Key Metabolic Parameters Research Articles

Update on bariatric surgery in adolescence.

Recent evidence highlighting the prevalence of severe obesity in the pediatric population, coupled with disappointing outcomes related to medical weight loss interventions, has led to increased interest in bariatric surgery. This article focuses on recent additions to the literature regarding the current indications and outcomes of adolescent bariatric surgery, emerging guidelines on the development of surgical weight loss programs and the status of access to bariatric surgical care for adolescents in the United States. Current data have shown a steady rise in the use of bariatric surgery among adolescents and serve to highlight the prevalence of several important obesity-related comorbidities. In addition to reports showing the safety and efficacy of adolescent bariatric surgery, a number of investigators have demonstrated significant improvement in key physiological and metabolic parameters (i.e., glucose metabolism, elevated blood pressure, dyslipidemia, etc.), offering updated consensus-driven guidelines for the indications for surgical intervention, as well as the development of multidisciplinary adolescent-specific care. Despite favorable outcomes, a disparity exists between the pediatric and adult populations related to access to such care. In contrast to previous small and mostly retrospective series, contemporary studies have shown that adolescent bariatric surgery is well tolerated and effective. Despite these findings and the emergence of a national consensus regarding multidisciplinary care, skepticism among primary care providers, as well as significant challenges related to healthcare access, remain. Longitudinal studies and open dialogue within the medical community are needed.

Metabolic profiling of hematopoietic stem and progenitor cells during proliferation and differentiation into red blood cells

An understanding of the metabolic profile of cell proliferation and differentiation should support the optimization of culture conditions for hematopoietic stem and progenitor cell (HSPC) proliferation, differentiation, and maturation into red blood cells. We have evaluated the key metabolic parameters during each phase of HSPC culture for red blood cell production in serum-supplemented (SS) and serum-free (SF) conditions. A simultaneous decrease in growth rate, total protein content, cell size, and the percentage of cells in the S/G2 phase of cell cycle, as well as an increase in the percentage of cells with a CD71(-)/GpA(+) surface marker profile, indicates HSPC differentiation into red blood cells. Compared with proliferating HSPCs, differentiating HSPCs showed significantly lower glucose and glutamine consumption rates, lactate and ammonia production rates, and amino acid consumption and production rates in both SS and SF conditions. Furthermore, extracellular acidification was associated with late proliferation phase, suggesting a reduced cellular metabolic rate during the transition from proliferation to differentiation. Under both SS and SF conditions, cells demonstrated a high metabolic rate with a mixed metabolism of both glycolysis and oxidative phosphorylation (OXPHOS) in early and late proliferation, an increased dependence on OXPHOS activity during differentiation, and a shift to glycolytic metabolism only during maturation phase. These changes indicate that cell metabolism may have an important impact on the ability of HSPCs to proliferate and differentiate into red blood cells.

Effect of Lurasidone On Metabolic Parameters in Patients with Bipolar Depression

Introduction Patients with bipolar disorder are at a higher risk of metabolic complications and associated mortality than the general population. Objective/Aims To evaluate the extent to which treatment with lurasidone was associated with clinically relevant shifts in key weight and metabolic parameters in patients with bipolar I depression (BPD). Methods Data were from 3 short-term studies in patients with BPD who were randomized to 6 weeks of double-blind, placebo-controlled treatment with lurasidone (18.5-111 mg/d), either as monotherapy (one study, N=499), or adjunctive therapy with lithium or valproate (2 studies, N=694). Patients completing the 6-week trials continued in a 6 month open-label extension study (N=494). The proportion of patients with shifts in metabolic parameters were analyzed at the 6 week and 6 month end-points, and are reported descriptively. Shifts were defined as changes in weight (≥7% change), BMI category, triglycerides (increase ≥50 mg/dL), total cholesterol (increase ≥40 mg/dL), LDL (increase ≥30 mg/dL), and glucose (shift to ≥110 mg/dL). Results At Week 6 in the monotherapy study, a similar proportion of patients treated with lurasidone vs placebo, respectively, had shifts in weight (2.0% vs 0.6%), triglycerides (15.7% vs 10.1%), total cholesterol (5.5% vs 3.4%), LDL (6.4% vs 3.4%), and glucose (11.3% vs 9.5%). Results were similar for lurasidone vs placebo in the adjunctive therapy study. At Month 6 of the extension study, a relatively low proportion of the patients on lurasidone met shift criteria. Conclusions These data add to the substantial and growing body of information regarding the metabolic safety of lurasidone. NCT00868699, NCT01284517, NCT00868452, NCT00868959. Sponsored by Sunovion Pharmaceuticals Inc.

