Beta Cell Dysfunction

Summary

Beta Cells and Diabetes

Environmental factors that can affect or stress beta cells may be involved in accelerating the progression of type 1 diabetes, and perhaps type 2 diabetes as well. As such, they may contribute to the increasing incidence of this disease in children and its appearance at younger ages. Whether beta cell stress can in fact trigger autoimmunity or increase an autoimmune attack on themselves is an interesting area of current research.

In type 1 diabetes, the beta cells do not produce enough insulin. This is generally due to the death of the beta cells. By the time someone is diagnosed with type 1 diabetes, they may have lost 70-80% of their beta cells (it is thought, although more recent studies are testing this number). Beta cell loss occurs gradually over time, beginning before diagnosis, and continuing afterwards, until most beta cells are lost (Cnop et al. 2005). However, new research is also finding that some people with type 1 continue to produce insulin for many years (Davis et al. 2015; Oram et al. 2015), as well as proinsulin (a precursor to insulin) (Steenkamp et al. 2017), and that beta cell dysfunction (not just death) may also be a significant cause of high blood sugar, at least around the time of diagnosis (Pugliese et al. 2014). While some research suggests that beta cell mass and function is maintained until just before diagnosis, and declines rapidly after diagnosis (Rodriguez-Calvo et al. 2017), others note that signs of beta cell dysfunction can occur even years before diagnosis (Sims and DiMeglio, 2019). The younger the age of onset, the less likely that the person will continue to have some beta cell function (Carr et al. 2022).

Interestingly, more new research is finding that some beta cells can be resistant to the autoimmune attack, which may be why some people keep some beta cell function for many years (Holmes 2017; Rui et al. 2017; Wang et al. 2022). A study of Joslin medalists who have had type 1 for over 50 years has found that all of them had some residual beta cells that were producing insulin! (Yu et al. 2019). New research also shows that beta cells are heterogeneous, that is, individual cells differ in their ability to produce and release insulin (Avrahami et al. 2017; Benninger et al. 2018). It appears that some beta cells do persist in some people with type 1 diabetes, although not everyone, and that new ones are not being made (Lam et al. 2017). Some have found that beta cell function declines rapidly in the first 7 years after type 1 diagnosis, with a more stable period thereafter (the younger the person, the lower the beta cell function, no matter what the duration of disease (Shields et al. 2018). There is also discussion about whether beta cells are actually "dead" or just "sleeping" (Oram et al. 2019). Interestingly, analysis of the pancreas of organ donors with type 1 diabetes (via NPOD, the Network of Pancreatic Organ Donors with Diabetes) shows that beta cell loss, beta cell dysfunction, and infiltration of immune cells into the islets was different in individual people all with type 1 diabetes, showing that the disease process varies depending on the individual person (Panzer et al. 2020). One case study, for example, found that in a 22 year old who had had type 1 for 8 years, after death, his pancreas was analyzed and it turns out that many beta cells were still secreting insulin (Haliyur et al. 2021). NPOD research also shows that some islet cells in people with type 1 still contain low levels of insulin, even if these aren't coming from beta cells. They hypothesize that maybe the alpha cells are the source of the insulin (Lam et al. 2019). This will be something to watch! NPOD research also shows that various genes are expressed (function) differently in the pancreatic tissue of people with autoimmunity and type 1 diabetes (Yip et al. 2020). A research topic in Frontiers in Endocrinology called "Footprints of Immune Cells in the Type 1 Diabetic Pancreas" discusses this idea further (Brusko et al. 2021).

Type 1 diabetes is an autoimmune disease, and beta cell death in type 1 is thought to be largely due to an autoimmune attack on the beta cells (Narendran et al. 2005). The attack on the beta cells is a type of inflammatory reaction called "insulitis" (i.e., inflammation of the islets). During the development of diabetes, beta cells are very susceptible to inflammatory proteins (cytokines). Inflammation can cause the beta cells to actually present themselves as targets of the immune system, enhancing the T cell attack that kills them (Gorasia et al. 2015). Whether the beta cells themselves play a key role in disease development or amplification due to their vulnerability or other features is a hypothesis under discussion (e.g., Hansen et al. 2024; James et al, 2023; Mallone and Eizirik 2020; Mallone et al. 2022; Roep et al. 2020; Roy et al. 2024; Thea and Buschard, 2024; Thompson et al. 2023; Toren et al. 2021). Surprisingly, researchers have found that the numbers of autoreactive T cells are just as common in the pancreatic tissue of people without type 1 as in people with type 1. During type 1 development, these T cells clustered around the islets. This finding implies that something about the islets attracts the T cells and perhaps invites the attack (Bender et al. 2021; Bender et al. 2020).

