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Principal Investigator:
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Brian Tobin, Ph.D.
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Organization:
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Mercer University School of Medicine
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Project Ended:
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2004
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The weightless environment disrupts the body's normal use and production of insulin, which could relate to muscle atrophy. Dr. Brian Tobin is exploring whether dietary supplements of protein (amino acids) will enhance and normalize insulin secretion and decrease muscle atrophy. This research will lead to ways to keep insulin uptake at normal levels in astronauts in space and in diabetic patients on Earth.
|
Principal Investigator:
|
Brian Tobin, Ph.D.
|
|
Organization:
|
Mercer University School of Medicine
|
|
Project Ended:
|
2004
|
Our specific aims in this study are to: 1). assess the effect of a microgravity-model cell culture on basal amino acid requirements and endocrine secretory function in human islets of Langerhans, and; 2). determine human islet endocrine function while testing amino acid countermeasures in the microgravity model.
Ground-based and inflight investigations illustrate changes in insulin, glucose and amino acid metabolism in space flight. These observations may relate to altered pancreatic endocrine function which is insufficient to meet the needs of microgravity-induced insulin resistance and altered amino-acid metabolism. The changes observed include decreased glucose tolerance, increased circulating insulin and increased reliance upon glucose in muscles. The metabolic meliu resembles an insulin-resistant syndrome, accompanied by a compensatory increase in pancreatic insulin secretion. However, the increase in insulin secretion is insufficient to ameliorate muscle atrophy. The increased insulin secretion is well correlated to muscle atrophy in space flight. The influence of these changes upon the loss of muscle mass and general endocrine metabolic state are not well established, however. Countermeasures that could modulate insulin and glucagon secretion in a compensatory manner to overcome insulin resistance and promote amino acid uptake by peripheral musculature might decrease muscle atrophy and reduce injury following re-adaptation to unit gravity.
We hypothesize that human pancreatic islets of Langerhans have an increased requirement for amino acids in microgravity. We further hypothesize that supplementation with specific additional amino acids will augment, enhance and normalize insulin secretion when space flight paradigm stressors known to decrease insulin secretion are applied.
It is anticipated that these studies will further refine our understanding of human pancreatic amino acid requirements and endocrine regulation: a phenomenon that may be limiting to extended-duration space flight missions. These studies will test countermeasures to augment pancreatic endocrine function while considering both insulin and glucagon production in a way that will involve supplementation of diet with additional amino acids. These measures are ultimately aimed at improving space flight-induced muscle atrophy and ameliorating current re-adaptation constraints.
Key Findings
We have accomplished a part of specific aim 1: To assess the effect of a microgravity model cell culture on basal amino acid requirements and endocrine secretory function in human islets of Langerhans.
Our results of experiments conducted this year in which human pancreatic islets of Langerhans were cultured in the High-Aspect Ratio Vessels (HARV) bioreactor and contrasted to controls reveals the following key findings:
- There is a tendency towards less glucose utilization in HARV-cultured islets of Langerhans;
- There is a tendency towards enhanced insulin secretion in islets maintained in the HARV;
- We observed differential alterations in the pattern of amino acid utilization in the HARV, and;
- Islet TNF production favors greater activity in the HARV cultures.
Impact of Findings
Observation A: The tendency towards decreased glucose utilization in HARV-cultured human islets of Langerhans supports the hypothesis that microgravity is associated with a sub-clinical diabetogenic state. The observation of lesser glucose utilization in human islets is consistent with observations of rat islets cultured in the HARV system when contrasted to controls.
Observation B: The increased insulin secretion in the pancreatic islets cultured in the HARV suggests that islets are responding to some stimuli similar to that observed in insulin-resistant states. It is well established that even in the face of severe insulin resistance, and decreased uptake of amino acids by muscle in diabetic individuals, the output of insulin by the pancreas is dramatically increased. This scenario is consistent with the observations in human pancreatic islets of Langerhans in the HARV microgravity model system.
Observation C. The differential pattern of amino acid utilization is consistent with the hypothesis that microgravity causes alterations in the pattern of metabolic substrate utilization. This is consistent with published data and supports the hypothesis that the peripheral tissues are not the only sites of altered amino-acid metabolism. The pancreatic islets of Langerhans also appear to be altered in their patterns of metabolite use when cultured in a microgravity model system.
Observation D: The greater TNF production in pancreatic islets of Langerhans supports the hypotheses that insulin secretion is suppressed from reaching an adequate level sufficient to overcome peripheral insulin resistance in muscle tissue. That TNF can suppress insulin action is well established. That TNF is secreted by pancreatic islets of Langerhans was previously reported by our laboratory. Given that TNF in HARV cultures is increased, this scenario suggests that even in the face of a need for increased insulin section to overcome insulin resistance in muscle, that TNF may be suppressing a maximal beneficial response in the islets of Langerhans
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