Impact of a community-based diabetes self-management program on key metabolic parameters.

Characterize the impact of a pharmacist-led diabetes self-management program on three key metabolic parameters: glycosylated hemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-C), and mean arterial blood pressure (MAP) among employee health program participants. A self-insured company in the Kansas City metropolitan area began offering a pharmacist-led diabetes self-management program to eligible company employees and their dependents in 2008. A retrospective pre-post analysis was conducted to determine if the program affected key metabolic parameters in participants by determining mean change after one year of participation. Among 183 program participants, 65 participants met inclusion criteria. All three key metabolic parameters were significantly reduced from baseline to one year of program participation: HbA1c decreased from 8.1 % to 7.3% (p=0.007); LDL-C decreased from 108.3 mg/dL to 96.4 mg/dL (p=0.009); and MAP decreased from 96.1 to 92.3 mm Hg (p=0.005). The pharmacist-led diabetes self-management program demonstrated significant reductions in HbA1c, LDL-C, and MAP from baseline to one year of program participation. Improvements were statistically significant and clinically relevant for each parameter. Previous studies indicate these reductions may cause reduced overall healthcare costs.

Effects of two different rearing protocols for Holstein bull calves in the first 3weeks of life on health status, metabolism and subsequent performance.

The aim of this study was to investigate the impact of weight gain of calves within the first 3weeks of life on health status and subsequent performance. Holstein bull calves were reared either intensively (IR; individual hutches and ad libitum milk feeding for the first 3weeks of life; n=24), or according to the established protocol [ER; 4l milk/day in hutches during week 1 and 720g/day milk replacer (MR) from day 8 to 21 in a group pen; n=24]. Water, hay and concentrates were freely available to all calves. From week 4, calves of both groups were housed together in a group pen and fed 720g MR/day; step-down weaning was performed between week 5 and 10. Key metabolic blood parameters were analysed on day 2, 12, 21 and 70 of life. After weaning, all animals were fed concentrates and corn silage until slaughter at an age of 8months. Within the first 3weeks, average daily weight gain was threefold higher in IR calves in relation to ER calves (1.28 vs. 0.38kg/day, p<0.001). Neither incidence nor duration of scouring differed significantly between groups. Starter intake (week 4-10) was higher in IR calves in relation to ER calves (49.7 vs. 38.0kg/calf, p=0.006). Serum glucose, urea, albumin and insulin were higher at an age of 21days in IR calves in relation to ER calves; no differences were obvious at an age of 70days. Plasma GH and IGF-I concentrations revealed an uncoupling of the somatotropic axis in ER calves within the first 3weeks of life. At slaughter, body weight of IR calves tended to be higher than that of the ER calves (320 vs. 309kg, p=0.07). In conclusion, intensive feeding and individual housing during the first 3weeks of life had positive long-term effects on subsequent performance.

Maternal short-chain fatty acids are associated with metabolic parameters in mothers and newborns

During the course of pregnancy, dynamic remodeling of the gut microbiota occurs and contributes to maternal metabolic changes through an undefined mechanism. Because short chain fatty acids (SCFAs) are a major product of gut microbiome fermentation, we investigated whether serum SCFA levels during pregnancy are related to key metabolic parameters in mothers and newborns. In this prospective study, 20 pregnant women without gestational diabetes were evaluated at 36-38 weeks of gestation, and their newborns were assessed after parturition. In this cohort, which included normal (n = 10) and obese (n = 10) subjects based on prepregnancy body mass index, serum levels of SCFAs (acetate, propionate, and butyrate), maternal adipokines, maternal glucose, and C-peptide were measured at 36-38 weeks of gestation. Maternal weight gain and newborn anthropometrics were also determined. Data were analyzed using linear regression to test for associations, adjusting for prepregnancy obesity. In this cohort, serum acetate levels were associated with maternal weight gain and maternal adiponectin levels. In addition, serum propionate correlated negatively with maternal leptin levels, newborn length, and body weight. Taken together, this study observed that novel relationships exist among maternal SCFA levels and multiple interrelated maternal/newborn metabolic parameters.

