars if fast-acting carbohydrate, like bread, is consumed.
This is the central problem for type 1 diabetics—the carbohydrate and the drastic surge it causes in blood sugar. Because I know my body produces no insulin, I have a shot of insulin before every meal. But I no longer eat meals with fast-acting or large amounts of carbohydrate, because the blood sugar swings they caused were what brought about my long-term complications. Even injection by means of an insulin pump (see discussion at the end of Chapter 19) cannot automatically fine-tune the level of glucose in my blood the way a nondiabetic’s body does naturally.
Now, if I ate only the protein portion of the meal, my blood sugar wouldn’t have the huge, and potentially toxic, surge that carbohydrates cause. It would rise less rapidly, and a small dose of insulin could act quickly enough to cover the glucose that’s slowly derived from the protein. My body would not have to endure wide swings in blood sugar levels. (Dietary fat, by the way, has no effect on blood sugar levels, except that it can slightly slow the digestion of carbohydrate.) In a sense, you could look at my insulin shot before eating only the protein portion of the meal as mimicking the nondiabetic’s phase II response. This is much easier to accomplish than trying to mimic phase I, because of the much lower levels of dietary carbohydrate (only the slow-acting kind) and injected insulin that I use.
The Type 2 Diabetic
Let’s say Jim, a type 2 diabetic, is 6 feet tall and weighs 300 pounds, much of which is centered around his midsection. Remember, at least 80 percent of type 2 diabetics are overweight. If Jim weighed only 170 pounds, he might well be nondiabetic, but because he’s insulin- resistant, Jim’s body no longer produces enough excess insulin to keep his blood sugar levels normal.
The overweight tend to be insulin-resistant as a group, a condition that’s not only hereditary but also directly related to the ratio of visceral and total body fat to lean body mass (muscle). The higher this ratio, the more insulin-resistant a person will be. Whether or not an overweight individual is diabetic, his weight, intake of carbohydrates, and insulin resistance all tend to make him produce considerably more insulin than a slender person of similar age and height (see Figure 1-3).
Many athletes, because of their low fat mass and high percentage of muscle, tend as a group to require and make less insulin than nonathletes. An overweight type 2 diabetic like Jim, on the other hand, typically makes two to three times as much insulin as the slender nondiabetic.
In Jim’s case, from many years of having to overcompensate, his pancreas has partially burned out, his ability to store insulin is diminished or gone, and his phase I insulin response is attenuated. Despite his huge output of insulin, he no longer can keep his blood sugars within normal ranges. (In my medical practice, a number of patients come to me for treatment of their obesity, not diabetes. On examination, however, most of these very obese “nondiabetics” have slight elevations of their HgbA1C test for average blood sugar.)
Let’s take another look at that mixed breakfast and see how it affects a type 2 diabetic. Jim has the same toast and jelly and juice and boiled egg that Jane, our nondiabetic, and I had. Jim’s blood sugar levels at waking may be normal.* Since he has a bigger appetite than either Jane or I, he has two glasses of juice, four pieces of toast, and two eggs. As soon as the toast and juice hit his mouth, his blood sugar begins to rise. Unlike mine, Jim’s pancreas eventually releases insulin, but he has very little or no stored insulin (his pancreas works hard just to keep up his basal insulin level), so he has impaired phase I secretion. His phase II insulin response, however, may be partially intact. So very slowly, his pancreas will struggle to produce enough insulin to bring his blood sugar down toward the normal range. Eventually it may get there, but not until hours after his meal, and hours after his body has been exposed to high blood sugars. Insulin is not only the major fat-building hormone, it also serves to stimulate the centers in the brain responsible for feeding behavior. Thus, in all likelihood, Jim will grow even more overweight, as demonstrated by the cycle illustrated in Figure 1-1.
