It’s been over 40 years now but I can still remember the plaintive cry of my father,” How can this be?!!? I ate nothing today. NOTHING!!!” He was talking about his blood sugar, of course. His diagnosis with type
2 diabetes was old news by that time and he did what his doctors told him: watch what you eat and measure your blood sugar regularly. An extensive clinical study (called the Diabetes Control and Complications Trial) which spanned 10 years and followed thousands of patients, demonstrated conclusively that high blood glucose is the major factor determining the likelihood of complications. Of course, it is the complications that destroy our health. Blood glucose acts like rust, eating away at body parts in characteristic ways. Clearly, then, it follows that if a patient keeps his or her blood glucose levels low, the chances of developing life destroying diabetes complications is vastly reduced. Indeed, one way to control blood glucose is to watch that you eat. Foods high in sugar are going to put lots of glucose in the blood. Even with insulin injections, the ability to get that glucose absorbed quickly is impaired in diabetic patients as compared to healthy individuals. This is only the beginning of the story, however.
To really understand the non-dietary sources of glucose we need to consider the ebb and flow of metabolism. Specifically we need to consider energy storage and release. The most famous molecule in metabolism is adenosine triphosphate (ATP). You’ll even find it advertised in sports energy drinks. The energy of ATP is found in the chemical bonds linking phosphorous and oxygen (phosphate = PO4). ATP is made in the mitochondria, of which, there are several thousand per cell. Glucose is easily converted to ATP, hence our ability to perk up when we cat a candy bar. Besides glucose, other molecules can serve as energy sources; particularly fatty acids and amino acids. These molecules also feed into the ATP generation machine – just not as quickly or directly. It is quite easy to envision our access to these fuels right after we eat. They are right there in the blood and each cell eagerly grabs what passes by. Several hours later things are a bit different. There are still some glucose, fatty acid, and amino acid molecules in the blood but if you could map their source you would find that they did not come from your last meal. They came out of storage. Combine 3 fatty acids and you get a molecule of fat. We all know where our fat is stored (and work hard to hide it). Actually, fat is the king of energy storage as far as biological materials are concerned. It carries the most energy per mass of the various food stuffs. For us, with food within easy reach all the time, it is our bane. For the hunter who does not know where (or when) comes the next meal, fat keeps things going. Fat is stored in a specific kind of cell called an adipocyte. If you string sugar molecules together you get carbohydrates. These are found in most cells throughout the body as they provide glucose to burn as needed to make ATP. Carbohydrates can also be used for structural purposes. Cellulose (cellulite) is one example. When you string amino acids together you make proteins and, as we know, proteins are the machines that make everything work. They are the gene products – our genetic selves made manifest – if you want to get philosophical about it. They are also food storage. Biology can be so ironic sometimes. While all cells have proteins, the major cell type used as a source of protein for food is muscle tissue. So, to reiterate; fat is stored as fat, carbs are everywhere, and proteins are stored as muscle mass.
Enter insulin and glucagon. Insulin orchestrates the storage of nutrients; fatty acids into fats, sugar into carbs, amino acids into proteins. It does so through a complicated set of signals initiated by the activation of the insulin receptor. I tell my students that insulin is the hormone of plenty. Glucagon serves the opposite function and so we think of it as the hormone of fasting. It orchestrates the release of nutrients. Enzymes which chew up carbohydrates to liberate sugars are activated as are similar enzymes in fat and muscle. The muscle story is a bit more complicated though and is integral to our story. Muscle is a bit too busy lifting heavy objects to be bothered with making glucose from amino acids. Instead, it contracts out the job to another body part. The organ that specializes in making glucose from amino acids is the liver. The process has to have a fancy name, of course, so we call it gluconeogenesis. This is the source of glucose in the blood during that time in between meals.
Let’s apply these concepts to the diabetic state. A critical feature of type 2 diabetes is insulin resistance. A good way to think about insulin resistance is to imagine that your satellite TV dish got turned a few degrees by a strong wind. You still get a signal but it is weak and your shows are full of static. If someone massively boosted the signal output from the satellite you might get better reception but the chances are that it will not be perfect. In the same fashion, something has happened to the insulin receptor signal detection process such that we need to put in a massive amount of signal (insulin) to get something that approaches a correct response. We are actually beginning to learn what happens to the receptor to create insulin resistance but that is a topic for another post. Instead, I want to focus here on the interplay between insulin and glucagon. The major stimulus of glucagon secretion is blood glucose BUT…..insulin is required for the alpha cells of the pancreas to detect that glucose. If the insulin signal is degraded, as is the case for the state of insulin resistance, then the alpha cells cannot tell that there is plenty of blood glucose present. They are perpetually sensing the fasting state and so they are perpetually secreting glucagon. Glucagon travels to the liver and initiates gluconeogenesis – pumping out sugar by the bucket loads.
The reason for my father’s frustration is now clear. The sugar he found in his urine (this was long before digital glucometers) came from muscle proteins via the liver. Besides the glucagon there is a second reason why the liver is the problem child for diabetic patients. When insulin is secreted from the pancreas it does not go into the blood stream proper. Instead, it goes into a special blood stream delivery system called a portal system. Where is it delivered? Straight to the liver. The concentration of insulin in the liver during is about twice that of the rest of the body under normal circumstances. Contrast this with the mode of insulin delivery for diabetes. It slowly enters the bloodstream via capillaries in the abdomen and immediately goes systemic. Here the concentration of insulin is more or less equal throughout the body. To fully control gluconeogenesis we have to overdose other parts of the body and risk hypoglycemia. The diabetic patient is between a rock and a hard place. We need to find new ways to target the liver if we are to truly recapitulate therapeutically what the healthy pancreas does.