DIABETES PHYSIOLOGY

Basics of physiology in diabetes

Insulin secretion by islets of Langerhans

Minimal model of diabetes

Basics of physiology in diabetes

Glucose is the main fuel in the human body. Every cell uses glucose for energy, and some organs such as the brain rely exclusively on glucose for their metabolism. Circulation of the blood provides the transport of this important fuel. In healthy people the absorption, creation, uptake and utilization of glucose are under tight control so that the level of glucose in the blood varies only a small amount from minute to minute and from hour to hour. This ensures that every cell in the body has the amount of food it requires. Normal blood glucose is 80 milligrams per deciliter (mg/dL) or 5 millimolar (mM).

Glucose is a carbohydrate. There are three principal sources for the glucose in blood: alimentary glucose from the breakdown of dietary carbohydrates in the gut, glucose released from stores in the liver, and glucose made from protein in the liver. As shown in the diagrams below when you eat glucose is taken up in the gut and transported to the liver. The liver acts as a reservoir for glucose for maintaining the constant concentration of glucose in the blood. Excess glucose is taken up by the liver and stored as glycogen or converted to fat. Between meals the liver maintains the blood glucose concentration by breaking down the stored glycogen.

Insulin is the hormone that tells the liver when to take up glucose and when to release it into the blood. Regulating blood sugar is the primary effect of insulin, and it occurs quickly, on the order of minutes. Insulin also has growth promotion (or mitogenic) effects; these take hours to induce and last hours to days. As we will discuss below, insulin is produced in the pancreas by specialized cells that maintain stores of this protein for quick release after a meal.

Blood circulation also provides for the transport of insulin from the pancreas to the liver and on to the rest of the body. This is demonstrated on the diagram to the right, showing a simple scheme of general circulation. It is well known that blood is pumped twice by the heart, once to perfuse the lungs (for gas exchange) and once to perfuse the rest of the body. It is less well known that blood sometimes passes through two tissues in sequence before returning to the heart.

Call 'portal' circulation, the most important of these systems involves the liver. In the diagram note that the vascular bed labeled "intestinal circulation" (which includes the pancreas) drains to the liver. The portal vein is colored purple in the diagram. The liver in perfused by two sources: blood fresh from the heart through the hepatic artery and as well as blood rich with newly absorbed nutrients through the portal vein.

The gut absorbs food carbohydrate including glucose (and other nutrients). It is relatively quiescent when there is no food. At left are shown the principal components of the gastrointestinal tract. All blood from the gut is collected in blood vessels in mesenteries and goes first to the liver via the portal vein before going on to the blood pool. The liver is privileged to receive nutrient enriched blood before the rest of the body.

For diabetes metabolism, the important points are:

  • insulin passes first through the liver
  • food nutrients pass first through the liver

(The Islet Sheet is designed to deliver insulin into the portal circulation. Any site in the abdomen can work. We think that suturing the sheet to a mesentery is promising. A large mesentery with the special name omentum, which wraps around the stomach (not shown in the diagram), is the most promising of all.)

The central actor in stabilizing blood sugar is the liver; it has been called the glucostat of the organism. After a normal carbohydrate-rich meal, it removes about 50% of the excess nutritional glucose to synthesize liver glycogen and to synthesize fat. Glycogen is a polymer of glucose that is readily mobilized from stores in the liver. It is very similar to muscle glycogen. During the short fast between meals or a longer fast for several days, as well as during exercise, the liver supplies over 90% of the glucose needed by the body cells via glycogenolysis (mobilization of glycogen) and gluconeogenesis (metabolic conversion of protein to glucose).

The short-term regulation of carbohydrate metabolism is the reversible shift from glycogen synthesis and glycolysis to glycogenolysis and gluconeogenesis. Three major factors are involved in the regulation of this balance: substrate concentrations, hormone levels, and activity of hepatic nerves. The longer-term, day-to-day control of carbohydrate metabolism is determined by whether the food carbohydrate supply falls short of or exceeds metabolic needs. In healthy metabolism excess fuel decreases appetite and increases metabolic rate. Put simply, excess fuel is burned. The major site of this activity is brown fat, a type of fat cell that uses "futile cycles" of metabolism to convert glucose into CO2 and heat.

The diagram at the left shows how the pancreas relates to the liver. 98% of the secreting cells in the pancreas make digestive enzymes that go to the intestines via the pancreatic duct. The remaining 2% of the cells, in the islet of Langerhans, make hormones that are secreted into the portal vein. (The endocrine system is the set of ductless glands that add hormones to blood; these include the adrenals and pituitary as well as the islets of Langerhans.)

