The Honeymoon Phase of T1D
The “honeymoon phase” that often occurs with type 1 diabetes usually doesn’t come with the blissful giddiness of the honeymoon phase of new relationships, but it’s still an important foundational period that can potentially be utilized to delay the development of full-blown type 1.
In type 1, there’s a progressive loss of insulin producing beta cells in the pancreas. Significant numbers of beta cells often remain at the time of diagnosis and can recover temporarily once insulin therapy is started. This is the “honeymoon period” when very little insulin at all is needed to keep the glucose levels normal. In some cases, no insulin is needed at all – for a time. The decline in beta cell number does inevitably continue though, and the honeymoon draws to a close. Many individuals do retain a trace of residual beta cell function after this period, and this can really help with improved glucose control with lower insulin requirements, improved variability, and a reduction in long-term complications.
Wouldn’t It Be Great to Extend the Honeymoon Period for Longer?
Might it be possible to stop all the beta cells from getting “burnt out” as we don’t yet have a way to replace them?About twenty years ago, research teams were following up on the two big clinical trials into type 1 diabetes from the ‘80s and ’90s. They noticed the patients in the glucose control arm that was labeled intensive (lots of glucose testing and frequent insulin injections) of the trial had enduring benefits long after the trials had finished – their diabetes was easier to manage over later years with fewer complications. They called this “metabolic memory”, but they couldn’t explain how it worked at the time.
Researchers are now exploring how beta cells might be preserved over long periods of time with all the attendant benefits. It’s difficult to follow beta cell numbers in a living person (we don’t have sufficiently high-resolution scans available yet), so we estimate this indirectly by measuring C-peptide levels in the blood or urine. C-peptide is the scaffolding used by the beta cell while it assembles insulin and is released along with it. Researchers also analyzed the pancreases from people with type 1 who kindly consented to post-mortems for medical research before they died. Amazingly, these show that some patients with even longstanding diabetes of over 50 years still have some beta cells producing small quantities of insulin.
The normal (non-diabetic) C-peptide level in a blood sample after a meal is up in the thousands (pmol/l). As we now know, type 1 diabetes is a progressive disease, slowly reducing the beta cell numbers over several years before we are even aware of it. The onset unfortunately tends to be faster in children than in adults. The C-peptide levels drop as the autoimmune attack progresses, and at around the 500 level we begin to see the typical symptoms of weight loss, thirst, and increased frequency of urination.
Researchers used to think that the magic C-peptide level for a useful beta cell reserve was 200 or above, and studies have clearly correlated this with improved glucose control, less variability, less hypoglycemia, and reduced complications. C-peptide tests have become even more sensitive over the years, and it now looks like even low levels of C-peptide (<50) are still stabilizing.
OK, so why can’t we just take a bit of extra insulin to compensate – how does having such a small number of beta cells in the pancreas really help?
As estate agents in the UK (realtors in the U.S.) are fond of saying, it’s all to do with “location, location, location”. Where you give the insulin really matters, and of course we’re giving it in the wrong place when we inject it under the skin into the subcutaneous tissue. More on this later.
Progressive Beta Cell Loss
Imagine working in an office with 100 staff. It’s a pleasant work environment, and there are enough of you to easily cope with the workload. Gradually a few staff leave, and over a couple of years you’re down to 80 colleagues. You’re all working that little bit harder, but everything gets done on time. This is like stage 1 of type 1 diabetes.
It gradually becomes a less pleasant place to work. More people quit and soon you’re down to 50. The boss asks everybody to work extra shifts. You start to make mistakes and are becoming burnt out. This is like stage 2 of type 1 diabetes.
Things start to go downhill as more staff leave, and soon there are only 10 colleagues left. We’re moving into stage 3 now.
Finally you’re exhausted, and you hand in your notice. At this point the company is put into what we call “special measures” in the UK. A new management team comes in and takes care of all the work (insulin injections) and you’re sent on a much-needed vacation. You recover, and the “honeymoon period” starts (the duration of this period is variable in terms of when it starts and how long it lasts). Surely something could have been done earlier though.
This scenario is rather like the decline in beta cell function. Stage 1 is where the autoimmune attack has started but everything is still working. We can identify this through autoantibody screening. Stage 2 is further down the line (months to a few years later) when the decline in beta cells leads to measurable changes in the blood glucose levels (dysglycaemia). After a meal the blood glucose is higher than it should be and it takes longer to come down, but you’re still in what we call the pre-diabetic phase. Stage 3 is when there are so few beta cells left that the blood glucose is chronically elevated. The usual symptoms develop and the HbA1c is high (above 48 mmol/mol, 6.5%). If left untreated for too long, the patient may present with diabetic ketoacidosis (DKA), a serious metabolic condition caused by lack of insulin that can be fatal.
In Stage 3 there’s an accelerated decline in the beta cell numbers. Beta cells are particularly susceptible to high glucose levels which act as a poison to them, and having to work continuously in the face of the autoimmune attacks leads to stress at the cellular level. The beta cells start to make mistakes when assembling the insulin protein. This further marks them out for attack by the immune system, and a rapid decline in beta cell numbers ensues.
