Expert BlogBlog RSS
Related Content
More Posts by this Author
Do Beta Cells Need Secretory Respite?
Posted October 15, 2010 by Christopher J. Rhodes, PhD
Evidence that protecting pancreatic beta cells from chronic overstimulation to maintain glucose homeostasis has led to the concept of “beta cell rest” to preserve or restore beta cell function by temporarily inhibiting insulin secretion. Under normal circumstances this is unnecessary, but in obesity-linked glucose-intolerance and type 2 diabetic conditions beta cells could do with a break.
Normal Beta Cell Function
Normally insulin secretion is required postprandially, so that beta cells are only active a few hours a day and during others already get ”secretory respite.” However, beta cells are not completely asleep functionally because of the balance between insulin production and secretion: for about an hour after insulin secretion is turned off, a parallel up-regulation of insulin production lingers, insuring that the insulin secreted is efficiently replenished to keep the intracellular store of insulin optimal.
Pathologic Beta Cell Function
The situation differs considerably in obesity-linked glucose intolerance or type 2 diabetes. Here, beta cells work strenuously to meet the demand caused by insulin resistance. The resulting hyperinsulinemia is symptomatic of a hardworking beta cell. If accompanied by hyperglycemia, that functional beta cell mass, however hardworking, struggles to compensate, and beta cell dysfunction sets in. This exasperates the situation: beta cells become increasingly vulnerable to stress and exhaustion, eventually prompting loss of additional beta cells.
In this pathologic situation, hardworking beta cells essentially secrete insulin as soon as it is produced. Symptomatic of an obesity-linked glucose-intolerant/type 2 diabetes environment are overworked beta cells with insufficient time to convert fully newly synthesized proinsulin to mature insulin, secreting an increased proportion of less biologically active proinsulin. Also under these conditions (pro)insulin production can fail to keep pace with the high insulin demand, slowly (without therapeutic intervention) decreasing beta cell secretory capacity.
Therapeutic Implications
Therapeutically, protecting and preserving whatever functional beta cells remain in obesity-linked glucose intolerance and type 2 diabetes is key. Insulin sensitizers (e.g., thiazolidinediones), and diet and exercise, alleviate some insulin resistance and consequently take pressure off beta cells. Metformin also helps reduce circulating glucose levels and relieves some glucose-induced secretory demand. Incretin-based therapies, by inducing satiety, can reduce some metabolic demand on the beta cell as well. Also, by up-regulating insulin production in parallel to insulin secretion, GLP-1 analogs augment beta cell function positively by preserving beta cell secretory capacity.
Unfortunately, sulfonylureas lack this balanced effect on the beta cell. Yes, they are potent stimulators of insulin secretion, but an underappreciated fact is that sulfonylureas conversely inhibit proinsulin biosynthesis. Thus they accelerate decreasing beta cell secretory capacity and precipitate the move towards insulin replacement therapy. Of course, exogenous insulin-based therapies can help beta cells by supplementing endogenously secreted insulin.
Some intriguing experimental data suggest that diazoxide (which has an opposing effect of sulfonylureas) and other agents might temporarily inhibit insulin secretion without affecting proinsulin biosynthesis. Several studies indicate that this inhibition can rescue a degree of beta cell secretory capacity and restore normal insulin secretory patterns in type 2 diabetes. While not yet approved for clinical use, the counterintuitive idea of transiently inhibiting endogenous insulin secretion to instigate a period of beta cell rest may soon regain some therapeutic momentum.
Comments
Gretchen,
Doubt the insulin antibodies were the problem...if really interested your doctor can actually measure them. In general, we only tend to see high-levels of these in people who used to take animal insulin prior to the introduction of human insulin in 1982.