The islets of Langerhans, found in the pancreas, have a special role in glucose control. They function as a glucose sensor, releasing insulin when blood glucose passes above 80 mg/dL and glucagon when glucose passes below 80 mg/dL. All insulin secreted by the islets passes through the liver where most is absorbed. Uniquely among peptide hormones, much of the absorbed insulin is returned to the blood after passing through liver cells. However, insulin has many effects on the liver as it passes through. It suppresses production of new glucose by glycogenolysis and gluconeogenesis and enhances uptake of glucose and its conversion to glycogen and fat. Furthermore insulin enhances the oxidation of glucose, which produces CO2 and heat.

All body cells take the glucose for their own energy as they need it. Muscle and fat cells are special because they take up much more than they immediately need, and either store it or burn it. Muscles all over the body participate. This 'extra' uptake of glucose is stimulated both by the glucose itself and insulin. The two signals work synergistically. In the healthy state the system is so responsive that under maximal stimulation over 4% of the glucose in blood can be removed per minute! This is why exercise can partially compensate for impaired insulin metabolism and is an important component of diabetes care.

The following diagram shows flow of principal fuels during two extreme states: feeding and fast. All the pathways shown during feeding are stimulated by insulin. Glucose from the meal is taken up by the liver and converted to glycogen and fat. During fasting the muscles and liver convert glycogen to glucose. The muscles can also convert fat into fuel, but this is a slower process. In an extended fast the muscles lyse their protein into amino acids, and the amino acids are taken up by the liver and partially converted to glucose. Thus, in starvation, the body breaks down muscle to make glucose to feed the brain, which can only use glucose as fuel.

Without insulin the 'feeding fuel flow' is turned off and the 'fasting fuel flow' is always on. Insulin would inhibit the release of fat by the fat cells, release of amino acids by muscles, and conversion of stored glycogen into glucose. Uptake of glucose by tissues, including muscle and fat, declines sharply to their insulin independent rate, and each cell takes only enough glucose to meet its minimal needs. Muscle cells need more energy than others (they do the work!), and so derive some of their energy from stored fat. In order to meet the energy needs for the rest of the body, most importantly to maintain a sufficient supply of energy to the brain to prevent death, the liver must continue to produces large amounts of glucose. It is forced to create glucose by breaking down muscle tissue. Muscle protein is converted to amino acids and transported to the liver for conversion to glucose.

IDDM, in the absence of treatment with insulin injections, results in the consumption of muscle tissue to provide sugar. This process of emaciation is followed by death, usually within months of diagnosis. Before the discovery of insulin the only therapy that extended the life of diabetics was fasting. In diabetes, blood sugar levels can become very high, many times normal. Instead of 4 grams of glucose, the blood might contain over 30 grams; at this concentration the renal threshold is surpassed and excess sugar passes into the urine. The resulting copious flow of sweet urine gives the disease its name: "sweet siphon." Renaissance physicians called diabetes "the pissing disease."

The discovery of insulin has made possible therapy that extends the life of people with IDDM. Before insulin, the life expectancy at diagnosis of IDDM was a few months. After insulin, the life expectancy at diagnosis of IDDM is about half that of nondiabetic persons, an improvement but not the ideal solution.

Insulin secretion by islets of Langerhans

The islets of Langerhans, which are found distributed throughout the pancreas of higher organisms including all mammals, collectively constitute a small but critical endocrine organ. By weight or volume the islets are approximately 1% of the pancreas. In a human, the pancreas is situated beneath the stomach and weighs a few hundred grams. It contains about a million islets, which altogether weigh only a few grams. Islets are well vascularized, and are also enervated by the autonomic nervous system. The bulk of the pancreas produces pancreatic juices that aid digestion of food.

An individual islet is made up of several types of cells each specializing in the secretion of a particular hormone. Three-quarters of the cells are beta cells that secrete insulin. Alpha cells secrete glucagon, and delta cells secrete somatostatin. Beta cells tend to be found in the heart of the islet, other cells at the periphery. In addition to these three main cell types which constitute the bulk of the islet, there exist in minute quantities rarer cell types which also produce hormones. Hormones secreted by each type of islet cell may suppress or enhance secretion by other islet cells.

The islet is more than a collection of cells. The islet cells are connected by gap junctions which permit the free flow of lower molecular weight substances from one cell to another. In effect, the cells of the whole islet share all their cytoplasm as one. This evidently aids in secretion.

Beta cells are a miracle of specialization. These cells can store a great deal of insulin in insulin-zinc granules in the cytoplasm. The cytoplasm appears dark in electron micrographs. When blood sugar rises to a critical level, within seconds granules containing insulin-zinc crystals fuse with the cell membrane; and the insulin and zinc are released into capillaries that wind through the islets destined for the portal vein and the liver.

The pattern of insulin secretion by islets is nonlinear. The first phase response is rapid, massive, and brief. The second phase response is slower and continues as long as food is being absorbed. The diagram shows this two-phase response. (This response is blunted in a fiber bio-artificial pancreas.) Mimicking this behavior is difficult to do by mechanical means. This is why we choose to let natural islet cells regulate insulin production in the Islet Sheet; other (e.g. Genetically engineered) cells just can match the insulin release profile of real islets.