Systems Genetics of Metabolism: The Use of the BXD Murine Reference Panel for Multiscalar Integration of Traits

Metabolic homeostasis is achieved by complex molecular and cellular networks that differ significantly among individuals and are difficult to model with genetically engineered lines of mice optimized to study single gene function. Here, we systematically acquired metabolic phenotypes by using the EUMODIC EMPReSS protocols across a large panel of isogenic but diverse strains of mice (BXD type) to study the genetic control of metabolism. We generated and analyzed 140 classical phenotypes and deposited these in an open-access web service for systems genetics (www.genenetwork.org). Heritability, influence of sex, and genetic modifiers of traits were examined singly and jointly by using quantitative-trait locus (QTL) and expression QTL-mapping methods. Traits and networks were linked to loci encompassing both known variants and novel candidate genes, including alkaline phosphatase (ALPL), here linked to hypophosphatasia. The assembled and curated phenotypes provide key resources and exemplars that can be used to dissect complex metabolic traits and disorders.

Motivation to obtain a food reward of pregnant ewes in negative energy balance: Behavioural, metabolic and endocrine considerations

Low food availability often coincides with pregnancy in grazing animals. This study investigated how chronic reductions in food intake affected feeding motivation, and metabolic and endocrine parameters in pregnant sheep, which might be indicative of compromised welfare. Ewes with an initial Body Condition Score of 2.7±0.3 (BCS; 0 indicates emaciation and 5 obesity) were fed to attain low (LBC 2.0±0.0,), medium (MBC 2.9±0.1) or high BCS (HBC 3.7±0.1) in the first trimester of pregnancy. A feeding motivation test in which sheep were required to walk a set distance for a palatable food reward was conducted in the second trimester. LBC and MBC ewes consumed more rewards (P=0.001) and displayed a higher expenditure (P=0.02) than HBC ewes, LBC ewes also tended to consume more rewards than MBC ewes (P=0.09). Plasma leptin and glucose concentrations were inversely correlated to expenditure (both P<0.05) and appear to be associated with hunger in sheep. LBC ewes were in negative energy balance, with lower muscle dimensions, plasma glucose, leptin, insulin, cortisol, and insulin-like growth factor-1 concentrations and higher free fatty acids concentrations compared to HBC ewes; metabolic and endocrine parameters of the MBC ewes were intermediate. The high feeding motivation and negative energy balance of low BCS ewes suggested an increased risk of compromised welfare. Imposing even a small cost on a food reward reduced motivation substantially in high BCS ewes (despite high intake when food was freely available). Assessment of a willingness to work for rewards, combined with measures of key metabolic and endocrine parameters, may provide sensitive barometers of welfare in energetically-taxed animals.

Differential effects of pro- and anti-inflammatory cytokines alone or in combinations on the metabolic profile of astrocytes

We have previously reported that the pro-inflammatory cytokines tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β) induce profound modifications of the metabolic profile of astrocytes. The present study was undertaken to further characterize the effects of cytokines in astrocytes and to determine whether similar effects could also be observed in neurons. To do so, selected pro-inflammatory (IL-6 and interferon-γ, in addition to the above-mentioned TNFα and IL-1β) and anti-inflammatory cytokines (IL-4, IL-10, transforming growth factor-β1 and interferon-β) were applied to primary neuronal and astrocytic cultures, and key metabolic parameters were assessed. As a general pattern, we observed that pro-inflammatory cytokines increased glucose utilization in astrocytes while the anti-inflammatory cytokines IL-4 and IL-10 decreased astrocytic glucose utilization. In contrast, no significant change could be observed in neurons. When pairs of pro-inflammatory cytokines were co-applied in astrocytes, several additive or synergistic modifications could be observed. In contrast, IL-10 partially attenuated the effects of pro-inflammatory cytokines. Finally, the modifications of the astrocytic metabolism induced by TNFα + IL-1β and interferon-γ modulated neuronal susceptibility to an excitotoxic insult in neuron-astrocyte co-cultures. Together, these results suggest that pro- and anti-inflammatory cytokines differentially affect the metabolic profile of astrocytes, and that these changes have functional consequences for surrounding neurons.

