Brian W. Tobin

Iron status and exercise

The prevalence of iron deficiency anemia is likely to be higher in athletic populations and groups, especially in younger female athletes, than in healthy sedentary individuals. In anemic individuals, iron deficiency often not only decreases athletic performance but also impairs immune function and leads to other physiologic dysfunction. Although it is likely that dietary choices explain much of a negative iron balance, evidence also exists for increased rates of red cell iron and whole-body iron turnover. Other explanations of decreased absorption and increased sweat or urine losses are unlikely. The young female athlete may want to consider use of low-dose iron supplements under medical and dietary supervision to prevent a decline in iron status during training.

Immune Responsiveness Following Academic Stress in First-Year Medical Students

Many studies illustrate that physical or psychologic stressors can alter human immune function, which might predispose one to an increased susceptibility to infections. In the present study, we monitored immune responsiveness in 16 first-year medical students (age 23.8 +/- 2.2 years) during the first examination session. Baseline blood samples were collected 30 days prior to the first examination session. Subsequently, subjects were randomly assigned to two groups, and blood samples were collected at 24 h (POST24h) or 48 h (POST48h) after an examination. The percentage of CD3(+), CD3(+)CD4(+), CD3(+)CD8(+), CD3(+)CD45RO(+), CD3(+)CD45RA(+), CD3(-)CD16(+)56(+), CD19(+), and CD14(+) cells in whole blood was examined to determine changes in circulating immune cell populations. Activation of peripheral blood mononuclear cells (PBMC) with a mixture of phorbol myristate acetate (PMA) and ionomycin or lipopolysaccharide (LPS) for 4 h was used to assess the distribution of interleukin-2 (IL-2)-secreting or interferon-gamma (IFN-gamma)-secreting CD4(+) and CD8(+) cells, as well as IL-1alpha-secreting CD14(+) cells. Activation with a combination of phytohemagglutinin (PHA) and LPS was used to assess secretion of IL-2, IFN-gamma, IL-4, IL-10, soluble IL-2 receptor-alpha (sIL-2Ralpha), IL-1beta, and IL-1R antagonist (IL-1Ra) by PBMC in 48-h cell culture. A significantly higher level of total T cells was found at POST24h, and CD14(+) was elevated at both POST24h and POST48h. The percentage of CD4(+) and CD8(+) cells significantly declined at POST24 and POST48h. A significant elevation in the percentage of memory T cells was observed at POST48h, whereas the percentage of naive T cells was elevated at POST24h and POST48h. These changes were accompanied by a significant decline in percentage of natural killer (NK) cells 24 h after the examination. The percentage of IL-2-producing CD4(+) and CD8(+) cells was significantly lower at POST24h, and the percentage of CD8(+)IFN-gamma(+) cells significantly declined at POST48h. The percentage of CD14(+)IL-1alpha(+) significantly declined at both POST24 and POST48h. A significant decrease was observed in IL-2 secretion 24 h after the examinations, and the secretion of IL-4 and IL-1beta significantly declined at POST48h. No changes in IFN-gamma, IL-10, sIL-2Ralpha, and IL-1Ra secretion were observed. We conclude that the stress outcomes of academic examinations in first-year medical students can significantly alter immune cell distribution and in vitro production and secretion of specific cytokines.

Dynamics of glycemic normalization following transplantation of incremental islet masses in streptozotocin-diabetic rats