A more interesting point not well appreciated (although you do!) is that it is very difficult to get A1C levels below 7% let alone 6.5% in type 2 DM. When we tried it in the ACCORD trial, we were hit with lots of hypoglycemia by the use of mealtime insulin. Another study, called the "Treat to Target Study" using insulin glargine (Lantus) tried as they could with basal insulin but could only get the average A1C down to 6.9%. That was one of the first, but now we have others that show there often is a "wall" when using basal insulin by itself to get below 7%. Mealtime insulin has been tried in other studies than ACCORD [ie, lispro (Humalog), aspart (Novolog), and glulisine (Apidra), but hypoglycemia and weight gain become a huge problem. That is one reason why many of us are excited about GLP-1 analogues [such as exenatide (Byetta) and liraglutide (Victoza)] to be used with basal insulin as a way to both improve A1C and potentialy improve beta-cell function. There were several studies presented at this year's ADA meeting in Orlando showing that basal insulin (in all studies glargine) with exenatide worked extremely well. Note: this is not yet FDA approved, but the research was encouraging and it is likely at some point in the future this will be an "approved" indication for type 2 patients like you.
I've experimented with Novolog, trying to match the insulin with bread, using a CGM so I could get a complete picture, and I concluded that it's simply impossible to do with a fast carb. I mean, you can somewhat lower the peak by using more Novolog, but when you do that, you go low 3 hours later. Even injecting a long time before eating didn't completely get rid of the peak.
Clearly, eating bread along with protein and fat would produce a lower peak. But I decided bread doesn't really taste all that good and I'd rather control by eliminating fast carbs, at least until researchers can figure out how to get the insulin into the portal vein.
I realize this is controversial, but I don't think yo-yo BGs are healthy.
It's very difficult to find the truth when people won't talk to you.
Needless to say, I've already brought up this issue with my endo, who didn't say anything. Clearly, she didn't have an answer. I'm interested in this issue not just for myself but for the theory. I've stopped using insulin, so the response will have no effect on my treatment.
I was going to ask in general terms but thought some details might help. Guess I was wrong. Let me rephrase the question:
Can injecting insulin stimulate the formation of anti-insulin antibodies that would then cross-react with a patient's own insulin?
Interesting question. I'd say there are two points. First, it is true that once someone starts taking insulin, low levels of anti-insulin antibodies can develop. In fact, this happens with almost any injected protein you give (pretty much anytime you take a shot for anything). In the early days of insulin, the levels of these antibodies were quite high and it was thought might contribute to some of the erratic glucose levels seen-not knowing if the insulin would bind to an antibody and not knowing when it would come off.
The other part of the question is still out. We are now nearing the end of the study called "ORIGIN" where patients with early type 2 DM or prediabetes are receiving glargine or usual care. One question will be if the glargine group preserves beta cell function better than usual care. We shall know in about 2 years. There have been other studies, including a large one in China showing putting newly diagnosed type 2 diabetes on insulin pump therapy for a few weeks preserves their beta cell function so they can come off all therapy often for a year. There have been similar studies to that over the years, but it again suggests to me that if insulin is used right it may preserve the beta cell lesion in type 2 diabetes.
Irl B. Hirsch, M.D.
Thanks. That old Biostator experiment showed the benefits of normal BG levels in preserving function. I hope the ORIGIN study will actually test beta cell function with clamp studies and not just infer from HOMA.
The parallel decline in beta cell function in the UKPDS study regardless of treatment suggested that resting or stimulating beta cells didn't matter. But the A1c's of the patients in that study were higher than some type 2s can maintain with low-carb diets, so the critical factor may be BG level rather than type of treatment.
What about resting beta cells by not having them produce the large amounts of insulin needed to metabolize and redistribute ingested carbohydrates?
Dear Dr. Hilts -
A good question, that has a complicated beta-cell biology answer.
It is not so much an issue of insulin production moreso of restoring appropriate functional secretory capacity of the beta-cell. As you probably know, insulin is stored in large dense-core secretory granules in the beta-cell (known as ß-granules). The ß-granules have a half-life of 3-5 days so insulin production is continually required to maintain the secretory pool. Also, there is preferential secretion of insulin from newly formed ß-granules – via the process of exocytosis – which is another reason for keeping insulin production.
In a normal beta-cell there are ~10,000 ß-granules per beta-cell but only about 100 ß-granules per hour are secreted in response to glucose. This is often referred to as the ‘readily releasable pool’ of insulin, and mostly contributes to the first phase of insulin secretion. It is thought that this ‘readily releasable pool’ comprises of ß-granules ‘docked’ at the plasma membrane ready and waiting to be ‘exocytosed’ when triggered to do so in response to a stimulus like an increase in circulating glucose.