Waterborne fluoxetine disrupts feeding and energy metabolism in the goldfish Carassius auratus

Fluoxetine (FLX) is one of the most commonly detected pharmaceuticals in wastewater and bioaccumulates in wild-caught fish, especially in brain, liver and muscle tissues. Previous studies indicated that FLX is pharmacologically active in fish species exerting anorexigenic effects, but it is not clear whether waterborne FLX has any potential effects on regulating food intake and energy metabolism. In this study, we investigated the effect of two doses of FLX, an environmental concentration of 540 ng/L, and 100-times this concentration (54 μg/L), on feeding and key metabolic parameters in goldfish. Fish were exposed for a period of 28 days and changes in food intake and body mass were assessed. Pair-fed groups were maintained to discern primary FLX-induced effects from secondary metabolic responses induced by the decreased food intake. Additionally, an untreated control group and a fasted group were used to further compare physiological changes in the context of nutritional status of the animals. Significant decreases in food intake and weight gain were recorded in goldfish exposed to 54 μg/L FLX. Furthermore a significant decrease occurred in circulating glucose levels in the group exposed to 540 ng/L FLX. To elucidate potential mechanisms, we investigated gene expression of feeding neuropeptides in the neuroendocrine brain of goldfish as well as gene expression and enzymatic activity of glycolytic and gluconeogenetic enzymes in liver and muscle tissues. The results confirm brain gene expression patterns in line with potential anorexigenic effects in the hypothalamus, with increased expression in corticotropin-releasing factor (CRF) and decreased expression of neuropeptide Y (NPY). With respect to glucose metabolism, liver gene expression of the gluconeogenic enzyme fructose-1,6-bisphosphatase decreased and muscle hexokinase activity increased in fish exposed to 540 ng/L FLX. Overall, this study demonstrated anorectic properties of FLX at a dose of 54 μg/L FLX and moderate but significant effects on glucose metabolism in goldfish exposed to 540 ng/L FLX. Future studies investigating the importance of these changes in fish are warranted.

Near Infrared Spectroscopy Measurements Of Muscle Metabolism In Elite Short-track Speed Skaters During On-ice Race Simulation

PURPOSE: To gain real-time information pertaining to the concentration and oxygenation changes of haemoglobin in the vastus lateralis muscle during short track race simulation, by using the wireless capabilities of a recently developed portable NIRS device. METHODS: A dual wavelength NIRS device was placed on both the right and left leg of each subject, positioned midway between the greater trachanter of the femur and the lateral epicondyl. Subjects were 6 male elite short track speed skaters, all of whom were members of the Great Britain Olympic squad (age: 22 ± 3 years, height: 172.6 ± 11.79 cm, mass: 70.75 ± 12.43 kg, mid-thigh skin fold thickness: 6.97 ± 1.3 mm). Each subject completed a race simulation for 2 Olympic race distances: 500m and 1500m. Changes in muscle oxyhaemoglobin, muscle deoxyhaemoglobin, heart rate, global oxygen consumption (VO2) and a video record were analysed for each race. RESULTS: Immediately following the start of 500m race there was an initial drop from baseline in total haemoglobin concentration as a consequence of constriction of the muscle (-5.96 ±1.6 μM). However, by the end of the race simulation, muscle haemoglobin concentration had increased significantly (+9.52 ± 8.69 μM), presumably consequent to a change in vessel diameter and blood flow. Significant differences between the right and left leg were seen at different phases of the lap. Most notably, during the 500m race, when skaters travel around the apex of the bend supported solely on the right leg ('hang' phase), the right leg shows a rapid drop in total blood haemoglobin, -6.7 ±1.06 μM, whereas the left leg shows no such drop, +2.1 ±0.6 μM. During the 1500 m athletes make less use of the hang phase, and this difference between right and left leg is not apparent. CONCLUSIONS: This is the first time that real-time NIRS measurements have been made of elite short track speeds skaters under on-ice race simulation conditions. The wireless capability of the NIRS device used allowed real-time monitoring of muscle oxygenation and blood volume. The difference in skating styles during events of different distances, reflected in changes in oxyhaemoglobin and deoxyhaemoglobin concentrations, is likely to map onto key haemodynamic (blood flow) and metabolic (oxygen consumption) parameters.