We examined the dynamics of glycemic normalization following intraportal infusion of an incremental number of islets of Langerhans in male Wistar-Furth rats. Non-fasted plasma glucose, 24-hr urine volume, and body weight were determined weekly during three weeks of streptozotocin-induced diabetes and for 5 weeks following transplantation of 250-3000 freshly isolated islets. At one week following transplantation, urine volume was inversely proportional to the mass of islets transplanted, but by 5 weeks posttransplantation urine volume was near-normal except in rats receiving only 250 islets. On the basis of the mean data, the nonfasted plasma glucose fell linearly at a rate of 66 mg/dl per week in rats receiving 500-1000 islets, with normoglycemia (147 +/- 9 mg/dl) being obtained 5 weeks posttransplantation. Examination of the individual time courses for nonfasted plasma glucose revealed a different pattern of glycemic normalization, which consisted of sustained hyperglycemia followed by a rapid fall in the plasma glucose level. During the week prior to normalization glucose fell at a rate of 170 mg/dl per week and normoglycemia was obtained from 1 to 5 weeks following transplantation. Examination of the frequency distribution of nonfasted glucose levels suggested a threshold of 300 mg/dl for glycemic normalization. We conclude that the dynamics of glycemic normalization following transplantation of a suboptimal islet mass include sustained hyperglycemia of variable duration, followed by a rapid fall in the nonfasted plasma glucose level. The contributions of changes in insulin secretion and insulin action underlying this dynamic behavior remain to be determined.

A New Model for the Study of Mild Diabetes During Pregnancy: Syngeneic Islet-Transplanted STZ-Induced Diabetic Rats

Diabetes during pregnancy carries short- and long-term consequences for the offspring. Improved obstetrical and diabetic care has resulted in decreased morbidity and mortality in the neonate of the diabetic mother. Mild hyperglycemia is still found in both IDDM pregnant women and women with GDM. The long-term consequences of exposure to mild hyperglycemia in utero remain to be determined. In an effort to develop an appropriate animal model of mild diabetes during pregnancy, we mated female STZ-induced diabetic rats previously transplanted with specific numbers of islets of Langerhans (2500,1000, 700, or 500 islets). Diabetic and nondiabetic sham-transplanted control groups also were studied. During pregnancy, the plasma glucose levels in the diabetic rats and the group receiving 500 islets (26.5 ± 1.1 and 10.0 ± 0.8 mM, respectively) were significantly greater than in control animals (5.4 ± 0.5 mM, P < 0.0001). The mean glucose levels in rats receiving 700 or 1000 transplanted islets (6.8 ± 0.2 and 6.5 ± 0.2 mM) also were significantly greater than in control animals (P < 0.001). No difference was evident between control rats and the group receiving 2500 islets (5.8 ± 0.2 mM). No gross congenital abnormalities were apparent in the offspring. The pup plasma glucose was significantly greater in the offspring of dams receiving either none (diabetic) or 500 islets (10.6 ± 0.7 and 11.1 ± 1.1 mM, respectively) compared with the offspring of nondiabetic control dams (4.4 ± 0.3 mM, P < 0.0001). The pup pancreatic insulin content was lower in the offspring of diabetic animals than in control animals (4.9 ± 0.3 vs. 15.2 ± 0.5 nM/mg, P < 0.0001), but no difference was found between the offspring of islet-transplanted dams compared with control offspring. In summary, the STZ-induced diabetic rat transplanted with a specified number of islets of Langerhans is a promising new animal model for the study of mild to moderate hyperglycemia during pregnancy. This model should be useful for study of the longer term consequences of diabetes during pregnancy.

Markedly Reduced β-Cell Function Does Not Result in Insulin Resistance in Islet Autografted Dogs