According to Dr. Ziegler, a long-time type 1 researcher, the question is, "When, how and why does the clock start" its countdown to type 1 diabetes?  She argues that the first two years of life is a susceptible time for acquiring beta cell autoimmunity, perhaps because of high beta cell activity and vulnerability to stress, early exposure to infections, and a heightened immune response. She argues that beta cell injury preceeds the initiation of autoimmunity (Ziegler 2023).

New research is finding that there are actually two types of insulitis, which somewhat depends on the age of onset (Morgan and Richardson 2018). New data is supporting the argument that beta cell damage happens earlier than previously thought in the development of type 1. This beta cell damage may even contribute to autoimmunity (Horwitz et al. 2018). Other authors are also pursuing looking at the early signs of type 1 in the pancreas (e.g., Crookshank et al. 2018). Some propose that autoimmunity may play a stronger role in people with a younger age of onset, and beta cell factors play a stronger role in those of older ages (Carré et al. 2021).

Identifying type 1 diabetes early in the disease process can help preserve beta cell function. The TEDDY study identifies children who test positive for autoantibodies before diabetes develops, and identifies children with diabetes before symptoms even develop. These children have more beta cell function for at least a year following diagnosis than those diagnosed in the community based on symptoms (Steck et al. 2017). Yet so far most efforts and trials to preserve beta cell function in people newly diagnosed have been unsuccessful unfortunately (with a couple of exceptions, however) (Narendran et al. 2021). Intensive diabetes control after diagnosis would presumably help preserve beta cell function, but actually some studies find that it does not (McVean et al. 2023).

Pregnancy is also a time of better beta cell function. Even women with type 1 diabetes can have increased beta cell function during pregnancy, and researchers are trying to figure out why (Nalla et al. 2020). It may be due to the fetus secreting insulin, and not due to beta cell regeneration (Meek et al. 2021). Yet there is at least one case study of a person with type 1 diabetes who had low beta cell function that increased ten years later (Fenner et al. 2022). I mean maybe there was some error in the earlier measurement, but maybe we should take note!

Newer human studies are finding ways to identify people who may develop type 1, very early in the process. High blood sugar is a sign of impending type 1 diabetes (Steck et al. 2019). It turns out that lower glucose levels are also a possible sign (Heinrich et al. 2018; Yamaguchi et al. 2019). This finding also implies that beta cell function is disrupted in different ways in early type 1. Beta cell dysfunction, in fact, has been found may precede type 1 diagnosis by more than 5 years (Evans-Molina et al. 2018). The TrialNet study of family members of people with type 1 diabetes found that beta cell function did not change significantly until 6 months before the clinical diagnosis of type 1 diabetes, when it started to decline rapidly, and then continued to decline postdiagnosis. The rates of decline for the first 6 months postdiagnosis were similar to the 6 months prediagnosis (Bogun et al. 2020). 

Both type 1 and type 2 diabetes may involve beta cell dysfunction or death, although perhaps for different reasons, and in different points in the disease process. There are a variety of mechanisms and processes involved in the eventual death of beta cells in both type 1 and type 2 (Rojas et al. 2018). There are also similarities in the mechanisms and processes involved in beta cell failure/death in type 1 and type 2 (Ikegami et al. 2021). Even in type 1 it seems there are various ways that beta cells can die, like both apoptosis and necrosis, and others involving inflammation (Colglazier et al. 2024). It appears there is a sort of "spectrum" of c-peptide (a marker of beta cell function) in diabetes of both types. In a Scottish study, c-peptide was lowest in those diagnosed at the youngest ages, and in those who have had diabetes the longest, and it varies by genetics. Interestingly, some beta cells might be "stunned" instead of "dead," which implies that perhaps they could be revived (Leslie and Vartak, 2019; McKeigue et al. 2019).

