Why doesn't the immune system ever destroy the glucagon-producing alpha cells in the pancreas? Why only insulin-making beta cells?

Question

Our pancreas does multiple thing, yet I only ever hear of the beta cells in the Islets of Langerhans being annihilated.

Why is this?

Hmmmm.....

Answer 1

As a result of differences in antigen presentation and recognition, the immune system targets the insulin-producing beta cells selectively within the pancreas, while the alpha cells that produce glucagon are left largely unaffected. There are a number of reasons why this might happen:

• Autoimmune Targeting: The most important antigens implicated in the autoimmune response to Type 1 Diabetes (T1D) are major antigens such as insulin and its precursors. Beta cells express these antigens and therefore are the major target of immune cells (see reference 1 for more details).

• Immune Cell Infiltration: Although numerous studies have shown that the immune cells that predominantly infiltrate pancreatic islets in T1D are biased towards CD8+ T cells against beta cells, the precise mechanisms that result in such selective targeting remain incompletely understood but are thought to include the unique antigenic properties of beta cells (see reference 2 for more details).

• The Islet Cell Composition: Alpha cells are less affected by the autoimmune process. This may be due to their different location within the islet and their lower expression of the antigens that trigger the autoimmune response (see reference 3 for more details).

Conclusion: The specific antigenic properties of the beta cell and the targeting mechanisms of the immune system will explain why, in T1D, such selective beta-cell destruction occurs without a similar involvement of the alpha cells.

References

1. Beyond the Hormone: Insulin as an Autoimmune Target in Type 1 Diabetes
2. Characterization of resident lymphocytes in human pancreatic islets
3. Islet Remodeling in Female Mice with Spontaneous Autoimmune and Streptozotocin-Induced Diabetes

Answer 2

The short answer is that it is these beta cells which produce Insulin, and since this may appear to be begging the question, consider the following argument in explanation.  Call it the 'Starving Queen Bee Hypothesis' of Type 1 Diabetes Mellitus.

Approaching the conundrum of type 1 Diabetes Mellitus that the body initiates or permits the so-called autoimmune destruction of insulin producing pancreatic beta islet cells, therefore effectively starving the body of glucose, as a detective story, in which one attempts first both to discern some underlying motive for such an assault -- and here it is further necessary to indulge the philosophical heresy that some deeper intention resides beneath such pathologies, that such disease syndromes as Diabetes Mellitus are responses to what may be regarded as more fundamental metabolic defects (not haphazard derangements or 'mistakes' in nature, rather variant configurations within it serving some more fundamental evolutionary purpose) --, and to ascertain which suspects or parties stand to benefit from it, consider as the first clue that as opposed to peripheral somatic tissue, the brain itself does not require Insulin in order to take up glucose; notwithstanding that glucose uptake by neurons is not entirely independent of Insulin, as was once thought, since GLUT-4 which transports glucose across the blood-brain barrier [BBB] is in fact Insulin-dependent.

Moreover Insulin itself is now known to cross the BBB, particularly in conditions in which the BBB is rendered more porous by various factors: systemic inflammation, certain EMR frequencies etc.  At the same time, it is not yet empirically clear whether Insulin detected within the brain and CNS, including in the CSF, is primarily or predominantly of peripheral or CNS origin, particularly in the context of the widespread distribution of Insulin Receptors in the brain.  In addition, given that there remains some scientific dispute about whether Insulin is synthesised in the brain, it is reasonable to ask whether such Insulin of CNS origin differs conformationally or otherwise at a molecular level from Insulin of pancreatic origin and is therefore potentially capable of being recognised as 'foreign' by immune cells.  This conjecture is potentially important in determining the mechanism of the autoimmune process, since it may conceivably be supposed that Insulin of peripheral origin is regarded as antigenically 'foreign' by immune cells within the CNS.

Continuing the argument then, imagine that in some critical group of neurons, some incapacity to metabolise glucose is inherent or innate, either congenitally or as a consequence of some early toxic insult to which given individuals are peculiarly susceptible, and that this intrinsic condition inevitably induces an insatiable craving for glucose, to the extent that in order to maintain what those cells perceive as a perpetually inadequate supply of glucose, the brain itself effectively orchestrates the immune-mediated destruction of pancreatic beta cells in order to circumvent the supply of that critical glucose to somatic cells necessarily mediated by Insulin.

Herein a motive is suggested simply by virtue of the observation that, as opposed to somatic cells, neurons do not require Insulin in order to transport glucose across their membranes; and it is in this sense that such a scenario may be considered analogous to that of a 'Queen Bee' starved of honey produced by the collective, and upon whose survival the life of the entire hive depends: in other words, if the Queen whose nutrition takes precedence is not receiving honey, no other bee will be permitted to receive it either, and the hive will die.