Autotransplantation of islets of Langerhans has resulted in long-term normoglycemia in pancreatectomized dogs. This canine model is useful in evaluating both the progress of islet transplantation and the effect of a reduced islet mass upon the determinants of glucose tolerance: i.e., insulin secretion, insulin sensitivity, and glucose effectiveness. To determine the effect of a reduced islet mass on these factors, we measured the acuteinsulin response to arginine (AIRa) and glucose (AIRg), the slope of glycemic potentiation of AIRa (SP), insulin sensitivity (S1), and glucose effectiveness (SG) in control (CN), diabetic (DM), and pancreatectomized dogs rendered normoglycemic with transplanted autografts of islets of Langerhans (TX). Normal fasting plasma glucose (FPG) (TX 4.7 ± 0.2 mM; CN 4.9 ± 0.1 mM; P > 0.05) was maintained despite a markedly reduced insulin secretion in TX (AIRa 24%, AIRg 15%, and SP 11% of CN). All measures of insulin secretion were significantly correlated (SP vs. AIRg r = 0.80, P < 0.0001; AIRa vs. AIRg r = 0.92, P < 0.0001) across all animals, but none of the measures of secretion were significantly correlated with either the number of islets transplanted or time posttransplant (P > 0.10). Insulin sensitivity was normal in islet autografted dogs (TX: 136 ±12 min−1/(nmol/ml); CN: 101 ±11 min−1/(nmol/ml), P > 0.05) but SG was reduced (TX:±1.93 ± 0.28 × 100 min−1; CN: 3.53 ± 0.35 × 100 min−1 P < 0.05), as determined by the minimal-model method. In diabetic animals (FPG = 16.1 ±1.3 mM), insulin secretion was negligible by all measures (P > 0.05), and was associated with insulin resistance (S1 = 28 ± 8 min−1/(nmol/ml)) and reduced SG (1.72 ±0.11 × 100 min−1). These studies indicate that across a range of insulin secretion in dogs, thesecretagogues arginine and glucose provide similar estimates of β-cell function. This markedly reduced β-cell function does not result in insulin resistance when fasting normoglycemia is maintained, but is associated with a decrease in glucose action at basal insulin.

Spaceflight Nutrition Research: Platforms and Analogs

Conducting research during actual or simulated weightlessness is a challenging endeavor, where even the simplest activities may present significant challenges. This article reviews some of the potential obstacles associated with performing research during space flight and offers brief descriptions of current and previous space research platforms and ground-based analogs, including those for human, animal, and cell-based research. This review is intended to highlight the main issues of space flight research analogs and leave the specifics for each physiologic system for the other papers in this section.

Differential Pulmonary Vascular Effects of Streptozotocin Diabetes in Male and Female Rats

Abstract We examined the effect of streptozotocin (STZ) diabetes on pulmonary pressor responses and segmental pulmonary vascular resistance in male and female Wistar-Furth rats. Pulmonary vascular reactivity was studied using isolated, salt-perfused lungs at a constant flow rate of 30 ml/min/kg body weight. Following STZ administration, pressor responsiveness to 1.0 μg of U-46619 (9,11 dideoxy-9α, 11α-methanoepoxy Prostaglandin F2α was diminished (p < 0.05) in lungs obtained from male diabetic rats when compared to sham treated controls (7.87 ± 1.67 vs. 13.59 ± 1.67 mmHg). In contrast, diabetes failed to affect pressor responsiveness in lungs from female animals. In another set of animals, segmental pulmonary vascular resistance was determined in lungs isolated from male and female diabetic or sham-treated (STZ carrier vehicle) animals. Total pulmonary vascular resistance was significantly elevated in male diabetic animals as compared to controls. This elevation was attributable to significant increases in resistance at the level of small pulmonary veins. In addition, diabetes was associated with a shift in the primary site of resistance from small arteries to small veins in male animals. We were unable to detect any effect of short-term diabetes on the segmental resistance profile in lungs obtained from female animals. These data indicate that both the pulmonary segmental resistance profile and pulmonary vascular reactivity are altered by short-term diabetes in male rats. Additionally, these studies demonstrate gender-related effects of short-term diabetes, which may suggest a more favorable pulmonary response to diabetes in female animals.

Alteration of segmental vascular resistance in the pulmonary circulation of diabetic rats

