Sisyphean Efforts to Understand and Treat Type 1 Diabetes
David M. Harlan
National Institutes of Health
About the Lecture
Diabetes mellitus, first described over 2000 years ago, is defined by an abnormally elevated blood glucose concentration. Current estimates suggest that 21 million Americans are afflicted, with devastating and expensive consequences for the affected individual and our society. The body lowers blood glucose concentrations by secreting the hormone insulin which promotes glucose movement into cells. In approximately 10% of cases, the individual develops the disease (called type 1 diabetes or T1D) because their immune system has destroyed their body’s only insulin-secreting cells (“beta cells” located within pancreatic cell clusters called the islets of Langerhans). Revolutionary treatment advances in the last century have allowed subjects once facing certain and imminent death to often lead full productive lives. Current research focuses on understanding the autoimmune process causing the beta cell death, the beta cells’ response to that autoimmune attack, and efforts to generate replacement beta cells for transplant-based therapy.
About the Speaker
David Harlan is a Branch Chief at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in the National Institutes of Health. His areas of research interest are autoimmune illnesses – especially type 1 diabetes mellitus – and immune tolerance mechanisms. From 1999-2003, he served as head of the NIDDK Transplantation and Autoimmunity Branch and more recently as head of the NIDDK’s Diabetes Branch.
He earned his Bachelor of Science degree at the University of Michigan and his medical degree at Duke University. He completed his postgraduate training in internal medicine and endocrinology at Duke. He has held academic medical appointments at the University of California, San Diego, Duke University, and, since 1992, Uniformed Services University of Health Sciences, where he is now Professor of Medicine.
He is a member of several scientific societies and a reviewer for scientific journals. He has published more than 100 scientific manuscripts and chapters. He received the Frank Brown Berry Prize for Federal Medicine in 1997 and the U.S. Navy Legion of Merit in 2000. He served as Ray A. Kroc and Robert L. Kroc Visiting Professor at Stanford University in 2005. In 2006, he received the U.S. Public Health Service Physician Researcher of the Year Award.
President Kenneth Haapala called the 2,241st meeting to order at 8:17 pm September 26, 2008 in the Powell Auditorium of the Cosmos Club. The minutes of the 2,240th meeting were read and approved.
Mr. Haapala introduced the speaker of the evening, Mr. David Harlan of the National Institutes of Health. Mr. Harlan spoke on the title, “Too Sweet: Sisyphean Efforts to Understand and Treat Type 1 Diabetes. He spoke about the illustrious history of Type 1, juvenile onset, diabetes (T1D), what we know and don’t know about the causes, and the current efforts to understand the big questions in treating it.
Many important scientific observations have come from diabetes research, Mr. Harlan began. About 21 million people in the United States have it. About 1 million have Type 1, about 20 million have Type 2, but about 1/3 of them don’t know it. Both types are increasing. The type 2 increase can be at least partially explained by the obesity epidemic, but type 1 is an autoimmune disorder.
It’s a costly disease. The American health care system spent $174 billion in 2007, 1 of every 8 health care dollars. It is the leading cause of blindness, kidney failure, heart disease, nerve defects, and premature death.
Diabetes has been known for more than 2000 years. One of the earliest descriptions, by Aretaeus in 150 AD, called it a “melt down” of the flesh and limbs into urine. Diabetes means siphon. Originally, all they knew was that the patients urinated a lot. Later they found the urine was sweet and they added the word, mellitus, which means sweet. As Aretaeus noted, it is chronic and inexorable. With no treatment, death is fast.
The first treatment was the Allen diet developed by Frederick Allen of the Psychiatric Institute, Morristown, New Jersey. It involved “thrice boiled vegetables.” This diet was akin to starvation. Patients could live weeks or even years.
By chance, Frederick G. Banting, a Toronto physician, was invited to lecture on diabetes. He agreed and then quickly boned up on it. Later, in the middle of a night, he woke up with an idea derived from his reading: ligate the pancreatic ducts of a dog, let the pancreatic enzymes destroy the pancreas leaving the islets of Langerhans where the insulin-making beta cells are located, then refine the leftovers. This led to the discovery of insulin. Banting, a practicing Toronto physician, went to John Macleod at the local University with this idea. Macleod offered to cooperate if Banting would work free and located a student to assist Banting. By the end of summer 1921, Banting and his research assistant, Charles Best, had a dog that was comatose from high blood sugar. They injected it with the extract, and an hour later the dog was standing up. James Collip joined the team in November of that year. He was the first to crystallize insulin.
At the end of that year they had a patient named Leonard Thompson. He was 13 and weighed 65 pounds and much of that was swelling. He was injected with McLeod’s serum, 7.5 ccs in each buttock. An absess was the only result, but when they tried again with an improved serum, the improvement was obvious. Thompson lived to the age of 35.
