Diabetes: tangled up and blue — the death of a cell
We’ve all heard about the central role of the protein insulin in the life of a diabetic. But did you know insulin’s job is helped/hindered by a partner protein?
One hundred and seventeen years ago, on January 15, 1901, Eugene L. Opie, an instructor in pathology at Johns Hopkins University published a paper in which he described seventeen autopsy cases with a specific focus on the pancreas. When writing about one of those cases, he said “I shall describe a very remarkable lesion of the organ occurring in a girl, who, for two years before death, had suffered from diabetes.” The patient had died at the age of 17. Her clinical history indicated that she had never been healthy, and that two years before her death she complained of extreme thirst and “sugar was found in the urine and has been constantly present in large amount until death. Record of the quantity has not been preserved. Upon diabetic diet the sugar diminished in amount but did not disappear. Marked loss of body-weight was not noted. Death occurred with coma which appeared suddenly and lasted hardly more than twenty-four hours.” Upon microscopic examination of her pancreas, he observed “very conspicuous, sharply defined, round, or oval, hyaline areas….that has at times an indistinctly striated appearance”. He goes on to say that “I have found in the literature no reference to a similar lesion of the gland.” These hyaline areas appeared to prevent adequate blood flow to the tissue they surrounded, eventually killing the tissue. In the field of pathology, the word hyaline is used to describe a substance that is glassy and appears pink when stained with a specific dye; the word is derived from Greek.
More than 80 years after Dr. Opie’s observation, the nature of the hyaline he described was finally determined in 1987 and was variously called amylin, diabetes associated protein (DAP), and islet amyloid polypeptide (IAPP). And this where the story of insulin’s partner protein starts.
Structure influences function
That structure influences function seems obvious — let’s say you have a sleeper sofa and open it out for a guest to sleep, to be closed back when the guest leaves, so that it can continue its main use as a sofa in your family room. The next morning, you find that when you try to close it, the mechanism to release it from the sleeper conformation and get it back into the sofa conformation is broken and unfixable. Much to your chagrin, you now have something that is going to have to function only as a bed. The new structure of that piece of furniture has now given it a different primary function.
Proteins are made up of amino acids that are molecules which are a combination of atoms of carbon, hydrogen, nitrogen and oxygen, with the occasional phosphorous and sulphur atom. These 4–6 atoms in various combinations, and satisfying strict rules, are responsible for about 15% of the body mass of a healthy individual.
Adding or removing an atom or two from any molecule can result in a new molecule that has very different properties — this can be appreciated using a molecule of caffeine as an example. Modifying a single part of the caffeine molecule results in a completely different molecule — theobromine.
Theobromine found in cocoa, while similar in form to caffeine, has very different properties — those who get a buzz from a morning cup of coffee, will not get the same buzz from a morning cup of hot cocoa. Biology is full of examples where small changes in the structure of a molecule result in massive changes in function.
Insulin’s partner
Under normal circumstances, specialized cells in the pancreas secrete insulin on an as needed basis to keep blood glucose levels within an acceptable range, by shepherding the glucose into cells that need it. [Pancreas might sound like a plural, but it is not; the plural is pancreases] In Type 2 diabetes, a condition that is primarily non-insulin dependent, glucose levels are abnormally high either because the pancreas doesn’t secrete adequate amounts of insulin, or that the insulin that is secreted is not able to do its job. These are relatively well known facts. What is less well known is that the pancreas also secretes insulin’s partner along with insulin — islet amyloid polypeptide (IAPP). IAPP, the substance first noted by Opie in 1901, is a protein made up of 37 amino acids, and is an important component of the glucose sensing/maintaining machinery in the body.
Structure of insulin’s partner
In Type 2 diabetes, the high blood glucose levels, cause islet cells — the insulin factories of the pancreas — to work very hard to keep up with the body’s insulin requirement. Along with the higher amounts of insulin produced, are also higher amounts of IAPP. Because of the nature and structure of the IAPP protein, at higher concentrations it tends to tangle up and becomes a disordered mess on the islet cell membranes. A gradual buildup of IAPP ultimately leads to the death of the cells, which means the insulin factory output becomes reduced with time, and blood glucose levels remain out of control — the change in form of IAPP effectively changes its function.
Researchers are working to design molecules that will prevent the tangling up of IAPP, thus helping to keep the insulin factories going, and perhaps reducing the progression of the disease. Initial results using some of these molecules in model systems show promise, and in fact these new molecules appear to be more effective than currently touted remedies like the essential components in green tea, or red wine.
What is particularly interesting in this story, is that the buildup of IAPP on islet cells is very similar to the buildup of beta amyloid in the brains of Alzheimer’s patients. Beta amyloid is almost the same size as IAPP, and they share some similarity in the organization of their amino acids. Both have normal functions in unaffected individuals. However, certain conditions appear to change their structure and function and render them toxic to the body. It is tempting to hope that a molecule that can prevent the tangling up of IAPP in the pancreas, might hold a clue to designing a molecule to prevent the tangling up of beta amyloid in the brain.
Questions
The story of type 2 diabetes is less clear than is that of type 1 — in the latter, previously known as juvenile diabetes, often it is an autoimmune disease accounting for about 5% of all diabetics. The immune system mistakenly attacks the insulin secreting cells, and patients need to get well-timed shots of insulin. Type 2 diabetes occurs later in life, and because of the contribution of insulin’s partner protein’s aberrant function, understanding what causes this aberrant function is important. One of the better understood conditions is stressing out of the pancreas —higher the intake of carbohydrates, higher the concentration of blood glucose (the carbohydrates you eat are broken down in the intestines to a simpler form — glucose); higher blood glucose, means the pancreas has to send out large amounts of insulin, which means it has to also send out large amounts of the partner protein; and at a certain point, the large amounts of IAPP lead to it sitting on the critical insulin factories, and effectively killing them.
Diabetes is one of four leading causes of death from noncommunicable diseases in the world, so keeping an eye on ones carbohydrate intake can go a long way in reducing your risk for diabetes. Exercising and keeping an eye on ones carbohydrate intake can go an even longer way. Don’t stress your pancreas!
