Astronauts And The Pancreas

Being An Astronaut Is Not Exactly Choosing A Healthy Lifestyle

The human body has evolved for a successful life on Earth. We are not beings who are built to survive in space. The first biological entity (Laika the dog) was launched into space in 1957. Since then, we have learned a great deal about the hazards of space travel, but clearly there is still much to learn. And learn we must because the field of space travel is in the midst of a dramatic revolution.

Until now space missions have generally been either of short distance (Low Earth Orbit—LEO) or short duration (Apollo Lunar Missions). However, upcoming missions are looking to push the boundaries of space travel, with plans to travel for longer distances and durations than ever before. Both the National Aeronautics and Space Administration (NASA) and several commercial space companies (e.g., Blue Origin, SpaceX) have already started the process of preparing for long distance, long-duration space exploration and currently plan to explore inner solar planets (e.g., Mars) by the 2030s.

Space travel is hazardous for at least five reasons, best summarized by the acronym RIDGE: Space?Radiation,?Isolation and Confinement,?Distance?from Earth,?Gravity?fields, and Hostile/Closed?Environments. Astronauts are at risk for any number of medical issues and there is no human system that appears immune to toxic effects. Astronauts have been diagnosed with neurologic, ocular, orthopedic, dermatologic, immunologic, pulmonary and cardiovascular conditions routinely. Astronauts have returned to Earth with genetic alterations and brain structural changes that are just now being understood.

Three studies have been published since 2019 showing profound genetic changes to astronauts. DNA damage was recently demonstrated based on directional genomic hybridization that detected an increase of intra-chromosomal inversions during and after spaceflight, a finding potentially related to stem-cell damage, clonal hematopoiesis, and/or instability. What this will mean in the long run is unknown, but the potential for carcinogenesis is high.

A study in the NEJM published in 2017 highlighted the brain structural changes seen in astronauts. Narrowing of the central sulcus occurred in 17 of 18 astronauts after long-duration flights (mean flight time, 164.8 days) and in 3 of 16 astronauts after short-duration flights (mean flight time, 13.6 days) (P<0.001). Cine clips from a subgroup of astronauts showed an upward shift of the brain after all long-duration flights (12 astronauts) but not after short-duration flights (6 astronauts). More study is required to see what the long-term clinical effects of these changes will be.

The gastrointestinal tract is significantly affected by space travel. Conditions include space motion sickness (SMS), space diarrhea, fatty liver disease, altered gut microbiomes, and increased risks of gallstone formation and appendicitis. Weirdly enough, astronauts also return to Earth with pre-diabetes.

The Pancreas In Space

Over the past 5 years, the fastest growing new area of physical activity research centers around the concept that the large amount of time people spend sitting inactive may have significant physiological consequences hazardous to human health, including risk for type 2 diabetes and poor metabolism of lipids and glucose. Meta-analysis (18 studies) suggest there is a 112% greater relative risk associated with a large duration of sedentary behavior for type 2 diabetes.

We can consider being an astronaut, for purposes of the pancreas, as being employed in the most sedentary job possible. The reason for this is the lack of gravity. All life on Earth has evolved and adapted to a single downward vector of gravity. In the space environment, this vector is mostly removed, resulting in microgravity conditions. Also, there is a range of varying gravity levels on other planetary bodies that will be experienced by space travelers, such as on the Earth’s Moon (1/6th gravity [G]) and Mars (1/3rd G). Additionally, there are often intense forces experienced during exit and descent transitions through atmospheres, at many times the force of gravity (3–6 G), which will subject biological systems to stress. Microgravity induces cellular and molecular adaptations and changes in the genome, epigenome, as well as the proteome, and these changes create risks for a range of pathologies.

Space flight is characterized by unloading-dependent muscle atrophy and impaired immune response as well as different degrees of metabolic dysregulation, which, if persisting long enough, as expected during interplanetary missions with extended duration, might result in increased risk of cardiovascular and metabolic diseases. More specifically, space flight research, ground-based studies (both bed rest and dry immersion), and experimental studies in animal models and on pancreatic islets of Langerhans support the observation that prolonged space flight and experimental exposure to microgravity result in peripheral insulin resistance at different sites (liver, skeletal muscle, adipose tissue and others). Vitamin D3 deficiency is also known to negatively affect insulin sensitivity and astronauts are at risk for vitamin D3 deficiency, due to chronic exposure to artificial light conditions.

In a study done during the D2 mission of Space Shuttle Spacelab (European Space Agency), four astronauts were studied to see if they developed glucose intolerance. Oral glucose tolerance tests were performed 15 days before launch, 7 days into the mission, and 15 days after return to Earth. All developed hyperinsulinemia and had elevated levels of glucose during the mission that returned to normal after landing.

Many other studies have confirmed these findings. Insulin resistance takes on even more urgency since it affects wound healing. Increasing evidence has accumulated on insulin's ability to stimulate cell migration and wound recovery, and insulin administration has been proposed to overcome the adverse effects of insulin resistance on wound healing on the ground. Patients (and presumably astronauts) have impaired wound healing in insulin-resistant states. This obviously becomes very critical if you are millions of miles from home and are injured.