Numerous environmental factors can affect beta cells, largely as shown in laboratory studies, including many factors discussed on this webpage, such as viruses, autoimmunity, pharmaceuticals, and environmental chemicals (Anděl et al. 2014).

Environmental chemicals can also affect alpha cells, which also play a role in blood glucose control by secreting glucagon (Al-Abdulla et al. 2023; Dos Santos et al. 2022; Mannino et al. 2022). Alpha cells can be affected by diabetes as well (Göke 2008; Yosten 2018). It seems that alpha cells may be dysfunctional in type 1 diabetes, but not dead, for a variety of reasons (Eizirik et al. 2023).

Other parts of the pancreas may also be affected by diabetes, including the exocrine pancreatic function (important for digestion) (Kondrashova et al. 2018; Radlinger et al. 2020; Vecchio et al. 2019). The exocrine pancreas may even play a role in type 1 diabetes development (Kusmartseva et al. 2019; Atkinson and Mirmira, 2023). The exocrine pancreas function decreases in children who progress to autoimmunity and type 1 diabetes, sometimes even before autoimmunity develops (Penno et al. 2020). The volume of the pancreas may also decline in the first year after diagnosis, and in those antibody positive (Virostko et al. 2019), and even in first degree relatives of people with type 1 diabetes (Campbell-Thompson et al. 2019). Changes in the levels of exocrine pancreas enzymes may be able to be used in identifying people at risk of developing type 1 diabetes (Ross et al. 2021). A review of exocrine pancreatic function in type 1 diabetes concludes, "Exocrine pancreas abnormalities often occur in T1D. Whether exocrine dysfunction occurs simultaneously with β-cell destruction, as a result of β-cell loss, or as a combination of both remains to be definitively answered." (Foster et al. 2020).

It seems pretty clear now though that non-immune processes like insulin resistance or obesity can stress beta cells, as well as amplify autoimmunity and contribute to type 1 diabetes (Redondo et al. 2019).

Using newer techniques, scientists have been able to start to measure beta cell decline and dysfunction in people before they are diagnosed with type 1. They have found that both beta cell death and dysfunction are present in people before diagnosis, along with a decline in insulin secretion. Around the time of diagnosis, there is a dramatic increase in beta cell death. Metabolic dysfunction is also found before diagnosis (Herold et al. 2015). Researchers are beginning to identify new markers of beta cell destruction that could be used to help predict the onset of type 1 diabetes (Yi et al. 2018).

Some authors propose that, "when autoimmunity leads to a fall of beta cell mass during the progression of type 1 diabetes, rising glucose levels cause major changes in beta cell identity. This then leads to profound changes in secretory function and less well-understood changes in beta cell susceptibility to autoimmune destruction, which may influence of rate of progression of beta cell killing" (Weir and Bonner-Weir, 2017). Thus, an interaction between autoimmunity and beta cells, or maybe a vicious circle.

Other authors propose that beta cells are particularly susceptible to endoplasmic reticulum (ER) stress, which can be caused by a variety of factors, and ER stress that is more severe or prolonged may contribute to the development of type 1 diabetes (Cao et al. 2019; Marré and Piganelli 2017).

Dr. Barbara Corkey and others propose that inflammation and oxidative stress (perhaps caused by a virus, for example) in sensitive people can target the beta cell and alead to autoimmunity (Corkey et al. 2022). I've discussed this with her but I can't say I fully understand it... it deserves a closer look however.

Traditional Chinese herbal medicine, meanwhile, is protective of beta cells, although so far this is only documented in animals (Nozaki et al. 2017). Some argue that treating people with type 2 drugs like metformin might help reactivate dormant beta cells, although this is also untested (Josefsen et al. 2022).