Numerous studies have shown that altered plasma glucose and (or) insulin have profound effects on the pulmonary circulation. Recently, we documented diminished pressor responses to the synthetic thromboxane analogue U-46619 (9,11-dideoxy-9 alpha, 11 alpha-methanoepoxy prostaglandin F2 alpha) following short-term streptozotocin-induced diabetes in rats. However, these earlier studies examined the effects of diabetes on resistance changes across the entire pulmonary vasculature and made no effort to localize the site(s) of any abnormalities. Thus, in the present study we examined segmental pulmonary vascular resistances using the double-occlusion method in isolated, perfused rat lungs 2 weeks after streptozotocin-induced diabetes. Under baseline conditions, total pulmonary vascular resistance (TPVR) did not differ in lungs isolated from control and diabetic animals (0.66 +/- 0.03 vs. 0.85 +/- 0.05 mmHg.mL-1.min-1, respectively (1 mmHg = 133.3 Pa)). However, control animals demonstrated greater arterial (Ra) than venous (Rv) contribution to TPVR (0.43 +/- 0.02 vs. 0.23 +/- 0.02 mmHg.mL-1.min-1, respectively). This relationship was reversed in diabetic animals (Ra = 0.30 +/- 0.02 mmHg.mL-1.min-1; Rv = 0.54 +/- 0.04 mmHg.mL-1.min-1). Following constriction with U-46619 this pattern persisted, although the absolute vasoconstrictor response to the agent was similar in each segment. Likewise, this pattern of resistance was unaffected following dilation of the pulmonary vascular bed with arginine vasopressin. These findings illustrate that pulmonary segmental vascular resistances are altered and, more specifically, that pulmonary venous resistance is selectively increased, 2 weeks following the induction of diabetes.

Insulin action in previously diabetic rats receiving graded numbers of islets of Langerhans

We characterized insulin sensitivity in islet transplanted rats receiving from 500 to 3000 islets. Male Wistar Furth rats made previously diabetic with streptozotocin (55 mg/kg) were infused intraportally with islets of Langerhans (500 islets: n = 8; 1000: n = 6; 2000: n = 6; 3000: n = 5) from syngeneic donors and compared with sham-operated controls (n = 7). At four weeks after islet transplantation, fasting blood glucose was not significantly different between groups (500: 5.1 +/- 0.3; 1000: 4.8 +/- 0.3; 2000: 5.1 +/- 0.3; 3000: 4.6 +/- 0.1; control: 4.7 +/- 0.2 mM; P = 0.6146), and fasting plasma insulin was also not different (P = 0.28). The acute insulin response to glucose (0.3 g/kg i.v.) was correlated with islet equivalent mass (r = 0.63, P = 0.004; transplant rats only); islet transplant animals presented a range of acute insulin secretion from 3 to 90% of control values. Insulin action was measured in vivo in fasted, conscious animals during a hyperinsulinemic-euglycemic glucose clamp with insulin infused at 29 and 72 nmol/kg/min. Despite a wide range of islet mass and insulin secretory capacity, there was no significant difference in the glucose infusion rate between islet groups at either insulin level (P = 0.8211, P = 0.8021). There was also no difference in the glucose infusion rate normalized to the prevailing insulin level (P = 0.1638, P = 0.2302). Thus, our results demonstrate that the islet transplanted rat is consistent with other animal studies and human studies illustrating that a diminished insulin secretion does not necessarily precipitate insulin resistance.

Comparison of therapeutic regimens in the amelioration of alterations in rat gastrointestinal mucosal DNA, RNA and protein induced by streptozotocin diabetes mellitus.

Type 1 diabetes mellitus is characterized by hyperglycemia, insulinopenia, and secondary neural, renal and vascular complications. Clinical manifestations in the gastrointestinal tract range from initial mild complications to more severe complications as the disease progresses, but as of yet, are poorly understood. The current study has two main foci 1) to monitor the alterations in gastrointestinal DNA, RNA and protein content induced by streptozotocin diabetes and 2) to use these parameters to monitor the efficacy of intensive insulin treatment versus pancreatic islet transplantation in the amelioration of the diabetes induced alterations. Female Wistar Furth rats were rendered diabetic by streptozotocin injection and measured for alterations in gastrointestinal DNA, RNA and protein content. Similarly, animals which had streptozotocin-induced diabetes were also treated by intensive insulin therapy or pancreatic islet transplant and monitored for alterations in gastrointestinal DNA, RNA and protein content. In general, diabetes induced increases in stomach, duodenal, jejunal and colonic macromolecular content. With few exceptions, treatment with either intensive insulin or pancreatic islet transplantation returned each variable measured back to control levels. In every case, pancreatic islet transplantation was comparable to intensive insulin therapy. In the short term the treatments are comparable, but long term analyses are needed to determine if the treatments offer any difference in their ability to prevent the long term complications related to diabetes mellitus.