OBJECTIVEWe sought to establish β-cell mass, β-cell apoptosis, and β-cell replication in humans in response to obesity and advanced age.RESEARCH DESIGN AND METHODSWe examined human autopsy pancreas from 167 nondiabetic individuals 20–102 years of age. The effect of obesity on β-cell mass was examined in 53 lean and 61 obese subjects, and the effect of aging was examined in 106 lean subjects.RESULTSβ-Cell mass is increased by ∼50% with obesity (from 0.8 to 1.2 g). With advanced aging, the exocrine pancreas undergoes atrophy but β-cell mass is remarkably preserved. There is minimal β-cell replication or apoptosis in lean humans throughout life with no detectable changes with obesity or advanced age.CONCLUSIONSβ-Cell mass in human obesity increases by ∼50% by an increase in β-cell number, the source of which is unknown. β-Cell mass is well preserved in humans with advanced aging.

Introduction Data are limited on the metabolic effects of resistance exercise (strength training) in adolescents. Purpose The objective of this study was to determine whether a controlled resistance exercise program without dietary intervention or weight loss, reduces body fat accumulation, increases lean body mass, and improves insulin sensitivity and glucose metabolism in sedentary obese Hispanic adolescents. Methods Twelve obese adolescents (15.5±0.5y; 35.3 ±0.8kg/m2;40.8±1.5% body fat), completed a 12 wk resistance exercise program (2×1h/wk, exercising all major muscle groups). At baseline and completion of the program, body composition was measured by DXA, abdominal fat distribution by Magnetic Resonance Imaging, hepatic and intramyocellular fat by Magnetic Resonance Spectroscopy, peripheral insulin sensitivity by the Stable Labeled IV Glucose Tolerance Test and hepatic insulin sensitivity by the Hepatic Insulin Sensitivity Index =1000/(GPR*fasting insulin). Glucose production rate (GPR), gluconeogenesis and glycogenolysis were quantified using Stable Isotope-Gas Chromatography/Mass Spectrometry techniques. Results All participants were normoglycemic. The exercise program resulted in significant strength gain in both upper and lower body muscle groups. Body weight increased from 97.0±3.8 to 99.6±4.2 kg (p<0.01). The major part (~80%) was accounted for by increased lean body mass (55.7±2.8 to 57.9±3.0 kg; p≤0.01).Total, visceral, hepatic and intramyocellular fat content remained unchanged. Hepatic insulin sensitivity increased by 24±9% (p<0.05), while peripheral insulin sensitivity did not change significantly. GPR decreased by 8±1% (p<0.01) due to a 12±5% decrease in glycogenolysis (p<0.05). Conclusion We conclude that a controlled resistance exercise program without weight loss increases strength and lean body mass, improves hepatic insulin sensitivity and decreases GPR without affecting total fat mass or visceral, hepatic and intramyocellular fat content.

This well accepted aerobic exercise program, without weight loss, is a promising strategy to improve peripheral and hepatic insulin sensitivity in lean and obese sedentary adolescents. The small decrease in GPR is probably of limited clinical relevance.

A very high number of different types of blood cells must be generated daily through a process called haematopoiesis in order to meet the physiological requirements of the organism. All blood cells originate from a population of relatively few haematopoietic stem cells residing in the bone marrow, which give rise to specific progenitors through different lineages. Steady-state dynamics are governed by cell division and commitment rates as well as by population sizes, while feedback components guarantee the restoration of steady-state conditions. In this study, all parameters governing these processes were estimated in a computational model to describe the haematopoietic hierarchy in adult mice. The model consisted of ordinary differential equations and included negative feedback regulation. A combination of literature data, a novel divide et impera approach for steady-state calculations and stochastic optimization allowed one to reduce possible configurations of the system. The model was able to recapitulate the fundamental steady-state features of haematopoiesis and simulate the re-establishment of steady-state conditions after haemorrhage and bone marrow transplantation. This computational approach to the haematopoietic system is novel and provides insight into the dynamics and the nature of possible solutions, with potential applications in both fundamental and clinical research.

Bone-marrow-derived progenitors must continually enter the thymus of an adult mouse to sustain T-cell homeostasis, yet only a few input cells per day are sufficient to support a yield of 5 Â 10 7 immature T-cells per dayand an eventual output of 1-2 Â 10 6 mature cells per day. While substantial progress has been made to delineate the developmental pathway of T-cell lineage commitment, still little is known about the relationship between differentiation competence and the remarkable expansion of the earliest (DN1 stage) T-cell progenitors. To address this question, we developed computational models where the probability to progress to the next stage (DN2) is related to division number. To satisfy differentiation kinetics and overall cell yield data, our models require that adult DN1 cells divide multiple times before becoming competent to progress into DN2 stage. Our findings were subsequently tested by in vitro experiments, where putative early and later-stage DN1 progenitors from the thymus were purified and their progression into DN2 was measured. These experiments showed that the two DN1 sub-populations divided with similar rates, but progressed to the DN2 stage with different rates, thus providing experimental evidence that DN1 cells increase their commitment probability in a cell-intrinsic manner as they undergo cell division. Proliferation-linked shifts in eligibility of DN1 cells to undergo specification thus control kinetics of T-cell generation.