Saturday Morning Research Review – January 16, 2016

Why does hypoglycemic unawareness happen?

by Adam Burrack, PhD

In a previous post, I described the ground-breaking work by James Shapiro and others on the “Edmonton protocol” for preventing T cell-mediated rejection of pancreatic islets following transplantation. In short, strong immune suppression is required to prevent destruction of islet transplants from one person to another (called an allograft), or from a different species – including pigs, which is an area of research at the University of Minnesota. Even in the case of an iPS-derived beta which is patient-specific, research into restraining or eliminating autoreactive beta cell-specific T cells is required to prevent eventual transplant rejection.

Due to the vanishingly small number of donor pancreas organs that become available, application of whole pancreas or isolated islet transplantation is limited to people with T1D who have hypoglycemia unawareness. Hypoglycemia unawareness is perhaps the most debilitating complication of poorly-controlled diabetes: individuals who have lost symptoms normally associated with low blood sugar levels must closely monitor using either continuous blood sugar level monitors or the traditional test strip methods and are at-risk for developing severe diabetic coma and neurological damage.

The bigger question is, why does this complication happen? In people with long-term T1D why do alpha cells die in the first place? T1D is characterized by destruction of beta cells which make insulin, not by the destruction of alpha cells which make glucagon. While these two hormones act in direct opposition: insulin promotes energy storage, glucagon promotes energy mobilization, and there is little evidence that autoimmunity against beta cells promotes autoimmunity against alpha cells.

That is, until a recent paper. Researcher Teresa DiLorenzo and colleagues searched for reactivity against proglucagon – the inactive precursor of glucagon which is stored in secretory granules of alpha cells, awaiting signals to trigger its release – among CD8 T cells from diabetic NOD (non-obese diabetic) mice. Dr DiLorenzo’s group found several candidate peptides derived from proglucagon which are candidate targets for attack by autoreactive CD8 T cells (ie killer T cells) in NOD mice.

This work is interesting for several reasons. First, over time – as beta cells are destroyed – the pancreatic islets of diabetic mice (and humans) become comprised of an ever-increasing proportion of alpha cells. Second, in the absence of beta cells, diabetic mice (and humans) have dysregulated production of the hormone amylin, which is also made by beta cells and is secreted within the same secretory granules as beta cells. A major function of amylin is appetite suppression following meals. Amylin’s other primary function is to suppress the production of glucagon by alpha cells. Interestingly, research from Katie Haskins’s group at the University of Colorado has shown that in the NOD mouse, amylin, or islet amyloid polypeptide (IAPP), is a target of autoreactive CD4 T cells. One could reasonably conclude that in the absence of amylin, glucagon levels are less-well-regulated in individuals with T1D, potentially leading to inappropriately high levels of glucagon – and therefore poor nutrient storage in the liver.

Combined with higher-than-normal levels of pancreatic inflammation in individuals (and research mice) with T1D and a general tendency toward autoimmunity in the presence of diabetes-associated HLA molecules DR4 and DQ8 – as described in our post about the TFH signature of T1D patients recently described by Lucy Walker’s group – one can envision a scenario in which autoimmunity against alpha cells could develop. That scenario might look something like this: (1) lack of amylin leads to over-production of glucagon, (2) high levels of pancreas inflammation, which is largely a result of genetic factors, leads to T cell responses against glucagon-derived peptides, and (3) destruction of glucagon-producing alpha cells leads to further perturbations in blood sugar level management, (4) and potentially, in part, to hypoglycemia unawareness.

If autoreactive T cell responses to glucagon could be prevented, perhaps individuals with T1D would develop hypoglycemia unawareness less frequently, and correspondingly fewer individuals with T1D would become candidates for islet transplantation. Preventing T cell responses to glucagon would likely require placing alpha under less metabolic demand. The genetics setting up the possibility of developing these inappropriate T cell responses is fixed. That is, less frequent and less severe hypoglycemia might, over time, help prevent the development of autoimmunity against glucagon-producing alpha cells. And preventing this autoimmune attack could potentially decrease the frequency of the development of hypoglycemia unawareness.

The absence of these T cell responses could be measured by the lack of autoantibody production against the glucagon hormone. B cells of the immune system require help from antigen-specific T cells to make antibodies, and without this help the autoantibody production will not happen. These ideas remain to be tested, but are intriguing possibilities to investigate in mouse models of T1D. Preventing the development of this life-altering complication of long-term T1D is worth the effort.

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