Saturday Morning Research Review – October 29, 2016

Beta cell biology of GABA in inflammation and exercise

by Adam Burrack, PhD

Several blogs in our series have focused on the role of insulin-derived peptides as targets of autoreactive T cells in the destruction of beta cells leading to development of type 1 diabetes. In particular my descriptions of the research of George Eisenbarth and Maki Nakayama have focused on CD4+ (or helper) T cells specific for peptides derived from the B chain of the insulin hormone. Today I will describe another major target of autoreactive T cells (and B cells) leading to development of T1D, glutamic acid decarboxylase, or GAD. There are two GAD enzymes, both of which produce the signaling molecule GABA (see below) which is key for communication within the nervous system. One of these enzymes is expressed in both neurons and in the pancreas (GAD67), and the other is expressed only in the pancreas (GAD65). The “isoform” of GAD expressed exclusively in the pancreas is a key target in T1D pathogenesis.

Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter in the nervous system. In fact, GABA is one of the most physiologically important suppressive signals in the nervous system of mammals. Both GAD65 and GAD67 can become targets of autoreactive B cells and T cells during T1D pathogenesis.

Today I will briefly summarize three recent papers from the journal Diabetes which each individually investigate the role of GAD65 as an autoantigen in T1D pathogenesis.

The first of these investigates endoplasmic reticulum stress and its role in beta cell death during diabetes pathogenesis – for example during type 2 diabetes onset. Another key concept for GAD65 as an autoantigen is palmitoylation – or secondary modifications to proteins after the protein itself is made. In general, palmitoylation (attaching a fatty acid chain to a protein) is a means of directing where that protein goes within a cell. If done inappropriately or unintentionally, palmitoylation will direct a protein to bind to the cell membrane, making that protein very prevalent if a cell dies (undergoes apoptosis) and “blebs” (which is a process by which the immune systems gains access to chunks of dead cells). Long story short, beta cells under metabolic stress (few beta cells trying to fill the function of all beta cells) accumulate GAD65 with palmitate attached in the Golgi apparatus (sorry for the jargon, this is where proteins are produced in cells). If beta cells die with lots of GAD65+palmitate in the protein-making machinery, those proteins will be available for the immune system to see. In other words – if death and blebbing of beta cells – occurs in the context of inflammation, the immune system will be “instructed” to attack cells expressing GAD65. Put directly, the above sequence of events may be one pathway directing the immune system to attack beta cells.

Another manuscript in the September 2016 issue of Diabetes investigated the cross-talk between insulin production and glucagon production, and how control of these two hormones is regulated in the brain. Without going into great detail, this manuscript shows data that different areas of the hypothalamus control insulin production (hypothalamic arcuate nucleus) and glucagon production (lateral hypothalamic area). This study is important for two reasons. First, it demonstrates direct influence of specific areas of the hypothalamus (in the brain-stem) on the production of endocrine hormones by the pancreatic islets. Second, this manuscript established that different areas of the hypothalamus control production of hormones that bring blood glucose level up (glucagon) and down (insulin). Thinking of blood sugar level control as a circuit, this makes logical sense: neither the same cells in the pancreatic islets nor the same area of the brain-stem control both arms of the system. This is clinically important, because it means that not only different cells in the pancreas should be targets of pharmacalogic treatments to promote insulin production or inhibit glucagon secretion, but different areas of the brain-stem are influenced by these treatments as well.

Lastly, researchers at the University of Maryland studied the effects of GABA production on the subsequent hormonal response to exercise. In particular these researchers were interested in the effects on glucagon production in response to exercise of “pre-activation” of GABA signaling. They used a pharmacologic approach to test the hypothesis that GABA activation would blunt subsequent glucagon responses to exercise (ie, they used drugs to either exacerbate the GABA pathway or block it completely). Long story short, subjects were either given an induced low blood sugar level (or not, for controls) on day 1 of the study, then on day 2 they completed 90 minutes of exercise at 50% VO2 max (in other words, a moderate duration, low intensity workout). Individuals who experienced an induced low blood sugar level event the day before exercise demonstrated blunted (reduced) glucagon response to exercise the next day. One could easily speculate that this would become a bigger problem the higher intensity the exercise. For example, this would probably set one up for a terrible interval session (>90% VO2 max, repeatedly). This is important for athletes with T1D for several reasons. First, we need to be flexible with our schedules. Sticking to the plan at all costs may be harmful – especially in the days following severe hypoglycemia. Second, we should watch our blood sugar levels after exercise carefully because hypoglycemia events during this time probably affect glycogen storage – and thereby future exercise sessions. Other work has suggested that 48 hours is the minimum to replenish glycogen (ie, stored sugar) reserves following races like half marathons. This time frame following severe hypoglycemia is probably also an appropriate span following hypoglycemia before hard training sessions.

In summary, T1D is not only about insulin. The production and function of other hormones – like glucagon – are also changed. And the hormonal response to exercise in the absence of insulin is not entirely normal. Adjustments must be made for some of these changes.

Posted in Exercise, Glucagon, Immunology.