MicroRNA Expression in Human Omental and Subcutaneous Adipose Tissue

MicroRNAs (miRNAs) are small non-coding RNAs, that play important regulatory roles in a variety of biological processes, including development, differentiation, apoptosis, and metabolism. In mammals, miRNAs have been shown to modulate adipocyte differentiation. Therefore, we performed a global miRNA gene expression assay in different fat depots of overweight and obese individuals to investigate whether miRNA expression in human adipose tissue is fat-depot specific and associated with parameters of obesity and glucose metabolism. Paired samples of abdominal subcutaneous (SC) and intraabdominal omental adipose tissue were obtained from fifteen individuals with either normal glucose tolerance (NGT, n = 9) or newly diagnosed type 2 diabetes (T2D, n = 6). Expression of 155 miRNAs was carried out using the TaqMan®MicroRNA Assays Human Panel Early Access Kit (Applied Biosystems, Darmstadt, Germany). We identified expression of 106 (68%) miRNAs in human omental and SC adipose tissue. There was no miRNA exclusively expressed in either fat depot, suggesting common developmental origin of both fat depots. Sixteen miRNAs (4 in NGT, 12 in T2D group) showed a significant fat depot specific expression pattern. We identified significant correlations between the expression of miRNA-17-5p, -132, -99a, -134, 181a, -145, -197 and both adipose tissue morphology and key metabolic parameters, including visceral fat area, HbA1c, fasting plasma glucose, and circulating leptin, adiponectin, interleukin-6. In conclusion, microRNA expression differences may contribute to intrinsic differences between omental and subcutaneous adipose tissue. In addition, human adipose tissue miRNA expression correlates with adipocyte phenotype, parameters of obesity and glucose metabolism.

In Silico Preclinical Trials: A Proof of Concept in Closed-Loop Control of Type 1 Diabetes

Arguably, a minimally invasive system using subcutaneous (s.c.) continuous glucose monitoring (CGM) and s.c. insulin delivery via insulin pump would be a most feasible step to closed-loop control in type 1 diabetes mellitus (T1DM). Consequently, diabetes technology is focusing on developing an artificial pancreas using control algorithms to link CGM with s.c. insulin delivery. The future development of the artificial pancreas will be greatly accelerated by employing mathematical modeling and computer simulation. Realistic computer simulation is capable of providing invaluable information about the safety and the limitations of closed-loop control algorithms, guiding clinical studies, and out-ruling ineffective control scenarios in a cost-effective manner. Thus computer simulation testing of closed-loop control algorithms is regarded as a prerequisite to clinical trials of the artificial pancreas. In this paper, we present a system for in silico testing of control algorithms that has three principal components: (1) a large cohort of n=300 simulated "subjects" (n=100 adults, 100 adolescents, and 100 children) based on real individuals' data and spanning the observed variability of key metabolic parameters in the general population of people with T1DM; (2) a simulator of CGM sensor errors representative of Freestyle Navigator™, Guardian RT, or Dexcom™ STS™, 7-day sensor; and (3) a simulator of discrete s.c. insulin delivery via OmniPod Insulin Management System or Deltec Cozmo(®) insulin pump. The system has been shown to represent adequate glucose fluctuations in T1DM observed during meal challenges, and has been accepted by the Food and Drug Administration as a substitute to animal trials in the preclinical testing of closed-loop control strategies.

Finding a way through the forest: A Biopsychosocial model of hot flashes.

Finding a way through the forest: A Biopsychosocial model of hot flashes.