If you take beta cells out of the line of fire at this stage, normalizing the glucose and removing the autoimmune attack, they do indeed recover. This has been demonstrated by looking at beta cells from patients who unfortunately died in DKA.
The current talk of the town is a new “mab” drug, teplizumab, which has been developed to selectively target, and delay, the autoimmune response in type 1 diabetes. More on this in a minute, but first let’s look at why it’s so important to preserve even a small number of functioning beta cells.
When we inject insulin under the skin, we’re limited by a couple of factors. First, it just doesn’t get absorbed quickly. Even the so-called rapid-acting insulins take about an hour to peak, and then hang around for up to four hours. The insulin is diluted into the whole blood volume and by the time it gets to the liver, it’s many times less concentrated than if it had been released by the pancreas sitting right next to the liver. That’s where the importance of “location, location, location” comes in. The insulin just isn’t as effective.
If some beta cells remain functioning, more glucose is able to be processed by the liver, which is the ideal scenario.
Can the Autoimmune Response Be Switched Off?
There has been a lot of research over the years looking at ways to stop, or at least reduce, the autoimmune attack in type 1 at an early stage (stages 1 and 2). We now know that autoimmunity is switched on by an environmental trigger in genetically susceptible individuals. Possible triggers include viruses and diet. We can use immune suppressants to stop the attacks, but the treatment can be worse than the cure. If we disable the whole immune system, then cancers and infections can take hold.
A new and more selective immune modulator, teplizumab, has recently been shown in clinical trials to reduce the rate of decline of beta cell loss in type 1 and is well tolerated. If given early in the course of the disease process (stages 1 and 2) this would add years of excellent control without insulin injections, followed by years of better glucose control and reduced complications. And very importantly, this strategy would reduce the number of patients presenting in DKA, which is a leading cause of morbidity and mortality, particularly in children with type 1 diabetes.
This is a real game-changer, and is currently awaiting approval by the FDA in the U.S. and NICE in the UK. It will likely be the first of many similar drugs to extend the complication-free period.
The Effects of Good Blood Glucose Control, Diet, and Exercise
Are there any other autoimmune modulators? In other autoimmune diseases, both exercise and diet have been shown to reduce the autoimmune response. Type 1 diabetes has been difficult to study, as people don’t present until there are only 10-20% of the beta cells left. And by then they are often in the rapid decline phase we described earlier. It’s like closing the stable door after the horse has bolted. Screening for autoantibodies will allow intervention at an earlier stage when many more beta cells remain, and the effects of interventions to retain beta cells will be more apparent.
What about tight glucose control and the concept of “metabolic memory”? Some of the research data does suggest a link between good early glucose control and maintaining C-peptide response, but overall, the jury’s still out on that one. My personal view is that it is likely to have a positive effect. A study is already underway using hybrid closed-loop automated insulin delivery systems from the time of diagnosis, with C-peptide levels as one of the endpoints in the study.
An interesting publication in 2019 reported that the “honeymoon period” is five times longer in men who did significant levels of physical exercise. Instead of measuring C-peptide levels, they used a surrogate marker: the insulin dose adjusted A1c. This is calculated as the HbA1c (in %) plus four times the total daily insulin dose (in units/Kg/day). The “honeymoon period” is when this number stays less than 9, and this does correlate well with measurable C-peptide levels. The average “honeymoon period” in those who exercised regularly was 33 months, compared to 6 months in those who didn’t. Further research is needed as regular exercise does also increase insulin sensitivity.
Diet is becoming increasingly recognized as a factor in the development of autoimmune disease. Probiotics and a more plant-based diet beneficially alter the gut microbiome and can influence the outcome of inflammation and autoimmunity. Studies are underway looking at this for the prevention of type 1 diabetes. Interestingly, one of the proteins in cow’s milk has a very similar amino acid sequence to a cell surface glucose transporter protein on the beta cell and it may be one of the triggers for autoimmunity. Breastfeeding in infancy is associated with a reduced risk of developing type 1 in later life, and this is likely to be through a combination of mechanisms.
So, What Can We Do Practically as Individuals Now?
We can’t control our genes, but we can control the dietary and exercise choices we make; and we can choose to engage with diabetes education, technology, and peer support. It is eminently sensible to achieve, and maintain, good blood glucose control as early as possible from the time of diagnosis. Education, support, and the use of CGMs are key here. Eating well, with a more plant-based diet has a multitude of health benefits. Regular exercise is recommended for everybody, but is particularly important for those living with diabetes.
We’ll have to wait a few years for the results of clinical trials to confirm or refute the potential effects of good glucose control, diet, and exercise on beta cell preservation. Clinical guidelines already recommend intensive glucose control from diagnosis. Maximizing time-in-range (blood glucose 4-10 mmol/l, 72-180 mg/dl), healthy eating, and regular exercise are all mainstays of diabetes self-management anyway. It’s hoped that these strategies may enhance the effectiveness of new autoimmune modulators such as teplizumab.
If you would like to learn more about the science involved including details of the individual research papers, I thoroughly recommend this article on John Pemberton’s blog. John is a remarkable pediatric diabetes dietician and educator, and has type 1 diabetes himself. What Type of Type 1 Diabetes Do You Have?