We all know that in Type 1 diabetes, the pancreas’ beta cells cease to function. But are they eliminated? Do they die? Or are they merely “stunned?”
The question remains hotly debated among researchers, and may have immense consequences for attempts to find a treatment or even a cure for the disease.
Dr. David Leslie, Professor of Diabetes and Immunology at London University’s Blizard Institute, believes that they are stunned: “Maybe these beta cells are there. Maybe they do respond, or can be induced to respond in some way.”
We came across Dr. Leslie when he published an analysis of the surprising persistence of C-peptide in patients with longstanding diabetes: C-peptide persistence in type 1 diabetes: ‘not drowning, but waving’? In our first conversation, Dr. Leslie explained to us that Type 1 diabetes is far more common than almost anyone understands, because such a high percentage of people with the condition are adults that do not necessarily require insulin. These adults are rarely identified with the correct diagnosis.
That study discussed a second complexity that is not commonly understood: many people with T1D are able to retain insulin production long after diagnosis. This is good news for experts who are working hard on the holy grail of beta-cell restoration.
First, a quick refresher. C-peptide is an amino acid that is formed as a byproduct of the body’s natural formation of insulin. The pancreatic beta-cells create and store an inactive substance named proinsulin. When the body requires more insulin, this proinsulin is split into two different substances: C-peptide and insulin itself. Whenever a healthy pancreas produces insulin, it also produces an equivalent amount of C-peptide.
C-peptide is considered a more accurate indicator of natural insulin levels than insulin itself, both because insulin levels in the blood can vary so much throughout the day and because injected insulin contains no C-peptide at all.
When patients with long-lasting diabetes are tested, the traditional tests used to detect C-peptide will usually return a result of zero. But in recent years researchers have developed more sophisticated and sensitive assays that can detect smaller amounts.
What they’ve learned is that C-peptide production (and thus insulin production) tends to persist for many years. And it does appear that even minuscule amounts can really matter: “People who have more C-peptide do have less difficulty, on average. Less risk of hypos, less variability in their glucose control, and less complications, as well.”
This fact was confirmed in a remarkable way by the Joslin Medalist survey, which analyzed over 400 people that had lived with T1D for over 50 years. Using the older, less sensitive C-peptide test, they found that the majority of “medalists” still showed signs of endogenous insulin production. This was something of a bombshell, and it still prompts significant questions. Are the Joslin medalists long-lived because they’ve retained some native capacity to secrete insulin?
C-peptide persistence is highly correlated with diabetes duration. Typically, those that were diagnosed recently at an older age have the highest C-peptide readings, and those diagnosed in childhood many years ago have the lowest. However, within each cohort there will be variations from one person to another, variations that we cannot entirely account for. Partly it is genetically determined – the luck of the draw – and interestingly, the genes that appear to be associated with C-peptide persistence are not among the genes that are associated with susceptibility to Type 1 diabetes itself.
Not Drowning, but Waving
In his paper Dr. Leslie uses a reference to a Stevie Smith poem, a metaphor of an ocean swimmer seen far from the coast. Are the beta-cells thrashing their arms, struggling against imminent death? Or are they waving to us?
“Epistemological studies are coming through that are showing that there are beta-cells which are still alive – are they producing or not? They’re certainly there.”
Sophisticated testing has also revealed that the beta-cells of people even with long-standing Type 1 diabetes are still chock full of proinsulin. The ability to secrete proinsulin appears to persist even as C-peptide levels fall below the detectable level, and proinsulin secretion even appears to respond to glucose levels. This suggests that the beta-cells are still alive and are still productive, but have somehow lost the ability to cleave proinsulin.
Nevertheless, the idea that beta-cells are “stunned” rather than dead ultimately remains an assumption. Actual stimulation or reactivation remains a holy grail of research and experimentation. But Dr. Leslie supports his assumption with evidence of other situations where beta-cells are known to lose and then recover effectiveness:
“There is evidence that in Type 2 diabetes that is the case. You go on a diet and you recover your beta-cell function.
“The pattern of change in so-called stunned beta-cells is the same in Type 2 diabetes as it is in very early or even pre-Type 1 diabetes. The loss of glucose sensitivity is common to both forms of the disease, and the increase in proinsulin and by implication the problems with conversion of proinsulin to insulin, are also features of both early stages of the disease.
“Then are these cases of gestational diabetes, where women develop diabetes during pregnancy and they recover after pregnancy. They have all the features of Type 1 – a significant proportion of them have autoantibodies – they recover after they’ve stopped being pregnant, and then later develop the disease. That suggests that there’s this potential for recovery.
“The other scenario with recovery is the so-called ‘honeymoon period.’ You can easily imagine that you present with diabetes, the glucose is very high, which is toxic to the beta-cells, the beta-cells are screwed, stunned, buggered, whatever you like to call it, and then the glucose comes down with treatment and suddenly they have a recovery period.”
Dr. Leslie is in close contact with investigators running several studies that are experimenting with different ways to get the beta-cells “tickled up” to start producing insulin. So far, however, he is pessimistic about the results.
“What we really don’t know is, will it work? It would be wonderful if it did, but we have no idea.”