Physiologically‐Based Pharmacokinetic Modeling of Benzene in Humans: A Bayesian Approach

Benzene is myelotoxic and leukemogenic in humans exposed at high doses (>1 ppm, more definitely above 10 ppm) for extended periods. However, leukemia risks at lower exposures are uncertain. Benzene occurs widely in the work environment and also indoor air, but mostly below 1 ppm, so assessing the leukemia risks at these low concentrations is important. Here, we describe a human physiologically-based pharmacokinetic (PBPK) model that quantifies tissue doses of benzene and its key metabolites, benzene oxide, phenol, and hydroquinone after inhalation and oral exposures. The model was integrated into a statistical framework that acknowledges sources of variation due to inherent intra- and interindividual variation, measurement error, and other data collection issues. A primary contribution of this work is the estimation of population distributions of key PBPK model parameters. We hypothesized that observed interindividual variability in the dosimetry of benzene and its metabolites resulted primarily from known or estimated variability in key metabolic parameters and that a statistical PBPK model that explicitly included variability in only those metabolic parameters would sufficiently describe the observed variability. We then identified parameter distributions for the PBPK model to characterize observed variability through the use of Markov chain Monte Carlo analysis applied to two data sets. The identified parameter distributions described most of the observed variability, but variability in physiological parameters such as organ weights may also be helpful to faithfully predict the observed human-population variability in benzene dosimetry.

Glyceraldehyde-3-phosphate dehydrogenase regulation in Lactococcus lactis ssp. cremoris MG1363 or relA mutant at low pH

To analyse the phenotype of a relA acid-resistant mutant of Lactococcus lactis ssp. cremoris MG1363, and to compare the glyceraldehyde-3-phosphate dehydrogenase regulation in both strains. Lactococcus lactis ssp. cremoris MG1363 and the relA mutant affected in the (p)ppGpp synthetase were grown in a series of batch-mode fermentation at different pH-regulated conditions with glucose as carbon substrate. All the determinants of the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) regulation were quantified. In L. lactis MG1363, the GAPDH was strongly inhibited in vitro by decreased pH values, but this inhibition was totally compensated in vivo by the lower NADH/NAD+ ratio and more efficiently by the important increase in the intracellular amount of GAPDH. In contrast to the wild type, GAPDH activity of the relA strain was not increased when grown at low pH but the level of GAPDH remained constitutively high. However, pH homeostasis was not improved in the relA mutant and it grew slower and exhibited a lower glycolytic flux than the wild-type strain at low pH. Despite a better resistance to acid stress, the increased survival in L. lactis relA mutant at low pH was not related with an improved pH homeostasis but was associated with a diminished capacity to maintain a high flux through glycolysis. The phenotype of a strong acid-resistant L. lactis strain was established in acid conditions and some key metabolic parameters compared with the wild type. This analysis led to the conclusion that growth and survival seem to be antinomic parameters, since improving one of them leads to a decrease in the other one.

A genetic redox sensor for mammalian cells

Nutrient and oxygen availability are key metabolic parameters for biopharmaceutical manufacturing. In order to enable mammalian cells to manifest their intracellular nutrient and oxygen levels we engineered a genetic sensor circuitry which converts signals impinging on the cellular redox balance into a robust reporter gene expression readout. Capitalizing on the Streptomyces coelicolor redox control system, consisting of REX modulating ROP-containing promoters in an NADH-dependent manner, we designed a mammalian dual sensor transcription control system by fusing REX to the generic VP16 transactivation domain of Herpes simplex, which reconstitutes an artificial transactivator (REDOX) able to bind and activate chimeric promoters assembled by placing a ROP operator module 5′ of a minimal eukaryotic promoter (P ROP). When nutrient levels were low and resulted in depleted NADH pools REDOX-dependent P ROP-driven expression of secreted (human-secreted alkaline phosphatase; SEAP) or intracellular (Renilla reniformis luciferase; rLUC) reporter genes was high as a consequence of increased REDOX–P ROP affinity. Conversely, at hypoxic conditions leading to high intracellular NADH levels, strongly reduced REDOX–P ROP interaction mediated low-level transgene expression in Chinese hamster ovary (CHO-K1) cells. Other molecules (for example, 2,4-dinitrophenol, cyanide or hydrogen peroxide) which are known to imbalance the intracellular NADH/NAD + poise could also be detected using the REDOX–P ROP sensor circuitry. REDOX's sensor capacity (nutrient and oxygen levels) operated seamlessly in transgenic CHO-K1 cell derivatives adapted for growth in serum-free suspension cultures and enabled precise monitoring of the population's metabolic state. As the first genetic metabolic sensor designed for mammalian cells, REDOX may foster advances in process development and biopharmaceutical manufacturing.