A number of environmental factors may be able to stress or overload beta cells, including increased growth rates (in height and weight), viruses, stress, puberty, and some nutritional factors. Vitamin D can protect beta cells from inflammation, while vitamin D deficiency can impair insulin secretion. Nicotine also affects beta cells, which may be one reason smoking is linked to an increased risk of type 2 diabetes (Sun et al. 2020). A review notes that "Both under- and over-nutrition in utero, or exposure to adverse environmental pollutants or maternal behaviors, can each lead to altered β-cell or function at birth, and a subsequent mismatch in pancreatic hormonal demands and secretory capacity postnatally. This can be further exacerbated by metabolic stress postnatally such as from obesity or pregnancy, resulting in an increased risk of gestational diabetes, type 2 diabetes, and even type 1 diabetes." (Hill, 2021).

An experimental study of humans finds that those with higher levels of persistent organic pollutants (POPs) had lower insulin secretion after a glucose-tolerance test-- the insulin levels of more highly exposed people were fully 30% lower than people with lower levels! Meanwhile, exposing laboratory beta cells to these POPs also decreased insulin secretion, even at very low levels (Lee et al. 2017).  A review of the evidence of beta cell toxicity and POPs (including PCBs, organochlorine and organophosphate pesticides, dioxin, PFAS, and flame retardants) finds that, "the available data provide convincing evidence implicating POPs as a contributing factor driving impaired glucose homeostasis, β-cell dysfunction, and altered metabolic and oxidative stress pathways in islets. These findings support epidemiological data showing that POPs increase diabetes risk and emphasize the need to consider the endocrine pancreas in toxicity assessments."  (Hoyeck et al. 2022).

Numerous endocrine disrupting chemicals that have been shown to affect beta cells could have implications in the development of type 1 diabetes (in addition to type 2) (Bonini and Sargis 2018). 

Hectors et al. (2011) review the effects of various chemicals on beta cells, including persistent organic pollutants, estrogenic compounds like bisphenol A, and organophosphorous pesticides. I asked these authors how chemicals could both increase and decrease insulin secretion? There may be a few reasons. One, some endocrine disruptors can have opposite effects at high or low doses (because of how hormones act). Two, the effect might vary depending on whether the experiment was done in animals or in cells, or which species of animal or type of cells were used.

Importantly, either increasing or decreasing insulin secretion could be significant for diabetes development. If secretion is decreased, high glucose could result. If insulin secretion is increased, that could lead to increased levels of insulin in the body (increasing insulin resistance), and eventual beta cell exhaustion (Hectors, T., pers. commun., 2011). Increasing insulin secretion may hasten beta cell dysfunction and death in the long-run (Aston-Mourney et al. 2008). "It is clear that some environmental pollutants affect pancreatic beta cell function" and these mechanisms may play a role in diabetes development (Hectors et al. 2011).

Dr. Hectors has worked to identify a line of beta cells that could be used in the laboratory to screen environmental chemicals (or pharmaceutical drugs) for their potential ability to affect these cells. One cell line that she tested did not seem to be appropriate to use as a screening system (Hectors et al. 2013). Other authors are also developing screening tools (Chen et al. 2018) with more success (Al-Abdulla et al. 2022). One screening tool, for example, seems to work appropriately for 6 chemicals. They found that BPA and TBT caused beta cell death, while PFOA decreased insulin secretion and TBT increased it (Dos Santos et al. 2022). Human pluripotent stem cells can also be used to help identify chemicals toxic to beta cells (MacFarlane and Bruin, 2021). And, zebrafish are also being used to identify chemicals that affect the pancreas during development (Sant et al. 2016). So the search continues. Identifying a screening system could more easily facilitate the identification of chemicals that may play a role in diabetes development.

As several nutrients and environmental toxic chemicals can stimulate insulin secretion without involving insulin resistance, some authors wonder whether beta cell dysfunction in type 2 diabetes is due to impaired beta cell function (beta cell "failure") or if chronic over-stimulation of the beta cells ("beta cell abuse") is the main abnormality in type 2 diabetes (Erion and Corkey 2018). Good question. And I think this question would apply to type 1 diabetes as well.

The exocrine (i.e. non-endocrine) pancreas can also be affected by environmental chemical exposures as well (e.g., Hu et al. 2020).