Banting and MacCleod were awarded a Nobel Prize in February, 1923. This stands as the shortest time between the reason for the award and the award ever. It is a little humbling to realize how much they knew then and how little we’ve learned since, Mr. Harlan said.
He showed a picture of Elizabeth Hughes and her father, Charles Evans Hughes, the governor of New York. At 11, in 1919, Elizabeth weighed 75 pounds. Diabetes set in, and at 13 she weighed 45 pounds. She was treated by Allen from 1919 to 1922. In August, 1922 they began insulin therapy and in January, 1923 she weighed 105 pounds. She attended Barnard College, married, had three children, and died in 1981 at the age of 74.
Life expectancy after diabetes diagnosis had been under a year for centuries. With the diet treatment, it rose to closer to two years. With insulin, it shot up to 40 years.
Three other Nobel prizes have been awarded for work on insulin. Rosalyn Yalow, a nuclear physicist, earned the 1977 prize for developing radioimmunoassay of insulin, which replaced the imprecise biological assay methods. Dorothy Hodgkin, a chemist, identified the structure of insulin using protein crystallography. She took the first X-ray picture of the insulin structure in 1934. In 1969 she finally revealed the structure of insulin. She also identified the structure of other molecules including penicillin. Frederick Sanger, in 1958, received the prize for determining the insulin amino acid sequence. Later, in 1980, Sanger received another Nobel prize for determining the base sequences of nucleic acids, including DNA and RNA.
Mr. Harlan showed a copy of a letter from the Journal of Clinical Investigation, dated in 1955, to Solomon Berson and Yalow rejecting their paper claiming that diabetes resulted from the immune system attacking beta cells. The reviewers could not believe a peptide as small as insulin could induce formation of antibodies.
The pancreas secretes insulin about every six minutes. A shot once or twice a day, while effective, is thought to be a poor substitute. There is considerable interest in improving the delivery schedule. Insulin pumps and insulin monitoring devices are under investigation. These methods do seem to improve the prognoses. Blindness and the other serious effects of diabetes seem to be improved. One man on a pump, Sam Anderson, has had the disease 82 years. Mr. Harlan showed pictures of people wearing patches that looked like big band-aids to monitor blood sugar. Mr. Anderson wore on his belt a box similar to the one Mr. Harlan wore to send microphone signals to the amplifier in the Powell room.
Much effort is going toward producing human insulin. People at the University of California San Francisco have made breakthroughs. Howard Goodman and William Rutter cloned the rat insulin cDNA. Axel Ullrich cloned human preproinsulin, a chemical predecessor of proinsulin which is a predecessor of insulin. Herbert Boyer made progress in recombinant DNA. At Harvard, Walter Gilbert, Argiris Estratiadis, and Lydia Villa-Komaroff made contributions in DNA sequencing, cDNA (complementary DNA) isolation, and using bacteria to make mammalian insulin. A group from Genentech and City of Hope is working on using chemically synthesized genes in e. coli to produce human insulin.
He showed a slide indicating the progress of T1D. Apparently the body has far more beta cells than it needs. The autoimmune disorder works for years to destroy beta cells without apparent effects. When the beta cells go below a certain level, effects turn critical rapidly and patients report to the hospital urinating sugar.
He described an identical twin study called the Sutherland “do-over” experiment. Three diabetic twins received transplants of beta cells from non-diabetic twins. In each case, the diabetic symptoms were relieved, but returned after a short, variable period.
Transplanting the islets of Langerhans from dying people to diabetics has similar effects. It helps about half of the patients, but only for a while.
Overall, the recent diabetes story gives little reason for optimism. Progress since the 1920's, while scientifically substantial, has had modest practical effects.
In the question and answer period, one person asked if autoimmune diseases disproportionately affect body structures that developed recently in evolution. Mr. Harlan said he’d never heard that question before. He didn’t know the answer.
He was asked about the potential for gene therapy. It’s a good idea, he said, but pretty risky. Cells, he said, are like cellophane bags. He would guess that the new cells produced by the new genes would also be attacked by the immune system.
There was a discussion of risks of some new drugs proposed for diabetes treatment. Mr. Harlan again advised against hubris, but he also reflected that aspirin and penicillin also kill some patients.
Reflecting about the nature of the pancreas, he mentioned the three survival rules of overstressed surgeons: Eat when you can, sleep when you can, and don’t touch the pancreas.
He answered a question about genetic determination of the types of diabetes by saying that the evidence is strong that both types are genetic. With T1D, if a person has a parent or a sibling with the disease, the probability of getting it is five times greater.
Mr. Haapala thanked Mr. Harlan, presented a plaque commemorating the occasion, and welcomed Mr. Harlan to membership.
He made the parking announcement. He encouraged visitors to consider membership. He announced the 2,242nd meeting. Finally, at 9:43 pm, he adjourned the 2241st meeting to the social hour.
The weather: Muggy and cool
The temperature: 20°C
Ronald O. Hietala,