Since he’s resistant to insulin, his pancreas has to work that much harder to produce insulin to enable him to utilize the carbohydrate he consumes. Because of insulin’s fat-building properties, his body stores away some of his blood sugar as fat and glycogen; but his blood sugar continues to rise, since his cells are unable to utilize all of the glucose derived from his meal. Jim, therefore, still feels hungry. As he eats more, his beta cells work harder to produce more insulin. The excess insulin and the “hungry” cells in his brain prompt him to want yet more food. He has just one more piece of toast with a little more jelly on it, hoping that it will be enough to get him through until lunch. Meanwhile, his blood sugar goes even higher, his beta cells work harder, and perhaps a few of them burn out.† Even after all this food, he still may feel many of the symptoms of hunger. His blood sugar, however, will probably not go as high as mine would if I took no insulin. In addition, his phase II insulin response could even bring his blood sugar down to normal after many hours without more food.
Postprandial (after-eating) blood sugar levels that I would call unacceptably high—140 mg/dl, or even 200 mg/dl—may be considered by other physicians to be unworthy of treatment because the patient still produces adequate insulin to bring them periodically down to normal, or “acceptable,” ranges. If Jim, our type 2 diabetic, had received intensive medical intervention before the beta cells of his pancreas began to burn out, he would have slimmed down, brought his blood sugars into line, and eased the burden on his pancreas. He might even have “cured” his diabetes by slimming down, as I’ve seen in several patients. But many doctors might decide such “mildly” abnormal blood sugars are only impaired glucose tolerance (IGT) and do little more than “watch” them. Again, it’s my belief that aggressive treatment at an early stage can save most patients considerable lost time and personal agony by preventing complications that will occur if blood sugar levels are left unchecked. Such intervention can make subsequent treatment of what can remain—a mild disease—elegantly simple.-
* Waking, or fasting, blood sugars are frequently normal in mild type 2 diabetics. After they eat carbohydrate, however, their postprandial blood sugars are usually elevated. † Beta cell burnout can be caused both by overactivity of the cells and by the toxicity of high glucose levels.
ON THE HORIZON
I include some hopeful forecasts of future treatments in this first chapter because as you’re learning how to control your diabetes, hope is a valuable asset. But your hope should be realistic. Your best hope for controlling your diabetes is normalizing your blood sugars now. That does not mean that the future will not bring great things. Diabetes research progresses on a daily basis, and I hope as much as you do for a cure, but it’s still on the horizon.
Researchers are currently trying to perfect methods for replicating insulin-producing pancreatic beta cells in the laboratory. Doing this in a fashion that’s comparatively easy and cost-effective should not be an insurmountable task, and indeed the preliminary results are quite encouraging. Once patients’ cells are replicated, they can be transplanted back into patients to actually cure their diabetes. After such treatment, unless you were to have another autoimmune event that would destroy these new beta cells, you would, at least in theory, remain nondiabetic for the rest of your life. If you had another autoimmune attack, you would simply have to receive more of your replicated cells. Another very hopeful approach currently undergoing clinical trials in humans is the transformation of the precursors of beta cells (the cells that line the ducts of the pancreas) into actual beta cells without even removing them from your body. This apparently can be achieved by the simple intramuscular injection of a special protein and is now being tested for adverse effects at three centers.
Another potential approach might be to insert the genes for insulin production into liver or kidney cells. These are potential opportunities for a cure, and have successfully cured diabetes in rats, but there are still obstacles to overcome.
Yet another approach to replacing lost beta cells has been used by two competing companies to cure diabetes in animals. The technique involves a series of ordinary injections of proteins that stimulate the remaining beta cells to replicate until the lost ones have been replaced. With respect to the replication of beta cells, the catch for me and other diabetics who no longer have any insulin-producing capacity is that the cells from which new beta cells would be replicated ideally should be your own, and I have none. Had my diabetes been diagnosed, say, a year earlier, or had my blood sugars been immaculately controlled immediately upon diagnosis, the injected insulin might have taken much of the strain off my remaining beta cells and allowed them to survive.
Many people (including the parents of diabetic children) view having to use insulin as a last straw, a final admission that they are (or their child is) a diabetic and seriously ill. Therefore they will try anything else—including things that will burn out their remaining beta cells—before using insulin. Many people in our culture have the notion that you cannot be well if you are using medication. This is nonsense, but some patients are so convinced that they must do things the “natural” way that I practically have to beg them to use insulin, which is as “natural” as one can go. In reality, nothing could be more natural. Diabetics who still have beta cell function left may well be carrying their own cure around with them—provided they don’t burn it out with high blood sugars and the refusal to use insulin.