With respect to the identity of those critical cells in which disruption of glucose metabolism, innate or induced, threatens the entire human being, this depends on some inevitably speculative consideration of the precise mechanism by which such an autoimmune response is induced.  The most likely candidates are cells in the hypothalamus or possibly the brain stem depending on how the presence of Insulin Receptors and their role in the brain is to be understood, since for example, according to a number of studies, Insulin Receptors are most densely distributed in the hypothalamus and olfactory bulb, and least densely distributed in the brain stem; that is, sensitivity of Insulin Receptors to Insulin of CNS origin is likely to be greater in the hypothalamus and olfactory bulb; conversely, for those receptors in the brain stem. [3].

Accordingly, to take the argument further, it may even be that the critical cells in which this fundamental defect in glucose metabolism is present are indeed peculiarly susceptible even in normal circumstances to what would amount to the toxic effect of such peripheral Insulin; that is, presuming that these receptors are exclusively sensitive to Insulin of brain origin -- assuming that Insulin is indeed synthesised in certain neurons --, it may be that Insulin of peripheral pancreatic origin is forbidden in certain locations, such as the hypothalamus or olfactory bulb, and that its presence at that site would induce an immune response ultimately directed at pancreatic beta cells.

(Evidence of CNS control of peripheral glucose metabolism via activity of Insulin at CNS Insulin Receptors [1] may suggest the implication of the CNS in the autoimmune destruction of pancreatic beta cells).

To summarise, since this initial fundamental craving for glucose integral to CNS metabolism and energy demands induces transient hyperinsulinaemia peripherally in response to persistent hyperglycaemia arising from dietary excess, then in the presence of an associated condition of generalised systemic inflammation arising as the consequence of that excessive blood glucose (and saturated fatty acids) which presumably renders the BBB more porous and thus permeable to Insulin itself* (generally exacerbated by the ingestion of 'ultra processed foods'), an excess of Insulin effectively floods the brain.  The presence of such excessive Insulin of peripheral origin in the brain may represent the circumstance that it is regarded by local immune cells, particularly at certain critical sites -- around the 'Queen Bee Cells' themselves -- as effectively 'foreign', so that the concomitant presence of T-cells, including those admitted across the same inflamed and consequently more porous BBB, arguably induces the autoimmune effect, not upon Insulin itself, but as indicated in the previous answer, on the beta cells themselves expressing these antigens on their surfaces.

• The mere condition of systemic inflammation itself is found to increase Insulin transport across the BBB, evidently separate from such increased permeability (although this effect of a so-called 'sickness syndrome' in such a condition of systemic inflammation raises the question whether the symptoms characteristic of that syndrome are not those of prodromal Diabetes Mellitus itself). [2].

Alternatively -- or even in conjunction with the above --, since beta islet cells are subject to neural control, both Vagal and sympathetic, and bearing in mind that the Vagus nerve is effectively part of CNS (with its cell body in the medulla), then it may also be presumed that the cell body of that nerve is to some more-or-less critical degree sensitive to glucose, and possibly to pancreatic Insulin itself, and that some loss of such sensitivity is implicated in the initiation of a cycle of hyperglycaemia/hyperinsulinaemia -- which is also to say that since such sensitivity to circulating glucose including in beta islet cells themselves under normal conditions is qualitatively equivalent to a condition of glucose toxicity, then the ensuing syndrome of autoimmune type 1 DM may be characterised as a condition of Insulin toxicity.

It may also be supposed that it is what amounts to an insatiable craving for glucose in somatic cells in which mitochondrial processes of glucose metabolism have become deranged -- viz, there is an increasing body of evidence and scientific opinion that this is due to the inflammatory effects of sugars and fats generally, and of these ingredients of 'ultra processed foods' in particular -- which is at the root of 'insulin resistance', the definitive condition in type 2 Diabetes in which cells become decreasingly responsive to Insulin synthesised and secreted in response to hyperglycaemia, exacerbating the latter and implying the tendency to fat accumulation in adipose tissue: in other words, in such conditions of 'insulin resistance', somatic cells are effectively starving: viz, obesity is a form of starvation.

[1] Insulin Action in the Brain [2021]: American Journal of Physiology [Endocrinology and Metabolism]. https://doi.org/10.1152/ajpendo.00642.2020 T

[2] Factors Influencing BBB Permeability. https://doi.org/10.1016/j.brainres.2022.147937

[3] Insulin in the Brain.

https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2014.00161/full