Ninety-two years elapsed between the publication of Rollo's account and the next turning point in understanding the disease. In 1889, a pair of German scientists, Drs. Oscar Minkowski and Joseph von Mering, associated diabetes mellitus with a malfunction of the pancreas when they noticed that a dog whose pancreas had been removed acquired the disease. The observation set in motion events that led to the first isolation and administration of insulin—in Toronto, Canada, in 1921-22. That seminal discovery was the result of a collaboration between a surgeon, Dr. Frederick Banting; a medical student, Charles Best; a physiologist, Dr. J.J.R. Macleod, who with Banting received the Nobel Prize in 1923; and a biochemist, Dr. J.B. Collip. (A compelling version of this oft-told story—including a still-raging debate over whose work was more central to the finding—can be found in Michael Bliss's classic 1982 book, The Discovery of Insulin.)
During this 90-year period, as the ancient disease grudgingly gave up its secrets, successive findings made their way into the classroom at Dartmouth. There was an early emphasis on therapies, especially the use of medications, even though Rollo had put greater stress on diet. Smith felt, according to notes by an anonymous student, that the best medication was "tinct. canth. given in a quantity sufficient to affect the urethra." This abbreviation for "tincture of cantharides" refers to an alcoholic extract of the blister beetle, sometimes referred to as the "Spanish fly." Cantharidin, a terpenoid, is its active ingredient; when ingested, it irritates the genitourinary tract during excretion, which may reduce minute-to-minute urine flow.
Smith also advised the use of opiates, James Tracy wrote in his 1814 notebook: "For Diabetes. Rx Liq. Laudanum. Tinct. Cantharides of each 1 ounce. Mix together. Dose 30 drops none et vespres in some vehicle." This, too, probably came from Rollo, for he prescribed opium-based medications, such as laudanum, to relieve the pain of diabetes. "None et
vespres" is Latin for "the ninth hour and evening"—a common way then to indicate twice-daily administration of a drug.
In an 1810 lecture, Smith mentioned that "the sympathy between the kidneys and the skin is very great." He apparently held the mistaken belief that increased demand on the kidneys to excrete water was the cause of glycosuria—the excess water purportedly having been absorbed through the lungs. As a result of this belief, both Rollo and Smith prescribed
topical ointments, warm flannel garb, and drugs that induced sweating (including extracts of a tropical plant called Pilocarpus)—all to open up another route of water excretion.
From 1816 on, Smith and his fellow faculty members made increasing mention of the disease's pathophysiology. Smith had actually left Dartmouth in the winter of 1814 but was invited back to teach in the fall of 1816. Ezekiel Allen chronicled a lecture he delivered at 8:00 a.m. on November 7 of that year, covering diseases of the liver, pancreas, and kidneys. Little could Smith have known, given the understanding of that day, but his grouping included three of the organs most important in diabetes mellitus.
Allen wrote: "Diabetes militis [this misspelling of "mellitus" marks the first documentation of Smith using the disease's full name] is apt to be fatal; the urine in this case is sweet. It varnishes the floor, stiffens cloth, the breath has a peculiar odor." Taken together, this appears to be Smith's first reference to diabetic ketoacidosis—a life-threatening stage in the diseasemarked by extreme polyuria and glycosuria, as well as ketosis (an increase in the production of acetone compounds, acetone being the odor referred to in Allen's notes).
Lecturing on a Saturday in November of 1822, according to the notes of student Amory Gale, Dr. Daniel Oliver, amember of the Dartmouth faculty, offered up an early theory about the cause of diabetes. Smith thought the kidneys were the primary organ affected, but Oliver emphasized the "morbid condition of the stomach of forming or evolving the aliment into saccharine matter." He acknowledged that postmortem examination of diabetics showed they often had enlarged kidneys. But Oliver focused, as did Rollo and others, on the gastrointestinal tract as the primary seat of the disease's pathology—though admitting that "the theory, it must be confessed, is in a great deal of obscurity."