The observed changes in insulin secretion and sensitivity, glucose tolerance, and protein and amino acid metabolism support the hypothesis that insulin also plays an essential role in maintaining muscle mass during long-term spaceflights.

Not only is insulin resistance found during space flight, but direct toxic effects may also occur on the pancreas itself. In a study on 19-20 week old C57BL/6 strain mice that were flown on a 30-day mission in space aboard the biosatellite Bion-M1, secretory activity of pancreatic beta cells decreased resulting in decreased levels of insulin production that returned to normal within 48 hours of landing back on Earth.

Finally, in a study of male and female astronauts who had flown 6 months on the International Space Station, significant changes in insulin resistance and carotid artery stiffness were documented that were comparable to 10-20 years of normal aging on Earth!

What Exactly Is Going On In Space?

Other than the effects of microgravity on insulin resistance, is anything else going on that negatively affects pancreatic function in astronauts. As it turns out, there is plenty else.

A series of studies performed in space flight found altered cytokine activity during space flight that may favor increased insulin resistance via altered TNF-α release. The Spacelab 3 mission demonstrated that immune responses may be altered by space flight. OnSTS-56, MC3T3-E1 osteoblasts activated in microgravity used less glucose and had reduced prostaglandin E2, a proposed regulator of cytokine production. As little as 8 s of microgravity has been demonstrated to alter macrophage responses.

Another in vitro microgravity experiment published in 2001 also illustrated altered immune cell cytokine activity in microgravity that favored increased insulin resistance via altered TNF-α release. That study also illustrated that basal insulin secretion was suppressed concomitantly with an increase in TNF-α and may be implicated in the hormonal alterations of spaceflight.

That TNF-α is associated with a decreased basal insulin secretion is intriguing as it relates to in-flight extrapolations and possible insight into the pathophysiology of type 1 and 2 diabetes mellitus. In-flight studies during the Skylab mission found a consistent decrease in the plasma insulin concentration from 38 to 82 d, and this seemed directly related to elevated levels of TNF-α.

Is There Any Way To Help Prevent These Side Effects Of Space Travel?

Based on microgravity simulation studies, NASA has proposed several potential biomedical countermeasures in space.

Mandatory exercise protocols in space are crucial and can be used to maintain physical fitness and counteract the effects of microgravity. While these protocols may be beneficial, exercise alone may not be enough to prevent certain effects of microgravity. However, NASA protocols currently provide for 2.5 hours of aerobic exercise daily for each astronaut. Two treadmills are in two different modules on the ISS.

In addition to exercise, dietary modification may be another potential area for optimization. The use of a diet based on caloric restriction (CR) in space remains up for debate. Based on data from terrestrial studies, caloric restriction may be useful for improving vascular and metabolic health; however, this benefit may be offset by the associated muscle atrophy and osteoporosis. Given that NASA encourages astronauts to consume adequate energy to maintain body mass, there has been an attempt to mimic the positive effects of CR on vascular health while providing appropriate nutrition. Further research is needed this area to identify the ideal space diet.

Based on current guidelines, only vitamin D supplementation during space travel is recommended.

What About Pancreatitis?

A very interesting exercise placing the reader in the "Flight Surgeon" seat was published in 2019. In this exercise, a 37 year old crewmember arrived on the lunar surface 5 weeks ago from Earth via a platform orbiting the Moon. After a physically-demanding 8 hour moonwalk to repair a failing solar panel array, he develops 7/10 dull epigastric pain with radiation to his back and left flank.

Further evaluation using microarray technology revealed normal labs except a lipase of 1122 U/L. The article then takes the reader on a journey of managing moderately severe pancreatitis on a patient that is 238,900 miles away from a hospital! The patient rapidly deteriorates, becomes hypoxic and develops fever. The final question posed to the reader/Flight Surgeon was whether the Flight Director should pull the plug on the multibillion dollar mission and get the astronaut home. Interesting indeed and well-worth reading.

This scenario raises the issues about whether anything can be done on Earth prior to launch to help prevent pancreatitis in the first place. Should the astronaut with asymptomatic gallstones undergo cholecystectomy prophylactically? Should astronauts ever drink alcohol? Are there any biomarkers that could be used to identify high-risk individuals? Recently, Malkani et?al. demonstrated that circulating miRNA signatures consisting of 13 miRNAs were associated with health risks induced by the space environment. These miRNAs were linked to biological pathways involved with mitochondrial regulation and oxidative damage through multiple different factors, such as TGFβ1 and mTOR, known to induce mitochondrial oxidative phosphorylation and ROS production.

Conclusion

Although many of these systemic and physiological health risks of spaceflight have been well documented, much is left to be discovered. As long-duration, deep-space missions to Mars and farther are planned, it is uncertain how prolonged exposure to the space environment will alter the known physiological responses. Also, individual sensitivity to spaceflight stressors can greatly modulate biological responses, depending on genetic, demographic, and lifestyle variability.

Although significant advances have been made in the past decade to understand these hazards and health risks, additional research is required to enable safer human space exploration beyond LEO, including lunar, Mars, and deep-space missions.

"To confine our attention to terrestrial matters would be to limit human spirit." ~ Stephen Hawking

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