Ongoing β-Cell Turnover in Adult Nonhuman Primates Is Not Adaptively Increased in Streptozotocin-Induced Diabetes

OBJECTIVE: \u3b2-Cell turnover and its potential to permit \u3b2-cell regeneration in adult primates are unknown. Our aims were 1) to measure \u3b2-cell turnover in adult nonhuman primates; 2) to establish the relative contribution of \u3b2-cell replication and formation of new \u3b2-cells from other precursors (defined thus as \u3b2-cell neogenesis); and 3) to establish whether there is an adaptive increase in \u3b2-cell formation (attempted regeneration) in streptozotocin (STZ)-induced diabetes in adult nonhuman primates. RESEARCH DESIGN AND METHODS: Adult (aged 7 years) vervet monkeys were administered STZ (45-55 mg/kg, n = 7) or saline (n = 9). Pancreas was obtained from each animal twice, first by open surgical biopsy and then by euthanasia. \u3b2-Cell turnover was evaluated by applying a mathematic model to measured replication and apoptosis rates. RESULTS: \u3b2-Cell turnover is present in adult nonhuman primates (3.3 \ub1 0.9 mg/month), mostly (~80%) derived from \u3b2-cell neogenesis. \u3b2-Cell formation was minimal in STZ-induced diabetes. Despite marked hyperglycemia, \u3b2-cell apoptosis was not increased in monkeys administered STZ. CONCLUSIONS: There is ongoing \u3b2-cell turnover in adult nonhuman primates that cannot be accounted for by \u3b2-cell replication. There is no evidence of \u3b2-cell regeneration in monkeys administered STZ. Hyperglycemia does not induce \u3b2-cell apoptosis in nonhuman primates in vivo

Asynchronous combinatorial action of four regulatory factors activates Bcl11b for T cell commitment

During T cell development, multipotent progenitors relinquish competence for other fates and commit to the T cell lineage by turning on Bcl11b, which encodes a transcription factor. To clarify lineage commitment mechanisms, we followed developing T cells at the single-cell level using Bcl11b knock-in fluorescent reporter mice. Notch signaling and Notch-activated transcription factors collaborate to activate Bcl11b expression irrespectively of Notch-dependent proliferation. These inputs work via three distinct, asynchronous mechanisms: an early locus 'poising' function dependent on TCF-1 and GATA-3, a stochastic-permissivity function dependent on Notch signaling, and a separate amplitude-control function dependent on Runx1, a factor already present in multipotent progenitors. Despite their necessity for Bcl11b expression, these inputs act in a stage-specific manner, providing a multitiered mechanism for developmental gene regulation

-Cell Mass and Turnover in Humans: Effects of obesity and aging

OBJECTIVE: We 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 METHODS: We 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. RESULTS: β-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. CONCLUSIONS: β-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

Modeling Nonsteady-State Metabolism From Arteriovenous Data

The use of arteriovenous (AV) concentration differences to measure the production of a substance at organ/tissue level by Fick principle is limited to steady state. Out of steady state, there is the need, as originally proposed by Zierler, to account for the nonnegligible transit time of the substance through the system. Based on this theory, we propose a modeling approach that adopts a parametric description for production and transit time. Once the unknown parameters are estimated on AV data, the transition time of the substance can be assessed and production can be reconstructed. As a case study, we discuss the estimation of pancreatic insulin secretion during a meal from C-peptide concentrations measured in femoral artery and hepatic vein in 12 subjects. Results support the importance of accounting for nonnegligible transit times, even if C-peptide mean transit time across the splanchnic bed is rather limited (3.3 \ub1 1.3 min), it affects the estimation of pancreatic insulin secretion which shows a significantly different profile in the early portion of the postprandial period when estimated either with the novel modeling approach or with the simplified steady state equation

Levels of circulating microparticles in septic shock and sepsis-related complications: A case-control study

BACKGROUND: Microparticles (MP) have been largely studied as potential biomarkers in septic shock (SS) though their biological and clinical relevance is still unclear. This case-control study describes the trend of various MP subtypes during SS to evaluate their possible association with severity of illness and sepsis-related complications (disseminated intravascular coagulation [DIC] and acute kidney injury [AKI]). METHODS: Forty patients admitted to the Intensive Care Unit with SS and 40 matched healthy volunteers were recruited. AnnexinV+, E-selectin+, thrombomodulin (TM+), leukocyte-derived (CD45+, CD36+) and platelet-derived MP (PMP-expressed as PMP/platelets ratio) were measured by flow-cytometry at baseline, on day 1, 3 and 7 after diagnosis. Severity of illness was assessed by Sequential Organ Failure Assessment Score, duration of vasoactive support and mechanical ventilation. Sepsis-related complications were considered. RESULTS: Overall, septic patients showed higher levels of all MP considered compared to controls. TM+MP were significantly lower in more severe sepsis, while CD36+MP and PMP/platelets ratio were significantly increased in patients requiring longer vasoactive support and mechanical ventilation. As for sepsis-related complications, a higher PMP/platelets ratio in patients who developed DIC and increased E-selectin+MP in subjects who developed AKI were observed. PMP/platelets ratio at baseline was significantly associated with longer vasoactive support (OR=1.59 [1.05-2.42]), longer mechanical ventilation (OR=1.6 [1.06-2.42]) and DIC occurrence (OR=1.45 [1.08-1.96]). CONCLUSIONS: A global response through extra-vesiculation of endothelial cells, leukocytes and platelets during the early stages of SS was confirmed. The cellular activation was detected until day 3 after diagnosis. PMP/platelets ratio at diagnosis may be useful to evaluate SS severity and DIC occurrence

β-cell mass and turnover in humans: effects of obesity and aging.

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