Effects of Simulated Microgravity on the Morphology and Function of Neonatal Porcine Cell Clusters Cultured with and without Sertoli Cells

Human islet allografts are well known to induce full and sustained remission of hyperglycemia, with complete normalization of key metabolic parameters. Nevertheless, acquiring human islets, even from cadaveric human donor pancreases, remains a significant impediment to successful transplantation therapy for diabetes. To overcome this difficulty, neonatal porcine cell clusters (NPCCs) have been considered for human islet substitutes because they are easily obtained by collagenase digestion of the neonatal piglet pancreas. Currently, the major hurdle in using NPCCs for xenograft is the delay (time lag) in achieving the posttransplant normalization of blood glucose levels in animal diabetic recipients. The present work is the first attempt to evaluate whether incubation of NPCCs in simulated microgravity, in the presence or absence of Sertoli cells (SC), may reduce the maturation time lag of beta-cells by differentiation acceleration in vitro, thereby expediting production, viability, and acquisition of functional competence of pretransplantation beta-cell-enriched islets. Following a 3-day incubation period, NPCCs maintained in conventional culture, NPCCs incubated in simulated microgravity in the HARV biochamber, and NPCCs plus co-incubated SC in simulated microgravity were examined for viability, morphology, and insulin secretion. Results show that NPCCs grown alone in the HARV biochamber are superior in quality, both in terms of viability and functional competence, when compared to other culture pretreatment protocols. This finding strongly suggests that NPCC pretreatment in simulated microgravity may enhance the transplantation success of NPCCs in the diabetic recipient.

Association of Humoral Immunity to Human Hsp60 with the IL-6 Gene Polymorphism C-174G in Patients with Type 2 Diabetes and Controls

The relationship between humoral immunity to hsp60 and type 2 diabetes along with other relevant metabolic, inflammatory and immunogenetic variables was studied in 76 non-diabetic and 74 diabetic persons aged 55-74 years selected from the population-based KORA Survey 2000. Antibodies to human hsp60 were measured in serum samples by ELISA. Hsp60 antibodies were detected in all but two individuals in a considerable range of titres (22-1,856 AU/ml). There was no significant association to age and sex, or to key clinical or metabolic parameters (BMI, WHR, HbA1c, total cholesterol, LDL cholesterol, HDL cholesterol, systolic and diastolic blood pressure, albumin, uric acid) or immunological parameters (CRP, IL-6, sIL-6R, TNFalpha, sTNFalpha R60, sTNFalpha R80). Analysis of antibody-positive individuals revealed an association between hsp60 antibodies and diabetes at borderline significance (p = 0.047), which was lost when the two antibody-negative individuals were included. Genetic analyses indicated that this association was significant in carriers of the C allele of the IL-6 promoter region polymorphism at nucleotide -174 (p = 0.02), but not in GG genotype carriers. We conclude that humoral immunity to human hsp60 may be enhanced in those diabetic patients carrying the -174C allele of the IL-6 gene. This finding may contribute to an understanding of the relationship between the -174C allele and increased risk of atherosclerosis.

Exhaustive exercise and the cellular stress response in rainbow trout, Oncorhynchus mykiss

The goal of this study was to examine the cellular response to exhaustive exercise in male and female rainbow trout to determine if HSPs are involved in the early stages of the recovery process. Levels of HSPs and key metabolic parameters were measured in white muscle, heart plasma, and blood plasma throughout 6 h of recovery from exhaustive burst exercise. Plasma creatine kinase (CK) was also quantified as an indicator of exercise-induced tissue damage. The observed trends in ATP and lactate were consistent with established patterns of exhaustion and the beginnings of metabolic recovery. However, no upregulation of hsp70, hsp30, or hsp90 was evident in heart or muscle tissue of males or females, and plasma CK measurements suggest that tissue damage was minimal. Our results indicate that hsp70, hsp30, and hsp90 are not part of the early recovery process from burst exercise in fish, perhaps due to the maintenance of core temperatures as well as a lack of exercise-induced tissue damage.