Almost 117 years ago to the date, Eugene L. Opie, an instructor in pathology at Johns Hopkins University published a paper on January 15, 1901, 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. 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 today’s cafe starts.
Using a molecular model of caffeine that each of us had a chance to manipulate, Professor Andrew Miranker introduced us to his scientific world that is centered around molecules. Among other things, he studies how atoms and molecules come together in biological systems, and tries to understand their functions both when the molecules are altered, and in their native state. To illustrate how modification of a single part of the caffeine molecule results in a completely different molecule, we removed a part of it as illustrated below.
The new molecule, theobromine found in cocoa, while similar in form 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 chocolate.
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. In Type 2 diabetes, a condition that is primarily non-insulin dependent, glucose levels are abnormally high either because the pancreas don’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 secrete IAPP along with insulin. 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.
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. The Miranker lab has been 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 exist in unaffected individuals and have normal functions. However, certain conditions appear to 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.
As always, this summary barely captures the essence of what was discussed, and if you weren’t able to attend, you’ll definitely want to catch the video recording of the afternoon.
Thank you, Andrew, for an enlightening and hopeful talk — and yes, it’s not simply eating excessively sugary stuff that can throw your glucose out of whack, but carbohydrates in general, including those of the beverage kind! As Ogden Nash famously said, “Candy is dandy, but liquor is quicker” in getting from your intestines to your blood stream.