In type 2 diabetes, there is a characteristic loss of this important first phase of insulin secretion, giving rise to the idea that the ‘readily releasable pool’ of ß-granules in the beta-cell is severely depleted. The newly formed ß-granules under these circumstances are rapidly targeted for exocytosis to meet the metabolic demand and the ‘readily releasable pool’ never has a chance to form. Consequently, regulated insulin secretion from a type 2 diabetic beta-cell is not so efficient. Actually, the term ‘beta cell rest’ is better titled ‘beta-cell secretory rest’. The idea is to retain insulin production/ß-granule formation but inhibit insulin secretion, to allow the ‘readily releasable pool’ of ß-granules to form again in beta-cells, so that once the ‘beta cell rest’ is removed insulin secretion to be more efficient in response to nutrient stimuli.
I hope that this goes some way to answering your question.
Butler's research has shown that by the time someone is diagnosed as IFG or IGT (prediabetic) they have lost 50% of their beta cells, and by the time they are diabetic they have lost 65-80% of their beta cells. In someone who is insulin resistant compared to someone who is not, the few cells that are left are still trying to produce 4-10 times normal amounts of insulin in response to a given carbohydrate load.
My understanding is that loss of first phase insulin release is one of the first things we see in both Type 1 and 2. It seems at least as likely that it is a result of exhausted, overworked beta cells rather than a primary defect. I'm not sure that forcing the few, the proud, the tired beta cells to resume timely, adequate secretory granule formation is the solution. Sulfonylureas make the beta cells work harder and kill them off faster. Until we can grow more beta cells it seems best to stop the overwork any way possible: reducing insulin resistance, earlier insulin use, and a very low carbohydrate diet being three therapies that address the problem at the root.
I teach my diabetic patients about the damage from glycation from high blood sugar, the effects of hyperinsulinemia and insulin resistance on all aspects of cardiovasular disease, and how few beta cells they have left. When they realize how carbohydrates promote damage in all these areas, they become very willing to try a very low carbohydrate diet. Normalizing blood sugars quickly without hypoglycemia helps them feel better fast, so they stay with the diet.
I think we are barking up the same tree in agreement here. Yes, once 'prediabetes' or IFG or early type 2 diabetes is diagnosed it is indeed very important to hold onto what functional beta-cells remain and not push them too hard. Dietary adjustments, reducing insulin resistance and early insulin use will all help alleviate the pressure on the beta-cells that are left.
Loss of glucose-induced 1st phase and regular pulsatile insulin secretion is a hallmark of beta-cell dysfunction in type 2 diabetes and restoring that would be beneficial. Actually, the same Butler group has shown experimentally that temporarily resting beta-cells, using diazoxide or somatostatin infusions, can restore normal pulsatile insulin secretion in human type 2 diabetes. So there is some evidence for the concept that transient beta-cell secretory rest would be beneficial.
I'm a type 2, and I couldn't seem to get my A1c much under 6 no matter how much I did. (I take metformin and am on a low-carb diet. My current BMI is about 23; at that time I think it was closer to 25.) I've had type 2 for 14 years, so I don't think I'm LADA.
I believed the "beta cell rest" thing, so I decided to try Lantus. Still couldn't get A1c much under 6. So after a year, when I went on Medicare and lost the insurance that had covered the Lantus, I decided to go off it.
Result: A1c went up to 6.6
Now, it's possible that this is simply normal progression of beta cell failure. But I wonder if the exogenous insulin had triggered anti-insulin antibodies that then reacted against my own insulin, requiring me to produce more, which my wimpy beta cells couldn't do.
I know that most people injecting insulin do have anti-insulin antibodies, but I've read that they tend to disappear after 6 months or so.
What's your opinion?
BTW, my last A1c was 5.2, but it turned out local hospital's machine was broken so they sent the samples to Mayo. Maybe the problem was lab error all along.
Thank you for visiting Betacellsindiabetes.org. This website is a resource for physicians and healthcare professionals. The information found here is not a substitute for medical advice, diagnosis or treatment. We encourage you to share this information with your physician.
Thank you!
Post new comment